WEB ANNEX B. SYSTEMATIC LITERATURE REVIEW AND NETWORK META … · WEB ANNEX B. SYSTEMATIC...

WEB ANNEX B. SYSTEMATIC LITERATURE REVIEW AND

NETWORK META-ANALYSIS ASSESSING FIRST-LINE ART

TREATMENTS

Steve Kanters, Jeroen Jansen, Michael Zoratti, Jamie Forrest,

Brittany Humphries, Jonathon Campbell

In:

Updated recommendations on first-line and second-line

antiretroviral regimens and post-exposure prophylaxis and

recommendations on early infant diagnosis of HIV: interim

guidelines. Supplement to the 2016 consolidated guidelines

on the use of antiretroviral drugs for treating and preventing

HIV infection

2

WHO/CDS/HIV/18.25

© World Health Organization 2018

Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-

ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-

sa/3.0/igo).

Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial

purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there

should be no suggestion that WHO endorses any specific organization, products or services. The use of

the WHO logo is not permitted. If you adapt the work, then you must license your work under the same

or equivalent Creative Commons licence. If you create a translation of this work, you should add the

following disclaimer along with the suggested citation: “This translation was not created by the World

Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The

original English edition shall be the binding and authentic edition”.

Any mediation relating to disputes arising under the licence shall be conducted in accordance with the

mediation rules of the World Intellectual Property Organization.

Suggested citation. Kanters S, Jansen J, Zoratti M, Forrest J, Humphries B, Campbell J. Web Annex B.

Systematic literature review and network meta-analysis assessing first-line antiretroviral treatments

In: Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure

prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to

the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV

infection. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.25). Licence: CC BY-NC-SA 3.0

IGO.

Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.

Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To

submit requests for commercial use and queries on rights and licensing, see

http://www.who.int/about/licensing.

Third-party materials. If you wish to reuse material from this work that is attributed to a third party,

such as tables, figures or images, it is your responsibility to determine whether permission is needed for

that reuse and to obtain permission from the copyright holder. The risk of claims resulting from

infringement of any third-party-owned component in the work rests solely with the user.

General disclaimers. The designations employed and the presentation of the material in this publication

do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status

of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers

or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there

may not yet be full agreement.

3

The mention of specific companies or of certain manufacturers’ products does not imply that they are

endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned.

Errors and omissions excepted, the names of proprietary products are distinguished by initial capital

letters.

All reasonable precautions have been taken by WHO to verify the information contained in this

publication. However, the published material is being distributed without warranty of any kind, either

expressed or implied. The responsibility for the interpretation and use of the material lies with the

reader. In no event shall WHO be liable for damages arising from its use.

The named authors alone are responsible for the views expressed in this publication.

This publication forms part of the WHO guideline entitled Updated recommendations on first-line and

second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant

diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of

antiretroviral drugs for treating and preventing HIV infection. It is being made publicly available as

supplied by those responsible for its development for transparency purposes and information, as

required by WHO (see the WHO handbook for guideline development, 2nd edition (2014)).

4

CONTENTS

Abbreviations .............................................................................................................................................. 14

Executive Summary ..................................................................................................................................... 17

1. Introduction ......................................................................................................................................... 23

2. Objectives ............................................................................................................................................ 24

3. Methodology ....................................................................................................................................... 25

3.1. Systematic literature review ........................................................................................................ 25

3.1.1. Sources ............................................................................................................................... 27

3.1.2. Search strategy ................................................................................................................... 27

3.1.3. Study selection .................................................................................................................... 28

3.1.4. Study quality ........................................................................................................................ 28

3.1.5. Data extraction .................................................................................................................... 29

3.2. Analyses ...................................................................................................................................... 30

3.2.1. Network meta-analyses ....................................................................................................... 30

3.2.2. Evaluation of consistency between direct and indirect comparisons .................................. 30

3.2.3. Node definitions and backbone adjustments ...................................................................... 31

3.2.4. Models ................................................................................................................................. 32

3.2.5. Adjusted analysis ................................................................................................................ 33

3.2.6. Presentation of results ........................................................................................................ 33

3.2.7. Software .............................................................................................................................. 33

4. Adults and adolescents ........................................................................................................................ 34

4.1. Systematic literature review study selection ............................................................................... 34

4.2. Analysis set study selection ........................................................................................................ 37

4.3. Results ........................................................................................................................................ 39

4.3.1. Viral suppression ................................................................................................................. 40

4.3.2. Increase in CD4 cell counts ................................................................................................ 41

4.3.3. Mortality ............................................................................................................................... 43

4.3.4. AIDS defining illnesses ....................................................................................................... 43

5

4.3.5. Discontinuations .................................................................................................................. 44

4.3.6. Discontinuations due to adverse events ............................................................................. 45

4.3.7. Treatment-related and emergent adverse events ............................................................... 45

4.3.8. Treatment-related and treatment-emergent serious adverse events .................................. 47

4.3.9. Regimen substitutions ......................................................................................................... 47

4.4. GRADE tables ............................................................................................................................. 48

5. TB Co-infected Individuals ................................................................................................................... 58

5.1. The INSPIRING trial .................................................................................................................... 58

5.1.1. Systematic literature review study selection ....................................................................... 60

5.2. Results ........................................................................................................................................ 62

5.2.1. Efficacy ................................................................................................................................ 62

5.2.2. Tolerability ........................................................................................................................... 63

5.2.3. Safety .................................................................................................................................. 65

5.3. GRADE tables ............................................................................................................................. 66

6. Pregnant and breastfeeding women ................................................................................................... 68

6.1. Systematic literature review study selection ............................................................................... 68

6.2. Summary of the evidence base ................................................................................................... 68

6.3. GRADE tables ............................................................................................................................. 73

7. Children and adolescents .................................................................................................................... 76

7.1. Summary of the evidence base ................................................................................................... 76

7.2. GRADE tables ............................................................................................................................. 78

8. Discussion ............................................................................................................................................ 87

9. Conclusions .......................................................................................................................................... 89

Appendix A: Search strategy ....................................................................................................................... 90

Appendix B: Search strategies for sub populations .................................................................................... 93

Appendix C: Trends in observed treatment effects across follow-up times............................................... 95

Appendix D: List of included studies ......................................................................................................... 100

Appendix E: Characteristics of included studies ....................................................................................... 125

Appendix F: Patient characteristics in included studies ........................................................................... 138

Appendix G: Quality assessments of included studies ............................................................................. 151

6

Appendix H: Network diagrams ................................................................................................................ 160

TB Subpopulation .................................................................................................................................. 173

Appendix I: Included trials by analysis ...................................................................................................... 181

Appendix J: Cross tables ............................................................................................................................ 185

Appendix K: GRADE summary tables for children and adolescents ......................................................... 208

References ................................................................................................................................................ 232

7

Tables

Table 1: Scope of the literature review in PICOS form ................................................................. 25

Table 2: Summary of the GRADE quality of evidence assessments for all outcomes for the DTG

vs EFV comparison ........................................................................................................................ 49

Table 3: Summary of the GRADE quality of evidence assessments for all outcomes for the

EFV400 vs EFV comparison ........................................................................................................... 53

Table 4: Summary of the GRADE quality of evidence assessments for all outcomes for the DTG

vs EFV400 comparison .................................................................................................................. 56

Table 5: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of

ARVs for viral suppression at 24 weeks from the fixed-effects network meta-analyses in HIV-TB

co-infected patients ...................................................................................................................... 62

Table 6: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of

ARVs for mean change in CD4 cell counts at 24 weeks from the fixed-effects network meta-

analyses in HIV-TB co-infected patients ....................................................................................... 63

Table 7: Data for treatment comparisons of interest for discontinuations due to adverse events

outcome in HIV-TB co-infected patients ....................................................................................... 64


outcome in HIV-TB co-infected patients ....................................................................................... 64

Table 10: Data for treatment comparisons of interest for the treatment-emergent serious

adverse events .............................................................................................................................. 65

Table 11: Summary of the GRADE quality of evidence assessments for outcomes in the first-line

treatment of HIV-TB co-infected patients .................................................................................... 66

Table 12: Summary of the Tsepamo study of DTG/TDF/FTC vs EFV/TDF/FTC in pregnant and

breastfeeding women initiated on first-line ART ......................................................................... 71

Table 13: Summary of evidence among pregnant and breastfeeding women on first-line ART . 72

Table 14: Summary of the GRADE quality of evidence assessments for outcomes in the first-line

treatment of pregnancy and breastfeeding women .................................................................... 73

Table 15: Studies of RAL-based regimens for neonates and infants ............................................ 77

8

Table 16: Summary of the GRADE quality of evidence assessments for efficacy, safety, and

tolerability outcomes for the use of DTG vs EFV, LPV/r, and RAL in the first-line treatment of

children and adolescents .............................................................................................................. 80

Table 17: Summary of the GRADE quality of evidence assessments for efficacy, safety, and

tolerability outcomes for the use of RAL vs EFV, LPV/r, and NVP in the first-line treatment of

children and adolescents .............................................................................................................. 84

Table 18: Systematic literature search strategy ........................................................................... 90

Table 19: Systematic literature search to identify non-RCT study designs .................................. 93

Table 20: Systematic literature review terms to identify the specific sub-populations of interest

....................................................................................................................................................... 93

Table 21: List of included studies with corresponding publications .......................................... 100

Table 22: List of included studies with corresponding publications for the TB sub-population 118

Table 23: List of included studies with corresponding publications for the children and

adolescent sub-population ......................................................................................................... 120

Table 24: List of included studies with corresponding publications for the pregnant and

breastfeeding women ................................................................................................................. 122

Table 25: Trial characteristics for principal systematic literature review .................................. 125

Table 26: Trial characteristics for studies selected in the systematic literature review among TB

co-infected patients .................................................................................................................... 136

Table 27: Patient characteristics across the 76 randomized controlled trials included in the

principal analysis ......................................................................................................................... 138

Table 28: Patient characteristics in the principal analysis in the systematic literature review

among TB co-infected patients ................................................................................................... 149

Table 29: Cochrane risk of bias quality assessment for randomized controlled trials, arranged by

review sub-population ................................................................................................................ 151

Table 30: Critical appraisal of non-randomized studies using the Tool to Assess the Risk of Bias

in Cohort Studies, developed by the Clinical Advances through Research and Information

Translation (CLARITY) group ....................................................................................................... 157

9

Table 31: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy

of ARVs for viral suppression at 48 weeks from the fixed-effects network meta-analyses ....... 185


of ARVs for viral suppression at 96 weeks from the fixed-effects network meta-analyses ....... 187


of ARVs for viral suppression at 144 weeks from the fixed-effects network meta-analyses ..... 189


of ARVs for mean change in CD4 cell counts at 48 weeks from network meta-analyses .......... 190


of ARVs for mean change in CD4 cell counts at 96 weeks from network meta-analyses .......... 192


of ARVs for mean change in CD4 cell counts at 144 weeks from network meta-analyses ........ 194

Table 37: Cross table of odds ratios with 95% credible intervals from network meta-analyses

comparing ARVs in terms of discontinuation ............................................................................. 196


comparing ARVs in terms of discontinuation due to adverse events ........................................ 198

Table 39: Cross table of odds ratios with 95% credible intervals from the network meta-analyses

comparing ARVs in terms of treatment-related adverse events ................................................ 200

Table 40: Cross table of odds ratios with 95% credible intervals from the network meta-analyses

comparing ARVs in terms of treatment-emergent adverse events ........................................... 202


comparing ARVs in terms of treatment emergent serious adverse events ............................... 204


of ARVs for viral suppression at 48 weeks from the fixed-effects network meta-analyses in HIV-

TB co-infected patients ............................................................................................................... 206


of ARVs for mean change in CD4 cell counts at 48 weeks from network meta-analyses in HIV-TB

co-infected patients .................................................................................................................... 206

10


comparing ARVs in terms of mortality in HIV-TB co-infected patients in HIV-TB co-infected

patients ....................................................................................................................................... 207

Table 45: GRADE summary of evidence for the DTG vs EFV comparison in children and

adolescents ................................................................................................................................. 208

Table 46: GRADE summary of evidence for the DTG vs LPV/r comparison in children and

adolescents ................................................................................................................................. 212

Table 47: GRADE summary of evidence for the DTG vs RAL comparison in children and

adolescents ................................................................................................................................. 216

Table 48: GRADE summary of evidence for the RAL vs EFV comparison in children and

adolescents ................................................................................................................................. 220

Table 49: GRADE summary of evidence for the RAL vs LPV/r comparison in children and

adolescents ................................................................................................................................. 224

Table 50: GRADE summary of evidence for the RAL vs NVP comparison in children and

adolescents ................................................................................................................................. 228

11

Figures

Figure 1: Flow diagram for principal systematic literature review on adults and adolescents ... 36

Figure 2: Network of all studies included in the principal analysis .............................................. 38

Figure 3: Forest plot of select ARVs comparisons with respect to viral suppression at A. 48

weeks and B. 96 weeks according to fixed-effects network meta-analysis ................................ 41

Figure 4: Forest plot of select ARVs comparisons with respect to mean change in CD4 cell counts

at A. 48 weeks and B. 96 weeks according to fixed-effects network meta-analysis ................... 42

Figure 5: Forest plot of select ARVs comparisons with respect to mortality according to fixed-

effects network meta-analysis ...................................................................................................... 43

Figure 6: Forest plot of select ARVs comparisons with respect to the proportion of patients

developing AIDS defining illnesses according to fixed-effects network meta-analysis................ 44

Figure 7: Forest plot comparing pair-wise and NMA estimated relative effects of different ARVs

with respect discontinuations (all cause) ..................................................................................... 45

Figure 8: Forest plot comparing pair-wise and NMA estimated relative effects of select ARVs

with respect discontinuations due to adverse events .................................................................. 45

Figure 9: Forest plot of select ARVs comparisons with respect to A. treatment related adverse

events and B. treatment emergent adverse events according to fixed-effects and random-

effects network meta-analysis ...................................................................................................... 46

Figure 10: Forest plot of select ARVs comparisons with respect to A. treatment related serious

adverse events and B. treatment emergent serious adverse events according to fixed-effects

network meta-analysis .................................................................................................................. 47

Figure 11: Forest plot comparing pair-wise and NMA estimated relative effects of different ARVs

with respect regimen substitution (48 weeks) ............................................................................. 48

Figure 12: Modified FDA snapshot analysis of the percentage of participants (95% CI) with HIV-1

RNA <50 copies/mL ....................................................................................................................... 59

Figure 13: Flow diagram for principal literature review on TB co-infected individuals and first-

line ART regimens ......................................................................................................................... 60

Figure 14: Complete network of evidence for patients with HIV-TB co-infection ....................... 61

12

Figure 15: Flow diagram for principal systematic literature review on pregnant and

breastfeeding women and first line ART regimens ...................................................................... 70

Figure 16: Flow diagram for principal systematic literature review on adolescents and first line

ART regimens ................................................................................................................................ 76

Figure 17: Proportion of patients experiencing a treatment emergent serious adverse event or

adverse event ................................................................................................................................ 95

Figure 18: Proportion of patients experiencing a treatment related serious adverse event or

adverse event ................................................................................................................................ 96

Figure 19: Proportion of patients discontinuing treatment and discontinuing treatment due to

an adverse event ........................................................................................................................... 97

Figure 20: Proportion of patients that died and developed an AIDS defining illness .................. 98

Figure 21: Proportion of patients switching treatments during study ......................................... 99

Figure 22: Network diagram of trials informing viral suppression at 48 weeks (A); 96 weeks (B);

and 144 weeks (C). ...................................................................................................................... 160

Figure 23: Network diagram of the 66 trials informing mean change from baseline in CD4 cell

counts at 48 weeks (A); 96 weeks (B); and 144 weeks (C). ........................................................ 162

Figure 24: Network diagram of the trials informing mortality ................................................... 164

Figure 25: Network diagram of the comparative trials reporting AIDS defining illnesses outcome

..................................................................................................................................................... 165

Figure 26: Network diagram of the trials informing discontinuation due adverse events among

first-line HIV patients .................................................................................................................. 166

Figure 27: Network diagram of the trials informing retention among first-line HIV patients ... 167

Figure 28: Network diagram of the trials informing the treatment-related adverse events

analysis ........................................................................................................................................ 168

Figure 29: Network diagram of the trials informing the treatment-emergent adverse events

analysis ........................................................................................................................................ 169

Figure 30: Network diagram of the trials informing the treatment-related serious adverse

events analysis ............................................................................................................................ 170

13

Figure 31: Network diagram of the trials informing drug emergent serious adverse events

among first-line HIV patients ...................................................................................................... 171

Figure 32: Network diagram of the trials informing regimen substitutions .............................. 172

Figure 33: Network diagram of trials informing viral suppression at the 24-week (A) and 48-

week (B) timepoints in HIV-TB co-infected patients. ................................................................. 173

Figure 34: Network diagram of the trials informing mean change from baseline in CD4 cell

counts at 24-week (A) and 48-week (B) timepoints in HIV-TB co-infected patients. ................. 174

Figure 35: Network diagram of the trials informing Mortality in HIV-TB co-infected patients . 176


in HIV-TB co-infected patients .................................................................................................... 177

Figure 37: Network diagram of the trials informing discontinuation due adverse events in HIV-

TB co-infected patients ............................................................................................................... 178

Figure 38: Network diagram of the trials informing retention among first-line HIV patients ... 178

Figure 39: Network diagram of the trials informing the treatment-related serious adverse

events analysis in HIV-TB co-infected patients ........................................................................... 179

Figure 40: Network diagram of the trials informing treatment emergent serious adverse events

in HIV-TB co-infected patients .................................................................................................... 180

14

Abbreviations

3TC Lamivudine

ABC Abacavir

ADI AIDS-defining illness

AIDS Acquired immunodeficiency syndrome

ATV/r Ritonavir-boosted atazanavir

ART Antiretroviral therapy

ARV Antiretroviral agent/drug

AZT Zidovudine

BIC Bictegravir

bid Twice daily

CD4 Cluster of differentiation 4

CENTRAL Cochrane Central Register of Controlled Trials

CI Confidence interval

CLARITY Clinical Advances through Research and Information Translation

CrI Credible interval

CROI Conference on Retroviruses and Opportunistic Infections

d4T Stavudine

ddI Didanosine

DIC Deviance information criterion

DOR Doravirine

DRV/r Ritonavir-boosted darunavir

DTG Dolutegravir

EFV Efavirenz – Standard 600mg once daily dose

EFV400 Efavirenz – 400mg once daily dose

EMBASE Excerpta Medica database

ETR Etravirine

EVG Elvitegravir

FTC Emtricitabine

15

GRADE Grading of Recommendations Assessment, Development and Evaluation

HBV Hepatitis B virus

HIV Human immunodeficiency virus

IAS International AIDS Society

IDU Injection drug user

INSTI Integrase strand transfer inhibitors

IQR Interquartile range

ITT Intention to treat

LPV/r Ritonavir-boosted lopinavir

MCMC Markov Chain Monte Carlo

MEDLINE Medical Literature Analysis and Retrieval System Online

NFV Nelfinavir

NMA Network meta-analysis

NNRTI Nonnucleoside reverse transcriptase inhibitor

NRTI Nucleoside reverse transcriptase inhibitors

MD Mean difference

OR Odds ratio

PI/r Ritonavir-boosted protease inhibitor

PICOS Population, interventions, comparisons, outcomes, study design

PLHIV People living with HIV

qd Once daily

RAL Raltegravir

RCT Randomized-controlled trial

RPV Rilpivirine

RR Relative risk

SD Standard deviation

SE Standard error

SLR Systematic literature review

TAF Tenofovir alafenamide

16

TB Tuberculosis

TDF Tenofovir disoproxil fumarate

XTC Lamivudine or Emtricitabine

17

Executive Summary

Background: In 2015, the WHO conducted evidence synthesis to update the 2013 Consolidated

guidelines on the use of antiretrovirals for treating and preventing HIV. At the time, the combination of

efavirenz, tenofovir disoproxil and lamivudine (or emtricitabine) [EFV + TDF + XTC] was the preferred

first-line therapy. Results of the 2015 systematic literature review (SLR) and network meta-analysis

(NMA) revealed improved tolerability and efficacy with dolutegravir (DTG) and low-dose efavirenz

(EFV400). Despite this evidence, DTG and EFV400 were recommended as alternative first-line regimens

rather than the preferred treatment. This was due to the high price of DTG and uncertainty around sub-

populations; rendering it difficult to recommend for low and middle income countries under the public

health approach. With numerous changes, including the availability of generic fixed dose combinations

of DTG +TDF + XTC and a growing evidence base among sub-populations, we sought to update the SLR

and NMA in order to determine the efficacy and safety of DTG and EFV400 relative to EFV.

Objective: The objective of this project is to compare the efficacy and safety of first-line ART regimens.

Given the knowledge accumulated through previous guidelines and knowledge of current literature

results, this project is centred on the following research question:

1. Should DTG be recommended as the preferred first-line antiretroviral agent in combination with

age-appropriate backbone (TDF + XTC for adults and adolescents) for the treatment of HIV?

2. Should EFV400 be preferred over EFV (standard-dose) for the first-line antiretroviral agent in

combination with age-appropriate backbone for the treatment of HIV?

Methods: Systematic database searches were conducted on 12 February 2018 to identify publications

reporting on relevant randomised controlled trials (RCTs) in the following databases: MEDLINE, EMBASE,

and Cochrane Central Register of Controlled Trials through Ovid. The current systematic review is an

update on a review completed in May 2015 (Global Evaluative Sciences). Further manual searches of the

2016, 2017 and 2018 Conference on Retroviruses and Opportunistic Infections (CROI), the 2016 AIDS

conference, and the 2017 International AIDS Society (IAS) conference were conducted. Additional

studies were identified through a review of clinical trial registries and the reference lists of identified

publications. All steps of the SLR were conducted independently and in duplicate. The same searches as

in 2015 were used in 2018. Study eligibility was expanded to include newer treatments. Namely

bictegravir, doravirine and tenofovir alafenamide. Data were extracted for trial characteristics, subject

characteristics and outcomes. The outcomes included: viral suppression at all available thresholds, mean

18

change in CD4 cell counts, mortality, AIDS defining illnesses, retention, discontinuation due to adverse

events, treatment related adverse events and regimen switching. This process was repeated for the

TBHIV co-infection, pregnant and breastfeeding women, and children sub-populations.

Data were analysed using NMA similar to in the 2015 evidence synthesis. NMA build upon the more

traditional pairwise meta-analyses by considering all treatment simultaneously for the analysis of a

single outcome. The analyses were performed in a Bayesian framework. For each outcome of interest,

fixed- or random-effects models were applied. Given that the research questions focus on the third

agents of ART with a specific backbone (XTC+ TDF), we chose to define the nodes in terms of specific

antivirals rather than specific ART regimens. Defining nodes according to a single ARV rather than the

full regimen significantly simplified the interpretation of modelling and results. The analyses used an

arm-specific meta-regression adjustment to account for differences in backbones, which was critical

given the importance of the SINGLE trial which compares DTG to EFV, but with different backbones. This

approach allowed us to use SINGLE rather than ignore it. Analyses restricting to comparisons with the no

differences in backbones were conducted as sensitivity analyses. Additionally, we conducted analyses

that made adjustments for differences in baseline CD4, HIV RNA and proportion of males.

To assess the overall quality of evidence, we used the Grading of Recommendations Assessment,

Development and Evaluation (GRADE) system for rating overall quality of evidence with adjustments for

the NMA methods employed. Adjustments to the direct or indirect estimate quality of evidence using

network estimates could be rated up for gained precision and rated down for evidence of lack of

transitivity.

Results: A total of 2815 citations were identified through database searches for the SLR update. Based

on the original review (May 2015) and the current update, 163 publications describing 90 trials were

identified and included in the systematic literature review for adults and adolescents. Of the 17 new

trials added to the evidence base, 4 included DTG (ARIA, GS-US380-1489; GS-US-380-1490, and

SSAT066), 3 included DOR (DRIVE AHEAD, DRIVE FORWARD, and 1439-007 Study), 2 included BIC, and 3

were endonodal on EVG/c comparing TAF to TDF. Despite the large number of trials in the evidence base

as a whole, there are three key trials that very much inform the comparisons of interest: SINGLE (DTG +

ABC + XTC vs EFV + TDF + XTC), SPRING-1 (DTG + 2 NRTIs vs EFV + 2 NRTIs) and ENCORE1 (DTG + TDF +

XTC vs EFV + TDF + XTC). These are the trials involved in the head to head comparisons of interest. No

evidence was available to describe the use of EFV400 in any of the sub-populations and as such only the

comparison of DTG vs EFV was considered in the sub-populations.

19

An analysis set was formed using a subset of the SLR. On the basis of our 2015 analysis, we removed

studies of indinavir, fosamprenavir, unboosted atazanavir, saquinavir, nelfinavir, and triple NRTIs from

the analysis set. Five trials were removed for having a raltegravir backbone, which could not be handled

in the model. From the review update, we excluded: GS-US-141-1475 used a non-FDA approved dose of

BIC; and GS-US-299-0102 was an endonodal trial that did not connect to the overall network (cobicistat

boosted darunavir). The network was well-connected, with EFV serving as the most well-connected

node. Overall, the principal analysis set of studies included 65 trials in which 33,148 patients were

randomized to 151 treatment arms (12 treatments). A combination of direct and indirect evidence was

available for all treatment comparisons except those involving EFV400, bictegravir and rilpivirine.

Results were quite similar to those from the 2015 review. All analyses appeared to meet the consistency

assumption for NMA. There were a few differences. We note that while no analysis required meta-

regression adjustments previously, there was one analysis that did require an adjustment for imbalances

in the proportion of males; namely, the analysis for discontinuations. Another difference is that the

fixed-effects model was more often favoured in these analyses, while the random-effects were more

commonly used in the 2015 analyses. This suggests a reduction in heterogeneity and it may be due to

the removal of the older treatment nodes.

There was high quality evidence of improved viral suppression (odds ratio [OR]: 1.93; 95% credible

interval [CrI]: 1.52, 2.47 at 96 weeks), discontinuations (OR: 0.49; 95% CrI: 0.44, 0.62) and

discontinuations due to AEs (OR: 0.30; 95% CrI: 0.19, 0.47) for DTG relative the EFV. This was supported

by moderate quality evidence of improvements in CD4 cell counts (mean difference: 22.87; 95% CrI:

8.29, 37.40), and both treatment-related (OR: 0.33; 95% CrI: 0.25, 0.44) and treatment-emergent AEs

(OR: 0.63; 95% CrI: 0.38, 1.11). Due to low numbers of events, imprecise estimates and some risk of bias,

there was on low to very low quality evidence for efficacy at 144 weeks, mortality and ADIs, SAEs and

regimen substitutions.

For EFV400 relative to standard dose EFV, high quality evidence was obtained for discontinuations due

to AEs (OR: 0.42; 95% CrI: 0.22, 0.77). Otherwise, efficacy and safety tended to have moderate quality

evidence due to imprecision. Similar to above, mortality and ADIs, treatment related AEs and SAEs, and

regimen substitutions had low to very low quality evidence. Finally with respect to adults and

adolescents, due to the indirectness, there was no high quality evidence comparing DTG to EFV400.

There was moderate evidence of DTG leading to less discontinuations and having better long-term viral

suppression.

20

The results of the systematic literature review failed to identify a wealth of evidence for the treatment

of patients with HIV-TB co-infection. However, an interim analysis from the ongoing INSPIRING trial was

identified from the CROI 2018 conference. INSPIRING (NCT02178592) is a Phase III, open-label

randomized controlled trial enrolling HIV-TB co-infected adult patients for treatment with twice-daily

DTG 50 mg or once-daily EFV 600 mg. It included 113 patients and only the 24 week interim analysis

results were available. The evidence base consisted of 1378 patients enrolled in 13 treatment arms

across 6 RCTs. The evidence was limited to 5 treatments: NVP, DTG, EFV, and RAL (400 mg; 800 mg). No

evidence was identified for patients treated with EFV400.

There was no statistically significant difference between DTG and EFV (OR: 0.54; 95% CrI: 0.19, 1.57) or

between RAL400 and RAL800; however, the estimate suggests lower odds of suppression (in accordance

with the FDA Snapshot algorithm). This difference appears to be driven by the larger number of

discontinuations among the DTG arm of the INSPIRING trial. DTG appeared to lead to larger increases in

CD4 (mean difference: 52.52 cells/mm3; 95% CrI: 14.93, 89.61). Outside of the moderate quality

evidence supporting DTG relative to EFV with respect to change in CD4 cell counts, the evidence was of

low to very low quality based on very small event counts and short follow-up.

Two studies were identified with respect to pregnant and breastfeeding women: the DolPHIN 1 trial and

the Tsepamo study. The Tsepamo study was a large cohort study of 1,729 pregnant women initiating

DTG/TDF/XTC and 4,593 women initiating EFV/TDF/XTC in Botswana. The proportion of pregnancies

with any adverse birth outcome was similar across treatment arms with 33.2% of DTG-managed

pregnancies and 35.0% of EFV-managed pregnancies resulting in an adverse outcome. Similarly, severe

birth outcomes were reported in 10.7% of DTG-managed and 11.3% of EFV-managed pregnancies. For a

variety of safety outcomes, there was moderate quality evidence due to the risk of bias associated with

an observational study, though with respect to safety, a large cohort study such as this one is among the

most desirable studies to have.

Finally for children, there was a real lack of evidence with respect to DTG, which was only reported in a

single study among treatment experienced patients (i.e., not eligible). No comparative studies included

RAL. However, two RAL studies were identified in neonates and infants, which both concluded that RAL

was tolerable among infants. Given the lack of comparative evidence in the children and adolescent

subgroup, we reference the results of the adult and adolescent review and downgrade the quality of

evidence by one level for indirectness.

21

Discussion: The purpose of this study was to support the 2018 update to the consolidated guidelines on

the use of antiretrovirals for treating and preventing HIV with respect to the choice of first-line ART. The

two questions of interest were whether DTG and/or EFV400, each with an XTC + TDF backbone, should

be the preferred first-line ART regimen rather than their current designation of alternative first-line ART

regimen. This extensive systematic literature review and network meta-analysis to evaluate the

comparative efficacy and safety of these and other ART regimens drew strong conclusions about the

improved efficacy and tolerability of DTG relative to EFV. Moreover, the evidence synthesis supports the

use of DTG among sub-populations, which was not the case in 2015. Specifically, results of this study

suggest comparable safety among pregnant women initiating treatment and results were not

demonstrably worse among TB-HIV co-infected individuals. Unfortunately, evidence was lacking with

respect to first-line children. Overall, the evidence more strongly supports the choice of DTG as the

preferred first-line regimen.

Our study has numerous strengths and limitations. First, the use of NMA allowed for analytic

adjustments to account for differences in backbones and provide an unbiased estimate of the

comparison between DTG and EFV despite the critical trial having different backbones. Second, by

combining direct and indirect evidence, some of findings can be seen as having stronger evidence than

previously perceived when strong findings are supported by both sources of evidence. With respect to

limitations, first, the evidence for the comparisons of interest continued to be somewhat limited in sub-

populations. For EFV400, it was completely missing. Most notably for DTG, there was an absence of

evidence within children. This was also the case in people pre-exposed to ARVs, though that was

somewhat expected. Even in pregnancy and TB, much of the evidence is still to come. Second, some

significant outcomes were limited by a very low number of events, including mortality, regimen

substitutions, serious adverse events, and ADIs. This influenced the precision of our estimates with

respect to these outcomes and, in some cases, precluded the conduct of evidence synthesis through

NMA. Third, treatment-related adverse events were both inconsistently defined and inconsistently

reported. This limitation was mitigated by considering both treatment-related and treatment-emergent

adverse events. Additionally, studies of shorter duration are, by their nature, less likely to identify

adverse events than longer-term trials. Despite this, the evidence was collected through a rigorous

systematic review process in accordance with the practices and recommendations set forth by the

Cochrane Collaboration, including both broad and targeted searches of the literature, critical appraisal

of the identified studies, and consultation with subject matter experts.

22

Dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate is an

effective, safe and tolerable ART regimen. Across a variety of outcomes, evidence strongly suggests that

it is superior to the current efavirenz-based preferred first-line ART regimen. With a new affordable

generic fixed dose combination and comparable outcomes among sub-populations, the evidence

supports the choice of a dolutegravir based preferred first-line regimen. Conclusions regarding low-dose

efavirenz are unchanged since 2015. Low-dose efavirenz appears to be more tolerable, but with lack of

evidence in sub-populations it is likely best to be considered an alternative first-line regimen.

23

1. Introduction

The efficacy and safety of initial HIV antiretroviral therapy (ART) has important improved over the years

and more than 17 million people living with HIV (PLHIV) are currently receiving life-saving ART.1

Improvements in potency, tolerability, simplicity and availability of first-line ART have resulted in

increased life expectancy and quality of life for PLHIV, when treatments are accessed in a timely and

consistent manner. Hence, the selection of first-line ART has important public health and programmatic

implications. With the effectiveness and safety of regimens as key considerations, many ART

programmes, particularly in low- and middle-income settings, are influenced by the World Health

Organization (WHO) ART guidelines.2

Clinical guidelines are developed through multi-step processes that ensure that they are feasible within

the current clinical environment and that they are evidence based. A key step involves evidence

synthesis whereby all of the evidence is collected and analysed so as to provide an overview of the

therapeutic landscape. In 2015, the WHO conducted evidence synthesis to update the 2013

Consolidated guidelines on the use of antiretrovirals for treating and preventing HIV. At the time, the

hypothesis was that integrase inhibitor (INSTI) based regimens or low-dose efavirenz (EFV400) based

regimens would challenge preferred recommended first-line regimen. The 2013 guidelines

recommended, for adults and adolescents, a first-line ART consisting of two nucleos(t)ide reverse

transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI).3 In

particular, the combination of efavirenz, tenofovir disoproxil and lamivudine (or emtricitabine) [EFV +

TDF + XTC] was the preferred option as first-line therapy.3 Results of the 2015 systematic literature

review (SLR) and network meta-analysis (NMA) revealed improved tolerability and efficacy with INSTIs

and EFV400, with dolutegravir (DTG) having the highest estimated tolerability and safety.4

Despite this evidence, DTG and EFV400 were recommended as alternative first-line regimens rather

than the preferred treatment.5 This was due to uncertainty around sub-populations and an expensive

price rendering it difficult to recommend for low and middle income countries. With numerous changes,

including the availability of generic fixed dose combinations of DTG +TDF + XTC, the 2018 SLR and NMA

aimed to determine the efficacy and safety of DTG and EFV400 relative to EFV600. This report presents

the findings of an updated SLR and NMA that was commissioned to shed light on this very topic.

24

2. Objectives

The objective of this project is to compare the efficacy and safety of first-line ART regimens. Given the

knowledge accumulated through previous guidelines and knowledge of current literature results, this

project is centred on the following research question:

3. Should DTG be recommended as the preferred first-line antiretroviral agent in combination with

age-appropriate backbone (TDF + XTC for adults and adolescents) for the treatment of HIV?

4. Should EFV400 be preferred over EFV (standard-dose) for the first-line antiretroviral agent in

combination with age-appropriate backbone for the treatment of HIV?

25

3. Methodology

3.1. Systematic literature review

Table 1 describes the PICOS (population, interventions, comparator, outcomes, study design) criteria

used to guide the selection of studies that were included in this systematic literature review. Note that

both research questions are captured by this single PICOS.

Table 1: Scope of the literature review in PICOS form

Criteria Definition

Population Inclusion criteria:

Treatment-naïve adults and adolescents (12 years and above) living with

HIV

Subgroups of interest:

Children

Adolescents

Pregnant and breastfeeding women

TB co-infected patients

People with prior exposure to ARVs

Interventions DTG + 2NRTI

EFV400 + 2NRTI

Raltegravir (RAL) + 2NRTI

Elvitegravir boosted with cobicistat EVG/c + 2NRTI

Bictegravir (BIC) + 2 NRTI

Doravirine (DOR) + 2NRTI

Rilpivirine (RPV) + 2 NRTI

Nevirapine (NVP) + 2 NRTI

Darunavir boosted with ritonavir (DRV/r) + 2 NRTI

Atazanavir boosted with ritonavir (ATV/r) + 2 NRTI

Lopinavir boosted with ritonavir (LPV/r) + 2 NRTI

Comparator EFV600 + 2 NRTI

Outcomes Viral suppression at 48 and 96 weeks

Change from baseline CD4 at 48 and 96 weeks

26

Mortality

Retention

Discontinuations due to adverse events

Treatment emergent adverse events

Severe adverse events

Development of drug resistance

Study design Inclusion criteria:

Randomized controlled trials (RCTs)

Additionally, for subgroups:

Single-arm non-randomized controlled trials

Prospective and retrospective cohort studies

Case-control studies

Controlled and uncontrolled longitudinal studies (cohorts or case series)

Language Only studies published in English will be included

*Note: Except for DTG, EFV400 and EFV600 treatments are required to provide indirect evidence

The population listed above, treatment-naïve adults and adolescents, represents the principal analysis

for this evidence synthesis project. This systematic literature review includes reviews and analyses for a

variety of sub-populations: Adolescents and children; TB co-infected patients; Pregnant and

breastfeeding women; and people with prior exposure to ARVs. Although the principal inclusion criteria

described above was broad enough to capture these sub-populations, less restrictive criteria on study

design were required to obtain meaningful evidence on them. Thus, additional searches were conducted

for each sub-population, with the exception of adults and people with prior exposure to ARVs. Note that

no RCTs pertaining to or describing patients with prior exposure to ARVs were identified and hence no

evidence base exists within the identified parameters for this sub-population. No analyses were

conducted for this sub-population either.

Treatments were differentiated according to the specific drugs, doses, and frequencies of administration.

The only drugs that were considered interchangeable were lamivudine (3TC) and emtricitabine (FTC)

due to their molecular likeness, referred to here as XTC. Non-standard doses were not considered

reason for exclusion at the study selection process; however, non-standard doses that did not serve as

connectors (i.e. were not compared to two or more treatments of interest) were excluded in the final

27

selection stage (following full text selection). ART regimens with a single antiviral agent and those with

two agents that included one or more NRTI were not considered eligible. Similarly, with the exception of

boosted regimens, ART regimens with four or more agents were not eligible (e.g. NNRTI+PI+2NRTI).

Trials that had mixed backbones were included if the backbones were equally distributed across arms.

Trials where backbones were selected prior to randomization were considered eligible. Trials failing to

report on backbone distribution or reporting imbalanced backbone distributions were excluded. Further

details on how regimens were defined for analytical purposes are provided below (Section 3.2.3).

The eligibility criteria remained generally unchanged relative to the 2015 SLR; however, there were a

few additions with respect to interventions. Two new treatments, BIC and DOR, were added to the

network. The motivation for adding them is that they might provide additional indirect evidence to the

comparisons of interest and that there may be some secondary utility to understanding their efficacy

and safety relative to the treatments of interest. Additionally, the use of tenofovir alafenamide (TAF) as

a backbone was now permitted given that the evidence base for this treatment has grown substantially

since 2015.

3.1.1. Sources

A comprehensive systematic search of the literature was conducted on using the following databases:

Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database

(EMBASE), and Cochrane Central Register of Controlled Trials (CENTRAL). The current systematic review

is an update on a review completed in May 2015 (Global Evaluative Sciences). Therefore, searches were

restricted from 01 January 2015 to the search date, 12 February 2018.

Further manual searches of the 2016, 2017 and 2018 Conference on Retroviruses and Opportunistic

Infections (CROI), the 2016 AIDS conference, and the 2017 International AIDS Society (IAS) conference

were conducted. Conference abstracts identified through the EMBASE search were eligible for inclusion.

Additional studies were identified through a review of clinical trial registries and the reference lists of

identified publications.

3.1.2. Search strategy

The general search strategy involved identifying papers according to the population of interest, and the

inclusion of interventions and comparators of interest, and the restriction to randomized controlled

trials. Population was identified as having HIV or AIDS and not being treatment experienced or failing

28

treatment. Our search further restricted on publication types that were not of interest (i.e., newsletters

and reviews). The specific search strategy is presented in Appendix A. The additional search strategies

for each subpopulation are presented in Appendix B.

3.1.3. Study selection

Two investigators, working independently, scanned all abstracts and proceedings identified in the

literature search. The same two investigators independently reviewed abstracts and proceedings

potentially relevant in full-text. If any discrepancies occurred between the studies selected by the two

investigators, a third investigator provided arbitration. Full-text screening was conducted for each

specific question.

3.1.4. Study quality

The validity of individual randomized controlled trials was assessed using the Risk of Bias instrument,

endorsed by the Cochrane Collaboration.6 This instrument is used to evaluate 7 key domains: sequence

generation; allocation concealment; blinding of participants and personnel; blinding of outcome

assessors; incomplete outcome data; selective outcome reporting; and other sources of bias.

The validity of non-randomized studies, including single-arm trials, cohort studies, and observational

study studies, were evaluated using the Tool to Assess the Risk of Bias in Cohort Studies, developed by

the Clinical Advances through Research and Information Translation (CLARITY) group at McMaster

University. This 8-item instrument is used to evaluate various aspects of the research design and study

execution, including selection of patients, differences in patient characteristics, and the assessment of

outcomes.

We employed the Grading of Recommendations Assessment, Development and Evaluation (GRADE)

system for rating overall quality of evidence.7-12 Most recently, GRADE has issued guidance on network

meta-analysis.13 We applied GRADE in the following manner. First, the GRADE system was applied to the

direct evidence as is done with pairwise meta-analyses. If only indirect evidence existed, we used the

NMA estimate and evaluated the shortest indirect pathway with the largest number of trials. As neither

of these combined direct and indirect evidence, we referred to this stage as the assessment of

uncombined evidence. Specifically, for each outcome, the rating began as high-quality evidence and

were potentially rated down by one or more of five categories of limitations: (1) risk of bias, (2)

consistency, (3) directness, (4) imprecision, and (5) reporting bias. The second stage involved rating the

combined evidence, which is the NMA evidence for comparisons assessed according to pairwise meta-

29

analyses in the first stage. In this stage, we began with the score from the first stage. We rated down if

the comparison was within a loop in which there was evidence on inconsistency (i.e. lack of transitivity)

or if the estimate became imprecise. Alternatively, we rated up if a direct estimate that was graded

down for imprecision in the first stage and became precise in the NMA. The quality of evidence for each

main outcome can be determined after considering each of these elements, and categorized as either

high (We are very confident that the true effect lies close to that of the estimate of the effect),

moderate (We are moderately confident in the effect estimate: The true effect is likely to be close to the

estimate of the effect, but there is a possibility that it is substantially different), low (Our confidence in

the effect estimate is limited: The true effect may be substantially different from the estimate of the

effect ), or very low (We have very little confidence in the effect estimate: The true effect is likely to be

substantially different from the estimate of effect).14

3.1.5. Data extraction

Two investigators, working independently, extracted data on study characteristics, interventions, patient

characteristics at baseline, and outcomes for the study populations of interest for the final list of

selected eligible studies. Any discrepancies observed between the data extracted by the two data

extractors were resolved by involving a third reviewer and coming to a consensus. Data is provided in a

Microsoft Excel Workbook with sheets corresponding to the different information categories.

For each continuous outcome, the change from baseline at the end of the randomized phase was

extracted, along with the corresponding sample size, standard deviation (SD) for mean change from

baseline and measures of uncertainty (i.e. standard error (SE), 95% confidence intervals (CI), and p-value)

for all relevant intervention groups.

If the change from baseline was not provided, we extracted the score at the follow-up time point of

interest and the baseline score, and calculated the change in such cases, the standard error of change

was estimated by combining the standard errors at both time points and using an outcome specific

correlation coefficient (ρ) in the following equation:

𝑆𝐸(𝜃) = √𝑉𝑎𝑟(𝑌1) + 𝑉𝑎𝑟(𝑌2) − 2𝑆𝐷1𝑆𝐷2𝜌 /√𝑛

The outcome specific correlation can be obtained by first deriving the correlation from studies that

reported both change and measurements at the both time points. Given that this was not available for

30

the outcomes of interest, we used the conservative measure of 0.5. In cases where interquartile ranges

(IQR) were provided, the length of the IQR was divided by 1.35 to estimate standard deviation.

If the SE was not reported, it was calculated according to the following hierarchy: based on the reported

95% CI by intervention group; SD by intervention group along with sample size; 95% CI of the difference

between intervention groups; p-values by intervention groups; p-values for the difference between

intervention groups. In cases where standard deviations were not provided, the average standard

deviation among reported studies was used. Measures of dispersion were imputed for trials in which

dispersion measures were not reported. Mean standard deviation was used for imputation and standard

errors were derived from these.

3.2. Analyses

In this section, we describe the methods used to conduct the statistical analyses.

3.2.1. Network meta-analyses

When sufficient data were available for quantitative evidence synthesis, a conventional pairwise meta-

analysis was employed as a first step. When multiple treatments were available within the evidence

base, we employed network meta-analyses (NMA). All NMAs were conducted within the Baian

framework using Baian hierarchical models. Under the assumption of consistency, the NMA model

relates the data from the individual studies to basic parameters reflecting the (pooled) relative

treatment effect and safety profiles between interventions. Based on these parameters, the relative

treatment effects between each of the contrasts in the network were obtained.

For each outcome and subgroup of interest, fixed or random-effects models were applied. Model

selection was conducted using the deviance information criterion (DIC) according to NICE conventions.15

The DIC provides a measure of model fit that penalizes for model complexity. Through the use of the DIC,

the fixed effects models were often favoured. Model fit was also assessed using leverage plots and any

outliers identified in this fashion were investigated further. The model with the best fit was chosen as

the primary analysis model. In situations with very limited and sparse data, a narrative review was used

as an alternative to quantitative analysis. The latter were restricted to the sub-population analyses.

3.2.2. Evaluation of consistency between direct and indirect comparisons

Prior to the NMA, the consistency between direct and indirect comparisons was evaluated for networks

that consisted of closed loops. For each of the comparisons (i.e. contrasts) that were part of a closed

31

loop made up of more than 1 RCT, we split the available trials into direct and indirect information. For

each contrast in question, two (pooled) relative treatment effect estimates were obtained, one with

independent-means (or independent-effects) models using only the trials providing direct comparisons,

and one based on an NMA of the remaining trials providing only indirect evidence. This iterative

technique is called edge-splitting.16 The difference in estimates generated by the two sets of evidence

was evaluated with the Bucher test for inconsistency.17

3.2.3. Node definitions and backbone adjustments

Given that the research questions for this project concern third agent antivirals (i.e., non-backbone

antivirals); we chose to define the nodes in terms of specific antivirals rather than specific ART regimens.

All treatments with multiple standard doses or frequency of administration were not differentiated on

this basis. For example, nevirapine 200 mg twice daily (bid) was considered equivalent to nevirapine 400

mg once daily (qd). The only treatment with multiple doses that were distinguished in the analysis was

efavirenz (600 mg qd) and low dose efavirenz (400 mg qd). Defining nodes according to a single ARV

rather than the full regimen importantly simplified the interpretation of modelling and results.

Nonetheless it is important to account for differences in backbone therapies. RCTs that use the same

backbone in all trial arms do not require any adjustment in terms of backbones; however, RCTs

employing different backbones require adjustments in order to properly measure the effect attributable

to the antiviral agent comparison being estimated. Two approaches were used to address differences in

backbone regimens. First, backbone regimens were categorized as TDF + XTC (the reference category),

TAF + XTC, abacavir (ABC) + XTC, zidovudine (AZT) + XTC, and as other. The other category included

treatments such as stavudine (d4T) and didanosine (ddI) as well as the agents contained in the previous

categories. We used arm-specific meta-regression to adjust estimates according to differences in

backbones according to these categories. The alternative approach was to simply reduce the evidence

base to trials that did not differ with respect to backbones.

The most notable trial to differ in backbones was the SINGLE trial comparing EFV to DTG,18 which is

central to the research questions. Otherwise, trials that differed in backbones tended to be older or to

be endonodal. Endonodal trials are those that compare a node to itself. Indeed, some trials differing in

backbone only were included to improve the backbone meta-regression adjustments. Such trials,

comparing EFV to EFV, were only of interest in the analysis using meta-regression adjustments for

32

differences in backbones. The adjusted model served as the primary analysis; however, in outcomes

where differences in backbones were restricted to endonodal trials or a few older trials with dated

regimens, the restricted model was used instead.

3.2.4. Models

All outcomes were either binary or continuous. Viral suppression and CD4 outcomes were frequently

reported at multiple time points and were analysed separately for each of the three time points of

interest: 24 weeks, 48 weeks, and 96 weeks. The remaining outcomes tended to be reported at a single

time point, which varied and typically coincided with trial duration. During the feasibility assessment

stage, the relationship between follow-up time and outcomes was explored. The figures in Appendix C

consider trends in both proportions and odds ratios across time. The odds ratios are the more important

consideration given they represent the effect being modelled. In these figures odds ratios at multiple

time points within a single trial were connected to further help determine whether follow-up time is an

effect modifier to relative treatment effects. As can be seen in these figures, the odds ratios tend to be

stable over time or include an equal amount of downward and upward trends. On this basis, we

modelled the relative treatment effects on all remaining variables using the outcomes combined across

multiple time points. For studies reporting one of these outcomes at multiple time points, the values at

longest follow-up were used.

For binary outcomes (mortality, AIDS defining illnesses, viral suppression, loss to follow-up, serious

adverse events, and regimen substitutions) we used a logistic regression model with the logit link

function and a binomial likelihood. We chose to present results as odds ratios (OR) for these models so

as to avoid the ceiling effect that limits relative risks (RR) for outcomes with proportions around 0.8 to

0.95. To test for the presence of heterogeneity both the fixed-effects and random-effects models were

employed. For the random-effects model, the conventional non-informative prior, a uniform distribution

between 0 and 2, was applied to the between-trial standard deviation.15 For continuous outcomes

(increase in CD4 count) we used linear regression models with an identity link and normal likelihood.

The data was arm based, and we modelled the differences in change from baseline between all

informed treatment comparisons. Estimates of comparative efficacy were represented as mean

differences.

33

3.2.5. Adjusted analysis

Adjusted analyses came in two flavours. First, we conducted meta-regression adjustments to evaluate

whether differences in baseline CD4, baseline log transformed viral load, and proportion of males

impacted relative efficacy and safety estimated. Second, we conducted sensitivity analyses. For viral

suppression, we deemed the intention-to-treat (ITT) outcomes for our primary analysis and considered

the per-protocol outcomes as a sensitivity analysis. Additionally, multiple cut-off values were reported

for the definition of viral suppression. Newer trials tend to use a cut-off of <50 copies/mL, but some

trials used higher cut-off values, <200 and <400 copies/ml, due to limited sensitivity of older assays.

While the cut-off does affect the absolute count, we found no evidence to suggest that these alter

relative treatment effects. Thus, for the primary analysis, all trials were included regardless of cut-off

used, and as a sensitivity analysis only trials using the <50 copies/mL were included. In trials where

multiple cut-off values were reported, <50 copies/ml was favoured to <200 copies/ml, which was

favoured to <400 copies/ml.

3.2.6. Presentation of results

The primary output of the Baian NMA are posterior distributions of the relative treatment effects

between all interventions in the networks, e.g. odds ratios for discontinuation and mean change from

baseline in CD4 cell counts. The results for all outcomes are presented with NMA cross-tables as OR or

mean differences (MD). The posterior distributions of relative treatment effects and modelled outcomes

were summarized by the median and 95% credible intervals (CrIs), which were constructed from the

2.5th and 97.5th percentiles. As this project pertains to questions particular to three treatments, forest

plots are used to describe these in the main text and cross tables are provided in the Appendices for a

more in-depth look.

3.2.7. Software

The parameters of the different models were estimated using a Markov Chain Monte Carlo (MCMC)

method implemented in the JAGS software package. A first series of iterations from the JAGS sampler

were discarded as ‘burn-in’ and the inferences were based on additional iterations using two chains.

Convergence of the chains was confirmed by the Gelman-Rubin statistic. All analyses were performed

using R version 3.4.1 (http://www.r-project.org/) and JAGS version 4.3 (OpenBUGS Project Management

Group).

http://www.r-project.org/

34

4. Adults and adolescents

4.1. Systematic literature review study selection

Following the PICOS outlined in Table 1 and employing the search strategies specified in Appendix A, a

total of 2815 citations were identified through database searches for the SLR update; of these 204 were

selected for full-text review. The flow diagram for study inclusion is presented Figure 1. Based on the

original review (May 2015) and the current update, 163 publications describing 90 trials were identified

and included in the systematic literature review.18-180 We note that these trials are restricted to those of

the primary analysis. Trials pertaining to subpopulations, such as TB, have been excluded from this study

selection. Further details on these sub-populations are provided in Sections 5, 6 and 7.

Of the 17 new trials added to the evidence base, 4 included DTG (ARIA, GS-US380-1489; GS-US-380-

1490, and SSAT066),34,55,124,148 3 included DOR (DRIVE AHEAD, DRIVE FORWARD, and 1439-007

Study),58,59,99,117 2 included BIC,55,148 and 3 were endonodal on EVG/c comparing TAF to TDF.24,147,149 With

respect to the DTG trials, ARIA compared DTG to ATV/r among a sample of women only; SSAT066

compared DTG to RAL and EVG/c; while the remaining two trials were comparisons to BIC. Standard

dose efavirenz continued to be central as it was included in 5 trials; however, there were no new trials

comparing EFV to DTG or to EFV400. Just as in 2015, ENCORE1 was the only trial that included EFV400,

pitting it against standard dose EFV. The NAMSAL trial (NCT02777229) is ongoing aiming to compare

EFV400 to DTG and results are expected later this year.

As such, despite the large number of trials in the evidence base as a whole, there are three key trials

that very much inform the comparisons of interest: SINGLE (DTG + ABC + XTC vs EFV + TDF + XTC),

SPRING-1 (DTG + 2 NRTIs vs EFV + 2 NRTIs) and ENCORE1 (DTG + TDF + XTC vs EFV + TDF +

XTC).18,21,22,64,159,166,170,171 These are the trials involved in the head to head comparisons of interest. They

were all multinational, double-blind, placebo-controlled randomized trials. SRING-1 was a Phase II trial,

while the others were Phase III trials. Spring-1 randomized 205 patients, SINGLE randomized 833

patients and ENCORE1 randomized 636 patients. Writing in The Lancet Infectious Diseases, the

ENCORE1 study investigators concluded that EFV400 was non-inferior to EFV over 96 weeks with fewer

treatment-related adverse events and supported the use of EFV400 in routine care. While positive

conclusions were also drawn for the SINGLE trial, there was confounding due to the difference in

backbones. This is why the adjustments for differences in backbones were critical to this evidence

synthesis.

https://clinicaltrials.gov/ct2/show/NCT02777229

35

We note that no evidence was available to describe the use of EFV400 in any of the sub-populations and

as such only the comparison of DTG vs EFV was considered in the sub-populations.

The full list of included trials, including the studies included in the various sub-population reviews, is

provided in Appendix D.

Figure 1: Flow diagram for principal systematic literature review on adults and adolescents

4.2. Analysis set study selection

Feasibility, applicability, and relevance considerations led to the removal of several studies or study

arms from the analysis set. Following our 2015 analysis, it became clear that older treatments that are

no longer used in most settings had very little connectivity to the network and therefore provided

negligible additional information regarding the research questions. In fact, at times they displayed

evidence of loop inconsistency (disagreement between direct and indirect evidence). As such, we chose

to remove studies of indinavir, fosamprenavir, unboosted atazanavir, saquinavir, nelfinavir, and triple

NRTIs from the analysis set. To be clear, these were included in the SLR, but were removed from the

analysis set. Five trials were excluded for having a RAL backbone, which could not be handled in the

model. From the review update, GS-US-141-1475 and GS-US-299-0102 were excluded: GS-US-141-1475

used a non-FDA approved dose of BIC; and GS-US-299-0102 was an endonodal trial that did not connect

to the overall network (Cobicistat boosted DRV). Figure 2 presents the analysis set represented as a

network diagram.

38

Figure 2: Network of all studies included in the principal analysis

Legend: Circles (nodes) in the diagrams represent individual treatments, lines between circles represent

availability of head-to-head evidence between two treatments, and the numbers on the lines are the

number of RCTs informing each head-to-head comparison. Blue: NNRTIs; Green: Protease inhibitors;

Orange: Integrase inhibitors.

The network was well-connected, with EFV serving as the most well-connected node. Overall, the

principal analysis set of studies included 65 trials in which 33,148 patients were randomized to 151

treatment arms (12 treatments). A single study compared EFV to EFV400, with no indirect evidence

identified. A combination of direct and indirect evidence was available for all other treatment

comparisons except BIC and RPV. We kept both so as to have comparisons of these with the remainder

of the therapeutic landscape, but their inclusion provided no additional information to the comparisons

of interest.

Summaries of trial characteristics, patient characteristics, and critical appraisal quality assessments are

presented in Appendices E, F, and G, respectively. With respect to trial characteristics, trials ranged from

39

Phase II to IV, but most were Phase III, double-blinded and multinational. With respect to baseline

characteristics, there were a number of notable differences across trials. Most notably, sex varied from

all females to all males. Mean CD4 varied from as low as 102 cells/mm3 (PHIDISA II) to 576.5 cells/mm3

(GS-US-236-0140). Similarly, baseline HIV RNA varied from 4.28 (Epzicom-Truvada) to 5.48 (ADVANZ; a

new trial). There were also notable differences with respect risk groups and other markers of disease

severity, but age, sex, CD4 and viral load were the best reported and the ones that were explored

further through meta-regression. Overall, study quality was generally high (i.e., low risk of bias).

Exceptions were restricted to open-label trials having a high risk of bias due to blinding and some of the

more recent trials that were only reported upon in posters having insufficient information to determine

with certainty that the risk of bias was either low or high.

4.3. Results

Results were quite similar to those from the 2015 review. We note that while no analysis required meta-

regression adjustments previously, there was one analysis that did require an adjustment for imbalances

in the proportion of males; namely, the analysis for discontinuations. For all other analyses, the

unadjusted model was favoured. Another difference is that the fixed-effects model was more often

favoured in these analyses, while the random-effects were more commonly used in the 2015 analyses.

This suggests a reduction in heterogeneity and it may be due to the removal of the older treatment

nodes. In the following subsections we present results for each outcome. The GRADE tables

summarizing the overall evidence are then presented in Section 4.4.

Prior to providing details regarding the analysis of each outcome individually, consider a few general

remarks. The network diagrams for each analysis are provided in Appendix H. To further facilitate the

reader in identifying which trials were used for the analyses of each outcome, Appendix I lists the trials

and indicates which outcome analysis each trial was included in. All analyses appeared to meet the

consistency assumption for NMA. There were very few exceptions and these were restricted to specific

loops in the treatment related SAEs. In our judgement, these did not justify a need to use an alternative

analysis to the NMA. Nonetheless, we adjusted the GRADE score by reducing the score for network

transitivity where these concerns arose.

40

4.3.1. Viral suppression

Viral suppression was among the best reported outcomes. The definition of viral suppression was a

composite of the various thresholds reported in the included studies (i.e. <20-50 copies/mL; <200

copies/mL; <400 copies/mL). The <50 mL threshold was favoured and was by far the most commonly

reported threshold. Sensitivity analyses restricting the evidence base to only trials using the <50 mL

threshold yielded similar results, thus supporting the composite approach (results not shown).

Additionally, many trials used the Food and Drug Administration Snapshot algorithm, whereby

discontinuations are considered failures. This approach was used throughout the evidence base, even in

trials that did not explicitly use this approach. A consequence of this approach is that differences in viral

load suppression can either be driven by differences in efficacy (i.e., improved ability of the drug to

suppress the virus) or differences in tolerability (i.e., an increased propensity to stay on the drug) or

both. As such, while we consider viral suppression an efficacy outcome, in actuality it is difficult to

disaggregate efficacy from tolerability and this should be kept in mind while interpreting the results. The

reported analyses are restricted to intention to treat (ITT) results, but per-protocol results were also

analysed (results not shown). The per-protocol results did not resolve the issue around determining

whether differences are due to efficacy or tolerability. We note that Walmsley et al note that a large

difference between DTG and EFV in the SINGLE trial was due to tolerability. The networks used for

analysis at the 48, 96, and 144-week timepoints are presented in Error! Reference source not found. in

Appendix H. Notably, evidence on EFV400 was only available at the 46 and 96- week time points.

For the analysis of viral suppression at 48 weeks, evidence was derived from 53 trials of 115 treatments

arms including 26,410 patients. The results of the fixed-effects NMA for the comparisons of interest are

presented in Figure 3, below, and all comparisons in Error! Reference source not found. of Appendix J.

Based on the available evidence, DTG was statistically significantly more effective than standard dose

EFV in achieving viral suppression at 48 weeks (OR: 1.86; 95% CrI: 1.44, 2.40). In fact, it was statistically

superior to all other treatments except EFV400 (OR 1.61, 95% CrI 0.97, 2.70) against which it was

marginally significantly better. The comparison between DTG and EFV400 was based only on indirect

evidence. EFV400 was not statistically distinguishable from standard dose EFV.

For the analysis of viral suppression at 96 weeks, evidence was derived from 28 trials of 63 treatments

arms including 16,495 patients. The results of the fixed-effects NMA for the comparisons of interest are

also presented in Figure 3, below, and all comparisons in Error! Reference source not found. of

Appendix J. Treatment was DTG was associated with a higher proportion of patients achieving viral

41

suppression compared to all other treatments, though the comparison to RPV was not statistically

significant (OR 1.44, 95% CrI 0.98, 2.10). At this time point, treatment with DTG was associated with a

statistically significantly higher proportion of patient achieving viral suppression compared to EFV400

(OR 2.00, 95% CrI 1.20, 3.37). Similarly to at 48 weeks, EFV400 was not statistically distinguishable from

standard dose EFV.

The analysis of viral suppression at 144 weeks was based on evidence from 6 trials of 13 treatment arms

enrolling 5,274 patients. Given that EFV400 was not available at this time point, results of the fixed-

effects NMA for viral suppression at 144 weeks are only presented in Error! Reference source not found.

of Appendix J. DTG continued to demonstrate superior viral suppression, although only half the

comparisons were statistically significant. This was likely due to the smaller number of trials and patients.

Nonetheless, among the significant comparisons was that against EFV (OR: 1.44; 95% CrI: 1.08, 1.94).

Figure 3: Forest plot of select ARVs comparisons with respect to viral suppression at A. 48 weeks and

B. 96 weeks according to fixed-effects network meta-analysis

4.3.2. Increase in CD4 cell counts

The network of evidence for change in CD4 cell count at 48 weeks is based on 44 trials comprising 94

treatment arms including 23,789 patients. The results of the fixed-effects NMA for the comparisons of

42

interest are presented in Figure 4, below, and all comparisons in Error! Reference source not found. of

Appendix J. Based on the available evidence, DTG was statistically significantly more effective than

standard dose EFV in increasing CD4 at 48 weeks (MD: 22.87; 95% CrI: 8.29, 37.40), as was EFV 400 (MD:

25.43; 95% CrI: 6.93, 43.97). As a result, both treatments were comparable to one another. Both

treatments had higher estimated increases in CD4 than almost all other treatments, albeit not

statistically significant.


treatment arms including 15,134 patients. The results of the fixed-effects NMA for the comparisons of

interest are also presented in Figure 4, below, and all comparisons in Error! Reference source not found.

of Appendix J. Results at this time point were very similar to those at 48 weeks, suggesting an

improvement over the first year that is sustained in the second.


treatment arms including 7,019 patients. Given that EFV400 was not available at this time point, results

of the fixed-effects NMA for viral suppression at 144 weeks are only presented in Error! Reference

source not found. of Appendix J. The improvement in CD4 for DTG relative to EFV increased to 49.44

cells/mm3 (95% CrI: 19.51, 79.39); however, we caution that network was much more sparse than at

earlier time points.

43

Figure 4: Forest plot of select ARVs comparisons with respect to mean change in CD4 cell counts at A.

48 weeks and B. 96 weeks according to fixed-effects network meta-analysis

4.3.3. Mortality

The evidence base for mortality in first-line treatment consisted of 21,604 patients enrolled in 29 trials

consisting of 62 treatment arms. The network of evidence is presented in Error! Reference source not

found. of Appendix H. Although mortality was considered a very important outcome by the guideline

development group, the trials were underpowered for this outcome. Mortality across trials was low,

with the exception of PHIDISA II which compared EFV (106/872, 12.2%) to LPV/r (102/873, 11.7%). In all,

there were 391 deaths in the evidence base, but many comparisons with 0 events can render estimates

unreliable. Consider that there were only 5 deaths in each of DTG and EFV400 in the evidence base As a

result

Given the small number of events, there are limitations to synthesizing the evidence through an NMA

which may produce wide credible intervals. However, select comparisons are presented in Error!

Reference source not found.. There was no statistically significant difference between mortality

outcomes in patients treated with DTG, EFV, and EFV400.

44

Figure 5: Forest plot of select ARVs comparisons with respect to mortality according to fixed-effects

network meta-analysis

4.3.4. AIDS defining illnesses

The evidence base for AIDS defining illnesses in first-line treatment consisted of 9,722 patients enrolled

in 18 trials consisting of 40 treatment arms. The network of evidence is presented in Error! Reference

source not found. of Appendix H. Similar issues to those seen in mortality were present in the ADI

analysis. For example, 12.3% (14/144) of patients enrolled in the EFV arm of the Altair trial reported

ADIs while no patients (0%) reported ADIs in the EFV arm of GS-US-236-0102 (0/352), SPRING-1 (0/50),

and Protocol 004 (0/38) trials. Few ADIs were reported for patients treated with DTG (SPRING-1, 2/51,

3.9%) and for patients treated with EFV400 (ENCORE1, 14/321, 4.4%). Given the small number of events,

there are limitations to synthesizing the evidence through an NMA which may produce wide and non-

meaningful CrIs. However, select comparisons are presented in Error! Reference source not found..

There was no statistically significant difference between mortality outcomes in patients treated with

DTG, EFV, and EFV400.

Figure 6: Forest plot of select ARVs comparisons with respect to the proportion of patients developing

AIDS defining illnesses according to fixed-effects network meta-analysis

45

4.3.5. Discontinuations

The evidence base for all-cause discontinuations (retention) was based on 26,399 patients enrolled

across 120 treatment arms in 54 trials. The network of evidence is presented in Error! Reference source

not found. of Appendix H.

The results of the fixed-effects NMA for the comparisons of interest are presented in Figure 8, below,

and all comparisons in Error! Reference source not found. of Appendix J. Recall that this was the

outcome that required an adjustment for the proportion of males in the trials. Based on the available

evidence, DTG was statistically significantly more effective than standard dose EFV in preventing

discontinuations (OR: 0.49; 95% CrI: 0.44, 0.62). In fact, it was statistically superior to all other

treatments except EVG/c, BIC, and DOR against which it still had a lower estimate of discontinuation.

The comparison between DTG and EFV400 was based only on indirect evidence. EFV400 was not

statistically distinguishable from standard dose EFV (OR: 0.91; 95% CrI: 0.50, 2.08); however, we note

that DTG did appear to be superior to EFV400.

Figure 7: Forest plot comparing pair-wise and NMA estimated relative effects of different ARVs with

respect discontinuations (all cause)

46

4.3.6. Discontinuations due to adverse events

The evidence base for discontinuations due to adverse events was based on 54 trials of 26,165 patients

enrolled in 118 treatment arms. The network of evidence is presented in Error! Reference source not

found. of Appendix H.

Figure 8: Forest plot comparing pair-wise and NMA estimated relative effects of select ARVs with

respect discontinuations due to adverse events

The results of the fixed-effects NMA for the comparisons of interest are presented in Figure 9, below,

and all comparisons in Error! Reference source not found. of Appendix J. It is for this outcome that both

DTG and EFV400 shine, with both having the lowest odds of discontinuation due to adverse events and

both being superior to standard dose EFV. This time EFV400 and DTG were not statistically differentiable.

4.3.7. Treatment-related and emergent adverse events

The evidence for treatment-related adverse events included 15,599 patients enrolled in 61 treatment

arms across 27 trials and that for emergent adverse events included 18,915 patients in 70 treatment

arms across 32 trials. The results of the fixed-effects NMAs are presented in Error! Reference source not

found. and Error! Reference source not found.. Key comparisons are presented in Figure 9. While none

of the treatments were distinguishable with respect to treatment emergent AEs, both DTG and EFV400

had lower odds of leading to a treatment-related AE. Moreover, DTG had lower odds than EFV400.

Overall, BIC had the lowest odds of treatment-related AEs, followed by DOR, DRV/r and then DTG.

Treatments were generally less distinguishable with respect to emergent AEs.

47

Figure 9: Forest plot of select ARVs comparisons with respect to A. treatment related adverse events

and B. treatment emergent adverse events according to fixed-effects and random-effects network

meta-analysis

4.3.8. Treatment-related and treatment-emergent serious adverse events

The evidence for treatment-related SAEs was based on 8,041 patients enrolled in 31 trial arms across 15

trials and for treatment-emergent SAEs was based on 26,706 patients enrolled in 98 trial arms across 45

trials. With only 81 treatment related SAEs reported across the evidence base, there were too few

events to obtain reliable estimates. Results of the analysis are nonetheless presented in Figure 10.

Treatment emergent SAEs did not have the same limitation. Full results are presented in Error!

Reference source not found.. Again, neither DTG nor EFV400 distinguished themselves from EFV, though

the estimates were lower.

Figure 10: Forest plot of select ARVs comparisons with respect to A. treatment related serious adverse

events and B. treatment emergent serious adverse events according to fixed-effects network meta-

analysis

4.3.9. Regimen substitutions

The evidence base for regimen substitutions by 48 weeks was based on 9,263 patients enrolled in 18

trials across 41 treatment arms. The network of evidence is illustrated in Error! Reference source not

found. of Appendix H. Figure 11 displays some of the key comparisons. Results of this analysis do not

match what is seen in practice. That is to say that in practice, regimen substitutions are less common

than with EFV. It is important to note that there was no direct evidence supporting the DTG to EFV

comparison and that there were very few observed regimen substitutions in the trials that did.

49

Figure 11: Forest plot comparing pair-wise and NMA estimated relative effects of different ARVs with

respect regimen substitution (48 weeks)

4.4. GRADE tables

The summary of evidence and overall quality of evidence for each outcome are presented for the DTG to

EFV comparison in Table 2, for the EFV400 to EFV comparison in Table 3, and for the DTG to EFV400

comparison in Table 4. There was high quality evidence of improved viral suppression, discontinuations

and discontinuations due to AEs for DTG relative the EFV. This was supported by moderate quality

evidence of improvements in CD4 cell counts, and both treatment-related and treatment-emergent AEs.

Due to low numbers of events, imprecise estimates and some risk of bias, there was on low to very low

quality evidence for efficacy at 144 weeks, mortality and ADIs, SAEs and regimen substitutions. Due to

the high propensity of zero counts, results of the mortality, ADIs, treatment-related SAEs and regimen

substitutions should be interpreted with great care (if not ignored).

For EFV400 relative to standard dose EFV, high quality evidence was obtained for discontinuations due

to AEs. Otherwise, efficacy and safety tended to have moderate quality evidence due to imprecision.

Similar to above, mortality and ADIs, treatment related AEs and SAEs, and regimen substitutions had low

to very low quality evidence.

Finally, due to the indirectness, there was no high quality evidence comparing DTG to EFV400. There

was moderate evidence of DTG leading to less discontinuations and having better long-term viral

suppression.

Table 2: Summary of the GRADE quality of evidence assessments for all outcomes for the DTG vs EFV comparison

Outcome Direct Effect

Uncombined Estimates Combined Estimates

Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks

1.79

(1.25, 2.58)

0 0 0 0 0

High

1.86

(1.44, 2.40)

74 per

1,000

(47 to 98)

0 0

High

Viral supp. at

96 weeks

1.65

(1.21, 2.24)

0 0 0 0 0

High

1.93

(1.52, 2.47)

94 per

1,000

(63 to 121)

0 0

High

Viral supp. at

144 weeks

1.44

(1.08, 1.92)

-1 0 0 -1 0

Low

1.44

(1.08, 1.92)

39 per

1,000

(-11 to 83)

0 0

Low

Change in

CD4 at 48

weeks

58.76

(36.80,

80.71)

0 0 0 0 0

High

-- 24.27

cells/ml

(5.89,

43.18)

0 -1

Modera

te

Change in

CD4 at 96

41.76

(13.83,

0 0 0 0 0

High

-- 25.94

cells/ml

-1 0

Modera

51



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

weeks 69.69) (2.95,

48.74)

te

Change in

CD4 at 144

weeks

46.91

(16.70,

77.12)

-1 0 -1 0 0

Low

-- 49.63

cells/ml

(20.12,

79.58)

0 0

Low

Mortality

0.20

(0.01, 4.16)

0 0 0 -2 0

Low

0.64

(0.09, 4.87)

-4 per

1,000

(-12 to 9)

0 0

Low

AIDS defining

illness

5.10

(0.24,

108.97)

0 0 0 -2 0

Low

8.08

(0.46,

66.45)

127 per

1,000

(-13 to 550)

0 0

Low

Discontinuati

ons

0.59

(0.44, 0.79)

0 0 0 0 0

High

0.49

(0.39, 0.62)

-78 per

1,000

(-54 to -

101)

0 0

High

Discontinuati 0.26 0 0 0 0 0 0.30 -43 per 0 0

52



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

ons due to AE (0.15, 0.45) High (0.19, 0.47) 1,000

(-30 to -54)

High

Emergent

SAEs

1.10

(0.77, 1.58)

0 -1 0 -1 0

Low

0.78

(0.49, 1.23)

-22 per

1,000

(-45 to 6)

0 0

Low

Emergent AEs

0.64

(0.27, 1.54)

0 0 0 -1 0

Modera

te

0.63

(0.38, 1.11)

-113 per

1000

(-160 to 70)

0 0

Modera

te

Treatment-

related SAEs

0.22

(0.05, 1.03)

-1 0 0 -2 0

Very

low

9.79

(0.02,

507.24)

126 per

1,000

(-12 to 822)

0 -1

Very

low

Treatment-

related AEs

0.38

(0.29, 0.50)

-1 0 0 0 0

Modera

te

0.33

(0.25, 0.44)

-215 per

1000

(-256 to -

170)

0 0

Modera

te

Regimen

substitutions

-- 0 0 -1 -2 0

Very

6.20

(0.87,

436 per

1,000

-- --

Very

53



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

low 74.94) (-53 to 925) low

Legend: Uncombined estimates represent either direct estimates, if available, or indirect NMA estimates otherwise. Combined estimates are

NMA estimates for comparisons where direct estimates were available. For uncombined estimates start with high quality evidence. -1

symbolizes a choice to rate down (e.g. high quality to moderate quality evidence); 0 symbolizes choice to not rate down; -- = not applicable

because the NMA estimate is the only estimate.

The final quality of evidence updates that of the uncombined evidence. The quality can be moved up if the uncombined score was penalized for

precision, which was overcome in network estimates. It can be moved down if the estimates are no longer precise or if there is evidence of

inconsistency in loops containing the comparison (i.e. violation of transitivity).

Precision – We rated down for precision if the confidence interval crossed 1.1 or 0.9. Consistency – We assessed the consistency for direct

treatment comparisons using I2 estimates and visual inspection of point estimates. An I2 of 75% or higher indicates considerable heterogeneity.

This was conducted along the shortest indirect pathway with the largest number of trials for indirect estimates. Risk of Bias – For direct

estimates we rated down for risk of bias if the majority of studies within a comparison were considered to be at high risk of bias and similarly

along the principal indirect pathway for indirect estimates. Indirectness – Estimates obtained solely from indirect evidence were rated down for

indirectness.

54

Table 3: Summary of the GRADE quality of evidence assessments for all outcomes for the EFV400 vs EFV comparison

Outcome Direct Effect Uncombined Estimates Combined Estimates

Risk of

Bias

Incons

istency

Indirec

tness

Imprec

ision

Public

ation

Bias

Quality of

direct

evidence

Odds

ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Network

Transitivit

y

Overall

quality

of

eviden

ce

Viral supp. at

48 weeks

1.16

(0.75, 1.79)

0 0 0 -1 0

Moderate

1.16

(0.74,

1.79)

20 per

1,000

(-48 to 71)

0 0

Modera

te

Viral supp. at

96 weeks

0.96

(0.61, 1.52)

0 0 0 -1 0

Moderate

0.97

(0.61,

1.52)

-6 per

1,000

(-48 to 71)

0 0

Modera

te

Change in

CD4 at 48

weeks

25.00

(6.57, 43.43)

0 0 0 -1 0

Moderate

-- 25.31

cells/ml

(-1.27,

51.49)

0 0

Modera

te

Change in

CD4 at 96

weeks

26.00

(2.95, 49.05)

0 0 0 -1 0

Moderate

-- 26.85

cells/ml

(4.30,

49.77)

0 0

Modera

te

Mortality 0.96 0 0 0 -2 0 0.99 0 per 1,000 0 0

55

(0.28, 3.36) Low (0.11,

7.69)

(-23 to 8) Low

AIDS defining

illness

1.97

(0.78, 4.94)

0 0 0 -2 0

Low

2.03

(0.82,

5.57)

20 per

1,000

(-4 to 81)

0 0

Low

Discontinuati

ons

0.91

(0.50, 1.68)

0 0 0 -1 0

Moderate

0.91

(0.50,

1.68)

-6 per

1,000

(-64 to 96)

0 0

Modera

te

Discontinuati

ons due to

AE

0.42

(0.23, 0.79)

0 0 0 0 0

High

0.42

(0.22,

0.77)

-35 per

1,000

(-50 to -13)

0 0

High

Emergent

SAEs

0.70

(0.40, 1.22)

0 0 0 -1 0

Moderate

0.69

(0.33,

1.47)

-30 per

1,000

(-64 to 21)

0 0

Modera

te

Emergent

AEs

0.82

(0.47, 1.43)

0 0 0 -1 0

Moderate

0.81

(0.31,

2.13)

-30 per

1,000

(-133 to 44)

0 0

Modera

te

Treatment-

related SAEs

0.48

(0.09, 2.63)

-1 0 0 -2 0

Very low

0.43

(0.01,

15.13)

-6 per

1,000

(-15 to 15)

0 -1

Very

low

Treatment-

related AEs

0.70

(0.51, 0.96)

-1 0 0 -1 0

Low

0.70

(0.51,

-80 per

1,000

0 0

Low

56

0.96) (-144 to -9)

Regimen

substitutions

0.66

(0.33, 1.33)

0 0 0 -1 0

Moderate

0.65

(0.32,

1.32)

-19 per

1,000

(-42 to 17)

0 0

Modera

te













indirectness.

57

Table 4: Summary of the GRADE quality of evidence assessments for all outcomes for the DTG vs EFV400 comparison



Risk of Bias

Inconsistency

Indirectness

Imprecision

Publication Bias

Quality of direct

evidence

Odds ratio (95% CrI)

Absolute effects Indirect

evidence precision

Network Transitivity

Overall quality of evidence

Viral supp. at 48 weeks

-- 0 0 -1 -1 0 Low

1.61 (0.97, 2.70)

53 per 1,000 (-4 to 126)

-- -- Low

Viral supp. at 96 weeks

-- 0 0 -1 0 0

Moderate 2.00

(1.20, 3.37) 100 per 1,000

(23 to 194) -- --

Moderate

Change in CD4 at 48 weeks

-- 0 0 -1 -1 0 Low

-- -0.90 cells/ml (-33.16, 31.78)

-- -- Low

Change in CD4 at 96 weeks

-- 0 0 -1 -1 0 Low

-- -1.03 cells/ml (-33.63, 31.3)

-- -- Low

Mortality -- 0 0 -1 -2 0

Very low 0.64

(0.04, 13.30) -4 per 1,000 (-14 to 27)

-- --

Very low

AIDS defining illness

-- 0 0 -1 -2 0

Very low 3.88

(0.19, 41.03) 103 per 1,000

(56 to 530) -- --

Very low

Discontinuations -- 0 0 -1 0 0

Moderate 0.45

(0.23, 0.88) -43 per 1,000

(-54 to 30) -- --

Moderate

Discontinuations due to AE

-- 0 0 -1 -1 0 Low

0.72 (0.33, 1.58)

-7 per 1,000 (-31 to 9)

-- -- Low

Emergent SAEs -- 0 0 -1 -1 0 Low

1.12 (0.46, 2.68)

8 per 1,000 (-47 to 52)

-- -- Low

Emergent AEs -- 0 0 -1 -1 0 Low

0.78 (0.26, 2.41)

-82 per 1,000 (-173 to 30)

-- -- Low

Treatment-related SAEs

-- -1 0 -1 -2 0

Very low 21.93

(0.02, 4256) 131 per 1,000

(-9 to 827) -- --

Very low

Treatment-related AEs

-- -1 0 -1 0 0 Low

0.48 (0.31, 0.73)

-134 per 1,000 (-215 to -58)

-- -- Low

Regimen substitutions

-- 0 0 -1 -2 0

Very low 9.43

(1.16, 126.79) 240 per 1,000

(8 to 779) -- --

Very low





58









indirectness.

5. TB Co-infected Individuals

The results of the systematic literature review failed to identify a wealth of evidence for the treatment

of patients with HIV-TB co-infection. However, an interim analysis from the ongoing INSPIRING trial was

identified from the CROI 2018 conference. Given the direct relevance and impact the findings of this trial

have in relation to the research question, we first provide an overall of the interim findings and

supplement this with an NMA of all available evidence to provide an overview of the evidence landscape.

5.1. The INSPIRING trial

In this review, the evidence for HIV-TB co-infected patients treated with DTG is based on a 24-week

interim analysis from the INSPIRING trial which was presented at the CROI 2018 conference.

INSPIRING (NCT02178592) is a Phase III, open-label randomized controlled trial enrolling HIV-TB co-

infected adult patients for treatment with twice-daily DTG 50 mg or once-daily EFV 600 mg. Patients

were receiving rifampin-based TB therapy. The trial is anticipated to be completed by the end of

December 2019.

A summary of the evidence on the DTG vs EFV comparison is presented in Treatment with DTG led to

relative increases in CD4 cell counts but was not distinguishable from EFV with respect to viral

suppression (Figure 12). By 24 weeks, DTG was well tolerated though the evidence on safety and

tolerability was based on very few events. As discussed in the previous section, viral suppression was

defined using the FDA Snapshot algorithm and differences here were driven by differences in

discontinuations. The difference in discontinuations were not due to AEs

60

Figure 12: Modified FDA snapshot analysis of the percentage of participants (95% CI) with HIV-1 RNA

<50 copies/mL

Adapted from Dooley et al 2018 (CROI 2018)

5.1.1. Systematic literature review study selection

A subgroup systematic literature review was conducted to describe and synthesize the evidence for the first-line treatment of HIV-TB co-infected

patients. While the primary search strategy did not exclude patients with TB co-infection, we supplemented this search with a more sensitive,

targeted strategy (Appendix B). The flow of information diagram is presented in Error! Reference source not found.. Overall, 10 studies were

identified.

62

Figure 13: Flow diagram for principal literature review on TB co-infected individuals and first-line ART regimens

As with the principal analysis, some studies were excluded from the analysis set. In this case, three trials

were non-comparative and could not be used in the analysis. These are ANRS 129 BKVIR, HIV-TB

Pharmagene and TB-HAART. This was determined at the feasibility stage and could not be determined at

the SLR stage. Also, the Sinha et al, 2013 was a prelude to Sinha et al, 2017 and was therefore not used

in the analyses.

The complete network of evidence for the analysis set of the HIV-TB co-infected sub-population is

presented in Error! Reference source not found.. The evidence base consisted of 1378 patients enrolled

in 13 treatment arms across 6 RCTs. The evidence was limited to 5 treatments: NVP, DTG, EFV, and RAL

(400 mg; 800 mg). No evidence was identified for patients treated with EFV400.

Figure 14: Complete network of evidence for patients with HIV-TB co-infection





64

5.2. Results

As compared with the principal analysis, there were less analytical adjustments used here. There were

no adjustments for differences in backbones and the network was too sparse to allow for meta-

regression adjustments for baseline characteristics. All network diagrams for specific analyses are

provided in Appendix H. In the following subsections, we present results for analyses that involved DTG.

For all other outcomes, cross-tables are provided in Appendix J as a reference.

5.2.1. Efficacy

For the analysis of viral suppression in HIV-TB co-infected patients at 24 weeks, 3 trials including 382

patients across 7 trial arms informed the network of evidence. Results of the fixed-effects NMA are

presented in Table 5. There was no statistically significant difference between DTG and EFV or between

RAL400 and RAL800; however, the estimate suggests lower odds of suppression (in accordance with the

FDA Snapshot algorithm). As previously mentioned, this difference appears to be driven by the larger

number of discontinuations among the DTG arm of the INSPIRING trial. All treatments were associated

with a higher proportion of patients achieving viral suppression compared to NVP, though this

difference was not statistically significant compared to DTG (OR 1.64).

Table 5: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs

for viral suppression at 24 weeks from the fixed-effects network meta-analyses in HIV-TB co-infected

patients

EFV 1.86

(0.64, 6.33)

0.51

(0.21, 1.19)

0.46

(0.19, 1.09)

3.09

(1.28, 7.98)

0.54

(0.16, 1.57) DTG

0.27

(0.06, 1.10)

0.24

(0.05, 0.98)

1.64

(0.36, 6.88)

1.95

(0.84, 4.74)

3.67

(0.91, 16.51) RAL400

0.89

(0.35, 2.27)

6.07

(1.77, 22.19)

2.19

(0.92, 5.39)

4.14

(1.02, 18.72)

1.12

(0.44, 2.89) RAL800

6.80

(2.00, 25.13)

0.32

(0.13, 0.78)

0.61

(0.15, 2.76)

0.16

(0.05, 0.57)

0.15

(0.04, 0.50) NVP

65

Values represent the effect of the treatment lower on the diagonal to the one higher on it. Bold values

indicate comparisons that are statistically significant. Odds ratios above 1 indicate higher efficacy in viral

suppression. DTG: dolutegravir; EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400; RAL800:

raltegravir 800

The network of evidence for change in CD4 count at 24 weeks in HIV-TB co-infected patients was based

on 3 trials of 8 treatment arms consisting of 371 patients. The network of evidence at the 24-, 48-, and

96-week time points are presented in Error! Reference source not found. of Appendix H.


for mean change in CD4 cell counts at 24 weeks from the fixed-effects network meta-analyses in HIV-


EFV -52.52

(-89.61, -14.93)

5.76

(-23.84, 35.48)

52.52

(14.93, 89.61) DTG

58.28

(10.72, 106.04)

-5.76

(-35.48, 23.84)

-58.28

(-106.04, -10.72) NVP

Values represent the effect of the row treatment relative to the column treatment. Bold values indicate

comparisons that are statistically differentiable. DTG: dolutegravir; EFV: efavirenz; NVP: nevirapine;

Results of the fixed effects NMA are presented in Error! Reference source not found.. Treatment with

DTG was associated with statistically significant increases in CD4 cell count compared to all other

treatments in the network. No other comparisons were statistically significant.

5.2.2. Tolerability

The evidence base for discontinuations due to adverse events was based on 4 trials of 524 patients

enrolled in 9 treatment arms. The network of evidence is presented in Error! Reference source not

found. of Appendix H. A summary of the evidence, arranged by treatment and trial, is presented in Error!

Reference source not found.. The proportion of patients with a discontinuation due to adverse events

varied across treatments. There are limitations to synthesizing evidence by NMA when there are a small

number of events and analyses may generate non-meaningfully wide CrIs. With no such events observed

in the DTG arm, an NMA was conducted for the GRADE table (below) but results should be disregarded.

66


outcome in HIV-TB co-infected patients

Trials EFV DTG RAL400 RAL800 NVP

INSPIRING 1/44 (2.3%) 0/69 (0%)

Swaminathan et

al, 2011 1/59 (1.7%)

2/57 (3.5%)

ANRS 12 180

Reflate TB trial 3/51 (5.9%)

0/51 (0%) 3/51 (5.9%)

N2R 3/71 (4.2%)

4/71 (5.6%)

EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400; RAL800: raltegravir 800; DTG: dolutegravir

The evidence base for all-cause discontinuations (retention) was based on 2,839 patients enrolled across

13 treatment arms in 6 trials. The network of evidence is presented in Error! Reference source not found.

of Appendix H. A summary of the evidence, arranged by treatment and trial, is presented in Error!

Reference source not found.. The number of patients who discontinued treatment varied across

treatments. There are limitations to synthesizing evidence by NMA when there are a small number of

events and analyses may generate non-meaningfully wide CrIs.


outcome in HIV-TB co-infected patients

Trials EFV DTG RAL400 RAL800 NVP LPV/r

INSPIRING 2/44 (4.5%) 5/69 (7.2%)

Swaminathan et

al, 2011 4/59 (6.8%)

10/57

(17.5%)

ANRS 12 180

Reflate TB trial

6/51

(11.8%) 5/51 (9.8%)

9/51

(17.6%)

CARINEMO 52/285

(18.2%)

43/285

(15.1%)

N2R 9/71

(12.7%)

16/71

(22.5%)

67

EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400; RAL800: raltegravir 800; DTG: dolutegravir;

LPV/r: ritonavir-boosted lopinavir

5.2.3. Safety

The network of evidence for all treatment emergent SAEs (i.e. all SAEs) is presented in Error! Reference

source not found. of Appendix H. This analysis was based on 2,726 patients enrolled in 5 trials consisting

of 11 treatment arms. Data collected from trials is presented in Error! Reference source not found..

Again, small sample sizes were a major limiting factor. The odds of experiencing an SAE while on DTG

were 0.48 times those of experiencing an SAE while on EFV (95% CrI: 0.12, 1.90). There were more

events when it came to overall AEs and here, DTG was found to be safer than EFV (OR: 0.26; 95% CrI:

0.08, 0.84).

Table 9: Data for treatment comparisons of interest for the treatment-emergent serious adverse

events

Trials EFV DTG RAL400 RAL800 NVP LPV/r

INSPIRING 5/44

(11.4%) 4/69 (5.8%)

Swaminathan et

al, 2011 4/59 (6.8%)

5/57 (8.8%)

ANRS 12 180

Reflate TB trial

19/51

(37.3%)

17/51

(33.3%)

17/51

(33.3%)

CARINEMO 70/288

(24.3%)

74/285

(26%)

EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400; RAL800: raltegravir 800; DTG: dolutegravir;

LPV/r: ritonavir-boosted lopinavir

5.3. GRADE tables

The summary of findings (GRADE) table, comparing DTG to EFV, is presented in Error! Reference source not found.. Most comparisons were

informed by low or very low-quality evidence, though the change in CD4 cell count at 24 weeks was based on moderate quality evidence. Risk of

bias was due to single trial used for the comparison of interest being small and of short duration.

Table 10: Summary of the GRADE quality of evidence assessments for outcomes in the first-line treatment of HIV-TB co-infected patients

Outcome Direct Effect Uncombined Estimates Combined Estimates

Risk of Bias Inconsisten

cy

Indirectnes

s

Imprecisio

n

Publication

Bias

Quality of

direct

evidence

Odds Ratio

(95% CrI)

Absolute effects Indirect

evidence

precision

Network

Transitivity

Overall

quality of

evidence

Viral suppression

at 24 weeks

0.55

(0.18, 1.67)

-1 0 0 -1 0

Low

0.54

(0.16, 1.57)

-75 per 1,000

(-225 to 75)

0 0

Low

Change in CD4 at

24 weeks

53.00

(14.96, 91.04)

-1 0 0 0 0

Moderate

-- 52.52

(14.93, 89.61)

0 0

Moderate

Discontinuations 1.64

(0.30, 8.85)

-1 0 0 -1 0

Low

1.82

(0.35, 15.02)

27 per 1,000

(-78 to 132)

0 0

Low

Discontinuations

due to AE

0.21

(0.01, 5.24)

-1 0 0 -2 0

Very Low

0.02

(0.00, 2.17)

-24 per 1,000

(-53 to 5)

0 0

Very Low

Emergent SAEs 0.48

(0.12, 1.90)

-1 0 0 -2 0

Very Low

0.47

(0.11, 1.90)

-56 per 1,000

(-183 to 72)

0 0

Very Low

Emergent AEs 0.26

(0.08, 0.84)

-1 0 0 -1 0

Low

0.24

(0.06, 0.73)

-184 per 1,000

(-338 to 30)

0 0

Low





69









indirectness.

6. Pregnant and breastfeeding women

6.1. Systematic literature review study selection

A subgroup systematic literature review was conducted to describe and synthesize the evidence for the

first-line treatment of pregnant and breastfeeding women. While the primary search strategy did not

exclude pregnant and breastfeeding women, we supplemented this search with a more sensitive,

targeted strategy (Appendix B). The flow of information diagram is presented in Figure 15. Overall, 15

studies were identified.

6.2. Summary of the evidence base

In the previous review (2015), 9 studies in treatment-naïve pregnant and breastfeeding women were

identified. However, no closed networks of evidence could be established (i.e. the evidence could not be

synthesized through an NMA). Several studies were identified through the current update, but most

were excluded from the analysis as they could only be synthesized through a descriptive summary.

With respect to the research question, which is focused on the efficacy and safety of DTG relative to EFV,

we identified two studies of relevance: the DolPHIN 1 trial and the Tsepamo study. The DolPHIN 1 trial is

an open-label, phase II/III randomized controlled pilot study comparing DTG/TDF/XTC to EFV/TDF/XTC

(standard of care). This is primarily a pharmacokinetics study with limited clinical outcomes and a very

small sample size with 8 patients in each treatment arm in the current interim analysis. A larger, phase

III trial is underway (DolPHIN-2, NCT03249181). This open-label randomized controlled trial was planned

to begin in January 2018 and is anticipated to be completed in March 2021 with an estimated enrolment

of 250 adult patients in South Africa and Uganda.

The Tsepamo study was a large cohort study of pregnant women initiating DTG/TDF/XTC or

EFV/TDF/XTC across 8 government hospitals in Botswana. A large sample of patients was enrolled, with

1,729 patients treated with DTG and 4,593 treated with EFV. It is noteworthy that Botswana was the

first country to recommend DTG/TDF/XTC for initiation in pregnancy. The proportion of pregnancies

with any adverse birth outcome was similar across treatment arms with 33.2% of DTG-managed

pregnancies and 35.0% of EFV-managed pregnancies resulting in an adverse outcome. Similarly, severe

birth outcomes were reported in 10.7% of DTG-managed and 11.3% of EFV-managed pregnancies. A

summary of the outcomes from the Tsepamo study is presented in Table 12.

Figure 15: Flow diagram for principal systematic literature review on pregnant and breastfeeding women and first line ART regimens

Table 11: Summary of the Tsepamo study of DTG/TDF/FTC vs EFV/TDF/FTC in pregnant and

breastfeeding women initiated on first-line ART

Outcome Dolutegravir/

TDF/FTC

(N=1729)

Efavirenz/

TDF/FTC

(N=4593)

Unadjusted

RR

(95% CI)

Adjusted RR

(95% CI)

Any Adverse Birth Outcome 576 (33·3%) 1611 (35·0%) 0·95

(0·88,1·03)

0.94 (0.87,

1.02)

Any Severe Adverse Birth Outcome 186 (10·8%) 520 (11·3%) 0.95

(0·81,1·11)

0.93

(0.79,1.11)

Preterm birth (<37 weeks) 309 (18·0%) 844 (18·5%) 0·97

(0·87,1·10)

0.98

(0.87,1.11)

Very preterm birth (<32 weeks) 66 (3·8%) 160 (3·5%) 1·10

(0·83,1·45)

1.09

(0.82,1.45)

Small for Gestational Age (<10th

%tile weight-for-gestational age) 297 (17·4%) 838 (18·5%)

0·94

(0·83,1·06)

0.94

(0.83,1.06)

Very small for Gestational Age (<3rd

%tile weight-for-gestational age) 104 (6·1%) 302 (6·7%)

0·91

(0·74,1·13)

0.91

(0.74,1.13)

Stillbirth 39 (2·3%) 105 (2·3%) 0·99

(0·69,1·42)

0.99

(0.69,1.42)

Neonatal death (<28 days) 21 (1·2%) 60 (1·3%) 0·93

(0·57,1·53)

0.96

(0.58,1.57)

RR: Relative risk; 95% CI: 95% confidence interval

Two additional studies of relevance were identified (IMPAACT 1026s and EPPICC/PANNA) though they

were not restricted to the treatment of first-line patients. In both studies, pregnant women were

initiated on DTG-based regimens, with 29 pregnancies in IMPAACT 1026s and 84 pregnancies in

EPPICC/PANNA. These studies were included in the evidence base to inform safety outcomes of interest.

A summary of the evidence for select outcomes of interest in patients treated with DTG and EFV is

presented in Error! Reference source not found.. It shows similar estimates to those seen in the

Tsepamo study and suggests that the results of the Tsepamo study may be generalisable to high and

middle-income settings.

74

Table 12: Summary of evidence among pregnant and breastfeeding women on first-line ART

Outcome DTG/TDF/FTC EFV/TDF/FTC Unadjusted OR

(95% CI)

Study

Viral suppression < 50 copies/ml

(2 weeks post-partum)

5 (62.5%) 4 (50%) 1.25 (0.52, 3.00) DolPHIN 1

Still births 1 (12.5%) 0 (0%) -- DolPHIN 1

1 (1.2%) -- -- EPPICC/PANNA

Congenital abnormalities 4 (4.9%) -- -- EPPICC/PANNA

Pre-term birth 4 (13.8%) -- -- IMPAACT 1026s

11 (13.8%) -- -- EPPICC/PANNA

Low birth weight (<2.5 kg) 4 (13.8%) -- -- IMPAACT 1026s

13 (16.9%) -- -- EPPICC/PANNA

Very low birth weight (<1.5 kg) 1 (3.4%) -- -- IMPAACT 1026s

0 (0%) -- -- EPPICC/PANNA

HIV transmissions 0 (0%) -- -- IMPAACT 1026s

OR: Odds ratio; 95% CI: 95% confidence interval

6.3. GRADE tables

The summary of findings (GRADE) table, comparing DTG to EFV, is presented in Error! Reference source not found.. Most outcomes were

evaluated to be of moderate quality evidence due to the risk of bias associated with an observational study, though with respect to safety, a

large cohort study such as this one is among the most desirable studies to have. The evidence for viral suppression 2-weeks post-partum was

considered to be of very low quality largely due to the very small sample sizes.

Table 13: Summary of the GRADE quality of evidence assessments for outcomes in the first-line treatment of pregnancy and breastfeeding

women

Outcome Risk of

bias

Inconsist

ency

Indirect-

ness

Imprecisi

on

Publicati

on Bias

Relative

risks

Absolute

effect

DTG

sample

size

EFV

sample

size

Quality

of

evidence

Viral supp. (2

weeks post-

partum)

-1 0 0 -2 0 1.25

(0.52, 3.00)

125 per

1,000

(260 to

1000)

5 (62.5%) 4 (50%)

Very low

Any Adverse

Birth

Outcome

-1 0 0 0 0 0.94

(0.87, 1.02)

22 per

1,000

(-50 to 5)

576

(33·3%)

1611

(35·0%)

Moderat

e

Any Severe

Adverse

Birth Outcome

-1 0 0 0 0 0.93

(0.79,1.11)

-9 per

1,000

(-26 to 9)

186

(10·8%)

520

(11·3%)

Moderat

e

Preterm birth -1 0 0 0 0 0.98 -3 per 309 844

76

(0.87,1.11) 1,000

(-25 to 18)

(18·0%) (18·5%) Moderat

e

Very preterm

birth

-1 0 0 0 0 1.09

(0.82,1.45)

4 per 1,000

(-7 to 14)

66 (3·8%) 160

(3·5%)

Moderat

e

Small for

Gestational

Age

-1 0 0 0 0 0.94

(0.83,1.06)

-9 per

1,000

(-31 to 12)

297

(17·4%)

838

(18·5%)

Moderat

e

Very small for

Gestational

Age

-1 0 0 0 0 0.91

(0.74,1.13)

3 per 1,000

(-16 to 11)

104

(6·1%)

302

(6·7%)

Moderat

e

Stillbirth -1 0 0 0 0 0.99

(0.69,1.42)

*

1 per 1,000

(-9 to 8)

39 (2·3%) 105

(2·3%)

Moderat

e

Neonatal

death

-1 0 0 0 0 0.96

(0.58,1.57)

-1 per

1,000

(-7 to 6)

21 (1·2%) 60 (1·3%)

Moderat

e





77









indirectness.

7. Children and adolescents

7.1. Summary of the evidence base

A subgroup systematic literature review was conducted to describe and synthesize the evidence for the

first-line treatment of children. While the primary search strategy did not exclude patients with TB co-

infection, we supplemented this search with a more sensitive, targeted strategy (Appendix B). The flow

of information diagram is presented in Error! Reference source not found..

Figure 16: Flow diagram for principal systematic literature review on adolescents and first line ART

regimens

79

The evidence base for these patients was limited. Although 13 studies were identified, few of them

provided relevant information. Children are a more complex population with multiple categories. These

are defined as neonates, infants and children (age 0-3 years), children (age 3-10 years) and adolescents

(age 10-19 years). There were six comparisons of interest in this category:

DTG vs EFV for adolescents and children

DTG vs LPVr for infants and children

DTG vs RAL for infants and children

RAL vs EFV for children

RAL vs LPV/r for infants and children

RAL vs NVP for neonates

There were no studies identified among first-line children, adolescents or infants that included DTG.

Indeed, the only DTG-focused study among children and adolescents was IMPAACT P1093, which

enrolled treatment-experienced patients. However, this study was cited by the US FDA as supporting

evidence for approving DTG use among children. The results of this trial are presented in the

accompanying, second-line report.

No comparative studies included RAL. However, two RAL studies were identified in neonates and infants

(Error! Reference source not found.). In the 24-week IMPAACT P1110 study, evidence from 42 patients

suggested that daily RAL was safe and well-tolerated during the first 6 weeks of life. The multinational,

non-randomized phase I/II IMPAACT P1066 study enrolled 5 cohorts of patients receiving various doses

and delivery methods (i.e. coated tablet, chewable tablet, granules for suspension) and reported on

safety outcomes and change in CD4 cell count. However, while the overall number of enrolled patients

was high (N=153), most cohorts consisted of relatively few patients. Therefore, conclusions based on

this study alone must be made with caution.

Table 14: Studies of RAL-based regimens for neonates and infants

Trial Sample

size

Age Study

design

Follow-

up

(weeks)

Outcomes Conclusion

IMPAACT

P1110

42 Eligible:

Birth to 48

Single-arm

trial

24 -Safety and

tolerability

Daily RAL was

safe and well

80

NCT01780831 hours tolerated during

the first 6 weeks

of life.

IMPAACT

P1066

NCT00485264

153 Eligible: 4

weeks to

18 years

Comparative

cohort

48 -Immunologic

response

-Safety and

tolerability

-Retention

Only available

from

ClinicalTrials.gov

record

7.2. GRADE tables

Given the lack of comparative evidence in the children and adolescent subgroup, we reference the

results of the adult and adolescent review and downgrade the quality of evidence by one level for

indirectness. Table 13 presents the summary of findings (GRADE) table for efficacy, safety, and

tolerability outcomes for comparisons to DTG. Treatment with DTG was associated with a higher

proportion of patients achieving viral suppression at both 48 and 96 weeks compared to either EFV,

LPV/r, or RAL, though this was based on moderate (vs EFV) and low-quality evidence (LPV/r; RAL). The

evidence on changes in CD4 cell count was mixed, however, with statistically significant increase at all

time points compared to EFV (low quality evidence) and not statistically significant differences

compared to either LPV/r or RAL based on very low-quality evidence. Given the lack of evidence

identified, conclusions regarding comparisons on mortality and ADIs should be avoided. However,

treatment was DTG was generally associated with fewer discontinuations, though only the comparison

with EFV was considered to be moderate quality. Evidence on serious adverse events, both treatment-

related and emergent, was based on low or very low-quality evidence. These findings, particularly the

relatively few studies identified relevant to the research question in children and adolescents, highlights

the need for ongoing research on the use of DTG in the first-line treatment of HIV-infected children.

The GRADE table for the efficacy, safety, and tolerability outcomes for comparisons to RAL is presented

in Error! Reference source not found.. Treatment with RAL was associated with a higher proportion of

patients achieving viral suppression at both 48 and 96 weeks compared to EFV, LPV/r, and NVP, though

81

this was largely based on low quality evidence. No statistically significant differences were observed

with respect to change in CD4 cell count based on low or very low-quality evidence. However, treatment

with RAL was associated with fewer discontinuations, discontinuations due to adverse events, and fewer

emergent serious adverse events compared to EFV (moderate quality evidence), LPV/r (low quality

evidence), and NVP (low quality evidence). The evidence for emergent adverse events, treatment-

related SAEs, and treatment-related adverse events was sparse and was largely considered to be of very

low quality. As with the evidence for DTG, the evidence on the use of RAL in the first-line treatment of

children is sparse and was generally considered to be low quality according to the GRADE assessments.

Again, we highlight the need for ongoing research to further inform this evidence base.

A detailed summary of the GRADE assessments for the evidence in children and adolescents is

presented in Appendix K.

Table 15: Summary of the GRADE quality of evidence assessments for efficacy, safety, and tolerability outcomes for the use of DTG vs EFV,

LPV/r, and RAL in the first-line treatment of children and adolescents

DTG VS. EFV DTG VS. LPV/r DTG VS. RAL

Odds

ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality

of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

Viral

suppression at

48 weeks

1.86

(1.44,

2.40)

74 per 1000

(47 to 98)

Moderate

2.70

(1.92, 3.70)

136 per

1000 (92 to

184)

Low

1.37

(1.03, 1.82)

33 per

1000

(3 to 64)

Low

Viral

suppression at

96 weeks

1.93

(1.52,

2.47)

94 per 1000

(63 to 121)

Moderate

2.70

(1.75, 4.00)

162 per

1000 (107 to

223)

Low

1.32

(0.98, 1.79)

34 per

1000

(4 to 66)

Low

Viral

suppression at

144 weeks

1.44

(1.08,

1.92)

39 per 1000

(-11 to 83)

Low - -- -

0.96

(0.01, 100)

31 per

1000

(-16 to 84)

Very low

Change in CD4

at 48 weeks -

24.27

cells/ml

(5.89,

43.18)

Low -

-2.40

cells/ml

(-28.99,

25.86)

Very low -

3.91

cells/ml

(-15.04,

23.85)

Very low

Change in CD4

at 96 weeks -

25.94

cells/ml

Low -

-18.63

cells/ml

Very low -

5.41

cells/ml

Very low

83


Odds

ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality

of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

(2.95,

48.74)

(-54.43,

18.83)

(-27.41,

40.74)

Change in CD4

at 144 weeks -

49.63

cells/ml

(20.12,

79.58)

Low -

9.27

cells/ml

(-89.80,

100.65)

Very low -

11.54

cells/ml

(-79.64,

95.93)

Very low

Mortality 0.64

(0.09,

4.87)

-4 per 1000

(--9 to 12)

Very low

0.47

(0.05, 4.17)

-4 per 1000

(-10 to 12)

Very low

0.87

(0.13, 7.14)

-1 per 1000

(-8 to 15)

Low

AIDS defining

illnesses

8.08

(0.46,

66.45)

127 per

1000

(-13 to 550)

Very low

7.14

(0.32,

100.00)

127 per

1000

(-12 to 551)

Very low

8.33

(0.30,

100.00)

126 per

1000 (-16

to 552)

Very low


(0.39,

0.62)

-43 per

1000

(-54 to -30)

Moderate

0.44

(0.32, 0.60)

-65 per 1000

(-104 to -38)

Low

0.76

(0.58, 0.99)

-8 per 1000

(-25 to 4)

Low

Discontinuations

due to AEs

0.30

(0.19,

0.47)

-78 per

1000

(-101 to -

Moderate

0.23

(0.11, 0.46)

-107 per

1000

(-146 to -69)

Low

0.72

(0.37, 1.41)

-9 per 1000

(--57 to --3)

Low

84


Odds

ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality

of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

54)

Emergent SAEs 0.63

(0.38,

1.11)

-22 per

1000

(-45 to 6)

Very low

0.52

(0.37, 0.74)

-20 per 1000

(-49 to 12)

Low

1.18

(0.94, 1.47)

-10 per

1000

(-36 to 17)

Low

Emergent AEs 0.78

(0.49,

1.23)

-113 per

1000 (-160

to -70)

Low

0.79

(0.56, 1.14)

-110 per

1000

(-168 to -52)

Very low

0.88

(0.64, 1.22)

33 per

1000

(-12 to 78)

Low

Treatment-

related SAEs

9.79

(0.02,

507.2)

126 per

1000

(-12 to 822)

Very low

33.33

(0.08,

1000)

124 per

1000

(-8 to 817)

Very low

12.5

(0.02, 1000)

126 per

1000 (-16

to 821)

Very low

Treatment-

related AEs 0.33

(0.25,

0.44)

-215 per

1000 (-255

to -170)

Very low

0.33

(0.21, 0.52)

-223 per

1000

(-295 to -

151)

Very low

0.28

(0.16, 0.50)

-265 per

1000 (-356

to -174)

Very low





85









indirectness.

86

Table 16: Summary of the GRADE quality of evidence assessments for efficacy, safety, and tolerability outcomes for the use of RAL vs EFV,

LPV/r, and NVP in the first-line treatment of children and adolescents

RAL vs EFV RAL vs LPV/r RAL vs NVP

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality

of

evidence

Odds ratio

(95% CrI)

Absolute

effects

Overall

quality

of

evidence

Viral

suppression at

48 weeks

1.36

(1.04,

1.78)

41 per 1000

(9 to 70)

Low

1.96

(1.43, 2.78)

103 per

1000 (56 to

153)

Low

1.56

(1.14, 2.17) 61 per 1000

(20 to 104)

Low

Viral

suppression at

96 weeks

1.47

(1.11,

1.97)

59 per 1000

(23 to 92)

Moderate

2.08

(1.35, 3.03)

128 per

1000 ( 71 to

190)

Low

2.50

(1.47, 4.35) 166 per 1000

(75 to 266)

Low

Viral

suppression at

144 weeks

1.50

(0.08,

29.57)

61 per 1000

(13 to 104)

Low - -- -

2.27

(0.03,

100.00)

143 per 1000

(29 to 275)

Very

low

Change in CD4

at 48 weeks

20.37

(3.34,

37.54)

20.37

cells/ml

(3.34 to

37.54)

Very low

-6.17

(-32.17,

20.40)

-6.17

cells/ml

(-32.17 to

20.40)

Very

low

15.09

(-6.87,

37.89)

15.09

cells/ml

(-6.87 to

37.89)

Very

low

Change in CD4

at 96 weeks

22.53

(-0.24,

22.53

cells/ml

Low

-23.81

(-55.27,

-23.81

cells/ml

Very

35.90

(-4.38,

35.90

cells/ml

Very

87

44.66) (-0.24 to

44.66)

6.57) (-55.27 to

6.57)

low 74.13) (-4.38 to

74.13)

low

Change in CD4

at 144 weeks

36.02

(-27.18,

86.33)

36.02

cells/ml

(-27.18 to

86.33)

Low

-2.32

(-88.18,

83.19)

-2.32

cells/ml

(-88.18 to

83.19)

Very

low

31.38

(-60.93,

113.50)

31.38

cells/ml

(-60.9 to

113.5)

Very

low

Mortality 0.72

(0.17,

3.13)

-3 per 1000

(-8 to 4)

Low

0.53

(0.09, 2.63) -3 per 1000

(-9 to 4)

Very

low

0.51

(0.08, 3.45) -7 per 1000

(-23 to 3)

Very

low

AIDS defining

illnesses

0.98

(0.29,

4.09)

-2 per 1000

(-15 to 26)

Low

0.89

(0.19, 4.00) -1 per 1000

(-16 to 27)

Very

low

3.7

(0.22,

100.00)

12 per 1000

(-32 less to

40)

Very

low


(0.54,

0.89)

-49 per

1000

(-75 to -20)

Moderate

0.58

(0.43, 0.79)

-77 per

1000

(-119 to -

38)

Low

0.50

(0.35, 0.69)

-105 per 1000

(-156 to- 56)

Low

Discontinuations

due to AEs

0.44

(0.24,

0.78)

-34 per

1000

(-49 to -17)

Moderate

0.32

(0.16, 0.66)

-57 per

1000

(-95 to -27)

Low

0.24

(0.10, 0.53) -85 per 1000

(-153 to -40)

Low

Emergent SAEs 0.44

(0.35,

0.55)

-12 per

1000

(-32 to -10)

Moderate

0.44

(0.32, 0.62)

-10 per

1000

(-34 to -6)

Low

0.36

(0.22, 0.58) -99 per 1000

(-166 to -44)

Low

Emergent AEs 0.88 -146 per 0.9 -143 per 0.44 -171 per 1000

88

(0.69,

1.11)

1000

(-193 to -

102)

Low (0.68, 1.18) 1000

(-199 to 87)

Very

low

(0.29, 0.68) (-235 to -99) Low

Treatment-

related SAEs

0.77

(0.02,

8.90)

-1 per 1000

(-11 to 20)

Very low

3.12

(0.01,

1000.00)

6 per 1000

(-89 to 28)

Very

low

0.68

(0, 1000.00) 0 per 1000

(-889 to 25)

Very

low

Treatment-

related AEs

1.23

(0.81,

1.90)

50 per 1000

(-29 to 133)

Very low

1.18

(0.69, 2.00) 41 per 1000

(-62 to 146)

Very

low

1.41

(0.85, 2.50) 78 per 1000

(-26 to 183)

Very

low













indirectness.

8. Discussion

The purpose of this study was to support the 2018 update to the consolidated guidelines on the use of

antiretrovirals for treating and preventing HIV with respect to the choice of first-line ART. The two

questions of interest were whether DTG and/or EFV400, each with an XTC + TDF backbone, should be

the preferred first-line ART regimen rather than their current designation of alternative first-line ART

regimen. This extensive systematic literature review and network meta-analysis to evaluate the

comparative efficacy and safety of these and other ART regimens drew strong conclusions about the

improved efficacy and tolerability of DTG relative to EFV. Moreover, the evidence synthesis supports the

use of DTG among sub-populations, which was not the case in 2015. Specifically, results of this study

suggest comparable safety among pregnant women initiating treatment and results were not

demonstrably worse among TB-HIV co-infected individuals. Unfortunately, evidence was lacking with

respect to first-line children. Overall, the evidence more strongly supports the choice of DTG as the

preferred first-line regimen.

Despite strong evidence of improved efficacy and tolerability of DTG relative to EFV in the 2015,4 other

factors prevented its recommendation as the preferred first-line regimen.5 These factors were: the

unavailability of a fixed-dose combination with XTC and TDF, the high price, and the uncertainty around

its use in sub-populations. All of these factors have now been overcome. A generic fixed-dose

combination with TDF and lamivudine, referred to as TLD,181 is now available and studies among sub-

populations have begun to report results. It is in this context that this study was undertaken. For adults

and adolescents, the principal population, there were only a few new trials with the treatments of

interest and no new trials for the comparisons of interest. It is therefore not at all surprising that the

conclusions were similar to the previous set of analyses. There continues to be high quality evidence of

improved viral suppression, discontinuations and discontinuations due to AEs for DTG relative the EFV.

Across all outcomes, the results of DTG were favourable, with the only exceptions being in outcomes

that are plagued with very low number of events. While we demonstrated improved safety with DTG

relative to EFV in terms of overall AEs, it is understood that the specific adverse events experienced with

each differ, where DTG is more likely to lead to headaches and EFV has a higher propensity for

neuropsychiatric side effects.182

The evidence on EFV400 compared to standard dose EFV (600mg qd) comes entirely from the ENCORE1

trial.21 Evidence from this trial suggests that low dose EFV is non-inferior to the standard dose, with

90

respect to efficacy and safety. It also suggests improved retention compared to standard dose EFV. Our

study also displayed improved discontinuations due to adverse events among EFV400. Despite this

difference, comparisons of low dose EFV to DTG using indirect evidence showed that DTG tended to

have better retention and lower discontinuations due to adverse events. Moreover, these showed that

DTG was more effective with respect to viral suppression.

Critical to the public health approach that is favoured by the WHO, is the ability to prescribe treatment

regardless of TB co-infection, pregnancy and ideally to children as well. By having the simplest treatment

algorithm, we can ensure that task shifting and non-centralized care can continue in low-income settings,

which has been so critical to the success of the fight against HIV/AIDS. No eligible studies were identified

with respect to EFV400 among sub-populations and thus the second research question could not be

tackled outside of the principal population. Only a handful of eligible studies providing insights on the

first research question (DTG vs EFV) were identified. None were identified for children, so we relied on

information on adults and adolescents to inform children and adolescents. Although we downgraded

the strength of evidence for indirectness, it may not be too much of a stretch to believe the efficacy

observed in adults would translate into children aged 3 years or more. For infants, the comparisons of

interest were with RAL and a similar was used.

Although a trial was available comparing DTG to EFV among TB-HIV co-infected patients, it must be

recognized that the trial was both small and that only 24 week results were available. As such the

evidence was of low quality. Evidence appears to suggest negligible difference between treatments.

Pregnancy was the sub-population with the richest evidence base. Pregnancy was also a focal point of

discussion during the Guideline Development Group meetings, but not exactly in line with this research.

While the evidence base was convincing with respect to the use of DTG as a first-line regimen among

pregnant women, there is a signal that DTG in preconception may be problematic.183 That issue falls

outside the scope of the current study.

Our study has numerous strengths and limitations. First, the use of NMA allowed for analytic

adjustments to account for differences in backbones and provide an unbiased estimate of the

comparison between DTG and EFV despite the critical trial having different backbones. Second, by

combining direct and indirect evidence, some of findings can be seen as having stronger evidence than

previously perceived when strong findings are supported by both sources of evidence. With respect to

limitations, first, the evidence for the comparisons of interest continued to be somewhat limited in sub-

populations. For EFV400, it was completely missing. Most notably for DTG, there was an absence of

91

evidence within children. This was also the case in people pre-exposed to ARVs, though that was

somewhat expected. Even in pregnancy and TB, much of the evidence is still to come. Second, some

significant outcomes were limited by a very low number of events, including mortality, regimen

substitutions, serious adverse events, and ADIs. This influenced the precision of our estimates with

respect to these outcomes and, in some cases, precluded the conduct of evidence synthesis through

NMA. Third, treatment-related adverse events were both inconsistently defined and inconsistently

reported. This limitation was mitigated by considering both treatment-related and treatment-emergent

adverse events. Additionally, studies of shorter duration are, by their nature, less likely to identify

adverse events than longer-term trials. Despite this, the evidence was collected through a rigorous

systematic review process in accordance with the practices and recommendations set forth by the

Cochrane Collaboration, including both broad and targeted searches of the literature, critical appraisal

of the identified studies, and consultation with subject matter experts.

9. Conclusions

Dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate is an

effective, safe and tolerable ART regimen. Across a variety of outcomes, evidence strongly suggests

that it is superior to the current efavirenz-based preferred first-line ART regimen. With a new affordable

generic fixed dose combination and comparable outcomes among sub-populations, the evidence

supports the choice of a dolutegravir based preferred first-line regimen. Conclusions regarding low-dose

efavirenz are unchanged since 2015. Low-dose efavirenz appears to be more tolerable, but with lack of

evidence in sub-populations it is likely best to be considered an alternative first-line regimen.

92

Appendix A: Search strategy

The search strategy presented in Table A1 was used for MEDLINE and EMBASE via OVID. The same

search strategy was adapted to the other search engines. Searches were restricted from 01 January

2015 to the search date, 12 February 2018.

Table 17: Systematic literature search strategy

No. Term Comments

1. exp HIV/ or exp HIV Infection/ HIV/AIDS terms

2. (HIV Infections OR HIV?1* OR HIV?2* OR HIV infect* OR human

immuno?deficiency virus OR human immune?deficiency virus).ti,ab.

3. ((human immun*) AND (deficiency virus)).ti,ab.

4. (acquired immuno?deficiency syndrome OR AIDS OR acquired

immunedeficiency syndrome OR acquired immune deficiency).ti,ab.

5. ((acquired immun*) AND (deficiency syndrome)).ti,ab.

6. (Salvage therapy).ti,ab. Treatment failure

and experienced 7. Exp Treatment Failure/

8. (Treatment-experienced OR Antiretroviral experienced OR ART-

experienced OR Experienced patients).ti,ab.

9. (treatment switch*).ti,ab.

10. (or/1-5) not (or/6-9) Population Final

11. exp Antiretroviral Therapy, Highly Active/ Intervention and

comparators

12. exp Integrase Inhibitors/

13. exp HIV Reverse Transcriptase/

14. exp Reverse Transcriptase Inhibitors/

15. Exp Anti-HIV Agents/

16. exp HIV Protease Inhibitors/

17. (atazanavir OR Reyataz OR a603019 OR BMS-232632 or atv*).ti,ab.

18. (cobicistat OR GS-9350 OR Tybost).ti,ab.

19. (dolutegravir OR Tivicay OR a613043 OR S?GSK1349572 OR

GSK1349572).ti,ab.

20. (darunavir OR Prezista OR TMC114 OR a607042 or drv*).ti,ab.

93

21. (Elvitegravir OR GS-9137 OR Vitekta).ti,ab.

22. (emtricitabine OR Emtriva OR Coviracil OR a604004).ti,ab.

23. (lopinavir OR ABT-378 OR a602015 or lpv*).ti,ab.

24. (nevirapine OR Viramune OR a600035).ti,ab.

25. (ritonavir OR Norvir OR a696029).ti,ab.

26. (raltegravir OR Isentress OR MK-0518 OR a608004).ti,ab.

27. (efavirenz OR Efavir OR Sustiva OR Stocrin OR Efcure OR Efferven OR

Estiva OR Evirenz OR Viranz OR a699004).ti,ab.

28. (Trizivir OR Aluvia OR Kaletra OR Stribild OR triumeq).ti,ab.

29. or/11-28 Intervention and

comparators final

30. (Randomized Controlled Trial or Controlled Clinical Trial).pt. Randomized

controlled trial terms 31. (Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or

Clinical Trial, Phase IV).pt.

32. Multicenter Study.pt.

33. Randomized Controlled Trial/ or Randomized Controlled Trials as

Topic/ or "Randomized Controlled Trial (topic)"/

34. Controlled Clinical Trial/ or Controlled Clinical Trials as Topic/ or

"Controlled Clinical Trial (topic)"/

35. Clinical Trial/ or Phase 2 Clinical Trial/ or Phase 3 Clinical Trial/ or

Phase 4 Clinical Trial/

36. Clinical Trials as Topic/ or Clinical Trials, Phase II as Topic/ or Clinical

Trials, Phase III as Topic/ or Clinical Trials, Phase IV as Topic/

37. "Clinical Trial (topic)"/ or "Phase 2 Clinical Trial (topic)"/ or "Phase 3

Clinical Trial (topic)"/ or "Phase 4 Clinical Trial (topic)"/

38. or/30-37 Study design final

39. 10 and 29 and 38 Complete Search

40. (healthy adj3 volunteer*).ti,ab. Features of

undesired

publications

41. (healthy adj3 subject*).ti,ab.

42. (cohort or observational study or case-control*).ti,ab.

43. 39 not (40 or 41 or 42)

94

44. 43 not (cost minimi* or cost-utilit* or health utility* or economic

evaluation* or economic review* or cost outcome or cost analys?s

or economic analys?s or budget* impact analys?s).ti,ab.

45. 44 not (review or letter or meta-analysis or case report or case

series or posters or News or Newspaper article or meeting abstracts

or lectures or interview or historical article or handbooks or

guidelines or guidebooks or essays or editorial or comment or

clinical conference or catalogs or case reports).pt.

mp denotes multi-purpose and implies a search through all fields; .sh. denotes a Medical Subject

Heading (MeSH) term; ti,ab. denotes a search for terms in title and abstract; exp denotes explode and

implies that a term and a collection of variations on that term are searched for; * is used for truncation;

? is a single space wildcard term.

95

Appendix B: Search strategies for sub populations

As discussed in Section 3, there were sub-populations for which we supplemented the principal search

with observational studies (principally cohort studies). The sub-populations included: TB co-infected

patients, HBV co-infected patients, and pregnant and breastfeeding women. These supplemental

searches replaced the study design section of the principal search with the study design terms shown in

Table A1.

Table 18: Systematic literature search to identify non-RCT study designs

No. Term Comments

1. (Nonrandom* or non random* or non-random* or quasi-random*

or quasirandom*).ti,ab,hw.

Observational study

design terms

2. cohort studies/ or cohort analysis/

3. longitudinal studies/ or longitudinal study/

4. prospective studies/ or prospective study/

5. follow-up studies/ or follow up/ or followup studies/

6. retrospective studies/ or retrospective study/

7. observational study/

8. quasi experimental methods/ or quasi experimental study/

9. (quasi adj (experiment or experiments or experimental)).ti,ab.

10. ((non experiment or nonexperiment or non experimental or

nonexperimental) adj3 (study or studies or design or analysis or

analyses)).ti,ab.

Additionally, the searches terms in Table A2 were added to the study population terms. Each section in

the table was conducted independently, not all at once.

Table 19: Systematic literature review terms to identify the specific sub-populations of interest

No. Term Comments

1. exp Tuberculosis/ TB terms

2. Mycobacterium tuberculosis/

3. (tuberculosis or tb).ti,ab.

96

4. exp Hepatitis B/ HBV terms

5. exp Hepatitis B virus/

6. (HBaSq).ti,ab,kw.

7. exp Pregnant Women/ Pregnant and

breastfeeding

women terms

8. exp Mothers/

9. exp Breast Feeding/

10. exp Infectious Disease Transmission, Vertical/

11. Adolescent/ Adolescents

12. (adolescent* or teen*).tw.

Appendix C: Trends in observed treatment effects across follow-up times

In this section we present exploratory plots investigating the effect of follow-up time on relative

treatment effects.

Figure 17: Proportion of patients experiencing a treatment emergent serious adverse event or adverse

event

98

Legend: The left panels present proportions reported at each time point. The right panels present the

odds ratios for each outcome over time. Connected points indicate a pair of odds ratios from a single RCT.

Figure 18: Proportion of patients experiencing a treatment related serious adverse event or adverse

event



99

Figure 19: Proportion of patients discontinuing treatment and discontinuing treatment due to an

adverse event



100

Figure 20: Proportion of patients that died and developed an AIDS defining illness



101

Figure 21: Proportion of patients switching treatments during study



102

Appendix D: List of included studies

In this appendix, we present the complete list of studies and corresponding publications, arranged by

review.

Table 20: List of included studies with corresponding publications

Trial ID Author Title Year

089

Study32,85,86

Bertz, R.J. et

al32

Pharmacokinetics and pharmacodynamics of atazanavir-

containing antiretroviral regimens, with or without ritonavir,

in patients who are HIV-positive and treatment-naive

2013

Malan, D.R. et

al86

Efficacy and safety of atazanavir, with or without ritonavir,

as part of once-daily highly active antiretroviral therapy

regimens in antiretroviral-naive patients

2008

Malan, D.R. et

al85

96-week efficacy and safety of atazanavir, with and without

ritonavir, in a HAART regimen in treatment-naive patients 2010

1439-007

Study58,59

Gatell et al58

Efficacy and safety of doravirine 100 mg qd vs. Efavirenz 600

mg qd with TDF/FTC in art-naive HIV-infected patients:

Week 24 results

2016

Gatell et al59 Doravirine 100mg qd vs efavirenz +TDF/FTC in art-naive HIV+

patients: Week 48 results 2017

2NN74,163,164

Kappelhoff,

B.S. et al74

Are adverse events of nevirapine and efavirenz related to

plasma concentrations? 2005

van Leth, F. et

al164

Nevirapine and efavirenz elicit different changes in lipid

profiles in antiretroviral-therapy-naive patients infected with

HIV-1

2004

van Leth, F. et

al163

Comparison of first-line antiretroviral therapy with regimens

including nevirapine, efavirenz, or both drugs, plus stavudine

and lamivudine: A randomised open-label trial, the 2nn

study

2004

ACTG

A509565,66,136

Gulick, R.M. et

al65

Three- vs four-drug antiretroviral regimens for the initial

treatment of HIV-1 infection: A randomized controlled trial 2006

Gulick, R.M. et Triple-nucleoside regimens versus efavirenz-containing 2004

103

al66 regimens for the initial treatment of HIV-1 infection

Ribaudo, H.J.

et al136

Efavirenz-based regimens in treatment-naive patients with a

range of pretreatment HIV-1 RNA levels and cd4 cell counts 2008

ACTG

A514269,137

Haubrich, R.H.

et al69

Metabolic outcomes in a randomized trial of nucleoside,

nonnucleoside and protease inhibitor-sparing regimens for

initial HIV treatment

2009

Riddler, S.A. et

al137

Class-sparing regimens for initial treatment of HIV-1

infection 2008

ACTG

A520244,62,146

Daar, E.S. et

al44

Atazanavir plus ritonavir or efavirenz as part of a 3-drug

regimen for initial treatment of HIV type-1: A randomized

trial

2011

Gotti, D. et al62

Increase in standard cholesterol and large HDL particle

subclasses in antiretroviral-naive patients prescribed

efavirenz compared to atazanavir/ritonavir

2012

Sax, P.E. et

al146

Abacavir/lamivudine versus tenofovir DF/emtricitabine as

part of combination regimens for initial treatment of HIV:

Final results

2011

ACTG A525782 Lennox, J.L. et

al82

Efficacy and tolerability of 3 nonnucleoside reverse

transcriptase inhibitor-sparing antiretroviral regimens for

treatment-naive volunteers infected with HIV-1: A

randomized, controlled equivalence trial

2014

ACTION77 Kumar, P.N. et

al77

A randomized, controlled trial of initial anti-retroviral

therapy with abacavir/lamivudine/zidovudine twice-daily

compared to atazanavir once-daily with

lamivudine/zidovudine twice-daily in HIV-infected patients

over 48 weeks (ess100327, the action study)

2009

Advanz-398 Miro et al98

Immune reconstitution in severely immunosuppressed

antiretroviral-naive HIV-1-infected patients starting

efavirenz, lopinavir-ritonavir, or atazanavir-ritonavir plus

tenofovir/emtricitabine: Final 48-week results (the advanz-3

trial)

2015

104

AI424-008106 Murphy, R.L. et

al106

Dose-ranging, randomized, clinical trial of atazanavir with

lamivudine and stavudine in antiretroviral-naive subjects:

48-week results

2003

Albini et al,

201220 Albini, L. et al20

A randomized, pilot trial to evaluate glomerular filtration

rate by creatinine or cystatin c in naive HIV-infected patients

after tenofovir/emtricitabine in combination with

atazanavir/ritonavir or efavirenz

2012

ALERT152 Smith, K.Y. et

al152

Fosamprenavir or atazanavir once daily boosted with

ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial

treatment of HIV infection: 48-week results of alert

2008

ALTAIR128 Puls, R.L. et

al128

Efavirenz versus boosted atazanavir or zidovudine and

abacavir in antiretroviral treatment-naive, HIV-infected

subjects: Week 48 data from the Altair study

2010

ARIA124 Porteiro et

al124

Fixed-dose combination dolutegravir, abacavir, and

lamivudine versus ritonavir-boosted atazanavir plus

tenofovir disoproxil fumarate and emtricitabine in previously

untreated women with HIV-1 infection (aria): Week 48

results from a randomised, open-label, non-inferiority,

phase 3b study

2017

ARTEMIS

23,52,79,96,115,119,16

0

Arathoon, E. et

al23

Effects of once-daily darunavir/ritonavir versus

lopinavir/ritonavir on metabolic parameters in treatment-

naive HIV-1-infected patients at week 96: Artemis

2013

Fatkenheuer,

G. et al52

Artemis 96-week comparison of liver tolerability of once-

daily darunavir/ritonavir (DRV/r) versus lopinavir/ ritonavir

(LPV/r) in treatment-naive patients

2009

Lazzarin, A. et

al79

Artemis: 192-week efficacy and safety of once daily

darunavir/ritonavir (DRV/r) versus lopinavir/r (LPV/r) in

treatment-naive HIV-1-infected adults

2011

Mills, A.M. et

al96

Once-daily darunavir/ritonavir vs. Lopinavir/ritonavir in

treatment-naive, HIV-1-infected patients: 96-week analysis 2009

Orkin, C. et Final 192-week efficacy and safety of once-daily 2013

105

al115 darunavir/ritonavir compared with lopinavir/ritonavir in HIV-

1-infected treatment-naive patients in the ARTEMIS trial

Ortiz, R. et al119

Efficacy and safety of once-daily darunavir/ritonavir versus

lopinavir/ritonavir in treatment-naive HIV-1-infected

patients at week 48

2008

Termini, R. et

al160

Use of once-daily darunavir/r (800/100mg) in treatment-

naive patients co-infected with hepatitis b and/or c. Data

from the ARTEMIS study

2009

ARTEN121,123,153

Podzamczer, D.

et al123

Comparison of lipid profile with nevirapine versus

atazanavir/ritonavir, both combined with tenofovir DF and

emtricitabine (TDF/FTC), in treatment-naive HIV-1-infected

patients: ARTEN study week-48 results

2009

Podzamczer, D.

et al121

Lipid profiles for nevirapine vs. Atazanavir/ritonavir, both

combined with tenofovir disoproxil fumarate and

emtricitabine over 48 weeks, in treatment-naive HIV-1-

infected patients (the ARTEN study)

2011

Soriano, V. et

al153

Nevirapine versus atazanavir/ritonavir, each combined with

tenofovir disoproxil fumarate/emtricitabine, in

antiretroviral-naive HIV-1 patients: The ARTEN trial

2011

ASSERT104,125,158

Moyle, G.J. et

al104

96-week results of abacavir/lamivudine versus

tenofovir/emtricitabine, plus efavirenz, in antiretroviral-

naive, HIV-1-infected adults: Assert study

2013

Post, F.A. et

al125

Randomized comparison of renal effects, efficacy, and safety

with once-daily abacavir/lamivudine versus

tenofovir/emtricitabine, administered with efavirenz, in

antiretroviral-naive, HIV-1-infected adults: 48-week results

from the assert study

2010

Stellbrink, H.J.

et al158

Comparison of changes in bone density and turnover with

abacavir-lamivudine versus tenofovir-emtricitabine in HIV-

infected adults: 48-week results from the assert study

2010

ATADAR90,91 Martinez et Differential body composition effects of protease inhibitors 2015

106

al91 recommended for initial treatment of HIV infection: A

randomized clinical trial

Martinez, E. et

al90

Early lipid changes with atazanavir/ritonavir or

darunavir/ritonavir 2014

ATLANTIC162 van Leeuwen,

R. et al162

A randomized trial to study first-line combination therapy

with or without a protease inhibitor in HIV-1-infected

patients

2003

Avihingsanon

et al, 201027

Avihingsanon,

A. et al27

Efficacy of tenofovir disoproxil fumarate/emtricitabine

compared with emtricitabine alone in antiretroviral-naïve

HIV-HBV coinfection in Thailand

2010

BASIC168 Vrouenraets,

S.M. et al168

Randomized comparison of metabolic and renal effects of

saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in

treatment-naive HIV-1-infected patients

2011

CASTLE73,87,101,1

02

Johnson, M.

and Moyle,

G.73

Castle study: 96-week efficacy & safety of ATV/r versus

LPV/r in antiretroviral-naive HIV-1-infected patients 2009

Malan, N. et

al87

Gastrointestinal tolerability and quality of life in

antiretroviral-naive HIV-1-infected patients: Data from the

castle study

2010

Molina, J.M. et

al102

Once-daily atazanavir/ritonavir compared with twice-daily

lopinavir/ritonavir, each in combination with tenofovir and

emtricitabine, for management of antiretroviral-naive HIV-1-

infected patients: 96-week efficacy and safety results of the

castle study

2010

Molina, J.M. et

al101

Once-daily atazanavir/ritonavir versus twice-daily

lopinavir/ritonavir, each in combination with tenofovir and

emtricitabine, for management of antiretroviral-naive HIV-1-

infected patients: 48 week efficacy and safety results of the

castle study

2008

CCTG 58933 Bowman, V. et

al33

48 week results of a pilot randomized study of an nucleoside

reverse 2011

107

transcriptase inhibitor (NRTI)-sparing regimen of raltegravir

(RAL) +

lopinavir/ritonavir (LPV/r) versus efavirenz/tenofovir

disoproxil fumarate

/emtricitabine (EFV/TDF/FTC) in antiretroviral

CNA3002446 DeJesus, E. et

al46

Abacavir versus zidovudine combined with lamivudine and

efavirenz, for the treatment of antiretroviral-naive HIV-

infected adults

2004

CNA3014167 Vibhagool, A.

et al167

Triple nucleoside treatment with abacavir plus the

lamivudine/zidovudine combination tablet (com) compared

to indinavir/com in antiretroviral therapy-naive adults:

Results of a 48-week open-label, equivalence trial (cna3014)

2004

CNAAB3005157 Staszewski, S.

et al157

Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-

zidovudine in antiretroviral-naive HIV-infected adults: A

randomized equivalence trial

2001

CNAF300793 Matheron, S.

et al93

Triple nucleoside combination

zidovudine/lamivudine/abacavir versus

zidovudine/lamivudine/nelfinavir as first-line therapy in HIV-

1-infected adults: A randomized trial

2003

COMBINE53 Fisac, C. et al53

A comparison of the effects of nevirapine and nelfinavir on

metabolism and body habitus in antiretroviral-naive human

immunodeficiency virus-infected patients: A randomized

controlled study

2003

COMBINE122 Podzamczer, D.

et al122

A randomized clinical trial comparing nelfinavir or nevirapine

associated to zidovudine/lamivudine in HIV-infected naive

patients (the combine study)

2002

CTN17767,68

Harris, M. et

al67

A randomized, open-label study of a nucleoside analogue

reverse transcriptase inhibitor-sparing regimen in

antiretroviral-naive HIV-infected patients

2009

Harris, M. et

al68

NRTI Sparing Trial (CTN 177): Antiviral and Metabolic Effects

of 2009

108

Nevirapine (NVP) + Lopinavir/ritonavir (LPV/r) vs.

Zidovudine/lamivudine (AZT/3TC) + NVP vs. AZT/3TC + LPV/r

DAUFIN133 Rey, D. et al133

High rate of early virological failure with the once-daily

tenofovir/lamivudine/nevirapine combination in naive HIV-

1-infected patients

2009

DAYANA78 Landman, R. et

al78

Evaluation of four tenofovir-containing regimens as first-line

treatments in Cameroon and Senegal: The ANRS 12115

Dayana trial

2014

DRIVE

AHEAD117 Orkin et al117

Similar Efficacy and Safety By Subgroup in DRIVE-AHEAD:

DOR/3TC/TDF vs EFV/FTC/TDF 2018

DRIVE

FORWARD99 Molina et al99

Doravirine is non-inferior to darunavir/r in phase 3

treatment naïve trial at week 48 2017

ECHO103 Molina, J.M. et

al103

Rilpivirine versus efavirenz with tenofovir and emtricitabine

in treatment-naive adults infected with HIV-1 (echo): A

phase 3 randomised double-blind active-controlled trial

2011

ENCORE121,22,64

Amin, J. et al21

Efficacy of 400 mg efavirenz versus standard 600 mg dose in

HIV-infected, antiretroviral-naive adults (encore1): A

randomised, double-blind, placebo-controlled, non-

inferiority trial

2014

Amin, J. et al22

Efficacy and safety of efavirenz 400 mg daily versus 600 mg

daily: 96-week data from the randomised, double-blind,

placebo-controlled, non-inferiority ENCORE1 study

2015

Encore1 Study

Group64

Efficacy and safety of efavirenz 400 mg daily versus 600 mg

daily: 96-week data from the randomised, double-blind,

placebo-controlled, non-inferiority encore1 study

2015

Epzicom-

Truvada

111,112

Nishijima, T. et

al112

Abacavir/lamivudine versus tenofovir/emtricitabine with

atazanavir/ritonavir for treatment-naive Japanese patients

with HIV-1 infection: A randomized multicenter trial

2013

Nishijima, T. et

al111

Once-daily darunavir/ritonavir and abacavir/lamivudine

versus tenofovir/emtricitabine for treatment-naive patients

with a baseline viral load of more than 100 000 copies/ml

2013

109

FLAMINGO37,10

0

Clotet, B. et

al37

Once-daily dolutegravir versus darunavir plus ritonavir in

antiretroviral-naive adults with HIV-1 infection (FLAMINGO):

48-week results from the randomised open-label phase 3b

study

2014

Molina, J. et

al100

Once-daily dolutegravir versus darunavir plus ritonavir for

treatment-naive adults with HIV-1 infection (FLAMINGO): 96

week results from a randomised, open-label, phase 3b study

2015

GEMINI169 Walmsley, S. et

al169

Gemini: A noninferiority study of saquinavir/ritonavir versus

lopinavir/ritonavir as initial HIV-1 therapy in adults 2009

GESIDA 390331 Berenguer, J.

et al31

Didanosine, lamivudine, and efavirenz versus zidovudine,

lamivudine, and efavirenz for the initial treatment of HIV

type 1 infection: Final analysis (48 weeks) of a prospective,

randomized, noninferiority clinical trial, gesida 3903

2008

GS-US-141-

1475

143,144

Sax et al144

Bictegravir versus dolutegravir, each with emtricitabine and

tenofovir alafenamide, for initial treatment of HIV-1

infection: A randomised, double-blind, phase 2 trial

2017

Sax et al143 Randomized trial of bictegravir or dolutegravir with FTC/TAF

for initial HIV therapy 2017

GS-US-236-

0102

145,178,180

Sax, P.E. et

al145

Co-formulated elvitegravir, cobicistat, emtricitabine, and

tenofovir versus co-formulated efavirenz, emtricitabine, and

tenofovir for initial treatment of HIV-1 infection: A

randomised, double-blind, phase 3 trial, analysis of results

after 48 weeks.[erratum appears in lancet. 2012 aug

25;380(9843):730]

2012

Wohl, D.A. et

al178

A randomized, double-blind comparison of single-tablet

regimen elvitegravir/cobicistat/emtricitabine/tenofovir df

versus single-tablet regimen

efavirenz/emtricitabine/tenofovir df for initial treatment of

HIV-1 infection: Analysis of week 144 results

2014

Zolopa, A. et

al180

A randomized double-blind comparison of co-formulated

elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 2013

110

fumarate versus efavirenz/emtricitabine/tenofovir disoproxil

fumarate for initial treatment of HIV-1 infection: Analysis of

week 96 results

GS-US-236-

0103

48,108,114,116,118,13

8,140

DeJesus, E. et

al48

Co-formulated elvitegravir, cobicistat, emtricitabine, and

tenofovir disoproxil fumarate versus ritonavir-boosted

atazanavir plus co-formulated emtricitabine and tenofovir

disoproxil fumarate for initial treatment of HIV-1 infection: A

randomised, double-blind, phase 3, non-inferiority trial

2012

Nathan, C. et

al108

Long-term efficacy and safety of

elvitegravir/cobicistat/emtricitabine/tenofovir df versus

atazanavir plus ritonavir plus emtricitabine/tenofovir

2014

Orkin, C. et

al118

A randomized study comparing a three- and four-drug

HAART regimen in first-line therapy (quad study) 2005

Orkin, C. et

al114

Week 144 efficacy and safety data:

Elvitegravir/cobicistat/emtricitabine/tenofovir df (stribild)

demonstrates durable efficacy and differentiated safety

compared to atazanavir boosted by ritonavir plus

emtricitabine/tenofovir df at week 144 in treatment-naive

HIV-1-infected patients

2014

Orkin, C. et

al116

Week 96 efficacy and safety data: Elvitegravir/cobicistat/

emtricitabine/tenofovir df (quad) compared to atazanavir

boosted by ritonavir plus emtricitabine/tenofovir df in

treatment-naive HIV-1-infected patients

2013

Rockstroh, J. et

al138

Elvitegravir/cobicistat/emtricitabine/tenofovir df (quad) has

durable efficacy and differentiated safety compared to

atazanavir boosted by ritonavir plus emtricitabine/tenofovir

df at week 96 in treatment-naive HIV-1-infected patients

2012

Rockstroh, J.K.

et al140

A randomized, double-blind comparison of coformulated

elvitegravir/ cobicistat/emtricitabine/tenofovir df vs

ritonavir-boosted atazanavir plus coformulated

emtricitabine and tenofovir df for initial treatment of HIV-1

2013

111

infection: Analysis of week 96 results

GS-US-236-

0104

38

Cohen, C. et

al38

Randomized, phase 2 evaluation of two single-tablet

regimens elvitegravir/cobicistat/emtricitabine/tenofovir

disoproxil fumarate versus efavirenz/emtricitabine/tenofovir

disoproxil fumarate for the initial treatment of HIV infection

2011

GS-US-236-

0140

61

Gilead

Science61

Renal Effect of Stribild or Other Tenofovir DF-containing

Regimens Compared to Ritonavir-boosted Atazanavir Plus

Abacavir/Lamivudine in Antiretroviral Treatment-naive HIV-1

Infected Adults

2016

GS-US-292-

0102

147

Sax et al147

Tenofovir alafenamide vs. Tenofovir disoproxil fumarate in

single tablet regimens for initial HIV-1 therapy: A

randomized phase 2 study

2014

GS-US-292-

0104;

GS-US-292-

011124,26,149,176,1

77

Arribas et al24 Significant efficacy and long-term safety difference with TAF-

based STR in naive adults 2017

Wolh et al176

Brief report: A randomized, double-blind comparison of

tenofovir alafenamide versus tenofovir disoproxil fumarate,

each coformulated with elvitegravir, cobicistat, and

emtricitabine for initial HIV-1 treatment: Week 96 results

2016

Sax et al149

Tenofovir alafenamide versus tenofovir disoproxil fumarate,

coformulated with elvitegravir, cobicistat, and emtricitabine,

for initial treatment of HIV-1 infection: Two randomised,

double-blind, phase 3, non-inferiority trials

2015

Wohl et al26

Brief report: Randomized, double-blind comparison of

tenofovir alafenamide (taf) vs tenofovir disoproxil fumarate

(tdf), each coformulated with elvitegravir, cobicistat, and

emtricitabine (e/c/f) for initial HIV-1 treatment: Week 144

results

2017

Wohl et al177 Tenofovir alafenamide (TAF) in a single-tablet regimen in

initial HIV-1 therapy 2015

GS-US-299-

0102 Mills et al95

Tenofovir alafenamide versus tenofovir disoproxil fumarate

in the first protease inhibitor-based single-tablet regimen for 2015

112

95 initial HIV-1 therapy: A randomized phase 2 study

GS-US-380-

1489

55

Gallant et al55

Bictegravir, emtricitabine, and tenofovir alafenamide versus

dolutegravir, abacavir, and lamivudine for initial treatment

of HIV-1 infection (gs-us-380-1489): A double-blind,

multicentre, phase 3, randomised controlled non-inferiority

trial

2017

GS-US-380-

1490

148

Sax et al148

Coformulated bictegravir, emtricitabine, and tenofovir

alafenamide versus dolutegravir with emtricitabine and

tenofovir alafenamide, for initial treatment of HIV-1

infection (gs-us-380-1490): A randomised, double-blind,

multicentre, phase 3, non-inferiority trial

2017

HEAT151 Smith, K.Y. et

al151

Randomized, double-blind, placebo-matched, multicenter

trial of abacavir/lamivudine or tenofovir/emtricitabine with

lopinavir/ritonavir for initial HIV treatment

2009

INITIO42

Initio Trial

International

Co-ordinating

Committee42

Virological and immunological outcomes at 3 years after

starting antiretroviral therapy with regimens containing non-

nucleoside reverse transcriptase inhibitor, protease

inhibitor, or both in INITIO: Open-label randomised trial

2006

Japanese Anti-

HIV-1

QD Therapy70

Honda, M. et

al70

Open-label randomized multicenter selection study of once

daily antiretroviral treatment regimen comparing ritonavir-

boosted atazanavir to efavirenz with fixed-dose abacavir and

lamivudine

2011

KLEAN51 Eron Jr, J. et

al51

The klean study of fosamprenavir-ritonavir versus lopinavir-

ritonavir, each in combination with abacavir-lamivudine, for

initial treatment of HIV infection over 48 weeks: A

randomised non-inferiority trial

2006

LAKE Study50 Echeverria, P.

et al50

Similar antiviral efficacy and tolerability between efavirenz

and lopinavir/ritonavir, administered with

abacavir/lamivudine (kivexa), in antiretroviral-naive

patients: A 48-week, multi-centre, randomized study (LAKE

study)

2010

113

Li et al, 200883 Li, T. et al83 Three generic nevirapine-based antiretroviral treatments in

chinese HIV/aids patients: Multicentric observation cohort 2008

M98-863173 Walmsley, S. et

al173

Lopinavir-ritonavir versus nelfinavir for the initial treatment

of HIV infection 2002

Maggiolo et al,

200384

Maggiolo, F. et

al84

Once-a-day therapy for HIV infection: A controlled,

randomized study in antiretroviral-naive HIV-1-infected

patients

2003

MASTER161 Torti, C. et al161

Early virological failure after tenofovir + didanosine +

efavirenz combination in HIV-positive patients upon starting

antiretroviral therapy

2005

METABOLIK19 Aberg, J.A. et

al19

Metabolic effects of darunavir/ritonavir versus

atazanavir/ritonavir in treatment-naive, HIV type 1-infected

subjects over 48 weeks

2012

NEAT001/ANR

S143129 Raffi, F. et al129

Ritonavir-boosted darunavir combined with raltegravir or

tenofovir-emtricitabine in antiretroviral-naive adults

infected with HIV-1: 96-week results from the

NEAT001/ANRS143 randomised non-inferiority trial

2014

NEWART47 Dejesus, E. et

al47

A randomised comparison of safety and efficacy of

nevirapine vs. Atazanavir/ritonavir combined with

tenofovir/emtricitabine in treatment-naive patients

2011

NORA45,105,109

Dart Trial

Team45

Twenty-four-week safety and tolerability of nevirapine vs.

Abacavir in combination with zidovudine/lamivudine as first-

line antiretroviral therapy: A randomized double-blind trial

(NORA)

2008

Munderi, P. et

al105

Nevirapine/zidovudine/lamivudine has superior

immunological and virological responses not reflected in

clinical outcomes in a 48-week randomized comparison with

abacavir/zidovudine/lamivudine in HIV-infected Ugandan

adults with low cd4 cell counts

2010

Ndembi, N. et

al109

Viral rebound and emergence of drug resistance in the

absence of viral load testing: A randomized comparison 2010

114

between zidovudine-lamivudine plus nevirapine and

zidovudine-lamivudine plus abacavir

OzCombo136 Carr, A. et al36

A randomised, open-label comparison of three highly active

antiretroviral therapy regimens including two nucleoside

analogues and indinavir for previously untreated HIV-1

infection: The OzCombo1 study

2000

OzCombo254 French, M. et

al54

Randomized, open-label, comparative trial to evaluate the

efficacy and safety of three antiretroviral drug combinations

including two nucleoside analogues and nevirapine for

previously untreated HIV-1 infection: The ozcombo 2 study

2002

PEARLS35 Campbell, T.B.

et al35

Efficacy and safety of three antiretroviral regimens for initial

treatment of HIV-1: A randomized clinical trial in diverse

multinational settings

2012

PHIDISA II94,132

Matthews,

G.V. et al94

Impact of lamivudine on HIV and hepatitis b virus-related

outcomes in HIV/hepatitis b virus individuals in a

randomized clinical trial of antiretroviral therapy in southern

Africa

2011

Ratsela, A. et

al132

A randomized factorial trial comparing 4 treatment regimens

in treatment-naive HIV-infected persons with aids and/or a

cd4 cell count <200 cells/mul in South Africa

2010

PROGRESS134,13

5

Reynes, J. et

al134

Examination of noninferiority, safety, and tolerability of

lopinavir/ritonavir and raltegravir compared with

lopinavir/ritonavir and tenofovir/ emtricitabine in

antiretroviral-naive subjects: The progress study, 48-week

results

2011

Reynes, J. et

al135

Lopinavir/ritonavir combined with raltegravir or

tenofovir/emtricitabine in antiretroviral-naive subjects: 96-

week results of the progress study

2013

Protocol

00463,88,89,107

Gotuzzo, E. et

al63

Sustained efficacy and safety of raltegravir after 5 years of

combination antiretroviral therapy as initial treatment of

HIV-1 infection: Final results of a randomized, controlled,

2012

115

phase II study (protocol 004)

Markowitz, M.

et al89

Rapid and durable antiretroviral effect of the HIV-1 integrase

inhibitor raltegravir as part of combination therapy in

treatment-naive patients with HIV-1 infection: Results of a

48-week controlled study

2007

Markowitz, M.

et al88

Sustained antiretroviral effect of raltegravir after 96 weeks

of combination therapy in treatment-naive patients with

HIV-1 infection

2009

Murray, J.M. et

al107

Antiretroviral therapy with the integrase inhibitor raltegravir

alters decay kinetics of HIV, significantly reducing the second

phase

2007

RADAR28-30

Bedimo, R.28

Radar study: Raltegravir combined with boosted darunavir

has similar safety and antiviral efficacy as

tenofovir/emtricitabine combined with boosted darunavir in

antiretroviral-naive patients

2011

Bedimo, R. et

al29

Standard Triple Therapy Controls HIV Better Than

Raltegravir/Darunavir at 48 Weeks RADAR Study 2013

Bedimo, R.J. et

al30

The RADAR study: Week 48 safety and efficacy of raltegravir

combined with boosted darunavir compared to

tenofovir/emtricitabine combined with boosted darunavir in

antiretroviral-naive patients. Impact on bone health

2014

SEARCH 003120 Phanuphak, N.

et al120

A 72-week randomized study of the safety and efficacy of a

stavudine to zidovudine switch at 24 weeks compared to

zidovudine or tenofovir disoproxil fumarate when given with

lamivudine and nevirapine

2012

SENC113 Nunez, M. et

al113

SENC (Spanish efavirenz vs. Nevirapine comparison) trial: A

randomized, open-label study in HIV-infected naive

individuals

2002

Sierra-Madero

et al, 2010150

Sierra-Madero,

J. et al150

Prospective, randomized, open label trial of efavirenz vs

lopinavir/ritonavir in HIV+ treatment-naive subjects with

cd4+<200 cell/mm3 in Mexico

2010

116

SINGLE18,170-172

Walmsley et

al170

Brief report: Dolutegravir plus abacavir/lamivudine for the

treatment of HIV-1 infection in antiretroviral therapy-naive

patients: Week 96 and week 144 results from the single

randomized clinical trial.[erratum appears in j acquir

immune defic syndr. 2016 jan 1;71(1):E33]

2015

Walmsley, S. et

al172

Dolutegravir regimen statistically superior to

tenofovir/emtricitabine/efavirenz: 96-wk data 2014

Walmsley, S. et

al171

Dolutegravir Regimen Statistically Superior to

Efavirenz/Tenofovir/Emtricitabine: 96-Week Results From

the SINGLE Study (ING114467)

2014

Walmsley, S.L.

et al18

Dolutegravir plus abacavir-lamivudine for the treatment of

HIV-1 infection 2013

SOLO60 Gathe, J.C., Jr.

et al60

SOLO: 48-week efficacy and safety comparison of once-daily

fosamprenavir /ritonavir versus twice-daily nelfinavir in

naive HIV-1-infected patients

2004

SPARTAN75 Kozal, M.J. et

al75

A nucleoside- and ritonavir-sparing regimen containing

atazanavir plus raltegravir in antiretroviral treatment-naive

HIV-infected patients: SPARTAN study results

2012

SPRING-1159,166

Stellbrink, H.J.

et al159

Dolutegravir in antiretroviral-naive adults with HIV-1: 96-

week results from a randomized dose-ranging study 2013

van Lunzen, J.

et al166

Once daily dolutegravir (S/GSK1349572) in combination

therapy in antiretroviral-naive adults with HIV: Planned

interim 48-week results from SPRING-1, a dose-ranging,

randomised, phase 2b trial

2012

SPRING-2130,131

Raffi, F. et al131

Once-daily dolutegravir versus raltegravir in antiretroviral-

naive adults with HIV-1 infection: 48-week results from the

randomised, double-blind, non-inferiority SPRING-2 study

2013

Raffi, F. et al130

Once-daily dolutegravir versus twice-daily raltegravir in

antiretroviral-naive adults with HIV-1 infection (SPRING-2

study): 96-week results from a randomised, double-blind,

non-inferiority trial

2013

117

SPRING-2/

SINGLE43

Curtis, LD. et

al43

Once-Daily Dolutegravir (DTG; GSK1349572) Has a Renal

Safety Profile Comparable to Raltegravir (RAL) and Efavirenz

in Antiretroviral (ART)-Naive Adults: 48 Week Results From

SPRING-2 (ING113086) and SINGLE (ING114467)

2013

SPRING-2/

SINGLE/

FLAMINGO/

SAILING97

Min, S. et al97

Efficacy and Safety of Dolutegravir (DTG) in Hepatitis (HBV or

HCV) Co-infected Patients: Results from the Phase 3

Program

2014

Squires et al,

200472,155

Jemsek, J.G. et

al72

Body fat and other metabolic effects of atazanavir and

efavirenz, each administered in combination with

zidovudine plus lamivudine, in antiretroviral-naive HIV-

infected patients

2006

Squires, K. et

al155

Comparison of once-daily atazanavir with efavirenz, each in

combination with fixed-dose zidovudine and lamivudine, as

initial therapy for patients infected with HIV

2004

SSAT06634 Bracchi et al34 A randomized comparison of integrase inhibitors with

TDF/FTC on renal markers 2017

STaR39,40,165

Cohen, C. et

al39

Star study: Single-tablet regimen rilpivirine/

emtricitabine/tenofovir DF maintains noninferiority to

efavirenz/emtricitabine/tenofovir DF and has minimal

impact on fasting lipids in art-naive adults through week 96

2013

Cohen, C. et

al40

Week 48 results from a randomized clinical trial of

rilpivirine/ emtricitabine/tenofovir disoproxil fumarate vs.

Efavirenz/emtricitabine/ tenofovir disoproxil fumarate in

treatment-naive HIV-1-infected adults

2014

Van Lunzen et

al165

Rilpivirine vs. Efavirenz-based single-tablet regimens in

treatment-naive adults: Week 96 efficacy and safety from a

randomized phase 3b study

2016

START i156 Squires, K.E. et

al156

A comparison of stavudine plus lamivudine versus

zidovudine plus lamivudine in combination with indinavir in

antiretroviral naive individuals with HIV infection: Selection

2000

118

of thymidine analog regimen therapy (start i)

STARTMRK49,80,

81,141,142

DeJesus, E. et

al49

Efficacy of raltegravir versus efavirenz when combined with

tenofovir/emtricitabine in treatment-naive HIV-1-infected

patients: Week-192 overall and subgroup analyses from

STARTMRK

2012

Lennox, J.L. et

al80

Raltegravir versus efavirenz regimens in treatment-naive

HIV-1-infected patients: 96-week efficacy, durability,

subgroup, safety, and metabolic analyses

2010

Lennox, J.L. et

al81

Safety and efficacy of raltegravir-based versus efavirenz-

based combination therapy in treatment-naive patients with

HIV-1 infection: A multi-centre, double-blind randomised

controlled trial

2009

Rockstroh, J.K.

et al141

Durable efficacy and safety of raltegravir versus efavirenz

when combined with tenofovir/emtricitabine in treatment-

naive HIV-1-infected patients: Final 5-year results from

STARTMRK

2013

Rockstroh, J.K.

et al142

Long-term treatment with raltegravir or efavirenz combined

with tenofovir/emtricitabine for treatment-naive human

immunodeficiency virus-1-infected patients: 156-week

results from STARTMRK

2011

STARTMRK/

BENCHMRK139

Rockstroh, J. et

al139

Safety and efficacy of raltegravir in patients co-infected with

HIV and hepatitis B and/or C virus: Complete data from

phase iii double-blind studies

2012

Study 90357,71

Gallant, J.E. et

al57

Efficacy and safety of tenofovir DF vs stavudine in

combination therapy in antiretroviral-naive patients: A 3-

year randomized trial

2004

Izzedine, H. et

al71

Long-term renal safety of tenofovir disoproxil fumarate in

antiretroviral-naive HIV-1-infected patients. Data from a

double-blind randomized active-controlled multi-centre

study

2005

Study Arribas, J.R. et Tenofovir disoproxil fumarate, emtricitabine, and efavirenz 2008

119

93425,56,126 al25 compared with zidovudine/lamivudine and efavirenz in

treatment-naive patients: 144-week analysis

Gallant, J.E. et

al56

Tenofovir DF, emtricitabine, and efavirenz vs. Zidovudine,

lamivudine, and efavirenz for HIV 2006

Pozniak, A.L. et

al126

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz

versus fixed-dose zidovudine/lamivudine and efavirenz in

antiretroviral-naive patients: Virologic, immunologic, and

morphologic changes - a 96-week analysis

2006

SUPPORT76 Kumar, P. et

al76

Evaluation of cardiovascular biomarkers in a randomized

trial of fosamprenavir/ritonavir vs. Efavirenz with

abacavir/lamivudine in underrepresented, antiretroviral-

naive, HIV-infected patients (support): 96-week results

2013

SWATCH92,110

Martinez-

Picado, J. et

al92

Alternation of antiretroviral drug regimens for HIV infection.

A randomized, controlled trial 2003

Negredo, E. et

al110

Alternation of antiretroviral drug regimens for HIV infection.

Efficacy, safety and tolerability at week 96 of the swatch

study

2004

THRIVE41 Cohen, C.J. et

al41

Rilpivirine versus efavirenz with two background nucleoside

or nucleotide reverse transcriptase inhibitors in treatment-

naive adults infected with HIV-1 (thrive): A phase 3,

randomised, non-inferiority trial

2011

TMC278-

C204127,175

Pozniak, A.L. et

al127

Efficacy and safety of tmc278 in antiretroviral-naive HIV-1

patients: Week 96 results of a phase IIb randomized trial 2010

Wilkin, A. et

al175

Long-term efficacy, safety, and tolerability of rilpivirine (RPV,

tmc278) in HIV type 1-infected antiretroviral-naive patients:

Week 192 results from a phase IIb randomized trial

2012

Tshepo174 Wester, C.W.

et al174

Non-nucleoside reverse transcriptase inhibitor outcomes

among combination antiretroviral therapy-treated adults in

Botswana

2010

WAVES154 Squires et al154 Integrase inhibitor versus protease inhibitor based regimen 2016

120

for HIV-1 infected women (WAVES): A randomised,

controlled, double-blind, phase 3 study

Zhang et al,

2015179 Zhang et al179

Randomized clinical trial of antiretroviral therapy for

prevention of HAND 2017

Table 21: List of included studies with corresponding publications for the TB sub-population


ANRS 12 180

Reflate TB

trial184

Grinsztejn, B.

et al184

Raltegravir for the treatment of patients co-infected with

HIV and tuberculosis (ANRS 12 180 Reflate TB): A multi-

centre, phase 2, non-comparative, open-label, randomised

trial

2014

ANRS 129

BKVIR185

Lortholary, O.

et al

Tenofovir DF/emtricitabine and efavirenz combination

therapy for HIV infection in patients treated for

tuberculosis: The ANRS 129 BKVIR trial

2016

CARINEMO186 Bonnet, M. et

al186

Nevirapine versus efavirenz for patients co-infected with

HIV and tuberculosis: A randomised non-inferiority trial 2013

HIV-TB

Pharmagene187

Habtewold, A.

et al

Is there a need to increase the dose of efavirenz during

concomitant rifampicin-based antituberculosis therapy in

sub-Saharan Africa? The HIV-TB Pharmagene study

2015

INSPIRING188 Dooley et al INSPIRING: Safety and efficacy of dolutegravir-based ART in

TB/HIV coinfected adults at week 24 2018

N2R189,190

Manosuthi, W.

et al189

A randomized trial comparing plasma drug concentrations

and efficacies between 2 nonnucleoside reverse-

transcriptase inhibitor-based regimens in HIV-infected

patients receiving rifampicin: The n2r study

2009

Mankhatitham,

W. et al190

Hepatotoxicity in patients co-infected with tuberculosis

and HIV-1 while receiving non-nucleoside reverse

transcriptase inhibitor-based antiretroviral therapy and

rifampicin-containing anti-tuberculosis regimen

2011

Sinha et al, Sinha, S. et Nevirapine versus efavirenz-based antiretroviral therapy 2013

121

2013191 al191 regimens in antiretroviral-naive patients with HIV and

tuberculosis infections in India: A pilot study

Sinha et al,

2017192

Sinha, S. et

al192

Nevirapine- versus efavirenz-based antiretroviral therapy

regimens in antiretroviral-naive patients with HIV and

tuberculosis infections in India: A multi-centre study

2017

Swaminathan

et al, 2011193

Swaminathan,

S. et al193

Efficacy and safety of once-daily nevirapine- or efavirenz-

based antiretroviral therapy in HIV-associated tuberculosis:

A randomized clinical trial

2011

TB-HAART194 Amogne, W. et

al

Efficacy and safety of antiretroviral therapy initiated one

week after tuberculosis therapy in patients with cd4 counts

< 200 cells/mul: TB-HAART study, a randomized clinical

trial

2015

122

Table 22: List of included studies with corresponding publications for the children and adolescent sub-

population


ARROW

(NCT02028676)195

Kekitiinwa, A.

et al195

Virologic response to first-line efavirenz-or nevirapine-

based antiretroviral therapy in HIV-infected African

children

2017

ATN 061196 Rudy, B. J. et

al196

Immune reconstitution but persistent activation after

48 weeks of antiretroviral therapy in youth with pre-

therapy cd4 >350 in ATN 061

2015

CHAPAS-3197 Bienczak, A. et

al197

Plasma efavirenz exposure, sex, and age predict

virological response in HIV-infected African children 2016

GS-US-236-0112;

GS-US-292-0106

(NCT01721109;

NCT01854775)198,199

Porter, D. P.

et al198

Lack of emergent resistance in HIV-1-infected

adolescents on elvitegravir-based STRS 2015

Porter, D. P.

et al199

Lack of emergent resistance in HIV-1-infected

adolescents on elvitegravir-based single-tablet

regimens

2015

GS-US-292-0106

(NCT01854775)200

Gaur, A. et

al200

Safety and efficacy of E/C/F/TAF in HIV-1 infected

treatment-naive adolescents 2016

Gaur, A. H. et

al200

Safety, efficacy, and pharmacokinetics of a single-tablet

regimen containing elvitegravir, cobicistat,

emtricitabine, and tenofovir alafenamide in treatment-

naive, HIV-infected adolescents: A single-arm, open-

label trial

2016

GS-US-292-1515

(NCT02276612)201-

203

Batra, J. et

al201

Week 24 data from a phase 3 clinical trial of E/C/F/TAF

in HIV-positive adolescents 2015

Kizito, H. et

al202

Week-24 data from a phase 3 clinical trial of E/C/F/TAF

in HIV-infected adolescents 2015

Shao, Y. et

al203

Week 24 data from a phase 3 clinical trial of E/C/F/TAF

in HIV-infected adolescents 2015

IMPAACT P1083 Pinto et al204 A Phase II/III Trial of Lopinavir/Ritonavir Dosed 2018

123

(NCT01172535)204 According to the WHO Pediatric Weight Band Dosing

Guidelines

IMPAACT P1093205 IMPAACT

Network205

IMPAACT P1093. Phase I/II, Multi-Center, Open-Label

Pharmacokinetic, Safety, Tolerability and Antiviral

Activity of Dolutegravir (GSK1349572), a Novel

Integrase Inhibitor, in Combination Regimens in HIV-1

Infected Infants, Children and Adolescents

2018

MONOD-ANRS-

12206

(NCT01127204)206,20

7

Amani-Bosse

C et al206

Virological response and resistances over 12 months

among HIV-infected children less than two years

receiving first-line lopinavir/ritonavir-based

antiretroviral therapy in Cote d'Ivoire and Burkina Faso:

The MONOD-ANRS 12206 cohort

2017

Pressiat C, et

al207

Suboptimal co-trimoxazole prophylactic concentrations

in HIV-infected children according to the WHO

guidelines

2017

PAINT

(NCT00799864)208

Lombaard, J.

et al208

Week 48 safety and efficacy of a rilpivirine (tmc278)-

based regimen in HIV-infected treatment-naive

adolescents: Paint phase ii trial

2015

Gopalan, B. P. et

al209

Gopalan, B. P.

et al209

Sub-therapeutic nevirapine concentration during

antiretroviral treatment initiation among children living

with HIV: Implications for therapeutic drug monitoring

2017

Shiau, S. et al210 Shiau, S. et

al210

Early age at start of antiretroviral therapy associated

with better virologic control after initial suppression in

HIV-infected infants

2017

124

Table 23: List of included studies with corresponding publications for the pregnant and breastfeeding

women


BAN211 Jamieson, D.J.

et al211

Maternal and infant antiretroviral regimens to prevent

postnatal HIV-1 transmission: 48-week follow-up of the

ban randomised controlled trial

2012

DART212 Gibb, D. et

al212

Pregnancy and infant outcomes among HIV-infected

women taking long-term ART with and without

tenofovir in the DART trial

2012

DolPHIN 1

(NCT02245022)213 Waitt et al213

DolPHIN-1: Dolutegravir vs Efavirenz when Initiating

Treatment in Late Pregnancy –An Interim Analysis 2018

IMPAACT 1026s

(NCT00042289)214,21

5

Stek, A. et

al214

Pharmacokinetics of increased dose darunavir during

late pregnancy and postpartum 2016

Mulligan et

al215

Dolutegravir pharmacokinetics in pregnant and

postpartum women living with HIV 2018

Lamorde et al216 Lamorde et

al216

Pharmacokinetics, pharmacodynamics and

pharmacogenomics of efavirenz 400mg once-daily

during pregnancy and postpartum

2017

MMA BANA Study

(NCT00270296)217,21

8

Shapiro R217 Antiretroviral regimens in pregnancy and breast-feeding

in Botswana 2010

Shapiro, R.L.

et al218

HIV transmission and 24-month survival in a

randomized trial of HAART to prevent MTCT during

pregnancy and breastfeeding in Botswana

2013

Ngoma 2015219 Ngoma, M. S.

et al219

Efficacy of who recommendation for continued

breastfeeding and maternal cart for prevention of

perinatal and postnatal HIV transmission in Zambia

2015

PROMISE

1077BF/1077FF

(NCT01061151;

NCT01253538)220,221

Fowler, M. G.

et al220

Benefits and risks of antiretroviral therapy for perinatal

HIV prevention 2016

Fowler, M.G.

et al221

PROMISE: Efficacy and safety of 2 strategies to prevent

perinatal HIV transmission 2015

125

PROMOTE

(NCT00993031)

222-226

Cohan, D. et

al222

Efficacy and safety of lopinavir/ritonavir versus

efavirenz-based antiretroviral therapy in HIV-infected

pregnant Ugandan women

2015

Koss, C. A. et

al223

Hair concentrations of antiretrovirals predict viral

suppression in HIV-infected pregnant and breastfeeding

Ugandan women

2015

Cohan, D. et

al224

Efficacy and safety of LPV/r versus EFV in HIV+ pregnant

and breast-feeding Ugandan Women 2014

Koss225

Risk Factors for Preterm Birth among HIV-Infected

Pregnant Ugandan Women Randomized to

Lopinavir/ritonavir- or Efavirenz-based Antiretroviral

Therapy

2011

Natureeba226

Lopinavir/Ritonavir-Based Antiretroviral Treatment

(ART) Versus Efavirenz-Based ART for the Prevention of

Malaria Among HIV-Infected Pregnant Women

2014

Samuel 2014227 Samuel, M. et

al227

Antenatal atazanavir: A retrospective analysis of

pregnancies exposed to atazanavir 2014

SMAC228-232

Giuliano, M.

et al228

High cmv igg antibody levels are associated to a lower

cd4+ response to antiretroviral therapy in HIV-infected

women

2017

Palombi, L. et

al229

Drug resistance mutations 18 months after

discontinuation of nevirapine-based art for prevention

of mother-to-child transmission of HIV in Malawi

2015

Andreotti, M.

et al230

The impact of HBV or HCV infection in a cohort of HIV-

infected pregnant women receiving a nevirapine-based

antiretroviral regimen in Malawi

2014

Palombi, L. et

al231

Antiretroviral prophylaxis for breastfeeding

transmission in Malawi: Drug concentrations, virological

efficacy and safety

2012

Giuliano, M.

et al232

Maternal Antiretroviral Therapy for the Prevention of

Mother-To-Child Transmission of HIV in Malawi: 2013

126

Maternal and Infant Outcomes Two Years after Delivery

Thorne et al233-235

Thorne et al233 Pregnancy and neonatal outcomes following prenatal

exposure to dolutegravir [Slides] --

Thorne et al234 Pregnancy and neonatal outcomes following prenatal

exposure to dolutegravir [Poster] --

Bollen et al235 A comparison of the pharmacokinetics of dolutegravir

in pregnancy and postpartum 2014

TSHEPISO236 Dooley, K. E.

et al236

Pharmacokinetics of efavirenz and treatment of HIV-1

among pregnant women with and without tuberculosis

coinfection

2015

Tshepo

(NCT00197613)237

Bussmann, et

al237

Pregnancy rates and birth outcomes among women on

efavirenz-containing highly active antiretroviral therapy

in Botswana.

2007

Zash et al238,239

Zash et al238 The comparative safety of dolutegravir or efavirenz

initiated during pregnancy in Botswana --

Zash et al239

DTG/TDF/FTC Started in Pregnancy is as Safe as

EFV/TDF/FTC in Nationwide Birth Outcomes

Surveillance in Botswana

2017

Appendix E: Characteristics of included studies

In this section we present the trial and patient characteristics of all RCTs included in the principal analyses.

Table 24: Trial characteristics for principal systematic literature review

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

Previous review (May 2015)

2NN

NVP XTC + d4T

1216 48 -- -- North and South America, Australia,

Europe, South Africa, and Thailand EFV XTC + d4T

NVP XTC + d4T

ACTG A5142

(NCT00050895)

EFV 2 NRTIs -- 144 2001 3 US

LPV/r 2 NRTIs

ACTG A5202

(NCT00118898)

EFV XTC + TDF

1857 96 2005 3B US and Puerto Rico ATV/r XTC + TDF

EFV XTC + ABC

ATV/r XTC + ABC

ACTG A5257

(NCT00811954)

ATV/r XTC + TDF 1814 96 2009 3 US and Puerto Rico

RAL XTC + TDF

128

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

DRV/r XTC + TDF

Albini et al, 2012 EFV XTC + TDF

91 48 2007 -- Italy ATV/r XTC + TDF

Altair

(NCT00335322)

EFV XTC + TDF 322 48 2007 4 Australia

ATV/r XTC + TDF

DAYANA Trial

(NCT00573001)

NVP XTC + TDF 120 96 2008 3 Senegal and Cameroon

EFV XTC + TDF

ARTEMIS

(NCT00258557)

DRV/r XTC + TDF 689 192 2005 3

North and South America, Europe,

and Asia LPV/r XTC + TDF

ARTEN

NVP XTC + TDF

576 48 -- --

Argentina, Germany, Italy, Mexico,

Portugal, Romania, Spain,

Switzerland, and the United

Kingdom

NVP XTC + TDF

ATV/r XTC + TDF

ASSERT

(NCT00549198)

EFV XTC + ABC 185 96 2007 4 Europe

EFV XTC + TDF

ATADAR

(NCT01274780)

DRV/r XTC + TDF 180 96 2011 4 Spain

ATV/r XTC + TDF

129

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

Avihingsanon et al,

2010

EFV XTC + AZT 16 48 2005 -- Thailand

EFV XTC + TDF

CASTLE

(NCT00272779)

ATV/r XTC + TDF 883 96 2005 3

Africa, Asia, Europe, North America,

South America LPV/r XTC + TDF

CNA30024

EFV XTC + ABC

649 48 2000 3

United States, Europe, South

America, Central America, and

Puerto Rico EFV XTC + AZT

CTN177

(NCT00143689)

LPV/r XTC + AZT 51 48 2002 4 Canada, France, Spain, Argentina

NVP XTC + AZT

DAUFIN

(NCT00199979)

NVP XTC + TDF 71 48 2005 3 France

NVP XTC + TDF

ECHO

(NCT00540449)

RPV XTC + TDF 690 106 2008 3

USA, Canada, Australia, South Africa,

Europe, Asia, and Latin America EFV XTC + TDF

ENCORE1

(NCT01011413)

EFV400 XTC + TDF

636 96 2011 4

Argentina, Australia, Chile, Germany,

China Hong Kong SAR, Israel,

Malaysia, Mexico, Nigeria,

Singapore, South Africa, Thailand,

EFV XTC + TDF

130

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

and the United Kingdom

Epzicom-Truvada

(NCT00544128)

ATV/r XTC + TDF 109 96 2007 4

Germany, China Hong Kong SAR,

Israel, Malaysia, Mexico, Nigeria ATV/r XTC + ABC

FLAMINGO

(NCT01449929)

DTG XTC + ABC

488 96 2011 3B Singapore, South Africa, Thailand,

and the United Kingdom

DRV/r XTC + ABC

DTG XTC + TDF

DRV/r XTC + TDF

GESIDA 3903

(NCT00256828)

EFV XTC + ddI 376 48 2004 4 Spain

EFV XTC + AZT

GS-US-236-0102

(NCT01095796)

EVG/c XTC + TDF 700 48 2010 3 North America

EFV XTC + TDF

GS-US-236-0103

(NCT01095796)

EVG/c XTC + TDF 715 96 2010 3

Australia, Europe, North America,

and Thailand ATV/r XTC + TDF

GS-US-236-0104

(NCT00869557)

EVG/c XTC + TDF 71 48 2009 2 the USA

EFV XTC + TDF

HEAT LPV/r XTC + ABC 694 96 2005 4 the USA and Puerto Rico

131

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

(NCT00244712) LPV/r XTC + TDF

Lake Study

(NCT00318123)

EFV XTC + ABC 126 48 2004 3 Spain and Italy

LPV/r XTC + ABC

Li et al, 2008

(NCT00618176)

NVP AZT + ddI

198 52 2005 4 China NVP XTC + d4T

NVP XTC + AZT

Maggiolo et al, 2003 EFV XTC + AZT

68 52 -- -- Italy EFV XTC + ddI

MASTER

LPV/r XTC + AZT

30 28 2003 -- Italy EFV XTC + TDF

EFV ddI + TDF

METABOLIK DRV/r XTC + TDF

65 48 -- 4 US ATV/r XTC + TDF

NEWART

(NCT00552240)

NVP XTC + TDF 152 48 2007 4 US

ATV/r XTC + TDF

OzCombo 2 NVP XTC + AZT 70 52 1997 -- Australia

132

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

NVP XTC + d4T

NVP ddI + D4T

PEARLS

(NCT00084136)

EFV XTC + TDF

1045 192 2005 4

Brazil, Haiti, India, Malawi, Peru,

South Africa, Thailand, the USA and

Zimbabwe EFV XTC + AZT

Protocol 004

(NCT00100048)

RAL XTC + TDF 201 240 2005 2

United States, Canada, Latin

America, Thailand, and Australia EFV XTC + TDF

SEARCH 003

(NCT00669487)

NVP XTC + d4T

150 72 2008 3 Thailand NVP XTC + AZT

NVP XTC + TDF

SENC NVP ddI + d4T

67 48 1999 -- Spain EFV ddI + d4T

Sierra-Madero et al,

2010

(NCT00162643)

EFV XTC + AZT

189 48 2004 4 Mexico LPV/r XTC + AZT

SINGLE

(NCT01263015)

DTG XTC + ABC 833 48 2011 3

Australia, Belgium, Canada,

Denmark, France, Germany, Italy, EFV XTC + TDF

133

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

Netherlands, Romania, Spain, United

Kingdom, and United States

SPRING-1

(NCT00951015)

DTG 2 NRTIs 205 48 2009 2

France, Germany, Italy, Russia,

Spain, and the USA EFV 2 NRTIs

SPRING-2

(NCT01227824)

DTG XTC + ABC

827 96 2010 3 Canada, the USA, Australia, and

Europe

RAL XTC + ABC

DTG XTC + TDF

RAL XTC + TDF

STaR

(NCT01309243)

RPV XTC + TDF

799 96 2011 3B

United States, Australia, Austria,

Belgium, Canada, France, Germany,

Italy, Netherlands, Portugal, Puerto

Rico, Spain, Switzerland, and United

Kingdom

EFV XTC + TDF

STARTMRK

(NCT00369941)

RAL XTC + TDF

566 96 2006 3

Australia, Brazil, Canada, Chile,

Colombia, France, Germany, India,

Italy, Mexico, Peru, Spain, Thailand,

and the USA

EFV XTC + TDF

Study 903 EFV XTC + TDF 602 144 2000 3 South America, Europe, and the USA

134

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

(NCT00158821) EFV XTC + D4T

Study 934

(NCT00112047)

EFV XTC + TDF 517 144 2003 3

France, Germany, Italy, Spain, the

United Kingdom, and the USA EFV XTC + AZT

THRIVE

(NCT00543725)

RPV 2 NRTIs

680 96 2008 3

the USA and Puerto Rico, Canada,

Australia, Europe, South Africa, Asia,

and Latin America EFV 2 NRTIs

TMC278-C204

(NCT00110305)

RPV 2 NRTIs 373 96 2005 2B The USA

EFV 2 NRTIs

Tshepo NVP 2 NRTIs

650 144 2002 3 Botswana EFV 2 NRTIs

Japanese Anti-HIV-1

QD Therapy

EFV XTC + ABC 71 96 2005 3 Japan

ATV/r XTC + ABC

Review update (2018)

1439-007 Study

(NCT01632345)

DOR XTC + TDF

217 96 2012 2

Australia, Belgium, Canada, France,

Germany, Netherlands, Russian

Federation, Romania, Spain, Puerto

Rico, and United States

EFV XTC + TDF

135

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

Advanz-3

(NCT00532168)

EFV XTC + TDF

89 48 2007 4 Spain ATV/r XTC + TDF

LPV/r XTC + TDF

ARIA

(NCT01910402)

DTG ABC + XTC

499 48 2013 3b

United States, Argentina, Canada,

France, Italy, Mexico, Portugal,

Puerto Ricco, Russian Federation,

South Africa, Spain, Thailand, and

United Kingdom

ATV/r XTC + TDF

DRIVE AHEAD

(NCT02403674)

DOR XTC + TDF 734 96 2015 3

Africa, Asia, Europe, Latin America,

and North America EFV XTC + TDF

DRIVE FORWARD

(NCT02275780)

DOR 2 NRTIs

769 96 2014 3

Argentina, Australia, Austria,

Canada, Chile, Denmark, France,

Germany, Italy, Romania, Russia,

South Africa, Spain, United Kingdom,

and United States

DRV/r 2 NRTIs

GS-US-236-0140

(NCT02246998)

EVG/c XTC + TDF 72 24 2014 4

Belgium, France, Ireland, Spain, and

United Kingdom ATV/r XTC + TDF

136

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

EFV XTC + TDF

ATv/r XTC + ABC

GS-US-292-0102

(NCT01497899)

EVG/c XTC + TAF 171 ≥48 2011 2 United States and Puerto Rico

EVG/c XTC + TDF

GS-US-292-0104

(NCT01780506)

EVG/c XTC + TAF

867 144 2012 3

United States, Australia, Austria,

Belgium, Canada, Italy, Japan, Puerto

Rico, Spain, Switzerland, Thailand,

and United Kingdom

EVG/c XTC + TDF

GS-US-292-0111

(NCT01797445)

EVG/c XTC + TAF

866 144 2013 3

United States, Canada, Dominican

Republic, France, Italy, Mexico,

Netherlands, Portugal, Puerto Rico,

Sweden, and United Kingdom

EVG/c XTC + TDF

GS-US-380-1489

(NCT02607930)

BIC XTC + TAF

631 144 2015 3

United States, Belgium, Canada,

Dominican Republic, France,

Germany, Italy, Puerto Rico, Spain,

and United Kingdom

DTG XTC + ABC

GS-US-380-1490

(NCT02607956)

BIC XTC + TAF 657 ≥96 2015 3

United States, Australia, Belgium,

Canada, Dominican Republic, France, DTG XTC + TAF

137

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

Germany, Italy, Puerto Rico, Spain,

and United Kingdom

SSAT066

(NCT02351908)

RAL XTC + TDF

60 48 2015 4 United Kingdom DTG XTC + TDF

EVG/c XTC + TDF

WAVES

(NCT01705574)

EVG/c XTC + TDF

575 96 2012 3

United States, Belgium, Dominican

Republic, France, Italy, Mexico,

Portugal, Puerto Rico, Russian

Federation, Thailand, Uganda, and

United Kingdom

ATV/r XTC + TDF

Zhang et al, 2015

(NCT01340950)

NVP XTC + AZT 250 96 2010 4 China

EFV XTC + TDF

ABC: abacavir; ATV/r: ritonavir-boosted atazanavir; AZT: zidovudine; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz;

EVG/c: Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; RAL:

raltegravir; RPV: rilpivirine; TDF: Tenofovir disoproxil fumerate; XTC: lamivudine or emtricitabine

138

Table 25: Trial characteristics for studies selected in the systematic literature review among TB co-infected patients

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting


ANRS 12 180 Reflate

TB trial

EFV XTC + TDF

155 48 2009 2 Brazil, France RAL400 XTC + TDF

RAL800 XTC + TDF

CARINEMO EFV XTC + TDF

570 48 2007 2-3 Mozambique RAL400 XTC + TDF

N2R EFV XTC + d4T

142 48 2007 3 Thailand NVP XTC + d4T

Phidisa II

(NCT00342355)

EFV ddI + AZT

1771 144 2004 4 South Africa LPV/r ddI + AZT

EFV XTC + d4T

LPV/r XTC + d4T

Sinha et al, 2013 EFV 2NRTIs

142 96 2007 3 India NVP 2NRTIs

Swaminathan et al, EFV XTC + ddI 116 96 2006 3 India

139

Study ID Treatment

Arm

Backbone Number

randomiz

ed

Trial

Duration

(weeks)

Year of

Initiation

Trial

Phase

Setting

2011 NVP XTC + ddI


ANRS 129 BKVIR EFV XTC + TDF 70 48 2006 3 France

HIV-TB Pharmagene EFV

XTC +

d4T/TDF/ZD

V

208 48 2007 -- Ethiopia

INSPIRING

DTG 2 NRTIs

113 52 2015 3

Argentina, Brazil, Mexico, Peru,

Russian Federation, South Africa,

Thailand EFV 2 NRTIs

Sinha et al, 2017 EFV XTC + AZT

302 96 2007 3 India NVP XTC + AZT

TB-HAART EFV

XTC +

AZT/d4T/Te

nofovir

163 48 2008 -- Ethiopia

ABC: abacavir; ATV/r: ritonavir-boosted atazanavir; AZT: zidovudine; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz;

EVG/c: Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; RAL:

raltegravir; RPV: rilpivirine; TDF: Tenofovir disoproxil fumerate; XTC: lamivudine or emtricitabine

140

Appendix F: Patient characteristics in included studies

Table 26: Patient characteristics across the 76 randomized controlled trials included in the principal analysis

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)


2NN

NVP 34† (0.6) 220 (63%) 44 (20%) 200† (12.24) 4.7† (0.05) 58 (26%) 11 (5%)

EFV 35† (0.37) 400 (64%) 84 (21%) 190† (10) 4.7† (0.04) 117 (29%) 21 (5%)

NVP 34† (0.41) 387 (61%) 86 (22%) 170† (9.41) 4.7† (0.04) 102 (26%) 13 (3%)

ACTG A5142 EFV 39 (0.57) 250 (81%) -- 195† (9.42) 4.8† (0.05) -- --

LPV/r 37 (0.57) 253 (77%) -- 190† (9.37) 4.8† (0.05) -- --

ACTG A5202

EFV 39† (0.45) 464 (85%) 70 (15%) 234† (7.94) 4.7 (0.02) -- --

ATV/r 39† (0.52) 465 (83%) 70 (15%) 224† (8.24) 4.7 (0.03) -- --

EFV 37† (0.48) 465 (79%) 88 (19%) 225† (7.59) 4.7 (0.02) -- --

ATV/r 38† (0.52) 463 (84%) 83 (18%) 236† (9.43) 4.6 (0.03) -- --

ACTG A5257 ATV/r 37† (0.37) 605 (76%) -- 309 (7.68) 4.6† (0.03) 330 (55%) 15 (3%)

RAL 36† (0.37) 603 (75%) -- 306 (8.1) 4.7† (0.03) 324 (54%) 15 (3%)

141

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

DRV/r 37† (0.37) 601 (76%) -- 310 (7.71) 4.6† (0.03) 323 (54%) 7 (1%)

Albini et al, 2012

EFV 41.7 (1.77) 43 (77%) 2 (5%) 269.9

(16.98) 4.7 (0.1) -- 4 (9%)

ATV/r 45.4 (1.63) 48 (81%) 2 (4%) 295.8

(18.21) 4.6 (0.09) -- 4 (8%)

Altair EFV 37.3 (0.84) 114 (79%) 6 (5%) 227 (8.9) 4.7 (0.06) 60 (53%) --

ATV/r 36.7 (0.83) 105 (71%) 4 (4%) 235 (11.13) 4.8 (0.06) 53 (50%) --

ANRS 12115 DAYANA

Trial

NVP 37† (1.22) 31 (45%) 2 (6%) 191† (10.49) 5.4† (0.1) -- --

EFV 40† (1.1) 30 (27%) 6 (20%) 201† (9.24) 5.6† (0.11) -- --

ARTEMIS DRV/r 36 (0.49) 343 (70%) 27 (8%) 228† (8.06) 4.9 (0.03) -- --

LPV/r 35 (0.48) 346 (70%) 35 (10%) 218† (7.66) 4.8 (0.03) -- --

ARTEN

NVP 38 (0.71) 188 (81%) 12 (6%) 177 (7.44) 5.1 (0.05) -- --

NVP 40 (0.77) 188 (87%) 16 (9%) 187 (6.71) 5.1 (0.04) -- --

ATV/r 38 (0.68) 193 (84%) 17 (9%) 188 (6.77) 5.1 (0.05) -- --

ASSERT EFV 38† (0.74) 192 (83%) 10 (5%) 240† (8.66) 5.0† (0.06) -- --

142

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

EFV 36† (0.69) 193 (80%) 18 (9%) 230† (8.49) 5.1† (0.05) -- --

ATADAR DRV/r 37 (0.95) 88 (89%) -- 341 (18.13) 4.8 (0.08) -- --

ATV/r 35 (0.84) 90 (87%) -- 328 (21.49) 4.8† (0.07) -- --

Avihingsanon et al,

2010

EFV 34 (2.34) 5 (83%) -- 46 (18.3) 4.91 (0.13) 1 (17%) --

EFV 33 (1.87) 7 (70%) -- 69 (27.6) 4.90 (0.12) 2 (20%) --

CASTLE ATV/r 34† (0.51) 440 (69%) 18 (4%) 205 (7.55) 5.0† (0.03) -- --

LPV/r 36† (0.49) 443 (69%) 22 (5%) 204 (7.66) 5.0† (0.02) -- --

CNA30024 EFV 35† (0.63) 324 (80%) -- 267† (20.42) 4.8† (0.04) -- --

EFV 35† (0.6) 325 (82%) -- 258† (12.97) 4.8† (0.04) -- --

CTN177 LPV/r 37† (1.81) 24 (88%) -- 229 (29.8) 4.9† (0.15) -- --

NVP 38.1† (1.74) 27 (63%) -- 210 (28.68) 4.9† (0.14) -- --

DAUFIN NVP 41.2 (1.08) 35 (71%) 3 (9%) 195 (15.25) 4.9† (0.09) 9 (26%) 1 (3%)

NVP 41.6 (1.63) 36 (78%) 3 (8%) 191 (12.13) 5.0† (0.13) 13 (36%) 0 (0%)

ECHO RPV 36† (0.65) 346 (77%) 14 (4%) 240† (9.54) 5.0† (0.05) -- --

143

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

EFV 36† (0.52) 344 (80%) 24 (7%) 257† (8.15) 5.0† (0.04) -- --

ENCORE1 EFV400 36.1 (0.56) 321 (69%) 11 (3%) 273 (5.39) 4.8† (0.03) -- 27 (8%)

EFV 35.8 (0.57) 309 (67%) 11 (4%) 272 (5.72) 4.7† (0.04) -- 20 (7%)

Epzicom-Truvada

ATV/r 35† (1.3) 55 (98%) -- 269† (12.88) 4.3† (0.07) 49 (89%) --

ATV/r 39† (1.53) 54 (98%) -- 236.5†

(10.82) 4.3† (0.08) 47 (87%) --

FLAMINGO DTG 35.7 (0.69) 242 (87%) -- 390 (10) 4.5† (0.05) -- --

DRV/r 36.2 (0.68) 242 (83%) -- 400 (10.95) 4.5† (0.05) -- --

GESIDA 3903 EFV 38† (0.65) 186 (77%) 28 (15%) 205 (10.37) 5.0† (0.05) 73 (39%) 24 (13%)

EFV 40† (0.77) 183 (76%) 44 (24%) 216 (8.76) 5.0† (0.05) 79 (43%) 31 (17%)

GS-US-236-0102 EVG/c 38 (0.56) 348 (88%) 28 (8%) 391 (10.11) 4.7 (0.03) 278 (80%) 10 (3%)

EFV 38 (0.56) 352 (90%) 24 (7%) 382 (9.07) 4.8 (0.03) 282 (80%) 11 (3%)

GS-US-236-0103 EVG/c 38 (0.56) 353 (92%) 32 (9%) 351† (7.57) 4.8 (0.03) 275 (78%) 4 (1%)

ATV/r 39 (0.52) 355 (89%) 24 (7%) 366† (7.55) 4.8 (0.03) 273 (77%) 7 (2%)

GS-US-236-0104 EVG/c 36 (1.28) 48 (92%) 3 (6%) 354† (21.51) 4.6 (0.11) -- --

144

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

EFV 35 (2) 23 (91%) 1 (4%) 436† (31.07) 4.6 (0.15) -- --

HEAT LPV/r 38† (0.53) 343 (84%) 55 (16%) 214 (10.18) 4.9† (0.05) -- --

LPV/r 38† (0.51) 345 (80%) 57 (17%) 193 (10.06) 4.8† (0.05) -- --

Lake Study EFV 39 (1.06) 63 (86%) 5 (7%) 193 (15.37) 5.4 (0.74) 30 (47%) --

LPV/r 37 (1.19) 63 (87%) 5 (8%) 191 (16) 5.3 (0.69) 25 (39%) --

Li et al, 2008

NVP 35.8 (1.08) 65 (52%) -- 221.8 (9.1) 4.4 (0.08) -- --

NVP 40.1 (1.3) 69 (45%) -- 218.5

(10.11) 4.5 (0.09) -- --

NVP 37.3 (1.19) 64 (48%) -- 224 (9.19) 4.4 (0.08) -- --

Maggiolo et al, 2003 EFV 37 (--) 26 (76%) 21 (64%) 175 (22.91) 5.22 (0.09) 5 (15%) 6 (18%)

EFV 40 (--) 28 (82%) 18 (55%) 184 (21.53) 5.21 (0.09) 3 (9%) 10 (28%)

MASTER

LPV/r 41† (2.96) 9 (78%) 2 (22%) 218† (47.41) 4.4† (0.26) 1 (11%) 3 (33%)

EFV 42† (0.94) 10 (100%) 2 (20%) 116† (21.55) 4.6† (0.27) 2 (20%) 4 (40%)

EFV 38† (2.68) 11 (73%) 1 (9%) 113† (42.21) 4.8† (0.2) 2 (18%) 2 (18%)

METABOLIK DRV/r 36.5† (1.34) 34 (85%) 0 (0%) 267 (17.9) 5 (0.14) -- --

145

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

ATV/r 35† (1.62) 31 (87%) 1 (3%) 316 (27.8) 4.6 (0.13) -- --

NEWART

NVP 38 (1.11) 75 (87%) -- 178.9

(12.16) 4.9 (0.09) -- --

ATV/r 36 (0.89) 77 (92%) -- 183.5

(12.68) 4.9 (0.08) -- --

OzCombo 2

NVP 40 (1.92) 34 (97%) -- 448 (50.98) 4.5 (0.16) -- --

NVP 37 (1.55) 37 (89%) -- 398 (50.95) 4.6 (0.15) -- --

NVP 39 (1.72) 20 (95%) -- 357 (57.55) 4.7 (0.16) -- --

PEARLS EFV 38.3 (2.03) 22 (96%) 57 (11%) 169 (6.54) 5.0† (0.03) -- --

EFV 35 (0.4) 519 (54%) 53 (10%) 162 (6.5) 5.0† (0.03) -- --

Phidisa II

EFV 35 (0.35) 526 (51%) -- 107† (3.8) 5.1 (0.02) -- --

LPV/r 35 (0.39) 526 (54%) -- 104† (3.81) 5.2 (0.03) -- --

EFV 35.3 (0.26) 444 (67%) -- 102† (4.11) 5.1 (0.02) -- --

LPV/r 35.3 (0.26) 440 (68%) -- 112† (3.62) 5.2 (0.02) -- --

Protocol 004 RAL 35.5† (0.26) 444 (69%) 12 (29%) 338 (29.83) 4.6 (0.09) -- --

146

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

EFV 35.6† (0.26) 443 (68%) 14 (37%) 280 (24.98) 4.8 (0.08) -- --

SEARCH 003

NVP 34 (0.97) 41 (76%) 0 (0%) 157 (13.43) 4.9 (0.1) -- --

NVP 36 (1.04) 38 (68%) 2 (4%) 174 (13.72) 4.9 (0.09) -- --

NVP 35 (1.29) 48 (48%) 3 (6%) 154 (12.74) 4.8 (0.09) -- --

SENC NVP 34† (1.13) 49 (43%) 2 (6%) 353† (23.67) 4.4† (0.07) 14 (39%) 14 (39%)

EFV 35† (0.98) 51 (45%) 5 (16%) 416† (31.93) 4.4† (0.08) 14 (45%) 10 (32%)

Sierra-Madero et al,

2010

EFV 35† (0.9) 36 (78%) 36 (38%) 79† (15.29) -- -- --

LPV/r 35† (1.04) 31 (77%) 43 (46%) 69.7†

(15.37) -- -- --

SINGLE DTG 36.7 (0.29) 95 (83%) 17 (4%) 334.5 (7.32) 4.7 (0.04) 277 (67%) 21 (5%)

EFV 36 (0.34) 94 (87%) 17 (4%) 339 (7.28) 4.7 (0.04) 297 (71%) 8 (2%)

SPRING-1 DTG 36 (0.57) 322 (70%) 0 (0%) 327 (20.86) 4.4 (0.1) -- --

EFV 36 (0.55) 327 (76%) 1 (2%) 328 (21.07) 4.5 (0.1) -- --

SPRING-2 DTG 37† (0.92) 51 (88%) 8 (2%) 359† (7.09) 4.5† (0.04) -- --

RAL 40† (1.67) 50 (88%) 8 (2%) 362† (7.38) 4.6† (0.03) -- --

147

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

STaR RPV 33 (0.53) 404 (64%) -- 395.7 (8.98) 4.8 (0) -- --

EFV 33 (0.55) 401 (66%) -- 385.2 (9.35) 4.8 (0.03) -- --

STARTMRK RAL 0 (0) 103 (77%) 52 (19%) 218.9 (7.41) 5 (0.04) -- --

EFV 0 (0) 101 (77%) 59 (21%) 217.4 (7.96) 5 (0.04) -- --

Study 903 EFV 37.6 (0.54) 281 (81%) -- 276 (11.62) 4.9 (0.04) -- --

EFV 36.9 (0.6) 282 (82%) -- 283 (11.53) 4.9 (0.04) -- --

Study 934 EFV 36† (0.49) 299 (74%) -- 233 (9.28) 5.0† (0.05) -- --

EFV 36† (0.53) 301 (75%) -- 241 (9.26) 5.0† (0.05) -- --

THRIVE RPV 36† (1.11) 52 (86%) 20 (6%) 263† (8.05) 5.0† (0.04) -- --

EFV 39† (0.82) 54 (70%) 17 (5%) 263† (12.36) 5.0† (0.04) -- --

TMC278-C204 RPV 36† (0.47) 340 (74%) 6 (7%) 176† (10.54) 4.8† (0.07) -- --

EFV 36† (0.54) 338 (72%) 8 (9%) 207† (20.5) 4.9† (0.06) -- --

Tshepo NVP 36† (1) 93 (70%) -- 199† (4.31) 5.3† (0.04) -- --

EFV 35† (0.89) 89 (67%) -- 199† (5.3) 5.3† (0.03) -- --

148

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

Japanese Anti-HIV-1

QD Therapy

EFV 35† (1.51) 36 (100%) -- 220 (6.73) 4.6 (0.09) -- --

ATV/r 36† (1.53) 35 (100%) -- 226 (7.47) 4.4 (0.08) -- --


1439-007 Study

(NCT01632345)

DOR 35 (0.93a) 99 (91.7%) -- 402 (19.6a) 4.6 (0.07a) -- --

EFV 34 (0.71a) 101 (93.5%) -- 430 (19.2a) 4.6 (0.07a) -- --

Advanz-3

(NCT00532168)

ATV/r 38.5 (1.2a) 27 (90%) 17 (57%) -- 5.48 (0.11c) 14 (46.7%) 1 (3.3%)

EFV 39 (1.6a) 21 (72.4%) 12 (41%) -- 5.12 (0.11c) 12 (41.4%) 1 (3.5%)

LPV/r 36.5 (1.57a) 25 (83.3%) 13 (44%) -- 5.15 (0.11c) 14 (46.7%) 0 (0%)

ARIA (NCT01910402) DTG 38.1 (0.71b) 0 (0%) 11 (4%) 340 (14.08c) 4.41 (0.06c) 1 (0.004%) 12 (5%)

ATV/r 37.8 (0.64b) 0 (0%) 9 (4%) 350 (11.55c) 4.43 (0.05c) 2 (1%) 8 (3%)

DRIVE AHEAD

(NCT02403674)

DOR 32 (0.54a) 305 (83.8%) 46 (12.6%) 414 (14.39a) 4.4 (0.04a) -- --

EFV 30 (0.53a) 311 (85.4%) 53 (14.6%) 388 (14.98a) 4.5 (0.04a) -- --

DRIVE FORWARD

(NCT02275780)

DOR 34.8 (0.54b) 319 (83%) 36 (9%) 433 (10.6b) 4.4 (0.04b) -- --

DRV/r 35.7 (0.55b) 326 (85%) 37 (10%) 412 (11.74b) 4.4 (0.04b) -- --

149

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

GS-US-236-0140

(NCT02246998)

ATV/r 34 (1.98b) 17 (100%) -- 600 (51.36b) -- -- --

ATV/r 34 (1.77b) 15 (93.8%) -- 524 (44.78b) -- -- --

EFV 34 (2.26b) 15 (93.8%) -- 553 (50.86b) -- -- --

EVG/c 36 (1.91b) 17 (100%) -- 552 (41.91b) -- -- --

GS-US-292-0102

(NCT01497899)

EVG/c 35 (1.06b) 108 (96.4%) -- 404 (17.08b) 4.63 (0.05b) -- --

EVG/c 37 (1.39b) 57 (98.3%) -- 394 (27.52b) 4.69 (0.08b) -- --

GS-US-292-0104

(NCT01780506)

EVG/c 35 (0.48b) 364 (83.7%) -- 437 (10.73b) 4.55 (0.03b) -- --

EVG/c 36 (0.51b) 376 (87%) -- 426 (10.21b) 4.55 (0.03b) -- --

GS-US-292-0111

(NCT01797445)

EVG/c 35 (0.52b) 369 (85.6%) -- 414 (9.96b) 4.53 (0.03b) -- --

EVG/c 36 (0.52b) 364 (83.7%) -- 431 (10.87b) 4.5 (0.03b) -- --

GS-US-380-1489

(NCT02607930)

DTG 32 (2.09c) 282 (90%) 15 (5%) 443 (12.13c) 4.51 (0.03c) 250 (79%) 4 (1%)

BIC 31 (2.21c) 285 (91%) 12 (4%) 450 (11.85c) 4.42 (0.04c) 251 (80%) 5 (2%)

GS-US-380-1490

(NCT02607956)

BIC 33 (0.78c) 280 (88%) 24 (8%) 440 (12.37c) 4.43 (0.04c) 237 (74%) 3 (1%)

DTG 34 (0.77c) 288 (89%) 26 (8%) 441 (12.23c) 4.45 (0.03c) 250 (77%) 6 (2%)

150

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

Sinha et al, 2017

(NCT01805258)

EFV 36.7 (0.62b) 111 (79.3%) 134 (97.8%) 133 (9.46a) 5.2 (0.07a) -- --

NVP 36.7 (0.71b) 104 (72.2%) 136 (97.1%) 127 (9.11a) 5.5 (0.07a) -- --

SSAT066

(NCT02351908)

DTG 36 (1.61a) 20 (100%) -- 488 (33.39d) -- -- --

EVG/c 31 (1.43a) 18 (90%) -- 548 (33.39d) -- -- --

RAL 40 (1.61a) 19 (95%) -- 450 (33.39d) -- -- --

WAVES

(NCT01705574)

ATV/r 35 (0.57c) 0 (0%) 13 (5%) 370 (10.73c) 4.56 (0.04c) -- --

EVG/c 34 (0.65c) 0 (0%) 12 (4%) 344 (9.59c) 4.46 (0.04c) -- --

Zhang et al, 2015

(NCT01340950)

NVP -- -- -- 222.1

(13.52d) 4.2 (0.07d) -- --

EFV -- -- -- 235.1

(13.2d) 4.2 (0.07d) -- --

GS-US-292-0104; GS-

US-292-0111

EVG/c 33 (0.4c) 733 (85%) -- 404 (6.72c) 4.58 (0.02c) 652 (75%) 5 (1%)

EVG/c 35 (0.4c) 740 (85%) -- 406 (6.31c) 4.58 (0.02c) 645 (74%) 6 (1%)

† Median value reported; aSE calculated from the range; bSE calculated from SD; cSE calculated from interquartile range; dSE imputed; ABC:

abacavir; ATV/r: ritonavir-boosted atazanavir; AZT: zidovudine; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c:

151

Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; RAL: raltegravir;

RPV: rilpivirine; TDF: Tenofovir disoproxil fumerate; XTC: lamivudine or emtricitabine

Table 27: Patient characteristics in the principal analysis in the systematic literature review among TB co-infected patients

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)


ANRS 12 180 Reflate

TB trial

EFV 35 (1.64c) 39 (76) -- 129 (27.02 c) 4.9 (0.1c) -- --

RAL400 37 (1.34c) 35 (69) -- 115 (16.91 c) 4.9 (0.12 c) -- --

RAL800 38 (1.03c) 38 (75) -- 166 (29.48 c) 5.5 (0.04 c) -- --

CARINEMO EFV 33 (0.53c) 171 (60) 15 (5) 86 (4.21 c) 5.5 (0.04 c) -- --

RAL400 33 (0.53c) 160 (56) 19 (7) 92 (4.56 c) 5.7 (0.04 c) -- --

N2R EFV 35.7 (0.95b) 46 (64.8) -- 74.8 (8.09 b) 5.75 (0.02 c) -- --

NVP 38 (1.07b) 49 (69) -- 55.8 (6.8 b) 5.75 (0.03 c) -- --

Sinha et al, 2013 EFV 34.8 (0.47b) 319 (83) -- 139 (7.12a) 5.19 (0.06a) -- --

152

Study ID Treatment

Arm

Age

mean (SE)

Males

n (%)

AIDS-

defining

illness

n (%)

Baseline

CD4

(cells/mm3)

Mean (SE)

Baseline

viral load

(log

copies/mL)

Mean (SE)

Men who

have sex

with men

n (%)

Persons

who inject

drugs

n (%)

NVP 35.7(0.48b) 326 (85) -- 137 (7.03a) 5.52 (0.06a) -- --

Swaminathan et al,

2011

EFV 34.4 (0.98b) 49 (83) -- 85 (3.66 c) 5.5 (0.04 c) -- --

NVP 37.8 (1.02b) 44 (77) -- 83 (10.01 c) 5.7 (0.04 c) -- --


ANRS 129 BKVIR EFV 34 (1.59c) 49 (71) -- 74 (12.04 c) 5.4 (0.09 c) 11 (16) --

HIV-TB Pharmagene EFV 35 (0.67c) 109 (52.6) -- 80 (4.73 c) 5.23 (0.05 c) -- --

INSPIRING DTG 33 (1.07a) 39 (57) 69 (100) 208 (25.15 c) 5.1 (0.07 c) -- --

EFV 32 (1.26a) 28 (64) 44 (100) 202 (29.26 c) 5.24 (0.13 c) -- --

Sinha et al, 2017 EFV 36.7(0.62b) 111 (79.3) 134 (97.8) 133 (9.46 a) 5.2 (0.07 a) -- --

NVP 36.7(0.71b) 104 (72.2) 136 (97.1) 127 (9.11 a) 5.5 (0.07 a) -- --

TB-HAART EFV 37(0.78b) 95 (57) -- 67 (3.89 c) 4.9 (0.05 b) -- --

† Median value reported; aSE calculated from the range; bSE calculated from SD; cSE calculated from interquartile range; dSE imputed; ABC:

abacavir; ATV/r: ritonavir-boosted atazanavir; AZT: zidovudine; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c:

Elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; RAL: raltegravir;

RPV: rilpivirine; TDF: Tenofovir disoproxil fumerate; XTC: lamivudine or emtricitabine

Appendix G: Quality assessments of included studies

The following table summarizes the critical appraisals for randomized and non-randomized studies using

the Cochrane Risk of Bias instrument and the Tool to Assess the Risk of Bias in Cohort Studies,

developed by the Clinical Advances through Research and Information Translation (CLARITY) group,

respectively.

Table 28: Cochrane risk of bias quality assessment for randomized controlled trials, arranged by

review sub-population

Trial Sequence

generation

Allocation

concealment

Blinding Incomplete

outcome

data

Selective

outcome

reporting

Other

sources

of bias

Population

1439-007 Study Unclear Unclear Unclear Low Low Unclear Principal,

2018

2NN Low Low High Low Low Low Principal,

2015

ACTG A5142 Low Low High Unclear Low Low Principal,

2015

ACTG A5202 Low Low High Low Low Low Principal,

2015

ACTG A5257 Low Low High Low Low Low Principal,

2015

Advanz-3 Low Low High High Low Unclear Principal,

2018

Albini et al, 2012 Low Low Unclear Low Low Low Principal,

2015

Altair Low Low High Low Low Low Principal,

2015

ANRS 12 180

Reflate TB trial Low Low High Low Low Low HIV/TB

ANRS 12115

DAYANA Trial Low Low High Low Unclear Low

Principal,

2015

154

ARIA Low Low High Low Low Unclear Principal,

2018

ARROW Unclear Unclear High Low Low High Children

ARTEMIS Low Low High Low Low Low Principal,

2015

ARTEN Unclear Low High Low Low Low Principal,

2015

ASSERT Unclear Low High High Low Low Principal,

2015

ATADAR Low Low High Low Low Low

Principal,

2015

(updated)

Avihingsanon et

al, 2010 Low Low High Low Low High

Principal,

2015

BAN Low Unclear High High Low High Pregnancy

CARINEMO Low Low High Low Low Low HIV/TB

CASTLE Low Low High Low Low Low Principal,

2015

CNA30024 Unclear Low Low Low Low Low Principal,

2015

CTN177 Low Low High Low Unclear Low Principal,

2015

DAUFIN Unclear Low High High Low Low Principal,

2015

DolPHIN 1 Unclear Unclear High Low Low High Pregnancy

DRIVE AHEAD Unclear Unclear Low Unclear Unclear Unclear Principal,

2018

DRIVE FORWARD Unclear Unclear Unclear Unclear Unclear Unclear Principal,

2018

ECHO Low Low Low Low Low Low Principal,

2015

155

ENCORE1 Low Low Unclear Low Low Low Principal,

2018

ENCORE1 Low Low Low Low Low Low Principal,

2015

Epzicom-Truvada Low Low High Low Low Low Principal,

2015

FLAMINGO Low Low High Low Low Low Principal,

2015

GESIDA 3903 Low Low High Low Low Low Principal,

2015

GS-US-141-1475 Low Low Low Low Low Low Principal,

2018


2015


2015


2015

GS-US-236-0140 Unclear Unclear Unclear Low Low Unclear Principal,

2018


2018

GS-US-292-0104 Low Low Low Unclear Low Unclear Principal,

2018

GS-US-292-0111 Low Low Low Unclear Low Unclear Principal,

2018


2018


2018


156

2018

HEAT Unclear Low Low High Low Low Principal,

2015

IMPAACT P1060 -

Cohort 1 Unclear Unclear High Low Low High Children

IMPAACT P1060 -

Cohort 2 Unclear Unclear High Low Low High Children

INSPIRING Unclear Unclear High Unclear Low Low HIV/TB

Lake Study Unclear Low High High Low Low Principal,

2015

Li et al, 2008 Unclear Low High High Low Low Principal,

2015

Maggiolo et al,

2003 Low Low Low Low Low Unclear

Principal,

2015

MASTER Low Low High Low Unclear High Principal,

2015

METABOLIK Unclear Low High Low Low Low Principal,

2015

MMA BANA

Study Unclear Unclear Unclear Low Low High Pregnancy

N2R Unclear Unclear High Low Low Low HIV/TB

NEWART Low Low High Low Low Low Principal,

2015

NVP Unclear Low High High High High HIV/TB

OzCombo 2 Unclear Low High Low Low Low Principal,

2015

PEARLS Low Low High Low Low Low Principal,

2015

Phidisa II Low Low High Low Low Low Principal,

2015

PHIDISA II Unclear Low High Low Low Low HIV/TB

157

PROMISE

1077BF/1077FF Unclear Unclear High Low Low High Pregnancy

PROMOTE Unclear Unclear High Low Low High Pregnancy

Protocol 004 Unclear Unclear Low Low Low Low Principal,

2015

SEARCH 003 Low Low High High Low Low Principal,

2015

SENC Unclear Low High High Low Low Principal,

2015

Sierra-Madero et

al, 2010 Low Low High High Low Low

Principal,

2015

SINGLE Low Low Unclear Low Low Low

Principal,

2015

(updated)

Sinha et al, 2017 Unclear Low Unclear Unclear Low High Principal,

2018

SPRING-1 Low Low High Low Low Low Principal,

2015

SPRING-2 Low Low Low Low Low Low Principal,

2015

SSAT066 Unclear Unclear Unclear High High Unclear Principal,

2018

STaR Low Low High Low Low Low

Principal,

2015

(updated)

STARTMRK Low Low Low Low Low Low Principal,

2015

Study 903 Low Low High High Low Low Principal,

2015

Study 934 Low Low High High Low Low Principal,

2015

158

Swaminathan et

al, 2011 Low Low High Low Low Low HIV/TB

TB-HAART Unclear Unclear High High Low Low HIV/TB

THRIVE Low Low Low Low Low Low Principal,

2015

TMC278-C204 Low Low High Low Low Low Principal,

2015

Tshepo Low Low High Unclear Low Low Principal,

2015

Tshepo Unclear Unclear High Unclear High Low Pregnancy

Japanese Anti-

HIV-1 QD Therapy Unclear Low High Low Unclear Low

Principal,

2015

WAVES Low Low Low Low Low Low Principal,

2018

Zhang et al, 2015 Unclear Unclear Unclear Unclear Unclear Unclear Principal,

2018

Table 29: Critical appraisal of non-randomized studies using the Tool to Assess the Risk of Bias in Cohort Studies, developed by the Clinical

Advances through Research and Information Translation (CLARITY) group

Trial

Was

selection of

exposed and

non-exposed

cohorts

drawn from

the same

population?

Can we be

confident

in the

assessment

of

exposure?

Can we

be

confident

that the

outcome

of

interest

was not

present

at start of

study?

Q4*

Can we be

confident

in the

assessment

of the

presence or

absence of

prognostic

factors?

Can we be

confident

in the

assessment

of

outcome?

Was the

follow up

of cohorts

adequate?

Were co-

Interventions

similar

between

groups?

Population

HIV-TB

Pharmagene Probably Probably

Definitely

Definitely

Definitely

Definitely

Probably

Definitely HIV/TB

ANRS 129

BKVIR N/A Probably

Definitely

N/A

Definitely

Definitely

Definitely

N/A HIV/TB

DART Definitely Definitely

Definitely

Probably

Probably

Definitely

Probably

Definitely Pregnancy

IMPAACT

1026s N/A Probably

Definitely

N/A Probably no

Definitely

Probably

N/A Pregnancy

Ngoma et al, N/A Probably Definitely N/A Probably Definitely Probably N/A Pregnancy

160

2015 no no

Samuel et al,

2014 N/A Probably

Definitely

N/A

Definitely

Definitely

Probably

no N/A Pregnancy

SMAC Definitely Probably Definitely

Probably

Probably Probably

Definitely


TSHEPISO Definitely Definitely

Definitely

Definitely

Probably no

Definitely

Definitely


Zash et al,

2018 Definitely Probably

Definitely

Definitely

Probably Probably

Probably


Thorne et al,

2017 N/A Probably

Definitely

N/A Probably

Definitely

Probably

N/A Pregnancy

Lamorde et al,

2017 N/A Probably

Probably

N/A Probably Probably

Probably

N/A Pregnancy

IMPAACT

P1030 N/A

Definitely

Definitely

N/A

Definitely

Definitely

Definitely

N/A Children

IMPAACT

P1083 N/A

Definitely

Definitely

N/A

Definitely

Definitely

Definitely

N/A Children

PACTG1030 N/A Definitely

Definitely

N/A Probably no

Definitely

Definitely

N/A Children

IMPAACT

P1110 N/A

Definitely

Definitely

N/A Probably no

Definitely

Definitely

N/A Children

IMPAACT

P1066 N/A Probably

Probably

N/A Probably no Probably

Definitely

N/A Children

161

IMPAACT

P1093 -

Cohort I

N/A Definitely

Definitely

N/A Probably

Definitely

Definitely

N/A Children

IMPAACT

P1093 -

Cohort IIA

N/A Probably Probably

N/A Probably no Probably

Probably

N/A Children

Q4: Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis

adjust for these prognostic variables?

Appendix H: Network diagrams

Figure 22: Network diagram of trials informing viral suppression at 48 weeks (A); 96 weeks (B); and

144 weeks (C).

(A)

163

(B)

(C)



164



Figure 23: Network diagram of the 66 trials informing mean change from baseline in CD4 cell counts at

48 weeks (A); 96 weeks (B); and 144 weeks (C).

(A)

(B)

165

(C)





166

Figure 24: Network diagram of the trials informing mortality





167






168

Figure 26: Network diagram of the trials informing discontinuation due adverse events among first-

line HIV patients





169

Figure 27: Network diagram of the trials informing retention among first-line HIV patients





170

Figure 28: Network diagram of the trials informing the treatment-related adverse events analysis





171

Figure 29: Network diagram of the trials informing the treatment-emergent adverse events analysis





172

Figure 30: Network diagram of the trials informing the treatment-related serious adverse events

analysis





173

Figure 31: Network diagram of the trials informing drug emergent serious adverse events among first-

line HIV patients





174

Figure 32: Network diagram of the trials informing regimen substitutions





175

TB Subpopulation

Figure 33: Network diagram of trials informing viral suppression at the 24-week (A) and 48-week (B)

timepoints in HIV-TB co-infected patients.

(A)

(B)





176

Figure 34: Network diagram of the trials informing mean change from baseline in CD4 cell counts at

24-week (A) and 48-week (B) timepoints in HIV-TB co-infected patients.

(A)

(B)

177





178

Figure 35: Network diagram of the trials informing Mortality in HIV-TB co-infected patients





179

Figure 36: Network diagram of the comparative trials reporting AIDS defining illnesses outcome in

HIV-TB co-infected patients





180

Figure 37: Network diagram of the trials informing discontinuation due adverse events in HIV-TB co-

infected patients





Figure 38: Network diagram of the trials informing retention among first-line HIV patients

181





Figure 39: Network diagram of the trials informing the treatment-related serious adverse events

analysis in HIV-TB co-infected patients





182

Figure 40: Network diagram of the trials informing treatment emergent serious adverse events in HIV-






Appendix I: Included trials by analysis

Trials

Vir

al s

up

pre

ssio

n

at 4

8 w

eeks

V

iral

su

pp

ress

ion

at 9

6 w

eeks

V

iral

su

pp

ress

ion

at 1

44

wee

ks

CD

4 a

t 4

8 w

eeks

CD

4 a

t 9

6 w

eeks

CD

4 a

t 1

44

we

eks

Mo

rtal

ity

AID

S d

efin

ing

illn

esse

s D

isco

nti

nu

atio

ns

Dis

con

tin

uat

ion

s

du

e to

AEs

Tr

eatm

ent

rela

ted

SA

Es

Trea

tmen

t

rela

ted

AEs

Em

erge

nt

SAEs

Emer

gen

t A

Es

Reg

imen

sub

stit

uti

on

s

2NN

ACTG A5142

A5202

ACTG A5257

Albini et al, 2012

Altair

ANRS 12115 DAYANA Trial

ARTEMIS

ARTEN

ASSERT

ATADAR

Avihingsan et al, 2010

CASTLE

CNA30024

CTN177

184

DAUFIN

ECHO

ENCORE1

Epzicom-Truvada

FLAMINGO

GESIDA 3903

GS-US-236-0102

GS-US-236-0103

GS-US-236-0104

HEAT

Japanese Anti-HIV-1 QD Therapy

Lake

Li et al, 2008

MASTER

METABOLIK

Maggiolo et al, 2003

NEWART

OzCombo2

PEARLS

PHIDISA II

Protocol 004

185

SEARCH 003

SENC

Sierra-Madero et al, 2010

SINGLE

SPRING-1

SPRING-2

STaR

STARTMRK

Study 903

Study 934

THRIVE

TMC278-C204

Tshepo

1439-007 Study

Advanz-3

ARIA

DRIVE AHEAD

DRIVE FORWARD

GS-US-236-0140

GS-US-292-0102

GS-US-292-0104

186

GS-US-292-0111

GS-US-380-1489

GS-US-380-1490

SSAT066

WAVES

Zhang et al, 2015

GS-US-292-0104; GS-US-292-

0111

187

Appendix J: Cross tables

Table 30: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for viral suppression at 48 weeks from

the fixed-effects network meta-analyses

EFV

0.86

(0.56,

1.35)

0.54

(0.42,

0.69)

0.78

(0.59,

1.01)

0.86

(0.53,

1.42)

0.73

(0.57,

0.94)

1.14

(0.94,

1.39)

0.84

(0.67,

1.04)

0.88

(0.67,

1.15)

1.18

(1.02,

1.37)

1.17

(0.93,

1.48)

1.46

(1.16,

1.85)

1.16

(0.74,

1.79)

EFV400

0.62

(0.37,

1.04)

0.90

(0.53,

1.50)

0.99

(0.51,

1.91)

0.85

(0.51,

1.40)

1.32

(0.81,

2.15)

0.97

(0.59,

1.58)

1.02

(0.61,

1.70)

1.36

(0.85,

2.17)

1.35

(0.82,

2.22)

1.69

(1.03,

2.78)

1.86

(1.44,

2.40)

1.61

(0.97,

2.70)

DTG

1.44

(1.02,

2.04)

1.59

(1.03,

2.48)

1.37

(1.03,

1.80)

2.12

(1.56,

2.89)

1.56

(1.12,

2.17)

1.64

(1.16,

2.31)

2.19

(1.70,

2.83)

2.17

(1.64,

2.89)

2.71

(1.98,

3.72)

1.29

(0.99,

1.69)

1.12

(0.67,

1.89)

0.69

(0.49,

0.98)

EVG/c

1.10

(0.64,

1.94)

0.95

(0.66,

1.34)

1.47

(1.07,

2.02)

1.08

(0.77,

1.53)

1.14

(0.79,

1.65)

1.52

(1.17,

1.97)

1.51

(1.07,

2.11)

1.88

(1.35,

2.64)

1.16

(0.71,

1.90)

1.01

(0.52,

1.95)

0.63

(0.40,

0.97)

0.91

(0.51,

1.57)

BIC

0.86

(0.51,

1.42)

1.34

(0.78,

2.23)

0.98

(0.56,

1.66)

1.03

(0.59,

1.76)

1.37

(0.83,

2.24)

1.36

(0.81,

2.27)

1.70

(0.99,

2.87)

1.36

(1.06,

1.76)

1.18

(0.71,

1.97)

0.73

(0.55,

0.97)

1.05

(0.75,

1.51)

1.17

(0.70,

1.96)

RAL

1.55

(1.15,

2.12)

1.14

(0.82,

1.59)

1.20

(0.85,

1.70)

1.60

(1.25,

2.08)

1.59

(1.20,

2.12)

1.99

(1.45,

2.73)

0.88 0.76 0.47 0.68 0.75 0.64 NVP 0.73 0.77 1.03 1.02 1.28

188

(0.72,

1.06)

(0.46,

1.23)

(0.35,

0.64)

(0.50,

0.93)

(0.45,

1.28)

(0.47,

0.87)

(0.55,

0.99)

(0.56,

1.06)

(0.84,

1.28)

(0.77,

1.36)

(0.96,

1.70)

1.19

(0.96,

1.49)

1.03

(0.63,

1.69)

0.64

(0.46,

0.90)

0.93

(0.65,

1.31)

1.02

(0.60,

1.77)

0.88

(0.63,

1.22)

1.36

(1.01,

1.83)

RPV

1.05

(0.75,

1.48)

1.41

(1.08,

1.83)

1.39

(1.02,

1.92)

1.74

(1.27,

2.41)

1.13

(0.87,

1.48)

0.98

(0.59,

1.64)

0.61

(0.43,

0.86)

0.88

(0.61,

1.27)

0.97

(0.57,

1.68)

0.83

(0.59,

1.17)

1.30

(0.94,

1.79)

0.95

(0.67,

1.34)

DOR

1.34

(1.01,

1.78)

1.33

(1.01,

1.76)

1.66

(1.19,

2.30)

0.85

(0.73,

0.98)

0.73

(0.46,

1.18)

0.46

(0.35,

0.59)

0.66

(0.51,

0.85)

0.73

(0.45,

1.20)

0.62

(0.48,

0.80)

0.97

(0.78,

1.20)

0.71

(0.55,

0.92)

0.75

(0.56,

0.99)

ATV/r

0.99

(0.79,

1.24)

1.24

(0.99,

1.55)

0.85

(0.68,

1.08)

0.74

(0.45,

1.22)

0.46

(0.35,

0.61)

0.66

(0.47,

0.93)

0.73

(0.44,

1.23)

0.63

(0.47,

0.83)

0.98

(0.73,

1.31)

0.72

(0.52,

0.98)

0.75

(0.57,

0.99)

1.01

(0.80,

1.27)

DRV/r

1.25

(0.97,

1.61)

0.68

(0.54,

0.87)

0.59

(0.36,

0.98)

0.37

(0.27,

0.50)

0.53

(0.38,

0.74)

0.59

(0.35,

1.01)

0.50

(0.37,

0.69)

0.78

(0.59,

1.04)

0.57

(0.41,

0.79)

0.60

(0.43,

0.84)

0.81

(0.65,

1.01)

0.80

(0.62,

1.04)

LPV/r

Values represent the effect of the treatment lower on the diagonal to the one higher on it. Bold values indicate comparisons that are statistically

significant. Odds ratios above 1 indicate higher efficacy in viral suppression. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted

darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP:

nevirapine; RAL: raltegravir; RPV: rilpivirine; BIC: bictegravir; DOR: doravirine

189

Table 31: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for viral suppression at 96 weeks from

the fixed-effects network meta-analyses

EFV 1.03

(0.66, 1.63)

0.52

(0.41, 0.66)

0.90

(0.67, 1.20)

0.68

(0.54, 0.87)

1.72

(1.13, 2.62)

0.74

(0.55, 0.99)

1.05

(0.89, 1.25)

1.01

(0.78, 1.32)

1.43

(1.09, 1.90)

0.97

(0.61, 1.52) EFV400

0.50

(0.30, 0.84)

0.87

(0.51, 1.49)

0.66

(0.39, 1.11)

1.66

(0.89, 3.09)

0.72

(0.42, 1.23)

1.02

(0.62, 1.66)

0.98

(0.58, 1.66)

1.39

(0.81, 2.37)

1.93

(1.52, 2.47)

2.00

(1.20, 3.37) DTG

1.74

(1.20, 2.50)

1.32

(1.03, 1.69)

3.32

(2.07, 5.38)

1.44

(0.98, 2.10)

2.04

(1.57, 2.64)

1.95

(1.49, 2.58)

2.77

(2.00, 3.84)

1.11

(0.83, 1.49)

1.15

(0.67, 1.97)

0.57

(0.40, 0.83) EVG/c

0.76

(0.53, 1.09)

1.90

(1.16, 3.18)

0.82

(0.55, 1.24)

1.17

(0.87, 1.57)

1.12

(0.78, 1.61)

1.59

(1.10, 2.32)

1.47

(1.15, 1.87)

1.52

(0.90, 2.55)

0.76

(0.59, 0.97)

1.32

(0.91, 1.89) RAL

2.52

(1.56, 4.09)

1.09

(0.75, 1.59)

1.55

(1.20, 1.99)

1.49

(1.12, 1.97)

2.10

(1.52, 2.91)

0.58

(0.38, 0.88)

0.60

(0.32, 1.12)

0.30

(0.19, 0.48)

0.53

(0.31, 0.87)

0.40

(0.24, 0.64) NVP

0.43

(0.26, 0.72)

0.61

(0.39, 0.96)

0.59

(0.36, 0.95)

0.83

(0.51, 1.35)

1.34

(1.01, 1.81)

1.39

(0.81, 2.41)

0.70

(0.48, 1.02)

1.21

(0.81, 1.83)

0.92

(0.63, 1.34)

2.31

(1.39, 3.85) RPV

1.42

(1.01, 1.99)

1.36

(0.93, 2.02)

1.93

(1.30, 2.89)

0.95

(0.80, 1.12)

0.98

(0.60, 1.60)

0.49

(0.38, 0.64)

0.86

(0.64, 1.14)

0.65

(0.50, 0.83)

1.63

(1.05, 2.55)

0.71

(0.50, 0.99) ATV/r

0.96

(0.76, 1.22)

1.36

(1.07, 1.73)

0.99

(0.76, 1.28)

1.02

(0.60, 1.74)

0.51

(0.39, 0.67)

0.89

(0.62, 1.28)

0.67

(0.51, 0.89)

1.70

(1.05, 2.77)

0.73

(0.49, 1.08)

1.04

(0.82, 1.32) DRV/r

1.42

(1.09, 1.84)

0.70

(0.53, 0.92)

0.72

(0.42, 1.23)

0.36

(0.26, 0.50)

0.63

(0.43, 0.91)

0.48

(0.34, 0.66)

1.20

(0.74, 1.95)

0.52

(0.35, 0.77)

0.74

(0.58, 0.93)

0.71

(0.54, 0.91) LPV/r

190

Values represent the effect of the treatment lower on the diagonal to the one higher on it. Bold values indicate comparisons that are statistically

significant. Odds ratios above 1 indicate higher efficacy in viral suppression. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted

darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP:

nevirapine; RAL: raltegravir; RPV: rilpivirine

Table 32: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for viral suppression at 144 weeks

from the fixed-effects network meta-analyses

EFV 0.69

(0.52, 0.93)

0.78

(0.57, 1.07)

0.67

(0.48, 0.92)

1.54

(0.87, 2.77)

0.95

(0.66, 1.38)

1.18

(0.76, 1.83)

1.44

(1.08, 1.94) DTG

1.13

(0.74, 1.74)

0.96

(0.63, 1.48)

2.22

(1.17, 4.28)

1.38

(0.86, 2.20)

1.71

(1.01, 2.88)

1.28

(0.94, 1.75)

0.89

(0.58, 1.36) EVG/c

0.85

(0.59, 1.24)

1.97

(1.03, 3.84)

1.22

(0.90, 1.66)

1.51

(0.99, 2.32)

1.50

(1.08, 2.08)

1.04

(0.68, 1.60)

1.17

(0.81, 1.70) RAL

2.30

(1.20, 4.50)

1.43

(1.02, 2.01)

1.77

(1.22, 2.57)

0.65

(0.36, 1.15)

0.45

(0.23, 0.86)

0.51

(0.26, 0.97)

0.43

(0.22, 0.83) NVP

0.62

(0.31, 1.22)

0.77

(0.37, 1.59)

1.05

(0.72, 1.52)

0.72

(0.45, 1.17)

0.82

(0.60, 1.11)

0.70

(0.50, 0.98)

1.61

(0.82, 3.20) ATV/r

1.24

(0.87, 1.77)

0.85

(0.55, 1.31)

0.59

(0.35, 0.99)

0.66

(0.43, 1.01)

0.57

(0.39, 0.82)

1.30

(0.63, 2.71)

0.81

(0.56, 1.15) DRV/r

Values represent the effect of the row treatment relative to the column treatment. Bold values indicate comparisons that are statistically

differentiable. Odds ratios above 1 indicate higher efficacy in viral suppression. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted

darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c: elvitegravir/cobicistat; NVP: nevirapine; RAL: raltegravir

Table 33: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for mean change in CD4 cell counts at

48 weeks from network meta-analyses

EFV

-25.43

(-43.97,

-6.93)

-22.87

(-37.40,

-8.29)

-21.96

(-36.95,

-6.24)

-15.22

(-39.69,

9.24)

-19.58

(-32.42,

-6.60)

-5.72

(-16.30,

5.01)

-12.24

(-24.04,

-0.19)

-7.82

(-33.08,

17.55)

-11.93

(-20.81,

-2.76)

-5.78

(-20.91,

9.36)

-25.78

(-43.95,

-7.31)

25.43

(6.93,

43.97)

EFV400

2.58

(-20.92,

26.38)

3.55

(-20.50,

27.74)

10.33

(-20.84,

41.31)

5.83

(-16.72,

28.24)

19.81

(-1.41,

41.02)

13.24

(-8.65,

34.97)

17.76

(-13.85,

49.28)

13.65

(-7.15,

33.94)

19.75

(-4.28,

43.36)

-0.29

(-26.86,

25.67)

22.87

(8.29,

37.40)

-2.58

(-26.38,

20.92)

DTG

1.01

(-19.05,

21.31)

7.54

(-12.78,

28.19)

3.24

(-11.22,

17.97)

17.17

(-0.96,

35.04)

10.61

(-8.12,

29.28)

15.09

(-12.07,

42.16)

10.96

(-4.09,

25.73)

17.08

(0.69,

33.57)

-3.05

(-24.88,

19.43)

21.96

(6.24,

36.95)

-3.55

(-27.74,

20.50)

-1.01

(-21.31,

19.05)

EVG/c

6.58

(-21.40,

35.03)

2.31

(-16.49,

20.57)

16.29

(-2.49,

34.46)

9.67

(-9.91,

29.05)

14.01

(-15.08,

43.03)

9.95

(-4.80,

24.33)

16.11

(-4.09,

36.12)

-3.94

(-26.17,

18.31)

15.22

(-9.24,

39.69)

-10.33

(-41.31,

20.84)

-7.54

(-28.19,

12.78)

-6.58

(-35.03,

21.40)

BIC

-4.55

(-28.95,

20.42)

9.49

(-17.06,

36.40)

2.95

(-23.89,

30.36)

7.48

(-26.43,

40.44)

3.29

(-21.42,

28.02)

9.51

(-16.30,

35.23)

-10.70

(-39.94,

18.95)

19.58

(6.60,

32.42)

-5.83

(-28.24,

16.72)

-3.24

(-17.97,

11.22)

-2.31

(-20.57,

16.49)

4.55

(-20.42,

28.95)

RAL

13.89

(-2.81,

30.52)

7.34

(-10.09,

25.05)

11.83

(-14.41,

37.82)

7.72

(-5.37,

20.58)

13.83

(-1.46,

29.03)

-6.27

(-26.77,

14.81)

193

5.72

(-5.01,

16.30)

-19.81

(-41.02,

1.41)

-17.17

(-35.04,

0.96)

-16.29

(-34.46,

2.49)

-9.49

(-36.40,

17.06)

-13.89

(-30.52,

2.81)

NVP

-6.58

(-22.46,

9.33)

-2.18

(-29.45,

25.28)

-6.26

(-19.89,

7.38)

-0.04

(-18.49,

18.35)

-20.06

(-41.12,

0.70)

12.24

(0.19,

24.04)

-13.24

(-34.97,

8.65)

-10.61

(-29.28,

8.12)

-9.67

(-29.05,

9.91)

-2.95

(-30.36,

23.89)

-7.34

(-25.05,

10.09)

6.58

(-9.33,

22.46)

RPV

4.45

(-23.45,

32.55)

0.32

(-14.52,

15.23)

6.53

(-12.84,

25.58)

-13.54

(-35.26,

8.47)

7.82

(-17.55,

33.08)

-17.76

(-49.28,

13.85)

-15.09

(-42.16,

12.07)

-14.01

(-43.03,

15.08)

-7.48

(-40.44,

26.43)

-11.83

(-37.82,

14.41)

2.18

(-25.28,

29.45)

-4.45

(-32.55,

23.45)

DOR

-4.23

(-29.79,

21.48)

2.02

(-21.04,

25.34)

-18.02

(-47.98,

11.76)

11.93

(2.76,

20.81)

-13.65

(-33.94,

7.15)

-10.96

(-25.73,

4.09)

-9.95

(-24.33,

4.80)

-3.29

(-28.02,

21.42)

-7.72

(-20.58,

5.37)

6.26

(-7.38,

19.89)

-0.32

(-15.23,

14.52)

4.23

(-21.48,

29.79)

ATV/r

6.19

(-8.31,

20.60)

-13.85

(-30.90,

3.13)

5.78

(-9.36,

20.91)

-19.75

(-43.36,

4.28)

-17.08

(-33.57,

-0.69)

-16.11

(-36.12,

4.09)

-9.51

(-35.23,

16.30)

-13.83

(-29.03,

1.46)

0.04

(-18.35,

18.49)

-6.53

(-25.58,

12.84)

-2.02

(-25.34,

21.04)

-6.19

(-20.60,

8.31)

DRV/r

-20.05

(-41.21,

1.46)

25.78

(7.31,

43.95)

0.29

(-25.67,

26.86)

3.05

(-19.43,

24.88)

3.94

(-18.31,

26.17)

10.70

(-18.95,

39.94)

6.27

(-14.81,

26.77)

20.06

(-0.70,

41.12)

13.54

(-8.47,

35.26)

18.02

(-11.76,

47.98)

13.85

(-3.13,

30.90)

20.05

(-1.46,

41.21)

LPV/r


differentiable. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400;

EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine; BIC: bictegravir; DOR:

doravirine

194

Table 34: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for mean change in CD4 cell counts at 96

weeks from network meta-analyses

EFV

-26.85

(-49.77, -

4.30)

-25.94

(-48.74, -

2.95)

-24.17

(-53.63,

5.27)

-22.44

(-39.46, -

5.48)

13.26

(-10.14,

36.49)

-9.68

(-30.50,

11.27)

-18.95

(-30.47, -

7.63)

-3.51

(-21.92,

14.98)

-46.19

(-65.16, -

27.10)

26.85

(4.30,

49.77)

EFV400

1.03

(-31.30,

33.63)

2.77

(-34.82,

39.82)

4.47

(-23.93,

33.12)

40.16

(7.41,

72.96)

17.15

(-13.24,

48.07)

7.94

(-17.45,

33.20)

23.34

(-5.87,

53.17)

-19.26

(-48.54,

10.39)

25.94

(2.95,

48.74)

-1.03

(-33.63,

31.30)

DTG

1.83

(-35.72,

38.79)

3.49

(-22.91,

30.16)

39.23

(7.15,

71.71)

16.20

(-14.75,

47.65)

6.90

(-16.96,

31.07)

22.45

(-1.17,

45.67)

-20.14

(-48.36,

8.44)

24.17

(-5.27,

53.63)

-2.77

(-39.82,

34.82)

-1.83

(-38.79,

35.72)

EVG/c

1.80

(-32.57,

35.90)

37.48

(0.27,

74.89)

14.31

(-21.64,

50.83)

5.18

(-26.24,

37.11)

20.65

(-14.07,

56.12)

-21.92

(-56.91,

13.33)

22.44

(5.48,

39.46)

-4.47

(-33.12,

23.93)

-3.49

(-30.16,

22.91)

-1.80

(-35.90,

32.57)

RAL

35.68

(6.97,

64.70)

12.68

(-14.18,

39.73)

3.51

(-13.56,

20.32)

18.97

(-0.32,

38.05)

-23.64

(-47.35, -

0.20)

-13.26

(-36.49,

10.14)

-40.16

(-72.96, -

7.41)

-39.23

(-71.71, -

7.15)

-37.48

(-74.89, -

0.27)

-35.68

(-64.70, -

6.97)

NVP

-23.02

(-54.01,

8.29)

-32.17

(-58.45, -

6.18)

-16.66

(-47.26,

12.88)

-59.43

(-89.69, -

29.06)

9.68

(-11.27,

-17.15

(-48.07,

-16.20

(-47.65,

-14.31

(-50.83,

-12.68

(-39.73,

23.02

(-8.29, RPV

-9.30

(-33.29,

6.19

(-21.89,

-36.38

(-64.60, -

195

30.50) 13.24) 14.75) 21.64) 14.18) 54.01) 14.45) 34.18) 8.54)

18.95

(7.63,

30.47)

-7.94

(-33.20,

17.45)

-6.90

(-31.07,

16.96)

-5.18

(-37.11,

26.24)

-3.51

(-20.32,

13.56)

32.17

(6.18,

58.45)

9.30

(-14.45,

33.29)

ATV/r

15.47

(-2.11,

32.73)

-27.13

(-45.10, -

9.32)

3.51

(-14.98,

21.92)

-23.34

(-53.17,

5.87)

-22.45

(-45.67,

1.17)

-20.65

(-56.12,

14.07)

-18.97

(-38.05,

0.32)

16.66

(-12.88,

47.26)

-6.19

(-34.18,

21.89)

-15.47

(-32.73,

2.11)

DRV/r

-42.53

(-65.80, -

19.34)

46.19

(27.10,

65.16)

19.26

(-10.39,

48.54)

20.14

(-8.44,

48.36)

21.92

(-13.33,

56.91)

23.64

(0.20,

47.35)

59.43

(29.06,

89.69)

36.38

(8.54,

64.60)

27.13

(9.32,

45.10)

42.53

(19.34,

65.80)

LPV/r


differentiable. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400;

EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine

196

Table 35: Cross table of odds ratios with 95% credible intervals comparing the relative efficacy of ARVs for mean change in CD4 cell counts at

144 weeks from network meta-analyses

EFV

-49.44

(-79.39, -

19.51)

-24.51

(-51.28, 2.07)

-37.76

(-64.84, -

11.20)

-4.54

(-31.35, 22.89)

-40.06

(-69.64, -

10.71)

-3.54

(-38.41, 30.57)

-40.09

(-60.51, -

19.15)

49.44

(19.51, 79.39) DTG

25.15

(-15.74, 64.93)

12.02

(-28.87, 51.45)

45.17

(4.68, 85.37)

9.50

(-33.40, 51.36)

45.83

(-0.30, 91.78)

9.49

(-26.90, 46.40)

24.51

(-2.07, 51.28)

-25.15

(-64.93, 15.74) EVG/c

-13.20

(-42.79, 16.15)

19.96

(-17.74, 58.17)

-15.67

(-39.76, 9.09)

20.94

(-12.84, 54.25)

-15.47

(-49.87, 18.04)

37.76

(11.20, 64.84)

-12.02

(-51.45, 28.87)

13.20

(-16.15, 42.79) RAL

33.21

(-4.61, 71.59)

-2.39

(-27.05, 22.23)

34.10

(7.29, 61.08)

-2.18

(-36.22, 32.00)

4.54

(-22.89, 31.35)

-45.17

(-85.37, -4.68)

-19.96

(-58.17, 17.74)

-33.21

(-71.59, 4.61) NVP

-35.57

(-75.77, 4.48)

0.89

(-43.41, 44.83)

-35.56

(-70.21, -1.64)

40.06

(10.71, 69.64)

-9.50

(-51.36, 33.40)

15.67

(-9.09, 39.76)

2.39

(-22.23, 27.05)

35.57

(-4.48, 75.77) ATV/r

36.50

(10.25, 62.49)

0.09

(-36.55, 36.28)

3.54

(-30.57, 38.41)

-45.83

(-91.78, 0.30)

-20.94

(-54.25, 12.84)

-34.10

(-61.08, -7.29)

-0.89

(-44.83, 43.41)

-36.50

(-62.49, -

10.25)

DRV/r -36.44

(-77.03, 4.07)

40.09

(19.15, 60.51)

-9.49

(-46.40, 26.90)

15.47

(-18.04, 49.87)

2.18

(-32.00, 36.22)

35.56

(1.64, 70.21)

-0.09

(-36.28, 36.55)

36.44

(-4.07, 77.03) LPV/r

197


differentiable. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EVG/c:

elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir; NVP: nevirapine; RAL: raltegravir

198

Table 36: Cross table of odds ratios with 95% credible intervals from network meta-analyses comparing ARVs in terms of discontinuation

EFV

0.90

(0.48,

1.69)

2.02

(1.60,

2.54)

1.56

(1.21,

2.02)

1.29

(0.76,

2.13)

1.56

(1.24,

1.97)

0.61

(0.47,

0.78)

1.36

(1.10,

1.69)

1.50

(1.02,

2.23)

1.14

(0.98,

1.32)

1.11

(0.89,

1.40)

0.78

(0.63,

0.97)

1.11

(0.59,

2.07)

EFV400

2.25

(1.14,

4.41)

1.74

(0.88,

3.45)

1.43

(0.63,

3.16)

1.74

(0.88,

3.39)

0.68

(0.35,

1.31)

1.52

(0.78,

2.94)

1.67

(0.79,

3.52)

1.27

(0.66,

2.42)

1.24

(0.63,

2.43)

0.88

(0.45,

1.67)

0.50

(0.39,

0.63)

0.45

(0.23,

0.88)

DTG

0.77

(0.56,

1.08)

0.64

(0.40,

1.00)

0.77

(0.60,

0.99)

0.30

(0.21,

0.43)

0.68

(0.49,

0.92)

0.75

(0.49,

1.14)

0.57

(0.45,

0.72)

0.55

(0.42,

0.72)

0.39

(0.29,

0.53)

0.64

(0.49,

0.82)

0.58

(0.29,

1.14)

1.29

(0.93,

1.78)

EVG/c

0.82

(0.47,

1.43)

1.00

(0.73,

1.36)

0.39

(0.27,

0.56)

0.87

(0.63,

1.21)

0.96

(0.62,

1.51)

0.73

(0.57,

0.93)

0.71

(0.52,

0.97)

0.50

(0.36,

0.69)

0.78

(0.47,

1.31)

0.70

(0.32,

1.58)

1.57

(1.00,

2.52)

1.21

(0.70,

2.13)

BIC

1.21

(0.73,

2.07)

0.47

(0.27,

0.84)

1.06

(0.61,

1.85)

1.17

(0.63,

2.20)

0.89

(0.53,

1.49)

0.87

(0.51,

1.48)

0.61

(0.36,

1.06)

0.64

(0.51,

0.81)

0.58

(0.29,

1.14)

1.29

(1.01,

1.65)

1.00

(0.74,

1.38)

0.83

(0.48,

1.38)

RAL

0.39

(0.28,

0.55)

0.87

(0.65,

1.19)

0.96

(0.64,

1.46)

0.73

(0.58,

0.92)

0.72

(0.55,

0.92)

0.50

(0.38,

0.68)

1.64

(1.28,

2.12)

1.48

(0.76,

2.86)

3.31

(2.35,

4.68)

2.57

(1.79,

3.68)

2.11

(1.19,

3.74)

2.56

(1.82,

3.61)

NVP

2.24

(1.60,

3.14)

2.47

(1.56,

3.94)

1.88

(1.45,

2.45)

1.83

(1.33,

2.53)

1.29

(0.96,

1.75)

199

0.73

(0.59,

0.91)

0.66

(0.34,

1.29)

1.48

(1.08,

2.03)

1.15

(0.83,

1.59)

0.94

(0.54,

1.63)

1.14

(0.84,

1.55)

0.45

(0.32,

0.62)

RPV

1.10

(0.71,

1.72)

0.84

(0.65,

1.08)

0.82

(0.60,

1.11)

0.58

(0.43,

0.78)

0.66

(0.45,

0.98)

0.60

(0.28,

1.26)

1.34

(0.88,

2.05)

1.04

(0.66,

1.62)

0.85

(0.45,

1.59)

1.04

(0.68,

1.57)

0.41

(0.25,

0.64)

0.91

(0.58,

1.42)

DOR

0.76

(0.51,

1.12)

0.74

(0.52,

1.05)

0.52

(0.34,

0.79)

0.88

(0.76,

1.02)

0.79

(0.41,

1.51)

1.77

(1.39,

2.24)

1.37

(1.07,

1.75)

1.13

(0.67,

1.88)

1.36

(1.09,

1.72)

0.53

(0.41,

0.69)

1.20

(0.92,

1.55)

1.32

(0.89,

1.95)

ATV/r

0.98

(0.79,

1.21)

0.69

(0.55,

0.85)

0.90

(0.71,

1.12)

0.81

(0.41,

1.58)

1.81

(1.39,

2.36)

1.40

(1.03,

1.92)

1.15

(0.68,

1.95)

1.40

(1.08,

1.80)

0.55

(0.39,

0.75)

1.22

(0.90,

1.66)

1.35

(0.95,

1.92)

1.02

(0.83,

1.27)

DRV/r

0.71

(0.55,

0.90)

1.27

(1.03,

1.58)

1.14

(0.60,

2.21)

2.57

(1.90,

3.48)

1.99

(1.45,

2.75)

1.64

(0.95,

2.81)

1.98

(1.48,

2.66)

0.78

(0.57,

1.04)

1.74

(1.28,

2.35)

1.92

(1.26,

2.91)

1.45

(1.17,

1.81)

1.42

(1.11,

1.83)

LPV/r

200

Table 37: Cross table of odds ratios with 95% credible intervals from network meta-analyses comparing ARVs in terms of discontinuation due

to adverse events

EFV

2.39

(1.30,

4.53)

3.34

(2.13,

5.28)

1.72

(1.13,

2.67)

2.35

(0.59,

9.55)

2.31

(1.41,

3.82)

0.52

(0.29,

0.90)

2.58

(1.80,

3.74)

2.45

(1.41,

4.38)

1.12

(0.80,

1.58)

1.43

(0.90,

2.27)

0.72

(0.46,

1.10)

0.42

(0.22,

0.77)

EFV400

1.39

(0.63,

3.05)

0.72

(0.33,

1.54)

0.99

(0.21,

4.68)

0.97

(0.44,

2.13)

0.22

(0.09,

0.50)

1.08

(0.51,

2.21)

1.03

(0.44,

2.36)

0.47

(0.23,

0.96)

0.60

(0.27,

1.30)

0.30

(0.14,

0.64)

0.30

(0.19,

0.47)

0.72

(0.33,

1.58)

DTG

0.52

(0.29,

0.93)

0.71

(0.19,

2.76)

0.69

(0.39,

1.22)

0.16

(0.08,

0.30)

0.77

(0.43,

1.39)

0.73

(0.37,

1.49)

0.34

(0.21,

0.55)

0.43

(0.25,

0.74)

0.22

(0.12,

0.38)

0.58

(0.37,

0.89)

1.38

(0.65,

3.02)

1.94

(1.07,

3.50)

EVG/c

1.36

(0.32,

5.94)

1.34

(0.72,

2.49)

0.30

(0.16,

0.55)

1.50

(0.85,

2.64)

1.42

(0.72,

2.89)

0.66

(0.44,

0.97)

0.84

(0.47,

1.46)

0.42

(0.24,

0.71)

0.43

(0.10,

1.70)

1.01

(0.21,

4.66)

1.41

(0.36,

5.40)

0.74

(0.17,

3.08)

BIC

0.98

(0.23,

4.16)

0.22

(0.05,

0.97)

1.10

(0.25,

4.66)

1.04

(0.23,

4.63)

0.48

(0.12,

1.96)

0.61

(0.15,

2.54)

0.31

(0.07,

1.29)

0.43

(0.26,

0.71)

1.03

(0.47,

2.30)

1.44

(0.82,

2.56)

0.75

(0.40,

1.39)

1.02

(0.24,

4.40)

RAL

0.22

(0.11,

0.45)

1.11

(0.60,

2.07)

1.06

(0.51,

2.24)

0.49

(0.28,

0.83)

0.62

(0.34,

1.12)

0.31

(0.17,

0.57)

1.92

(1.11,

4.63

(2.00,

6.45

(3.32,

3.32

(1.83,

4.56

(1.03,

4.45

(2.23, NVP

4.99

(2.58,

4.74

(2.20,

2.17

(1.36,

2.77

(1.48,

1.39

(0.76,

201

3.43) 10.90) 12.77) 6.24) 20.98) 9.10) 9.89) 10.41) 3.55) 5.29) 2.57)

0.39

(0.27,

0.55)

0.92

(0.45,

1.95)

1.30

(0.72,

2.32)

0.67

(0.38,

1.17)

0.91

(0.21,

3.95)

0.90

(0.48,

1.67)

0.20

(0.10,

0.39)

RPV

0.95

(0.49,

1.90)

0.44

(0.26,

0.72)

0.56

(0.31,

1.00)

0.28

(0.16,

0.49)

0.41

(0.23,

0.71)

0.97

(0.42,

2.27)

1.36

(0.67,

2.73)

0.70

(0.35,

1.38)

0.96

(0.22,

4.26)

0.94

(0.45,

1.94)

0.21

(0.10,

0.45)

1.05

(0.53,

2.02)

DOR

0.46

(0.24,

0.85)

0.58

(0.31,

1.09)

0.29

(0.15,

0.56)

0.89

(0.63,

1.25)

2.12

(1.04,

4.43)

2.96

(1.80,

4.87)

1.53

(1.03,

2.29)

2.09

(0.51,

8.67)

2.05

(1.20,

3.54)

0.46

(0.28,

0.74)

2.29

(1.39,

3.82)

2.17

(1.18,

4.11)

ATV/r

1.27

(0.82,

1.99)

0.64

(0.42,

0.97)

0.70

(0.44,

1.11)

1.66

(0.77,

3.66)

2.32

(1.35,

4.06)

1.20

(0.69,

2.14)

1.65

(0.39,

6.87)

1.60

(0.89,

2.93)

0.36

(0.19,

0.68)

1.80

(1.00,

3.25)

1.71

(0.92,

3.25)

0.78

(0.50,

1.22)

DRV/r

0.50

(0.31,

0.78)

1.39

(0.91,

2.16)

3.32

(1.56,

7.20)

4.64

(2.63,

8.30)

2.40

(1.40,

4.16)

3.27

(0.77,

13.93)

3.21

(1.76,

5.98)

0.72

(0.39,

1.32)

3.59

(2.05,

6.35)

3.40

(1.78,

6.76)

1.56

(1.03,

2.40)

1.99

(1.27,

3.20)

LPV/r

Values represent the effect of the row treatment relative to the column treatment. Odds ratios above 1 indicate higher rates of discontinuation

due to adverse events. Bold values indicate comparisons that are statistically differentiable. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-

boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir;

NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine; BIC: bictegravir; DOR: doravirine

Table 38: Cross table of odds ratios with 95% credible intervals from the network meta-analyses comparing ARVs in terms of treatment-

related adverse events

EFV

1.42

(1.04,

1.95)

2.99

(2.26,

3.93)

2.79

(2.01,

3.90)

4.33

(3.02,

6.24)

0.81

(0.58,

1.13)

1.13

(0.85,

1.49)

2.43

(1.70,

3.54)

3.56

(2.75,

4.64)

1.19

(1.02,

1.39)

3.35

(2.29,

4.88)

0.96

(0.74,

1.25)

0.70

(0.51,

0.96)

EFV400

2.09

(1.38,

3.20)

1.96

(1.24,

3.09)

3.05

(1.88,

4.92)

0.57

(0.36,

0.90)

0.79

(0.52,

1.21)

1.71

(1.06,

2.79)

2.51

(1.66,

3.77)

0.84

(0.59,

1.19)

2.35

(1.43,

3.83)

0.68

(0.44,

1.01)

0.33

(0.25,

0.44)

0.48

(0.31,

0.73)

DTG

0.94

(0.62,

1.42)

1.45

(1.10,

1.91)

0.27

(0.18,

0.42)

0.38

(0.26,

0.56)

0.82

(0.52,

1.30)

1.20

(0.82,

1.76)

0.40

(0.30,

0.53)

1.12

(0.70,

1.81)

0.32

(0.22,

0.47)

0.36

(0.26,

0.50)

0.51

(0.32,

0.81)

1.07

(0.71,

1.62)

EVG/c

1.55

(0.96,

2.49)

0.29

(0.18,

0.47)

0.40

(0.27,

0.61)

0.87

(0.53,

1.43)

1.28

(0.84,

1.94)

0.43

(0.32,

0.57)

1.20

(0.73,

1.97)

0.34

(0.23,

0.51)

0.23

(0.16,

0.33)

0.33

(0.20,

0.53)

0.69

(0.52,

0.91)

0.64

(0.40,

1.04)

BIC

0.19

(0.11,

0.31)

0.26

(0.16,

0.41)

0.56

(0.34,

0.94)

0.82

(0.52,

1.29)

0.28

(0.19,

0.40)

0.77

(0.46,

1.30)

0.22

(0.14,

0.34)

1.23

(0.88,

1.72)

1.75

(1.11,

2.77)

3.67

(2.37,

5.65)

3.43

(2.15,

5.55)

5.33

(3.25,

8.73)

RAL

1.39

(0.90,

2.14)

2.99

(1.83,

4.95)

4.38

(2.87,

6.67)

1.47

(1.02,

2.12)

4.12

(2.49,

6.82)

1.18

(0.77,

1.82)

0.89

(0.67,

1.27

(0.83,

2.65

(1.79,

2.48

(1.63,

3.85

(2.44,

0.72

(0.47, NVP

2.15

(1.37,

3.17

(2.17,

1.06

(0.78,

2.97

(1.86,

0.86

(0.59,

203

1.18) 1.92) 3.89) 3.76) 6.07) 1.12) 3.44) 4.61) 1.42) 4.74) 1.25)

0.41

(0.28,

0.59)

0.58

(0.36,

0.94)

1.23

(0.77,

1.93)

1.15

(0.70,

1.88)

1.78

(1.06,

2.97)

0.33

(0.20,

0.55)

0.46

(0.29,

0.73)

RPV

1.47

(0.93,

2.27)

0.49

(0.33,

0.73)

1.37

(0.81,

2.32)

0.40

(0.25,

0.62)

0.28

(0.22,

0.36)

0.40

(0.27,

0.60)

0.84

(0.57,

1.22)

0.78

(0.52,

1.19)

1.22

(0.78,

1.91)

0.23

(0.15,

0.35)

0.32

(0.22,

0.46)

0.68

(0.44,

1.08)

DOR

0.33

(0.25,

0.45)

0.94

(0.70,

1.26)

0.27

(0.19,

0.39)

0.84

(0.72,

0.98)

1.20

(0.84,

1.70)

2.51

(1.88,

3.34)

2.35

(1.74,

3.16)

3.63

(2.51,

5.26)

0.68

(0.47,

0.98)

0.95

(0.70,

1.28)

2.04

(1.38,

3.07)

2.99

(2.21,

4.04)

ATV/r

2.81

(1.88,

4.19)

0.81

(0.63,

1.03)

0.30

(0.20,

0.44)

0.43

(0.26,

0.70)

0.89

(0.55,

1.42)

0.84

(0.51,

1.37)

1.30

(0.77,

2.19)

0.24

(0.15,

0.40)

0.34

(0.21,

0.54)

0.73

(0.43,

1.23)

1.07

(0.79,

1.43)

0.36

(0.24,

0.53)

DRV/r

0.29

(0.18,

0.45)

1.04

(0.80,

1.36)

1.48

(0.99,

2.25)

3.10

(2.14,

4.46)

2.90

(1.98,

4.27)

4.50

(2.92,

6.93)

0.84

(0.55,

1.29)

1.17

(0.80,

1.71)

2.52

(1.61,

4.01)

3.70

(2.56,

5.37)

1.24

(0.97,

1.59)

3.46

(2.20,

5.49)

LPV/r

Values represent the effect of the row treatment relative to the column treatment. Odds ratios above 1 indicate higher rates of treatment-related

adverse events. Bold values indicate comparisons that are statistically differentiable. ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-

boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted lopinavir;

NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine; BIC: bictegravir; DOR: doravirine

Table 39: Cross table of odds ratios with 95% credible intervals from the network meta-analyses comparing ARVs in terms of treatment-

emergent adverse events

EFV

1.23

(0.47,

3.21)

1.58

(0.90,

2.66)

1.34

(0.66,

2.84)

1.94

(0.51,

7.32)

1.88

(1.07,

3.14)

0.95

(0.43,

2.13)

1.62

(0.98,

2.60)

1.74

(0.97,

3.07)

1.00

(0.67,

1.46)

2.06

(1.19,

3.57)

0.96

(0.44,

2.07)

0.81

(0.31,

2.13)

low EFV

1.29

(0.42,

3.78)

1.09

(0.33,

3.73)

1.58

(0.31,

8.16)

1.53

(0.50,

4.48)

0.77

(0.23,

2.74)

1.32

(0.44,

3.86)

1.42

(0.46,

4.30)

0.81

(0.29,

2.28)

1.67

(0.56,

5.08)

0.78

(0.23,

2.68)

0.63

(0.38,

1.11)

0.78

(0.26,

2.41)

DTG

0.85

(0.37,

2.12)

1.22

(0.34,

4.61)

1.19

(0.67,

2.07)

0.60

(0.25,

1.53)

1.02

(0.50,

2.15)

1.10

(0.53,

2.30)

0.63

(0.37,

1.11)

1.31

(0.74,

2.38)

0.61

(0.25,

1.48)

0.75

(0.35,

1.52)

0.92

(0.27,

2.99)

1.18

(0.47,

2.71)

EVG/c

1.46

(0.31,

6.21)

1.40

(0.57,

3.17)

0.71

(0.25,

1.98)

1.21

(0.48,

2.80)

1.30

(0.51,

3.08)

0.74

(0.36,

1.47)

1.54

(0.65,

3.50)

0.72

(0.26,

1.87)

0.52

(0.14,

1.96)

0.63

(0.12,

3.21)

0.82

(0.22,

2.98)

0.69

(0.16,

3.19)

BIC

0.97

(0.25,

3.77)

0.49

(0.11,

2.34)

0.83

(0.20,

3.40)

0.90

(0.22,

3.72)

0.51

(0.14,

1.96)

1.07

(0.27,

4.28)

0.49

(0.11,

2.25)

0.53

(0.32,

0.93)

0.65

(0.22,

1.99)

0.84

(0.48,

1.49)

0.71

(0.32,

1.76)

1.03

(0.27,

4.07)

RAL

0.50

(0.21,

1.31)

0.86

(0.42,

1.80)

0.93

(0.45,

1.93)

0.53

(0.32,

0.92)

1.10

(0.63,

2.01)

0.51

(0.22,

1.25)

1.06

(0.47,

1.29

(0.36,

1.66

(0.65,

1.40

(0.50,

2.05

(0.43,

1.98

(0.76, NVP

1.71

(0.66,

1.83

(0.69,

1.05

(0.46,

2.18

(0.86,

1.01

(0.35,

205

2.31) 4.38) 3.97) 3.96) 9.40) 4.71) 4.19) 4.68) 2.28) 5.27) 2.80)

0.62

(0.38,

1.02)

0.76

(0.26,

2.26)

0.98

(0.47,

2.01)

0.83

(0.36,

2.07)

1.20

(0.29,

5.07)

1.16

(0.56,

2.38)

0.59

(0.24,

1.52)

RPV

1.07

(0.50,

2.33)

0.62

(0.33,

1.16)

1.28

(0.63,

2.65)

0.59

(0.24,

1.51)

0.57

(0.33,

1.04)

0.71

(0.23,

2.17)

0.91

(0.44,

1.87)

0.77

(0.32,

1.97)

1.12

(0.27,

4.59)

1.08

(0.52,

2.21)

0.55

(0.21,

1.46)

0.93

(0.43,

1.99)

DOR

0.57

(0.30,

1.10)

1.19

(0.64,

2.26)

0.55

(0.22,

1.42)

1.00

(0.68,

1.49)

1.23

(0.44,

3.46)

1.59

(0.90,

2.69)

1.35

(0.68,

2.76)

1.94

(0.51,

7.32)

1.89

(1.08,

3.17)

0.95

(0.44,

2.15)

1.63

(0.86,

3.00)

1.75

(0.91,

3.31)

ATV/r

2.07

(1.24,

3.45)

0.96

(0.47,

1.94)

0.49

(0.28,

0.84)

0.60

(0.20,

1.78)

0.77

(0.42,

1.35)

0.65

(0.29,

1.53)

0.94

(0.23,

3.69)

0.91

(0.50,

1.59)

0.46

(0.19,

1.16)

0.78

(0.38,

1.59)

0.84

(0.44,

1.57)

0.48

(0.29,

0.80)

DRV/r

0.47

(0.19,

1.09)

1.04

(0.48,

2.28)

1.28

(0.37,

4.37)

1.65

(0.67,

3.94)

1.40

(0.53,

3.87)

2.02

(0.44,

8.96)

1.97

(0.80,

4.63)

0.99

(0.36,

2.90)

1.70

(0.66,

4.23)

1.82

(0.71,

4.59)

1.04

(0.51,

2.12)

2.14

(0.92,

5.20)

LPV/r

Values represent the effect of the row treatment relative to the column treatment. Odds ratios above 1 indicate higher rates of treatment-

emergent (all cause) adverse events. Bold values indicate comparisons that are statistically differentiable. ATV/r: ritonavir-boosted atazanavir;

DRV/r: ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-

boosted lopinavir; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine; BIC: bictegravir; DOR: doravirine

Table 40: Cross table of odds ratios with 95% credible intervals from network meta-analyses comparing ARVs in terms of treatment emergent

serious adverse events

EFV

1.43

(0.82,

2.52)

1.29

(0.94,

1.77)

1.24

(0.94,

1.64)

1.45

(0.71,

3.00)

1.14

(0.90,

1.45)

0.50

(0.35,

0.72)

0.92

(0.70,

1.19)

1.53

(1.00,

2.36)

0.97

(0.79,

1.18)

1.33

(1.03,

1.72)

1.02

(0.84,

1.24)

0.70

(0.40,

1.22)

EFV400

0.90

(0.47,

1.70)

0.87

(0.46,

1.62)

1.01

(0.41,

2.53)

0.79

(0.43,

1.45)

0.35

(0.18,

0.68)

0.64

(0.34,

1.17)

1.06

(0.53,

2.16)

0.68

(0.37,

1.22)

0.93

(0.50,

1.72)

0.72

(0.39,

1.29)

0.78

(0.57,

1.06)

1.11

(0.59,

2.13)

DTG

0.96

(0.65,

1.43)

1.12

(0.57,

2.26)

0.88

(0.64,

1.22)

0.39

(0.24,

0.62)

0.71

(0.47,

1.07)

1.19

(0.71,

1.98)

0.75

(0.54,

1.04)

1.03

(0.71,

1.49)

0.80

(0.55,

1.14)

0.80

(0.61,

1.07)

1.15

(0.62,

2.18)

1.04

(0.70,

1.55)

EVG/c

1.16

(0.55,

2.51)

0.92

(0.66,

1.27)

0.40

(0.25,

0.63)

0.74

(0.50,

1.08)

1.23

(0.75,

2.03)

0.78

(0.60,

1.01)

1.07

(0.77,

1.49)

0.82

(0.60,

1.14)

0.69

(0.33,

1.40)

0.99

(0.40,

2.43)

0.89

(0.44,

1.76)

0.86

(0.40,

1.82)

BIC

0.79

(0.38,

1.61)

0.35

(0.15,

0.76)

0.63

(0.29,

1.34)

1.06

(0.46,

2.39)

0.67

(0.32,

1.37)

0.92

(0.43,

1.91)

0.71

(0.34,

1.46)

0.88

(0.69,

1.11)

1.26

(0.69,

2.32)

1.13

(0.82,

1.56)

1.09

(0.79,

1.51)

1.27

(0.62,

2.63)

RAL

0.44

(0.29,

0.68)

0.81

(0.57,

1.15)

1.35

(0.85,

2.13)

0.85

(0.68,

1.06)

1.17

(0.91,

1.49)

0.90

(0.68,

1.18)

2.00

(1.39,

2.87

(1.47,

2.58

(1.61,

2.49

(1.58,

2.89

(1.32,

2.28

(1.48, NVP

1.83

(1.17,

3.06

(1.76,

1.93

(1.29,

2.66

(1.72,

2.05

(1.37,

207

2.89) 5.58) 4.15) 3.93) 6.54) 3.50) 2.86) 5.41) 2.91) 4.14) 3.09)

1.09

(0.84,

1.42)

1.56

(0.85,

2.92)

1.41

(0.94,

2.13)

1.36

(0.92,

1.99)

1.58

(0.75,

3.42)

1.24

(0.87,

1.77)

0.55

(0.35,

0.85)

RPV

1.67

(1.02,

2.77)

1.06

(0.76,

1.46)

1.45

(1.00,

2.08)

1.12

(0.81,

1.55)

0.65

(0.42,

1.00)

0.94

(0.46,

1.90)

0.84

(0.50,

1.41)

0.81

(0.49,

1.33)

0.94

(0.42,

2.17)

0.74

(0.47,

1.18)

0.33

(0.18,

0.57)

0.60

(0.36,

0.98)

DOR

0.63

(0.41,

0.99)

0.87

(0.56,

1.34)

0.67

(0.42,

1.05)

1.03

(0.85,

1.26)

1.48

(0.82,

2.70)

1.33

(0.96,

1.86)

1.29

(0.99,

1.67)

1.50

(0.73,

3.12)

1.18

(0.94,

1.47)

0.52

(0.34,

0.78)

0.95

(0.68,

1.32)

1.59

(1.01,

2.46)

ATV/r

1.37

(1.10,

1.72)

1.06

(0.84,

1.34)

0.75

(0.58,

0.97)

1.08

(0.58,

2.01)

0.97

(0.67,

1.40)

0.94

(0.67,

1.30)

1.09

(0.52,

2.30)

0.86

(0.67,

1.10)

0.38

(0.24,

0.58)

0.69

(0.48,

1.00)

1.15

(0.75,

1.79)

0.73

(0.58,

0.91)

DRV/r

0.77

(0.59,

1.01)

0.98

(0.80,

1.18)

1.40

(0.78,

2.54)

1.26

(0.88,

1.80)

1.21

(0.88,

1.67)

1.41

(0.68,

2.96)

1.11

(0.85,

1.46)

0.49

(0.32,

0.73)

0.89

(0.65,

1.24)

1.49

(0.95,

2.37)

0.94

(0.75,

1.19)

1.30

(0.99,

1.70)

LPV/r


differentiable. Odds ratios above 1 indicate higher rates of drug-emergent serious adverse events. ATV/r: ritonavir-boosted atazanavir; DRV/r:

ritonavir-boosted darunavir; DTG: dolutegravir; EFV: efavirenz; EFV400: efavirenz 400; EVG/c: elvitegravir/cobicistat; LPV/r: ritonavir-boosted

lopinavir; NVP: nevirapine; RAL: raltegravir; BIC: bictegravir; DOR: doravirine


for viral suppression at 48 weeks from the fixed-effects network meta-analyses in HIV-TB co-infected

patients

EFV 0.61

(0.25, 1.44)

1.19

(0.53, 2.74)

1.23

(0.89, 1.69)

1.64

(0.69, 4.00) RAL400

1.96

(0.83, 4.76)

2.02

(0.81, 5.27)

0.84

(0.36, 1.90)

0.51

(0.21, 1.21) RAL800

1.03

(0.43, 2.49)

0.81

(0.59, 1.12)

0.49

(0.19, 1.23)

0.97

(0.40, 2.35) NVP

Values represent the effect of the treatment lower on the diagonal to the one higher on it. Bold values

indicate comparisons that are statistically significant. Odds ratios above 1 indicate higher efficacy in viral

suppression. EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400; RAL800: raltegravir 800


for mean change in CD4 cell counts at 48 weeks from network meta-analyses in HIV-TB co-infected

patients

EFV -32.13

(-92.09, 28.96)

-5.98

(-69.15, 57.26)

22.66

(-9.01, 54.54)

32.13

(-28.96, 92.09) RAL400

26.11

(-36.82, 89.30)

54.77

(-13.44, 123.59)

5.98

(-57.26, 69.15)

-26.11

(-89.30, 36.82) RAL800

28.39

(-41.45, 99.67)

-22.66

(-54.54, 9.01)

-54.77

(-123.59, 13.44)

-28.39

(-99.67, 41.45) NVP


comparisons that are statistically significant. EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400;

RAL800: raltegravir 800; LPV/r: ritonavir-boosted lopinavir

209


comparing ARVs in terms of mortality in HIV-TB co-infected patients in HIV-TB co-infected patients

EFV 2.48

(0.19, 73.13)

0.44

(0.05, 2.51)

0.71

(0.45, 1.13)

0.40

(0.01, 5.38) RAL400

0.18

(0.01, 1.49)

0.29

(0.01, 3.93)

2.29

(0.40, 18.50)

5.64

(0.67, 161.45) RAL800

1.63

(0.27, 13.91)

1.41

(0.89, 2.23)

3.46

(0.25, 109.84)

0.61

(0.07, 3.69) NVP


comparisons that are statistically significant. EFV: efavirenz; NVP: nevirapine; RAL400: raltegravir 400;

RAL800: raltegravir 800; LPV/r: ritonavir-boosted lopinavir

Appendix K: GRADE summary tables for children and adolescents

Table 44: GRADE summary of evidence for the DTG vs EFV comparison in children and adolescents



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks

1.79

(1.25, 2.58) 0 0 -1 0 0

Modera

te

1.86

(1.44, 2.40)

74 per

1000 (47 to

98)

0 0

Modera

te

Viral supp. at

96 weeks

1.65

(1.21, 2.24) 0 0 -1 0 0

Modera

te

1.93

(1.52, 2.47)

94 per

1000 (63 to

121)

0 0

Modera

te

Viral supp. at

144 weeks

1.44

(1.08, 1.92) -1 0 -1 -1 0

Low

1.44

(1.08, 1.92)

39 per

1000

(-11 to 83)

0 0

Low

Change in

CD4 at 48

weeks

58.76

(36.80,

80.71)

0 0 -1 0 0

Modera

te

-

24.27

cells/ml

(5.89,

43.18)

0 -1

Low

211



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Change in

CD4 at 96

weeks

41.76

(13.83,

69.69)

0 0 -1 0 0

Modera

te

-

25.94

cells/ml

(2.95,

48.74)

-1 0

Low

Change in

CD4 at 144

weeks

46.91

(16.70,

77.12)

-1 0 -1 0 0

Low -

49.63

cells/ml

(20.12,

79.58)

0 0

Low

Mortality 0.20

(0.01, 4.16) 0 0 -1 -2 0

Very

low

0.64

(0.09, 4.87)

-4 per 1000

(--9 to 12) 0 0

Very

low

AIDS defining

illness

5.10

(0.24,

108.97)

0 0 -1 -2 0

Very

low

8.08

(0.46,

66.45)

127 per

1000

(-13 to 550)

0 0

Very

low

Discontinuati

ons

0.59

(0.44, 0.79) 0 0 -1 0 0

Modera

te

0.49

(0.39, 0.62)

-43 per

1000

(-54 to -30)

0 0

Modera

te

212



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Discontinuati

ons due to AE

0.26

(0.15, 0.45) 0 0 -1 0 0

Modera

te

0.30

(0.19, 0.47)

-78 per

1000

(-101 to -

54)

0 0

Modera

te

Emergent

SAEs

1.10

(0.77, 1.58) 0 -1 -1 -1 0

Very

low

0.63

(0.38, 1.11)

-22 per

1000

(-45 to 6)

0 0

Very

low

Emergent AEs 0.64

(0.27, 1.54) 0 0 -1 -1 0

Low

0.78

(0.49, 1.23)

-113 per

1000 (-160

to -70)

0 0

Low

Treatment-

related SAEs

0.22

(0.05, 1.03) -1 0 -1 -2 0

Very

low

9.79

(0.02,

507.2)

126 per

1000

(-12 to 822)

0 -1

Very

low

Treatment-

related AEs

0.38

(0.29, 0.50) -1 0 -1 0 0

Very

low

0.33

(0.25, 0.44)

-215 per

1000 (-255

to -170)

0 0

Very

low

213



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Regimen

substitutions -- 0 0 -2 -2 0

Modera

te

6.20

(0.87,

74.94)

223 per

1,000

(-7 to 764)

-- --

Modera

te




because the NMA estimate is the only estimate.The final quality of evidence updates that of the uncombined evidence. The quality can be

moved up if the uncombined score was penalized for precision, which was overcome in network estimates. It can be moved down if the

estimates are no longer precise or if there is evidence of inconsistency in loops containing the comparison (i.e. violation of transitivity).






indirectness.

214

Table 45: GRADE summary of evidence for the DTG vs LPV/r comparison in children and adolescents



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks -- 0 0 -2 0 0

Low

2.70

(1.92, 3.70)

136 per

1000 (92 to

184)

-- --

Low

Viral supp. at

96 weeks -- 0 0 -2 0 0

Low

2.70

(1.75, 4.00)

162 per

1000 (107

to 223)

-- --

Low

Viral supp. at

144 weeks -- 0 0 -2 -1 0 - - -- -- -- -

Change in

CD4 at 48

weeks

-- 0 0 -2 -1 0

Very

low

-

-2.40

cells/ml

(-28.99,

25.86)

-- --

Very

low

Change in

CD4 at 96

weeks

-- 0 0 -2 -1 0

Very

low

-

-18.63

cells/ml

(-54.43,

-- --

Very

low

215



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

18.83)

Change in

CD4 at 144

weeks

-- 0 0 -2 -1 0

Very

low

-

9.27

cells/ml

(-89.80,

100.65)

-- --

Very

low

Mortality -- 0 0 -2 -1 0

Very

low

0.47

(0.05, 4.17)

-4 per 1000

(-10 to 12) -- --

Very

low

AIDS defining

illness -- 0 0 -2 0 0

Very

low

7.14

(0.32,

100.00)

127 per

1000

(-12 to 551)

-- --

Very

low

Discontinuati

ons -- 0 0 -2 0 0

Low

0.44

(0.32, 0.60)

-65 per

1000

(-104 to -

38)

-- --

Low

Discontinuati

ons due to AE -- 0 0 -2 0 0

Low

0.23

(0.11, 0.46)

-107 per

1000 -- --

Low

216



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

(-146 to -

69)

Emergent

SAEs -- 0 0 -2 -1 0

Low

0.52

(0.37, 0.74)

-20 per

1000

(-49 to 12)

-- --

Low

Emergent AEs -- -1 0 -2 -1 0

Very

low

0.79

(0.56, 1.14)

-110 per

1000

(-168 to -

52)

-- --

Very

low

Treatment-

related SAEs -- -1 0 -2 0 0

Very

low

33.33

(0.08,

1000)

124 per

1000

(-8 to 817)

-- --

Very

low

Treatment-

related AEs -- 0 0 -2 0 0

Very

low

0.33

(0.21, 0.52)

-223 per

1000

(-295 to -

151)

-- --

Very

low

Regimen -- 0 0 -2 -1 0 7.69 234 per -- --

217



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

substitutions Very

low

(1.09, 100) 1000 (4 to

775)

Very

low













indirectness.

218

Table 46: GRADE summary of evidence for the DTG vs RAL comparison in children and adolescents



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks

1.23(0.83,

1.85) 0 0 -1 -1 0

Low

1.37

(1.03, 1.82)

33 per

1000

(3 to 64)

0 0

Low

Viral supp. at

96 weeks

1.3(0.93,

1.82) 0 0 -1 -1 0

Low

1.32

(0.98, 1.79)

34 per

1000

(4 to 66)

0 0

Low

Viral supp. at

144 weeks -- 0 0 -2 -1 0

Very

low

0.96

(0.01, 100)

31 per

1000

(-16 to 84)

-- --

Very

low

Change in

CD4 at 48

weeks

0(-22, 22) 0 0 -1 -1 0

Low -

3.91

cells/ml

(-15.04,

23.85)

0 -1

Very

low

Change in

CD4 at 96 -- 0 0 -2 -1 0

Very -

5.41

cells/ml -- --

Very

219



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

weeks low (-27.41,

40.74)

low

Change in

CD4 at 144

weeks

-- 0 0 -2 -1 0

Very

low

-

11.54

cells/ml

(-79.64,

95.93)

-- --

Very

low

Mortality 1(0.06,

16.67) 0 0 -1 -1 0

Low

0.87

(0.13, 7.14)

-1 per 1000

(-8 to 15) 0 0

Low

AIDS defining

illness -- 0 0 -2 -1 0

Very

low

8.33

(0.30,

100.00)

126 per

1000 (-16

to 552)

-- --

Very

low

Discontinuati

ons

0.74(0.51,

1.06) 0 0 -1 -1 0

Low

0.76

(0.58, 0.99)

-8 per 1000

(-25 to 4) 0 0

Low

Discontinuati

ons due to AE 1(0.41, 2.44) 0 0 -1 -1 0

Low

0.72

(0.37, 1.41)

-9 per 1000

(--57 to --3) 0 0

Low

Emergent 0.92(0.69, 0 0 -1 -1 0 1.18 -10 per 0 0

220



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

SAEs 1.22) Low (0.94, 1.47) 1000

(-36 to 17)

Low

Emergent AEs 0.84(0.54,

1.3) 0 0 -1 -1 0

Low

0.88

(0.64, 1.22)

33 per

1000

(-12 to 78)

0 0

Low

Treatment-

related SAEs -- -1 0 -2 -1 0

Very

low

12.5

(0.02,

1000)

126 per

1000 (-16

to 821)

-- --

Very

low

Treatment-

related AEs -- -1 0 -2 0 0

Very

low

0.28

(0.16, 0.50)

-265 per

1000 (-356

to -174)

-- --

Very

low

Regimen


Very

low

1.72

(0.40, 9.09)

70 per

1,000

(-185 to

358)

-- --

Very

low



221











indirectness.

222

Table 47: GRADE summary of evidence for the RAL vs EFV comparison in children and adolescents



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks

1.33

(0.87, 2.04) 0 0 -1 -1 0

Low

1.36

(1.04, 1.78)

41 per

1000 (9 to

70)

0 0

Low

Viral supp. at

96 weeks

1.12

(0.77, 1.64) 0 0 -1 -1 0

Low

1.47

(1.11, 1.97)

59 per

1000

(23 to 92)

+1 0

Modera

te

Viral supp. at

144 weeks

1.44

(1.00, 2.08) 0 0 -1 -1 0

Low

1.50

(0.08,

29.57)

61 per

1000

(13 to 104)

0 0

Low

Change in

CD4 at 48

weeks

7.01

(-42.06,

56.08)

0 0 -1 -1 0

Low

20.37

(3.34,

37.54)

20.37

cells/ml

(3.34 to

37.54)

0 -1

Very

low

Change in

CD4 at 96

10.06

(-14.76, 0 0 -1 -1 0

Low

22.53

(-0.24,

22.53

cells/ml 0 0

Low

223



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

weeks 34.89) 44.66) (-0.24 to

44.66)

Change in

CD4 at 144

weeks

36.50

(3.75, 69.25) 0 0 -1 -1 0

Low

36.02

(-27.18,

86.33)

36.02

cells/ml

(-27.18 to

86.33)

0 0

Low

Mortality 4.06

(0.45, 36.53) 0 0 -1 -1 0

Low

0.72

(0.17, 3.13)

-3 per 1000

(-8 to 4) 0 0

Low

AIDS defining

illness

0.84

(0.32, 2.17) 0 0 -1 -1 0

Low

0.98

(0.29, 4.09)

-2 per 1000

(-15 to 26) 0 0

Low

Discontinuati

ons

0.73

(0.50, 1.06) 0 0 -1 -1 0

Low

0.70

(0.54, 0.89)

-49 per

1000

(-75 to -20)

+1 0

Modera

te

Discontinuati

ons due to AE

0.61

(0.31, 1.21) 0 0 -1 -1 0

Low

0.44

(0.24, 0.78)

-34 per

1000

(-49 to -17)

+1 0

Modera

te

224



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Public

ation

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Emergent

SAEs

0.75

(0.42, 1.33) 0 0 -1 -1 0

Low

0.44

(0.35, 0.55)

-12 per

1000

(-32 to -10)

+1 0

Modera

te

Emergent AEs 0.96

(0.64, 1.45) 0 0 -1 -1 0

Low

0.88

(0.69, 1.11)

-146 per

1000

(-193 to -

102)

0 0

Low

Treatment-

related SAEs

1.00

(0.33, 2.99) -1 0 -1 -1 0

Very

low

0.77

(0.02, 8.90) -1 per 1000

(-11 to 20)

0 0

Very

low

Treatment-

related AEs

1.23

(0.88, 1.71) -1 0 -1 -1 0

Very

low

1.23

(0.81, 1.90)

50 per

1000

(-29 to 133)

0 0

Very

low

Regimen

substitutions

--

0 0 -1 -1 0

Very

low

3.60

(0.27,

62.66)

124 per

1,000

(-42 to 739)

-- --

Very

low

225













indirectness.

226

Table 48: GRADE summary of evidence for the RAL vs LPV/r comparison in children and adolescents



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Publi

catio

n

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks -- 0 0 -2 0 0

Low

1.96

(1.43, 2.78)

103 per 1000

(56 to 153) -- --

Low

Viral supp. at

96 weeks -- 0 0 -2 0 0

Low

2.08

(1.35, 3.03)

128 per 1000

( 71 to 190) -- --

Low

Viral supp. at

144 weeks -- 0 0 -2 -1 0 - - -- -- -- -

Change in

CD4 at 48

weeks

-- 0 0 -2 -1 0

Very

low

-6.17

(-32.17,

20.40)

-6.17

cells/ml

(-32.17 to

20.40)

-- --

Very

low

Change in

CD4 at 96

weeks

-- 0 0 -2 -1 0

Very

low

-23.81

(-55.27,

6.57)

-23.81

cells/ml

(-55.27 to

6.57)

-- --

Very

low

Change in -- 0 0 -2 -1 0 -2.32 -2.32 -- --

227



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Publi

catio

n

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

CD4 at 144

weeks

Very

low

(-88.18,

83.19)

cells/ml

(-88.18 to

83.19)

Very

low

Mortality -- 0 0 -2 -1 0

Very

low

0.53

(0.09, 2.63)

-3 per 1000

(-9 to 4) -- --

Very

low

AIDS defining

illness -- 0 0 -2 0 0

Very

low

0.89

(0.19, 4.00)

-1 per 1000

(-16 to 27) -- --

Very

low

Discontinuati

ons -- 0 0 -2 0 0

Low

0.58

(0.43, 0.79)

-77 per 1000

(-119 to -38) -- --

Low

Discontinuati

ons due to AE -- 0 0 -2 0 0

Low

0.32

(0.16, 0.66)

-57 per 1000

(-95 to -27) -- --

Low

Emergent

SAEs -- 0 0 -2 -1 0

Low

0.44

(0.32, 0.62)

-10 per 1000

(-34 to -6) -- --

Low

Emergent AEs -- -1 0 -2 -1 0 0.9 -143 per -- --

228



Risk of

Bias

Incons

istenc

y

Indirec

tness

Impre

cision

Publi

catio

n

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Very

low

(0.68, 1.18) 1000

(-199 to 87)

Very

low

Treatment-

related SAEs -- -1 0 -2 -1 0

Very

low

3.12

(0.01,

1000)

6 per 1000

(-89 to 28) -- --

Very

low

Treatment-

related AEs -- 0 0 -2 0 0

Very

low

1.18

(0.69, 2.00)

41 per 1000

(-62 to 146) -- --

Very

low

Regimen


Very

low

4.55

(0.34,

100.00)

71 per 1,000

(-104 to 688) -- --

Very

low





229









indirectness.

230

Table 49: GRADE summary of evidence for the RAL vs NVP comparison in children and adolescents

Outcome Direct

Effect


Risk of

Bias

Inconsi

stency

Indirec

tness

Imprec

ision

Publica

tion

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

Viral supp. at

48 weeks -- 0 0 -2 0 0

Low

1.56

(1.14, 2.17)

61 per 1000

(20 to 104) -- --

Low

Viral supp. at

96 weeks -- 0 0 -2 0 0

Low

2.50

(1.47, 4.35)

166 per 1000

(75 to 266) -- --

Low

Viral supp. at

144 weeks -- 0 0 -2 -1 0

Very

low

2.27

(0.03,

100.00)

143 per 1000

(29 to 275) -- --

Very

low

Change in

CD4 at 48

weeks

-- 0 0 -2 -1 0

Very

low

15.09

(-6.87, 37.89)

15.09 cells/ml

(-6.87 to

37.89)

-- --

Very

low

Change in

CD4 at 96

weeks

-- 0 0 -2 -1 0

Very

low

35.90

(-4.38, 74.13)

35.90 cells/ml

(-4.38 to

74.13)

-- --

Very

low

Change in

CD4 at 144 -- 0 0 -2 -1 0

Very

31.38

(-60.93,

31.38 cells/ml

(-60.9 to -- --

Very

231

Outcome Direct

Effect


Risk of

Bias

Inconsi

stency

Indirec

tness

Imprec

ision

Publica

tion

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

weeks low 113.50) 113.5) low

Mortality -- 0 0 -2 -1 0

Very

low

0.51

(0.08, 3.45) -7 per 1000

(-23 to 3) -- --

Very

low

AIDS defining

illness -- 0 0 -2 -1 0

Very

low

3.7

(0.22,

100.00)

12 per 1000

(-32 less to 40) -- --

Very

low

Discontinuati

ons -- 0 0 -2 0 0

Low

0.50

(0.35, 0.69)

-105 per 1000

(-156 to- 56) -- --

Low

Discontinuati

ons due to AE -- 0 0 -2 0 0

Low

0.24

(0.10, 0.53)

-85 per 1000

(-153 to -40) -- --

Low

Emergent

SAEs -- 0 0 -2 0 0

Low

0.36

(0.22, 0.58)

-99 per 1000

(-166 to -44) -- --

Low

Emergent AEs -- 0 0 -2 0 0

Low

0.44

(0.29, 0.68)

-171 per 1000

(-235 to -99) -- --

Low

Treatment- -- -1 0 -2 -1 0 0.68 0 per 1000 -- --

232

Outcome Direct

Effect


Risk of

Bias

Inconsi

stency

Indirec

tness

Imprec

ision

Publica

tion

Bias

Quality

of direct

evidenc

e

Odds ratio

(95% CrI)

Absolute

effects

Indirect

evidenc

e

precisio

n

Networ

k

Transiti

vity

Overall

quality

of

evidenc

e

related SAEs Very

low

(0, 1000.00) (-889 to 25) Very

low

Treatment-

related AEs -- -1 0 -2 -1 0

Very

low

1.41

(0.85, 2.50) 78 per 1000

(-26 to 183)

-- --

Very

low

Regimen

substitutions

-- 0 0 -1 -2 0

Very

low

1.79

(0.13, 33.33)

136 per 1,000

(-31 to 749)

-- --

Very

low










233




indirectness.

234

References

1. World Health Organization. Global update on HIV treatment 2013: results, impact and

opportunities. 2013.

2. World Health Organization. March 2014 supplement to the 2013 consolidated guidelines on

the use of antiretroviral drugs for treating and preventing HIV infection: recommendations

for a public health approach. 2014.

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for

treating and preventing HIV infection. Geneva Switzerland2013.

4. Kanters S, Vitoria M, Doherty M, et al. Comparative efficacy and safety of first-line

antiretroviral therapy for the treatment of HIV infection: a systematic review and network

meta-analysis. Lancet HIV. Nov 2016;3(11):e510-e520.

5. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for

treating and preventing HIV infection Recommendations for a public health approach -

Second edition. Geneva, Switzerland2016.

6. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing

risk of bias in randomised trials. BMJ. 2011;343:d5928.

7. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 6. Rating the quality of evidence--

imprecision. J Clin Epidemiol. Dec 2011;64(12):1283-1293.

8. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence--

inconsistency. J Clin Epidemiol. Dec 2011;64(12):1294-1302.

9. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of evidence-

-publication bias. J Clin Epidemiol. Dec 2011;64(12):1277-1282.

10. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 8. Rating the quality of evidence--

indirectness. J Clin Epidemiol. Dec 2011;64(12):1303-1310.

11. Guyatt GH, Oxman AD, Sultan S, et al. GRADE guidelines: 9. Rating up the quality of

evidence. J Clin Epidemiol. Dec 2011;64(12):1311-1316.

12. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence--

study limitations (risk of bias). J Clin Epidemiol. Apr 2011;64(4):407-415.

13. Puhan MA, Schunemann HJ, Murad MH, et al. A GRADE Working Group approach for rating

the quality of treatment effect estimates from network meta-analysis. BMJ. 2014;349:g5630.

14. Guyatt G, Oxman A, Vist G, et al. GRADE: an emerging consensus on rating quality of

evidence and strength of recommendations. BMJ. 2008;336:924-926.

235

15. Dias S, Welton N, Sutton A, Ades A. Technical Support Document 2: A generalized linear

modelling framework for pairwise and network meta-analysis of randomized controlled

trials. 2011.

16. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment

comparison meta-analysis. Statistics in medicine. 2010;29(7-8):932-944.

17. Bucher HC, Guyatt Gh Fau - Griffith LE, Griffith Le Fau - Walter SD, Walter SD. The results of

direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.

19970826 DCOM- 19970826 (0895-4356 (Print)).

18. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the

treatment of HIV-1 infection. N Engl J Med. Nov 7 2013;369(19):1807-1818.

19. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus

atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS

Res Hum Retroviruses. Oct 2012;28(10):1184-1195.

20. Albini L, Cesana BM, Motta D, et al. A randomized, pilot trial to evaluate glomerular filtration

rate by creatinine or cystatin C in naive HIV-infected patients after tenofovir/emtricitabine in

combination with atazanavir/ritonavir or efavirenz. J Acquir Immune Defic Syndr. Jan 1

2012;59(1):18-30.

21. Amin J, Becker S, Belloso W, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose

in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebo-

controlled, non-inferiority trial. Lancet. 2014;383(9927):1474-1482.

22. Amin JML, Praphan Phanupak SF, Lerato Mohapi,, Brenda Crabtree-Ramirez HJ, Suresh

Kumar, Alan Winston,, Man-Po Lee WB, David A Cooper, and Sean Emery. Efficacy and safety

of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-

blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015.

23. Arathoon E, Schneider S, Baraldi E, et al. Effects of once-daily darunavir/ritonavir versus

lopinavir/ritonavir on metabolic parameters in treatment-naive HIV-1-infected patients at

week 96: ARTEMIS. Int J STD AIDS. Jan 2013;24(1):12-17.

24. Arribas J, Thompson M, Sax PE, et al. Significant efficacy & long-term safety difference with

taf-based str in naïve adults. Conference on Retroviruses and Opportunistic Infections; 2017;

Seattle, USA.

25. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and

efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients:

144-week analysis. J Acquir Immune Defic Syndr. Jan 1 2008;47(1):74-78.

236

26. Arribas JR, Thompson M, Sax PE, et al. Brief Report: Randomized, Double-Blind Comparison

of Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF), Each Coformulated

With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144

Results. Journal of Acquired Immune Deficiency Syndromes: JAIDS. Jun 01 2017;75(2):211-

218.

27. Avihingsanon A, Lewin SR, Kerr S, et al. Efficacy of tenofovir disoproxil

fumarate/emtricitabine compared with emtricitabine alone in antiretroviral-naive HIV-HBV

coinfection in Thailand. Antivir Ther. 2010;15(6):917-922.

28. Bedimo R. RADAR study: Raltegravir combined with boosted Darunavir has similar safety and

antiviral efficacy as tenofovir/emtricitabine combined with boosted darunavir in

antiretroviral-naive patients. the 6th IAS Conference on HIV Pathogenesis, Treatment and

Prevention (IAS 2011); 2011; Rome Italy

29. Bedimo R. Standard Triple Therapy Controls HIV Better Than Raltegravir/Darunavir at 48

Weeks RADAR Study 2013.

30. Bedimo RJ, Drechsler H, Jain M, et al. The RADAR study: Week 48 safety and efficacy of

RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine

combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health.

PLoS ONE. 2014;9(8).

31. Berenguer J, Gonzalez J, Ribera E, et al. Didanosine, lamivudine, and efavirenz versus

zidovudine, lamivudine, and efavirenz for the initial treatment of hiv type 1 infection: Final

analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903.

Clin Infect Dis. 15 Oct 2008;47(8):1083-1092.

32. Bertz RJ, Persson A, Chung E, et al. Pharmacokinetics and pharmacodynamics of atazanavir-

containing antiretroviral regimens, with or without ritonavir, in patients who are HIV-

positive and treatment-naive. J Hum Pharma Drug Ther. Mar 2013;33(3):284-294.

33. Bowman V. GR, S. Jain, M. Goicoechea, M. Dube, S. Kerkar, S. Schneider, C. Kemper, C.,

Diamond SS, A. Hermes, K. Bailey, E. Daar, R. Haubrich, California Collaborative Treatment,

Group AICT. 48 week results of a pilot randomized study of an nucleoside reverse

transcriptase inhibitor (NRTI)-sparing regimen of raltegravir (RAL) + lopinavir/ritonavir

(LPV/r) versus efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) in

antiretro. the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011).

2011.

34. Bracchi M, Pagani N, Dalla Pria A, et al. A randomized comparison of integrase inhibitors

with TDF/FTC on renal markers. Antiviral Therapy. 2017;22 (Supplement 1):A25.

237

35. Campbell TB, Smeaton LM, Kumarasamy N, et al. Efficacy and safety of three antiretroviral

regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational

settings. PLoS Med. 2012;9(8):e1001290.

36. Carr A, Chuah J, Hudson J, et al. A randomised, open-label comparison of three highly active

antiretroviral therapy regimens including two nucleoside analogues and indinavir for

previously untreated HIV-1 infection: the OzCombo1 study. AIDS. Jun 2000;14(9):1171-1180.

37. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus

ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results

from the randomised open-label phase 3b study. Lancet. Jun 28 2014;383(9936):2222-2231.

38. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet

regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus

efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV

infection. AIDS. Mar 27 2011;25(6):F7-12.

39. Cohen C, Wohl D, Arribas J, et al. STaR Study: Single-Tablet Regimen

Rilpivirine/Emtricitabine/Tenofovir DF Maintains Non-Inferiority to

Efavirenz/Emtricitabine/Tenofovir DF in ART-Naïve Adults Week 96 Results. European AIDS

Conference; 2013; Brussels, Belgium.

40. Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized clinical trial of

rilpivirine/ emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/ tenofovir

disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS. 2014;28(7):989-997.

41. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two

background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive

adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. Jul

16 2011;378(9787):229-237.

42. Committee ITIC-o, Yeni P, Cooper DA, et al. Virological and immunological outcomes at 3

years after starting antiretroviral therapy with regimens containing non-nucleoside reverse

transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

Lancet. Jul 22 2006;368(9532):287-298.

43. Curtis LD SM, G Nichols, B Wynne, C Stainsby, A Aylott, S Piscitelli, J Goodrich, SPRING-2 and

SINGLE teams Once-Daily Dolutegravir (DTG; GSK1349572) Has a Renal Safety Profile

Comparable to Raltegravir (RAL) and Efavirenz in Antiretroviral (ART)-Naive Adults: 48 Week

Results From SPRING-2 (ING113086) and SINGLE (ING114467) 2013.

238

44. Daar ES, Tierney C, Fischl MA, et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug

regimen for initial treatment of HIV-1: A randomized trial. Ann Intern Med. April

2011;154(7):445-456.

45. Dart Trial T. Twenty-four-week safety and tolerability of nevirapine vs. abacavir in

combination with zidovudine/lamivudine as first-line antiretroviral therapy: a randomized

double-blind trial (NORA). Tropical Med Int Health. Jan 2008;13(1):6-16.

46. DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine

and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis.

Oct 1 2004;39(7):1038-1046.

47. Dejesus E, Mills A, Bhatti L, Conner C, Storfer S. A randomised comparison of safety and

efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in

treatment-naive patients. Int J Clin Pract. Dec 2011;65(12):1240-1249.

48. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine,

and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated

emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a

randomised, double-blind, phase 3, non-inferiority trial. Lancet. Jun 30

2012;379(9835):2429-2438.

49. DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when

combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-

192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. Jul-Aug 2012;13(4):228-

232.

50. Echeverria P, Negredo E, Carosi G, et al. Similar antiviral efficacy and tolerability between

efavirenz and lopinavir/ritonavir, administered with abacavir/lamivudine (Kivexa), in

antiretroviral-naive patients: a 48-week, multicentre, randomized study (Lake Study).

Antiviral Research. Feb 2010;85(2):403-408.

51. Eron J, Jr., Yeni P, Gathe J, Jr., et al. The KLEAN study of fosamprenavir-ritonavir versus

lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of

HIV infection over 48 weeks: a randomised non-inferiority trial.[Erratum appears in Lancet.

2006 Oct 7;368(9543):1238]. Lancet. Aug 5 2006;368(9534):476-482.

52. Fatkenheuer G, Kelly M, Van Wijngaerden E, et al. ARTEMIS 96-week comparison of liver

tolerability of once-daily darunavir/ritonavir (DRV/r) versus lopinavir/ ritonavir (LPV/r) in

treatment-naive patients. HIV Medicine. October 2009;10:100.

53. Fisac C, Virgili N, Ferrer E, et al. A comparison of the effects of nevirapine and nelfinavir on

metabolism and body habitus in antiretroviral-naive human immunodeficiency virus-

239

infected patients: a randomized controlled study. J Clin Endocrinol Metab. Nov

2003;88(11):5186-5192.

54. French M, Amin J, Roth N, et al. Randomized, open-label, comparative trial to evaluate the

efficacy and safety of three antiretroviral drug combinations including two nucleoside

analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study.

HIV Clin Trials. May-Jun 2002;3(3):177-185.

55. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide

versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-

380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

The Lancet. 4 - 10 November 2017;390(10107):2063-2072.

56. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.

zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. Jan 19 2006;354(3):251-260.

57. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in

combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. Jul 14

2004;292(2):191-201.

58. Gatell J RFPASDPJHCAKTMHDM-RJXXTH. Efficacy and safety of doravirine 100 mg QD vs.

efavirenz 600 mg QD with TDF/FTC in ART-naive HIV-infected patients: Week 24 results.

Journal of the International AIDS Society. IAS Conference on HIV Pathogenesis, Treatment

and Prevention Vancouver, BC Canada;Vol.18, pp.36-7, CONFERENCE START:2015 Jul 2019

CONFERENCE END: 2015 Jul 2022.

59. Gatell Jm RFPASDPJHCAKTMXXTH. Doravirine 100mg QD vs efavirenz +TDF/FTC in ART-naive

HIV+ patients: week 48 results. Topics in antiviral medicine. Conference: 23rd conference on

retroviruses and opportunistic infections, CROI. 2016. United states. Conference start:

20160222.Conference end: 20160225 24(E-1):183.

60. Gathe JC, Jr., Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-

daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients.

AIDS. Jul 23 2004;18(11):1529-1537.

61. Gilead Sciences. Renal Effect of Stribild or Other Tenofovir DF-containing Regimens

Compared to Ritonavir-boosted Atazanavir Plus Abacavir/Lamivudine in Antiretroviral

Treatment-naive HIV-1 Infected Adults. 2018;

https://clinicaltrials.gov/ct2/show/NCT02246998.

62. Gotti D, Cesana BM, Albini L, et al. Increase in standard cholesterol and large HDL particle

subclasses in antiretroviral-naive patients prescribed efavirenz compared to

atazanavir/ritonavir. HIV Clin Trials. Sep-Oct 2012;13(5):245-255.

https://clinicaltrials.gov/ct2/show/NCT02246998

240

63. Gotuzzo E, Markowitz M, Ratanasuwan W, et al. Sustained efficacy and safety of raltegravir

after 5 years of combination antiretroviral therapy as initial treatment of HIV-1 infection:

final results of a randomized, controlled, phase II study (Protocol 004). J Acquir Immune Defic

Syndr. Sep 1 2012;61(1):73-77.

64. Group ES, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg daily versus 600 mg

daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority

ENCORE1 study.[Erratum appears in Lancet Infect Dis. 2015 Jul;15(7):761; PMID: 26122437].

The Lancet Infectious Diseases. Jul 2015;15(7):793-802.

65. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for

the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. Aug 16

2006;296(7):769-781.

66. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-

containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. Apr 29

2004;350(18):1850-1861.

67. Harris M, Cote H, Ochoa C, et al. A randomized, open-label study of a nucleoside analogue

reverse transcriptase inhibitor-sparing regimen in antiretroviral-naive HIV-infected patients.

J Acquir Immune Defic Syndr. Mar 1 2009;50(3):335-337.

68. Harris MCO, C. Allavena3, E. Negredo4, A. Thorne1, P. Cahn2, C. Zala2,, F. Raffi3 BC, J.

Singer1, J.S.G. Montaner1 and the CTN 177 study team. NRTI Sparing Trial (CTN 177):

Antiviral and Metabolic Effects of Nevirapine (NVP) + Lopinavir/ritonavir (LPV/r) vs.

Zidovudine/lamivudine (AZT/3TC) + NVP vs. AZT/3TC + LPV/r. International AIDS Conference;

2014; Melbourne Australia.

69. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of

nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment.

AIDS. Jun 1 2009;23(9):1109-1118.

70. Honda M, Ishisaka M, Ishizuka N, Kimura S, Oka S, Japanese Anti HIVQDTSG. Open-label

randomized multicenter selection study of once daily antiretroviral treatment regimen

comparing ritonavir-boosted atazanavir to efavirenz with fixed-dose abacavir and

lamivudine. Internal Medicine. 2011;50(7):699-705.

71. Izzedine H, Hulot JS, Vittecoq D, et al. Long-term renal safety of tenofovir disoproxil

fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind

randomized active-controlled multicentre study. Nephrol Dial Transplant. Apr

2005;20(4):743-746.

241

72. Jemsek JG, Arathoon E, Arlotti M, et al. Body fat and other metabolic effects of atazanavir

and efavirenz, each administered in combination with zidovudine plus lamivudine, in

antiretroviral-naive HIV-infected patients. Clin Infect Dis. Jan 15 2006;42(2):273-280.

73. Johnson M, Moyle G. CASTLE study: 96-week efficacy & safety of ATV/r versus LPV/r in

antiretroviral-naive HIV-1-infected patients. HIV Medicine. April 2009;10:17.

74. Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz

related to plasma concentrations? Antivir Ther. 2005;10(4):489-498.

75. Kozal MJ, Lupo S, DeJesus E, et al. A nucleoside- and ritonavir-sparing regimen containing

atazanavir plus raltegravir in antiretroviral treatment-naive HIV-infected patients: SPARTAN

study results. HIV Clin Trials. May-Jun 2012;13(3):119-130.

76. Kumar P, DeJesus E, Huhn G, et al. Evaluation of cardiovascular biomarkers in a randomized

trial of fosamprenavir/ritonavir vs. efavirenz with abacavir/lamivudine in underrepresented,

antiretroviral-naive, HIV-infected patients (SUPPORT): 96-week results. BMC Infectious

Diseases. 07 Jun 2013;13(1).

77. Kumar PN, Salvato P, LaMarca A, et al. A randomized, controlled trial of initial anti-retroviral

therapy with abacavir/lamivudine/zidovudine twice-daily compared to atazanavir once-daily

with lamivudine/zidovudine twice-daily in HIV-infected patients over 48 weeks (ESS100327,

the ACTION Study). AIDS Res Ther. Apr 9 2009;6:3.

78. Landman R, Koulla-Shiro S, Sow PS, et al. Evaluation of four tenofovir-containing regimens as

first-line treatments in Cameroon and Senegal: The ANRS 12115 DAYANA trial. Antivir Ther.

2014;19(1):51-59.

79. Lazzarin A, Orkin C, De Jesus E, et al. Artemis: 192-Week efficacy and safety of once daily

darunavir/ritonavir (DRV/r) versus lopinavir/R (LPV/r) in treatment-naive HIV-1-infected

adults. Infection. March 2011;39:S26-S27.

80. Lennox JL, Dejesus E, Berger DS, et al. Raltegravir versus Efavirenz regimens in treatment-

naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic

analyses.[Erratum appears in J Acquir Immune Defic Syndr. 2011 Dec 1;58(4):e120 Note:

Dosage error in article text]. J Acquir Immune Defic Syndr. Sep 2010;55(1):39-48.

81. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus

efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a

multicentre, double-blind randomised controlled trial. Lancet. Sep 5 2009;374(9692):796-

806.

82. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside

reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive

242

volunteers infected with HIV-1: A Randomized, controlled equivalence trial. Ann Intern Med.

07 Oct 2014;161(7):461-471.

83. Li T, Dai Y, Kuang J, et al. Three generic nevirapine-based antiretroviral treatments in Chinese

HIV/AIDS patients: multicentric observation cohort. PLoS ONE. 2008;3(12):e3918.

84. Maggiolo F, Ripamonti D, Gregis G, et al. Once-a-day therapy for HIV infection: a controlled,

randomized study in antiretroviral-naive HIV-1-infected patients. Antivir Ther. Aug

2003;8(4):339-346.

85. Malan DR, Krantz E, David N, et al. 96-week efficacy and safety of atazanavir, with and

without ritonavir, in a HAART regimen in treatment-naive patients. JIAPAC. Jan-Feb

2010;9(1):34-42.

86. Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without

ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-

naive patients. J Acquir Immune Defic Syndr. Feb 1 2008;47(2):161-167.

87. Malan N, Su J, Mancini M, et al. Gastrointestinal tolerability and quality of life in

antiretroviral-naive HIV-1-infected patients: data from the CASTLE study. AIDS Care. Jun

2010;22(6):677-686.

88. Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained antiretroviral effect of raltegravir after

96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir

Immune Defic Syndr. Nov 1 2009;52(3):350-356.

89. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-

1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients

with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. Oct

1 2007;46(2):125-133.

90. Martinez E, Gonzalez-Cordon A, Ferrer E, et al. Early lipid changes with atazanavir/ritonavir

or darunavir/ritonavir. HIV Medicine. July 2014;15(6):330-338.

91. Martinez E, Gonzalez-Cordon A, Ferrer E, et al. Differential body composition effects of

protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical

trial. Clinical Infectious Diseases. Mar 01 2015;60(5):811-820.

92. Martinez-Picado J, Negredo E, Ruiz L, et al. Alternation of antiretroviral drug regimens for

HIV infection. A randomized, controlled trial. Ann Intern Med. Jul 15 2003;139(2):81-89.

93. Matheron S, Descamps D, Boue F, et al. Triple nucleoside combination

zidovudine/lamivudine/abacavir versus zidovudine/lamivudine/nelfinavir as first-line

therapy in HIV-1-infected adults: a randomized trial. Antivir Ther. Apr 2003;8(2):163-171.

243

94. Matthews GV, Manzini P, Hu Z, et al. Impact of lamivudine on HIV and hepatitis B virus-

related outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of

antiretroviral therapy in southern Africa. Aids. Sep 10 2011;25(14):1727-1735.

95. Mills A, Crofoot G, Jr., McDonald C, et al. Tenofovir Alafenamide Versus Tenofovir Disoproxil

Fumarate in the First Protease Inhibitor-Based Single-Tablet Regimen for Initial HIV-1

Therapy: A Randomized Phase 2 Study. Journal of Acquired Immune Deficiency Syndromes:

JAIDS. Aug 01 2015;69(4):439-445.

96. Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir

in treatment-naive, HIV-1-infected patients: 96-week analysis. Aids. Aug 24

2009;23(13):1679-1688.

97. Min S, Roberts J, Almond S, et al. Efficacy and Safety of Dolutegravir (DTG) in Hepatitis (HBV

or HCV) Co-infected Patients: Results From the Phase 3 Program International AIDS

Conference; 2014; Melbourne, Australia.

98. Miro JM, Manzardo C, Ferrer E, et al. Immune Reconstitution in Severely Immunosuppressed

Antiretroviral-Naive HIV-1-Infected Patients Starting Efavirenz, Lopinavir-Ritonavir, or

Atazanavir-Ritonavir Plus Tenofovir/Emtricitabine: Final 48-Week Results (The Advanz-3

Trial). Journal of Acquired Immune Deficiency Syndromes: JAIDS. Jun 01 2015;69(2):206-215.

99. Molina et al. Doravirine is non-inferior to darunavir/r in phase 3 treatment naïve trial at

week 48. Conference of Retroviruses and Opportunistic Infection (CROI); 2017; Seattle WA.

100. Molina JBCM, JvLP, ALP, et al. Once-daily dolutegravir versus darunavir plus ritonavir for

treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a

randomised, open-label, phase 3b study. 2015.

101. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus

twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for

management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety

results of the CASTLE study. Lancet. Aug 23 2008;372(9639):646-655.

102. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and

emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week

efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. Mar

2010;53(3):323-332.

103. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and

emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised

double-blind active-controlled trial. Lancet. Jul 16 2011;378(9787):238-246.

244

104. Moyle GJ, Stellbrink HJ, Compston J, et al. 96-Week results of abacavir/lamivudine versus

tenofovir/emtricitabine, plus efavirenz, in antiretroviral-naive, HIV-1-infected adults: ASSERT

study. Antivir Ther. 2013;18(7):905-913.

105. Munderi P, Walker AS, Kityo C, et al. Nevirapine/zidovudine/lamivudine has superior

immunological and virological responses not reflected in clinical outcomes in a 48-week

randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan

adults with low CD4 cell counts. HIV Medicine. May 2010;11(5):334-344.

106. Murphy RL, Sanne I, Cahn P, et al. Dose-ranging, randomized, clinical trial of atazanavir with

lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS. Dec 5

2003;17(18):2603-2614.

107. Murray JM, Emery S, Kelleher AD, et al. Antiretroviral therapy with the integrase inhibitor

raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS. Nov 12

2007;21(17):2315-2321.

108. Nathan C, Jean-Michel M, Keith H, et al. Long-term efficacy and safety of

elvitegravir/cobicistat/emtricitabine/tenofovir DF versus atazanavir plus ritonavir plus

emtricitabine/tenofovir. J Intern AIDS Soc. May 2014;17:23-24.

109. Ndembi N, Goodall RL, Dunn DT, et al. Viral rebound and emergence of drug resistance in

the absence of viral load testing: A randomized comparison between zidovudine-lamivudine

plus nevirapine and zidovudine-lamivudine plus abacavir. J Infect Dis. January

2010;201(1):106-113.

110. Negredo E, Paredes R, Peraire J, et al. Alternation of antiretroviral drug regimens for HIV

infection. Efficacy, safety and tolerability at week 96 of the Swatch Study. Antivir Ther. Dec

2004;9(6):889-893.

111. Nishijima T, Komatsu H, Teruya K, et al. Once-daily darunavir/ritonavir and

abacavir/lamivudine versus tenofovir/emtricitabine for treatment-naive patients with a

baseline viral load of more than 100 000 copies/ml. AIDS. Mar 13 2013;27(5):839-842.

112. Nishijima T, Takano M, Ishisaka M, et al. Abacavir/lamivudine versus tenofovir/emtricitabine

with atazanavir/ritonavir for treatment-naive Japanese patients with HIV-1 infection: a

randomized multicenter trial. Internal Medicine. 2013;52(7):735-744.

113. Nunez M, Soriano V, Martin-Carbonero L, et al. SENC (Spanish efavirenz vs. nevirapine

comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clin

Trials. May-Jun 2002;3(3):186-194.

114. Orkin C, Clumeck N, Girard PM, et al. Week 144 efficacy and safety data:

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (Stribild) demonstrates durable efficacy

245

and differentiated safety compared to Atazanavir boosted by Ritonavir plus

Emtricitabine/Tenofovir DF at week 144 in treatment-naive HIV-1-infected patients. HIV

Medicine. April 2014;15:114.

115. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily

darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive

patients in the ARTEMIS trial. HIV Medicine. Jan 2013;14(1):49-59.

116. Orkin C, Rockstroh J, DeJesus E, et al. Week 96 efficacy and safety data:

Elvitegravir/cobicistat/ emtricitabine/tenofovir DF (Quad) compared to atazanavir boosted

by ritonavir plus emtricitabine/tenofovir DF in treatment-naive HIV-1-infected patients. HIV

Medicine. April 2013;14:56.

117. Orkin CM, Squires KE, Molina J, et al. Similar Efficacy and Safety By Subgroup in DRIVE-

AHEAD: DOR/3TC/TDF vs EFV/FTC/TDF. Conference for Retroviruses and Oportunistic

Infections; 2018; Boston MA.

118. Orkin C, Stebbing J, Nelson M, et al. A randomized study comparing a three- and four-drug

HAART regimen in first-line therapy (QUAD study). J Antimicrob Chemother. Feb

2005;55(2):246-251.

119. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir

versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. Jul 31

2008;22(12):1389-1397.

120. Phanuphak N, Ananworanich J, Teeratakulpisarn N, et al. A 72-week randomized study of the

safety and efficacy of a stavudine to zidovudine switch at 24 weeks compared to zidovudine

or tenofovir disoproxil fumarate when given with lamivudine and nevirapine. Antivir Ther.

2012;17(8):1521-1531.

121. Podzamczer D, Andrade-Villanueva J, Clotet B, et al. Lipid profiles for nevirapine vs.

atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine

over 48 weeks, in treatment-naive HIV-1-infected patients (the ARTEN study). HIV Medicine.

Jul 2011;12(6):374-382.

122. Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or

nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine

Study). Antivir Ther. Jun 2002;7(2):81-90.

123. Podzamczer D, Soriano V, Andrade-Villanueva J, et al. Comparison of lipid profile with

nevirapine versus atazanavir/ritonavir, both combined with tenofovir DF and emtricitabine

(TDF/FTC), in treatment-naive HIV-1-infected patients: ARTEN study week-48 results. HIV

Medicine. October 2009;10:26.

246

124. Porteiro N, Walmsley S, Falco V, et al. Fixed-dose combination dolutegravir, abacavir, and

lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and

emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results

from a randomised, open-label, non-inferiority, phase 3b study. The Lancet HIV. December

2017;4(12):e536-e546.

125. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and

safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered

with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the

ASSERT study. J Acquir Immune Defic Syndr. Sep 2010;55(1):49-57.

126. Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and

efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive

patients: virologic, immunologic, and morphologic changes--a 96-week analysis. J Acquir

Immune Defic Syndr. Dec 15 2006;43(5):535-540.

127. Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy and safety of TMC278 in

antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. Jan

2 2010;24(1):55-65.

128. Puls RL, Srasuebkul P, Petoumenos K, et al. Efavirenz versus boosted atazanavir or

zidovudine and abacavir in antiretroviral treatment-naive, HIV-infected subjects: week 48

data from the Altair study. Clin Infect Dis. Oct 1 2010;51(7):855-864.

129. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or

tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results

from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet. Nov 29

2014;384(9958):1942-1951.

130. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir

in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a

randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935.

131. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in

antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised,

double-blind, non-inferiority SPRING-2 study. Lancet. Mar 2 2013;381(9868):735-743.

132. Ratsela A, Polis MA, Dhlomo S, et al. A randomized factorial trial comparing 4 treatment

regimens in treatment-naive HIV-infected persons with AIDS and/or a CD4 cell count <200

Cells/muL in South Africa. J Infect Dis. 15 Nov 2010;202(10):1529-1537.

247

133. Rey D, Hoen B, Chavanet P, et al. High rate of early virological failure with the once-daily

tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients. J Antimicrob

Chemother. Feb 2009;63(2):380-388.

134. Reynes J, Lawal A, Pulido F, et al. Examination of noninferiority, safety, and tolerability of

lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/

emtricitabine in antiretroviral-naive subjects: the progress study, 48-week results. HIV Clin

Trials. Sep-Oct 2011;12(5):255-267.

135. Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir or

tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS

study. AIDS Res Hum Retroviruses. Feb 2013;29(2):256-265.

136. Ribaudo HJ, Kuritzkes DR, Lalama CM, et al. Efavirenz-based regimens in treatment-naive

patients with a range of pretreatment HIV-1 RNA levels and CD4 cell counts. J Infect Dis. Apr

1 2008;197(7):1006-1010.

137. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of

HIV-1 infection. N Engl J Med. May 15 2008;358(20):2095-2106.

138. Rockstroh J, DeJesus E, Henry K, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF

(QUAD) has durable efficacy and differentiated safety compared to atazanavir boosted by

ritonavir plus emtricitabine/tenofovir DF at week 96 in treatment-naive HIV-1-infected

patients. J Intern AIDS Soc. 11 Nov 2012;15:23.

139. Rockstroh J, Teppler H, Zhao J, et al. Safety and efficacy of raltegravir in patients with HIV-1

and hepatitis B and/or C virus coinfection. HIV Med. Feb 2012;13(2):127-131.

140. Rockstroh JK, Dejesus E, Henry K, et al. A randomized, double-blind comparison of

coformulated elvitegravir/ cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted

atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1

infection: Analysis of week 96 results. J Acquir Immune Defic Syndr. 15 Apr 2013;62(5):483-

486.

141. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus

efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected

patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. May 1

2013;63(1):77-85.

142. Rockstroh JK, Lennox JL, Dejesus E, et al. Long-term treatment with raltegravir or efavirenz

combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-

1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. Oct 2011;53(8):807-

816.

248

143. Sax PE. Randomized trial of bictegravir or dolutegravir with FTC/TAF for initial HIV therapy.

Conference on Retroviruses and Opportunistic Infections; 2017; Seattle, WA.

144. Sax PE, DeJesus E, Crofoot G, et al. Bictegravir versus dolutegravir, each with emtricitabine

and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-

blind, phase 2 trial. The Lancet. HIV. Apr 2017;4(4):e154-e160.

145. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and

tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment

of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48

weeks.[Erratum appears in Lancet. 2012 Aug 25;380(9843):730]. Lancet. Jun 30

2012;379(9835):2439-2448.

146. Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as

part of combination regimens for initial treatment of HIV: final results. J Infect Dis. Oct 15

2011;204(8):1191-1201.

147. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in

single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir

Immune Defic Syndr. Sep 1 2014;67(1):52-58.

148. Sax Pe PAMMLKEDESHJAAWKSJRJGWC. Coformulated bictegravir, emtricitabine, and

tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for

initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind,

multicentre, phase 3, non-inferiority trial. Lancet. 2017(pagination).

149. Sax Pe WDYMTPFDESMPATMPDMJMOSK. Tenofovir alafenamide versus tenofovir disoproxil

fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment

of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet

(London, England).385(9987):2606-2615.

150. Sierra-Madero J, Villasis-Keever A, Mendez P, et al. Prospective, randomized, open label trial

of Efavirenz vs Lopinavir/Ritonavir in HIV+ treatment-naive subjects with CD4+<200

cell/mm3 in Mexico. J Acquir Immune Defic Syndr. Apr 2010;53(5):582-588.

151. Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter

trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV

treatment. AIDS. Jul 31 2009;23(12):1547-1556.

152. Smith KY, Weinberg WG, DeJesus E, et al. Fosamprenavir or atazanavir once daily boosted

with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection:

48-week results of ALERT. AIDS Res Ther 2008;5(5).

249

153. Soriano V, Arasteh K, Migrone H, et al. Nevirapine versus atazanavir/ritonavir, each

combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1

patients: the ARTEN Trial. Antivir Ther. 2011;16(3):339-348.

154. Squires K, Kityo C, Hodder S, et al. Integrase inhibitor versus protease inhibitor based

regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase

3 study. The Lancet. HIV. Sep 2016;3(9):e410-e420.

155. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz,

each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for

patients infected with HIV. J Acquir Immune Defic Syndr. Aug 15 2004;36(5):1011-1019.

156. Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus lamivudine versus

zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals

with HIV infection: selection of thymidine analog regimen therapy (START I). AIDS. Jul

2000;14(11):1591-1600.

157. Staszewski S, Keiser P, Montaner J, et al. Abacavir-lamivudine-zidovudine vs indinavir-

lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence

trial.[Erratum appears in JAMA 2001 Jun 13;285(22):2858]. JAMA. Mar 7 2001;285(9):1155-

1163.

158. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover

with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week

results from the ASSERT study. Clin Infect Dis. Oct 15 2010;51(8):963-972.

159. Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-

1: 96-week results from a randomized dose-ranging study. AIDS. Jul 17 2013;27(11):1771-

1778.

160. Termini R, Lazzarin A, Orani A, Vanden Abeele C, Lavreys L. Use of once-daily darunavir/r

(800/100mg) in treatment-naive patients co-infected with hepatitis b and/or c. Data from

the artemis study. Vol 372009.

161. Torti C, Quiros-Roldon E, Regazzi M, et al. Early virological failure after tenofovir +

didanosine + efavirenz combination in HIV-positive patients upon starting antiretroviral

therapy. Antivir Ther. 2005;10(4):505-513.

162. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line

combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS.

May 2 2003;17(7):987-999.

163. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral

therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and

250

lamivudine: a randomised open-label trial, the 2NN Study. Lancet. Apr 17

2004;363(9417):1253-1263.

164. van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and efavirenz elicit different changes in

lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med. Oct

2004;1(1):e19.

165. van Lunzen J, Antinori A, Cohen CJ, et al. Rilpivirine vs. efavirenz-based single-tablet

regimens in treatment-naive adults: week 96 efficacy and safety from a randomized phase

3b study. AIDS. Jan 2016;30(2):251-259.

166. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in

combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results

from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. Feb

2012;12(2):111-118.

167. Vibhagool A, Cahn P, Schechter M, et al. Triple nucleoside treatment with abacavir plus the

lamivudine/zidovudine combination tablet (COM) compared to indinavir/COM in

antiretroviral therapy-naive adults: results of a 48-week open-label, equivalence trial

(CNA3014). Curr Med Res Opin. Jul 2004;20(7):1103-1114.

168. Vrouenraets SM, Wit FW, Fernandez Garcia E, et al. Randomized comparison of metabolic

and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-

naive HIV-1-infected patients. HIV Medicine. Nov 2011;12(10):620-631.

169. Walmsley S, Avihingsanon A, Slim J, et al. Gemini: a noninferiority study of

saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir

Immune Defic Syndr. Apr 1 2009;50(4):367-374.

170. Walmsley S, Baumgarten A, Berenguer J, et al. Brief Report: Dolutegravir Plus

Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive

Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical

Trial.[Erratum appears in J Acquir Immune Defic Syndr. 2016 Jan 1;71(1):e33]. Journal of

Acquired Immune Deficiency Syndromes: JAIDS. Dec 15 2015;70(5):515-519.

171. Walmsley S, Berenguer J, Khuong-Josses MA, et al. Dolutegravir Regimen Statistically

Superior to Efavirenz/Tenofovir/Emtricitabine: 96-Week Results From the SINGLE Study

(ING114467). Conference on Retrovirues and Opportunistic Infections; 2014; Boston, USA.

172. Walmsley S, Berenguer J, Khuong-Josses MA, et al. Dolutegravir Regimen Statistically

Superior To Tenofovir/Emtricitabine/Efavirenz: 96-Wk Data. Topics in Antiviral

Medicine.Conference:21st Conference on Retroviruses and Opportunistic Infections, CROI

2014 (2021)United States. Conference Start: 20140303 Conference End: 20140306.

251

Conference Publication: (20140568 pages). 20140322 (e-20140301) (pp 20140261-

20140262).

173. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial

treatment of HIV infection. N Engl J Med. Jun 27 2002;346(26):2039-2046.

174. Wester CW, Thomas AM, Bussmann H, et al. Non-nucleoside reverse transcriptase inhibitor

outcomes among combination antiretroviral therapy-treated adults in Botswana. AIDS. Jan

2010;24 Suppl 1:S27-36.

175. Wilkin A, Pozniak AL, Morales-Ramirez J, et al. Long-term efficacy, safety, and tolerability of

rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192

results from a phase IIb randomized trial. AIDS Res Hum Retroviruses. May 2012;28(5):437-

446.

176. Wohl D, Oka S, Clumeck N, et al. Brief Report: A Randomized, Double-Blind Comparison of

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With

Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results.

Journal of Acquired Immune Deficiency Syndromes: JAIDS. May 01 2016;72(1):58-64.

177. Wohl D PATMDEPDMJMCGCCMHMS. Tenofovir alafenamide (TAF) in a single-tablet regimen

in initial HIV-1 therapy. Topics in antiviral medicine.Vol.23, pp.47-8, CONFERENCE

START:2015 Feb 2023 CONFERENCE END: 2015 Feb 2026.

178. Wohl DA, Cohen C, Gallant JE, et al. A Randomized, Double-Blind Comparison of Single-

Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Versus Single-Tablet

Regimen Efavirenz/Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection:

Analysis of Week 144 Results. J Acquir Immune Defic Syndr. 2014;65(3):e118-e121.

179. Zhang F, Heaton R, Wu H, et al. Randomized clinical trial of antiretroviral therapy for

prevention of HAND. Topics in Antiviral Medicine. July 2015;23 (E-1):25.

180. Zolopa A, Sax PE, DeJesus E, et al. A randomized, double-blind comparison of co-formulated

elvitegravir/cobicistat/emtricitabine/tenofovir DF versus efavirenz/emtricitabine/tenofovir

DF for initial treatment of HIV-1 infection: Analysis of week 96 results. J Acquir Immune Defic

Syndr. 2013.

181. UNAIDS. New high-quality antiretroviral therapy to be launched in South Africa, Kenya and

over 90 low-and middle-income countries at reduced price. 2017.

182. Kenedi CA, Goforth HW. A systematic review of the psychiatric side-effects of efavirenz. AIDS

Behav. Nov 2011;15(8):1803-1818.

183. Organization WH. Potential safety issue affecting women living with HIV using dolutegravir

at the time of conception. 2018;

252

http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018fi

nal.pdf?ua=1. Accessed 18 May 2018.

184. Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-

infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): A multicentre, phase 2, non-

comparative, open-label, randomised trial. The Lancet Infectious Diseases. June

2014;14(6):459-467.

185. Lortholary O, Roussillon C, Boucherie C, et al. Tenofovir DF/emtricitabine and efavirenz

combination therapy for HIV infection in patients treated for tuberculosis: the ANRS 129

BKVIR trial. Journal of Antimicrobial Chemotherapy. Mar 2016;71(3):783-793.

186. Bonnet M, Bhatt N, Baudin E, et al. Nevirapine versus efavirenz for patients co-infected with

HIV and tuberculosis: a randomised non-inferiority trial. Lancet Infect Dis. Apr

2013;13(4):303-312.

187. Habtewold A, Makonnen E, Amogne W, et al. Is there a need to increase the dose of

efavirenz during concomitant rifampicin-based antituberculosis therapy in sub-Saharan

Africa? The HIV-TB pharmagene study. Pharmacogenomics. 2015;16(10):1047-1064.

188. Dooley K, Kaplan R, Mwelase N, et al. Safety and efficacy of dolutegravir-based ART in

TB/HIV coinfected adults at week 24. Conference on Retroviruses and Opportunistic

Infections (CROI); 2018; Boston MA.

189. Manosuthi W, Sungkanuparph S, Tantanathip P, et al. A randomized trial comparing plasma

drug concentrations and efficacies between 2 nonnucleoside reverse-transcriptase inhibitor-

based regimens in HIV-infected patients receiving rifampicin: the N2R Study. Clin Infect Dis.

Jun 15 2009;48(12):1752-1759.

190. Mankhatitham W, Lueangniyomkul A, Manosuthi W. Hepatotoxicity in patients co-infected

with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-

based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen. Southeast

Asian J Trop Med Public Health. 2011;42(3):651-658.

191. Sinha S, Raghunandan P, Chandrashekhar R, et al. Nevirapine versus efavirenz-based

antiretroviral therapy regimens in antiretroviral-naive patients with HIV and tuberculosis

infections in India: a pilot study. BMC infectious diseases. 2013;13:482.

192. Sinha S GKTSDSRSPRM. Nevirapine- versus Efavirenz-based antiretroviral therapy regimens

in antiretroviral-naive patients with HIV and Tuberculosis infections in India: a multi-centre

study. BMC infectious diseases. 2017;17(1).

http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf?ua=1

http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf?ua=1

253

193. Swaminathan S, Padmapriyadarsini C, Venkatesan P, et al. Efficacy and safety of once-daily

nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a

randomized clinical trial. Clinical Infectious Diseases. Oct 2011;53(7):716-724.

194. Amogne W, Aderaye G, Habtewold A, et al. Efficacy and Safety of Antiretroviral Therapy

Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/muL:

TB-HAART Study, a Randomized Clinical Trial. PLoS ONE [Electronic Resource].

2015;10(5):e0122587.

195. Kekitiinwa A, Szubert AJ, Spyer M, et al. Virologic Response to First-line Efavirenz-or

Nevirapine-based Antiretroviral Therapy in HIV-infected African Children. Pediatric Infectious

Disease Journal. 01 Jun 2017;36(6):588-594.

196. Rudy Bj KBGWCSKBJLSWCMAAEPPGHSG. Immune reconstitution but persistent activation

after 48 weeks of antiretroviral therapy in youth with pre-therapy CD4 >350 in ATN 061.

Journal of acquired immune deficiency syndromes. 2015;69(1 // NIAID):52-60.

197. Bienczak A, Denti P, Cook A, et al. Plasma efavirenz exposure, sex, and age predict virological

response in HIV-infected African children. Journal of Acquired Immune Deficiency

Syndromes. 01 Oct 2016;73(2):161-168.

198. Porter DP, Bennett SR, Quirk E, Miller MD, White KL. Lack of emergent resistance in HIV-1-

infected adolescents on elvitegravir-based STRs. Topics in Antiviral Medicine. July 2015;23 (E-

1):438.

199. Porter DP, Bennett SR, Quirk E, Miller MD, White KL, Robinson C. Lack of emergent

resistance in HIV-1-infected adolescents on elvitegravir-based single-tablet regimens. HIV

Medicine. April 2015;2):14-15.

200. Gaur A, Kizito H, Chakraborty R, et al. Safety and efficacy of E/C/F/TAF in HIV-1 infected

treatment-naive adolescents. Topics in Antiviral Medicine. June 2016;24 (E-1):343.

201. Batra J, Kizito H, Gaur A, et al. Week 24 data from a phase 3 clinical trial of E/C/F/TAF in HIV-

positive adolescents. Journal of the International AIDS Society. April 2015;2):22.

202. Kizito H, Gaur A, Prasitsuebsai W, et al. Week-24 data from a phase 3 clinical trial of

E/C/F/TAF in HIV-infected adolescents. Topics in Antiviral Medicine. July 2015;23 (E-1):438-

439.

203. Shao Y BSRCAQELEGAPWKKWT. Week 24 data from a Phase 3 clinical trial of E/C/F/TAF in

HIV-infected adolescents. HIV medicine. Annual Conference of the British HIV Association,

BHIVA 2015 Brighton United Kingdom;Vol.16, pp.15, CONFERENCE START:2015 Apr 2021

CONFERENCE END: 2015 Apr 2024.

254

204. Pinto JA, Capparelli EV, Warshaw M, et al. A Phase II/III Trial of Lopinavir/Ritonavir Dosed

According to the WHO Pediatric Weight Band Dosing Guidelines. Pediatr Infect Dis J. Feb

2018;37(2):e29-e35.

205. IMPAACT Network. Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability

and Antiviral Activity of Dolutegravir (GSK1349572), a Novel Integrase Inhibitor, in

Combination Regimens in HIV-1 Infected Infants, Children and Adolescents.

206. Amani-Bosse C DDLMKA-FMCMDSEABMRCNGSYC. Virological response and resistances over

12 months among HIV-infected children less than two years receiving first-line

lopinavir/ritonavir-based antiretroviral therapy in Cote D'Ivoire and Burkina Faso: the

MONOD ANRS 12206 cohort. Journal of the international AIDS society. 2017;20(1).

207. Pressiat C M-AVYCTJMDDLA-FMBSEFYDLGMK. Suboptimal cotrimoxazole prophylactic

concentrations in HIV-infected children according to the WHO guidelines. British journal of

clinical pharmacology. 2017;83(12):2729-2740.

208. Lombaard J, Bunupuradah T, Flynn P, et al. Week 48 safety and efficacy of a rilpivirine

(TMC278)-based regimen in HIV-infected treatment-naive adolescents: PAINT phase II trial.

Journal of the International AIDS Society. 2015;4):9.

209. Gopalan BP, Mehta K, D'Souza R R, et al. Sub-therapeutic nevirapine concentration during

antiretroviral treatment initiation among children living with HIV: Implications for

therapeutic drug monitoring. PLoS ONE. August 2017;12 (8) (no pagination)(e0183080).

210. Shiau S, Strehlau R, Technau KG, et al. Early age at start of antiretroviral therapy associated

with better virologic control after initial suppression in HIV-infected infants. Aids. 28 Jan

2017;31(3):355-364.

211. Jamieson DJ, Chasela CS, Hudgens MG, et al. Maternal and infant antiretroviral regimens to

prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled

trial. Lancet. Jun 30 2012;379(9835):2449-2458.

212. Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected

women taking long-term ART with and without tenofovir in the DART trial. PLoS Med.

2012;9(5):e1001217.

213. Waitt CJ, Walimbwa SI, Orrell C, et al. DolPHIN-1: Dolutegravir vs Efavirenz when Initiating

Treatment in Late Pregnancy – An Interim Analysis. Conference on Retroviruses and

Opportunistic Infections; 2018; Boston, USA.

214. Stek A, Best BM, Capparelli E, et al. Pharmacokinetics of increased dose darunavir during late

pregnancy and postpartum. Topics in Antiviral Medicine. June 2016;24 (E-1):324.

255

215. Mulligan N, Best BM, Wang J, et al. Dolutegravir pharmacokinetics in pregnant and

postpartum women living with HIV. Aids. Mar 27 2018;32(6):729-737.

216. Lamorde M, Wang X, Neary M, et al. Pharmacokinetics, pharmacodynamics and

pharmacogenomics of efavirenz 400mg once-daily during pregnancy and

postpartum. IAS Conference on HIV Science; 2017; Paris, France.

217. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-

feeding in Botswana. N Engl J Med. Jun 17 2010;362(24):2282-2294.

218. Shapiro RL, Kitch D, Ogwu A, et al. HIV transmission and 24-month survival in a randomized

trial of HAART to prevent MTCT during pregnancy and breastfeeding in Botswana. Aids. Jul

31 2013;27(12):1911-1920.

219. Ngoma MS, Misir A, Mutale W, et al. Efficacy of WHO recommendation for continued

breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission

in Zambia. Journal of the International AIDS Society. 2015;18:19352.

220. Fowler MG, Qin M, Fiscus SA, et al. Benefits and Risks of Antiretroviral Therapy for Perinatal

HIV Prevention. New England Journal of Medicine. 11 03 2016;375(18):1726-1737.

221. Fowler MG, Qin M, Fiscus SA, et al. PROMISE: Efficacy and safety of 2 strategies to prevent

perinatal HIV transmission. Topics in Antiviral Medicine. July 2015;23 (E-1):13-14.

222. Cohan D, Natureeba P, Koss CA, et al. Efficacy and safety of lopinavir/ritonavir versus

efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women. Aids. 14

Jan 2015;29(2):183-191.

223. Koss CA, Natureeba P, Mwesigwa J, et al. Hair concentrations of antiretrovirals predict viral

suppression in HIV-infected pregnant and breastfeeding Ugandan women. Aids. 24 Apr

2015;29(7):825-830.

224. Cohan D, Natureeba P, Plenty A, et al. Efficacy and safety of LPV/r versus EFV in HIV+

pregnant and breast-feeding Ugandan women. Conference on Retroviruses and

Opportunistic Infections; 2014; Boston, USA.

225. Koss CA, Natureeba P, Plenty A, et al. Risk factors for preterm birth among HIV-infected

pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based

antiretroviral therapy. J Acquir Immune Defic Syndr. Oct 1 2014;67(2):128-135.

226. Natureeba P, Ades V, Luwedde F, et al. Lopinavir/ritonavir-based antiretroviral treatment

(ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected

pregnant women. J Infect Dis. Dec 15 2014;210(12):1938-1945.

227. Samuel M, Bradshaw D, Perry M, et al. Antenatal atazanavir: a retrospective analysis of

pregnancies exposed to atazanavir. Infect Dis Obstet Gynecol. 2014;2014:961375.

256

228. Giuliano M, Pirillo MF, Liotta G, et al. High CMV IgG antibody levels are associated to a lower

CD4+ RESPONSE to antiretroviral therapy in HIV-infected women. J Clin Virol. Nov

2017;96:17-19.

229. Palombi L, Galluzzo CM, Andreotti M, et al. Drug resistance mutations 18 months after

discontinuation of nevirapine-based ART for prevention of mother-to-child transmission of

HIV in Malawi. Journal of Antimicrobial Chemotherapy. October 2015;70(10):2881-2884.

230. Andreotti M, Pirillo MF, Liotta G, et al. The impact of HBV or HCV infection in a cohort of HIV-

infected pregnant women receiving a nevirapine-based antiretroviral regimen in Malawi.

BMC Infect Dis. Apr 4 2014;14:180.

231. Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding

transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther.

2012;17(8):1511-1519.

232. Giuliano M, Andreotti M, Liotta G, et al. Maternal antiretroviral therapy for the prevention

of mother-to-child transmission of HIV in Malawi: maternal and infant outcomes two years

after delivery. PLoS One. 2013;8(7):e68950.

233. Thorne C, Favarato G, Peters G, et al. Pregnancy and neonatal outcomes following prenatal

exposure to dolutegravir (Slides). IAS Conference on HIV Science; 2017; Paris, France.

234. Thorne C, Favarato G, Peters G, et al. Pregnancy and neonatal outcomes following prenatal

exposure to dolutegravir (Poster). IAS Conference on HIV Science; 2017; Paris, France.

235. Bollen P. A comparison of the pharmacokinetics of dolutegravir in pregnancy and

postpartum. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy;

2017; Chicago, USA.

236. Dooley KE, Denti P, Martinson N, et al. Pharmacokinetics of efavirenz and treatment of HIV-1

among pregnant women with and without tuberculosis coinfection. Journal of Infectious

Diseases. 15 Jan 2015;211(2):197-205.

237. Bussmann H, Wester CW, Wester CN, et al. Pregnancy rates and birth outcomes among

women on efavirenz-containing highly active antiretroviral therapy in Botswana. J Acquir

Immune Defic Syndr. Jul 1 2007;45(3):269-273.

238. Zash R, Jacobson D, Diseko M, et al. The comparative safety of dolutegravir or efavirenz

initiated during pregnancy in Botswana. The Lancet Global Health.

239. Zash R, Jacobson D, Diseko M, et al. DTG/TDF/FTC Started in Pregnancy is as Safe as

EFV/TDF/FTC in Nationwide Birth Outcomes Surveillance in Botswana. IAS Conference on

HIV Science; 2017; Paris, France.

WEB ANNEX B. SYSTEMATIC LITERATURE REVIEW AND NETWORK META … · WEB ANNEX B. SYSTEMATIC...

Documents

Transcript of WEB ANNEX B. SYSTEMATIC LITERATURE REVIEW AND NETWORK META … · WEB ANNEX B. SYSTEMATIC...