Hiv Update Arv Treatment Medscape Jun 2014

8/10/2019 Hiv Update Arv Treatment Medscape Jun 2014

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HIV Update --A Review of the Latest Data With NovelAntiretroviral TherapiesCMEJose R. Arribas, MD

Faculty and Disclosures

CME Released: 06/23/2014 ; Valid for credit through 06/23/2015

CME Information Earn CME Credit

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SUMMARY

Antiretroviral therapy (ART) has revolutionized the treatment of patients with HIV; and,unlike in the 1980s, an HIV diagnosis now constitutes a chronic disease. With manyantiretroviral (ARV) drugs and combinations available, treatment choices are complex.Various treatment guidelines are available to help clinicians select therapy options fortreatment-naive patients as well as for simplification of therapy and for rescue therapy.However, because of delays in updating guidelines, clinicians may not be aware of newdevelopments in ART. The ongoing emergence of HIV drug resistance presents achallenge to successful use of ART, but this is being countered by the development of newdrugs that attack new targets. More than 20 ART drugs are currently available, categorized

into 6 mechanistic classes: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotidereverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors(NNRTIs), ritonavir-boosted protease inhibitors (bPIs or PI/rs), C-C chemokine receptorantagonists (CCR5s), and integrase strand transfer inhibitors (INSTIs). Each has its ownbarrier of resistance, and when resistance develops with an ART regimen, the clinicianneeds to switch to a new regimen.

INSTIs are the newest class of agents to become available, and 3 have been approved:raltegravir, elvitegravir, and dolutegravir. Clinical trial data have established INSTIs asnoninferior to other ARTs, and they are safe and effective in patients with various HIVsubtypes. They have proven to be a good option when switching regimens because ofvirologic failure. To date, dolutegravir has not been associated with any drug resistance.INSTIs have recently all been recommended as treatment options in the US Department ofHealth and Human Services (DHHS) guidelines for ART in HIV-1 infected adults andadolescents, and they are an important addition to the treatment options available to theclinician.

INTRODUCTION

HIV/AIDS continues to be a significant public health problem. Worldwide, in 2011,approximately 34 million people were living with HIV, 2.5 million individuals were newlyinfected, and there were 1.7 million HIV/AIDS-related deaths.[1]In 2012, an estimated 35.3
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million people were HIV-positive. The number of AIDS deaths is in decline, with 1.6 milliondeaths in 2012 compared with 2.3 million in 2005 and 3.4 million in 2001.[1]

ART, which has revolutionized HIV treatment, suppresses viral load, thus reducing AIDS-related morbidity and mortality as well as the risk for transmission. The European AIDSClinical Society (EACS) guidelines recommend ART in any HIV-positive person with a

CD4 count


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drugs in 6 mechanistic classes are available for use in combination regimens (Table 1).The 6 classes are NRTIs, NtRTIs, NNRTIs, bPIs or PI/rs, CCR5s, and INSTIs.

Table 1. The 6 Mechanistic Classes of Antiretroviral Therapy

Nucleoside reverse

transcriptase inhibitors[NRTIs]

Abacavir [ABC], didanosine [ddI], emtricitabine [FTC],

lamivudine [3TC], stavudine [d4T], and zidovudine [AZT]

Nucleotide reverse

transcriptase inhibitors

[NtRTIs]

Tenofovir [TDF]

Nonnucleoside reverse

transcriptase inhibitors

[NNRTIs]

Efavirenz [EFV], etravirine [ETV], nevirapine [NVP],rilpivirine [RLP]

Ritonavir-boosted

protease inhibitors [bPIs

or PI/rs]

Atazanavir + ritonavir [ATV/r], darunavir + ritonavir[DRV/r], fosamprenavir + ritonavir [FPV/r], indinavir +

ritonavir [IDV/r], lopinavir/ritonavir [LPV/r], saquinavir +

ritonavir [SQV/r])

C-C chemokine receptor

antagonists [CCR5s]

Maraviroc [MVC]

Integrase strand transferinhibitors [INSTIs]

Raltegravir (RAL), elvitegravir [EVG], dolutegravir [DTG]

The WHO, DHHS, IAS, and EACS produce guidelines for the clinical management of HIVinfection and describe how the different regimens should be used.[2-4,9]

The most recent class of drugs to be developed is INSTIs. The HIV integrase enzymecatalyzes the irreversible integration of the HIV reverse transcribed viral DNA into the hostgenome through 2 successive catalytic reactions called 3' processing and strandtransfer.[10]All 3 approved drugs specifically target the second step of the integrationprocess through pi-stacking with the long terminal repeats that are located at bothextremities of reverse transcribed HIV DNA molecules and through coordinating Mg2+ionsthat are necessary for integration.[10]Three INSTIs have been licensed for use as ART.Raltegravir was approved in 2007 as a twice-daily INSTI and is recommended in variousguidelines. In the last few months, 2 new INSTIs, elvitegravir and dolutegravir, have beenapproved and included in recommended ART regimens in the recently updated DHHSguidelines. They are also expected to be included in the other guidelines.

Raltegravir is usually administered with tenofovir and emtricitabine, although it can also beused with abacavir and lamivudine. Dolutegravir can be administered with tenofovir andemtricitabine. In the United States, dolutegravir is also administered with abacavir andlamivudine. It is expected that the single-pill formulation of dolutegravir will soon be


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available. Elvitegravir is available in a quad pill, a once-daily single-tablet regimen alsocontaining the novel pharmacoenhancer cobicistat (a CYP3A4 inhibitor that boosts levelsof other drugs but has no antiviral activity itself), and with tenofovir/emtricitabine.

RESISTANCE PATTERNS WITH OLD AND NEW DRUGS

The use of highly active ART in patients with HIV can lead to the development of drug

resistance, which can cause therapeutic failure, an increase in the transmission of resistant

virus, and a decrease in therapeutic options and survival. Clinicians should test patients for

drug resistance prior to starting therapy with most classes of drugs and then regularly monitor

them for indications of the development of drug resistance.[2-4]

Overview of Resistance

The future efficacy of drugs or drug classes can be affected by resistance that emerged

previously, as HIV drug-resistant strains are archived in cellular reservoirs.[10]

An updated list ofsurveillance drug resistance mutations has identified 93 mutations, including 34 NRTI-

resistance mutations at 15 reverse transcriptase (RT) positions, 19 NNRTI-resistance

mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease

positions.[11]Current guidelines recommend switching to a new therapeutic regimen when

virologic failure is confirmed,[3,9]but the guidelines differ on the best approach to managing

treatment-resistant patients.

The WHO recommends that second-line ART consists of a ritonavir-bPI plus 2 NRTIs when

NNRTI-containing regimens were used in the frontline setting.[3]

The IAS recommendsswitching to a PI combined with an INSTI or a CCR5 antagonist (if tropism test shows R5 virus

only) in cases of NRTI/NNRTI failure. For NRTI/bPI failures, because mutations to PIs are

uncommon, alternative regimens may include replacing the 2 NRTIs with an approved or

investigational INSTI.[4]According to the EACS, in general, any regimen should use at least 1

fully active PI/r plus 1 drug from a class not used previously (eg, fusion, integrase, or CCR5

antagonist) or 1 NNRTI, assessed by genotypic testing.[2]

Drug Resistance With INSTIs

Novel drugs are being developed to address the problem of drug-resistant HIV strains, with the

newest class of therapeutics being INSTIs. A subgroup analysis of 699 HIV patients with triple-

class drug resistance in the BENCHMARK-1 and BENCHMARK-2 trials showed that raltegravir

is active in HIV patients with triple-class drug resistance.[12]A case study demonstrated that the

combination of dolutegravir and peginterferon alfa-2a achieved long-term control of HIV

replication in a man with sextuple-class resistance.[13]


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The principles of INSTI resistance parallel those of NRTI, NNRTI, and PI resistance --

resistance is caused by primary mutations, and the development of secondary mutations

further decreases virus susceptibility to treatment.[14]In addition, the genetic barrier to INSTI

resistance is defined by the number of mutations required for the loss of clinical INSTI activity.

There is extensive but incomplete cross-resistance among the INSTIs.[14]Data from clinical

trials and other investigations show that because primary integrase mutations are rare,

resistance testing is not needed before starting therapy with this class of agents. Studies

estimate that fewer than 0.1% of INSTI-naive individuals harbor viruses with primary INSTI

resistance mutations.[14]Raltegravir and elvitegravir are susceptible to the emergence of drug

resistance, whereas dolutegravir is associated with a higher barrier to resistance (Table 2).[12,15-

22]

Table 2. Mutations Detected in Treatment-Naive Patients Progressing on INSTI Therapy

Major Resistance Mutations Minor Resistance Mutations

RAL Y143N155HQ148

Multiple

EVG T66IE92QN155HQ148

Multiple

DTG None None

DTG = dolutegravir; EVG = elvitegravir; RAL = raltegravir

Data from Cooper DA, et al[12];Sichtig N, et al[16];Canducci F, et al[17];Hatano H, et al[18];Sax

PE, et al[19];DeJesus E, et al[20];Walmsley SL, et al[21];Feinberg J, et al. ICAAC 2013. Abstract

H-1464.

Dolutegravir is the only INSTI that has not, to date, been associated with de novo emergence

of resistance mutations in treatment-naive individuals. Several clinical trials provide evidence ofdolutegravir's ability to evade the development of resistance. In the FLAMINGO trial, which

evaluated dolutegravir against darunavir/ritonavir in 484 ARV-naive adults, none of the patients

who received either regimen developed treatment-resistant mutations.[22]No antiviral resistance

to dolutegravir was detected in the 414 patients who received dolutegravir in the SINGLE study

(Study ING114467).[21]


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In another analysis of 1222 treatment-naive patients who received first-line therapy with

dolutegravir, no individuals developed resistance against the compound after 48-96 weeks of

follow-up.[23]In previously treatment-experienced patients who received dolutegravir as a first-

time integrase inhibitor as a component of a second-line regimen, clinicians documented only 4

virologic failures with resistance mutations. The R263K integrase resistance mutation was

observed in 2 of these 4 instances. In in vitro studies, dolutegravir-resistant viruses were

impaired in their ability to acquire further resistance to lamivudine and nevirapine because of

the inability of the virus to develop resistance mutations associated with these 2 compounds.[23]

Raltegravir and elvitegravir show extensive cross-resistance and should not be used

sequentially.[15]Raltegravir and elvitegravir-resistant strains show variable levels of cross-

resistance to dolutegravir, which can partially be overcome by doubling the dose of dolutegravir

to twice daily and ensuring the presence of other active drugs in an ARV regimen.[15]In VIKING

3, if a baseline genotype did not harbor the Q148 integrase resistance mutation and the

background regimen had an overall susceptibility score of 1, then the proportion of patients

with HIV-RNA


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combination.[3]The IAS recommendations, most recently updated in 2012, continue to be

based on a combination of 2 NRTIs/NtRTIs (eg, tenofovir/emtricitabine or abacavir/lamivudine)

and a potent third agent, generally an NNRTI (eg, efavirenz), a PI/r (eg, atazanavir or

darunavir), an INSTI (eg, raltegravir), or, rarely, an agent that blocks the CCR5.[9]The 2013

EACS guidelines recommend combining the NRTIs abacavir and lamivudine or tenofovir and

emtricitabine with either efavirenz or rilpivirine, a PI/r (atazanavir or darunavir), or raltegravir

(Table 3).[2]The guidelines also suggest alternative regimens that can be used in patients who

may not be suited to the recommended ones.

Table 3. EACS-Recommended Regimens for Treatment-Naive HIV Patients: A Drug From

Column A Should Be Combined With the Drugs Listed in Column B

A B Remarks

NNRTI NRTI

EFVRPV

ABC/3TCorTDF/FTC

ABC/3TC coformulatedTDF/FTC coformulatedEFV/TDF/FTC coformulatedRPV/TDF/FTC coformulated

PI/r

ATV/r

DRV/r

ABC/3TC

orTDF/FTC

ATV/r: 300/100 mg qd

DRV/r: 800/100 mg qd

INSTI

RAL TDF/FTCor

ABC/3TC

RAL: 400 mg bid

3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; bid = twice daily; DRV/r =

darunavir/ritonavir; EFV = efavirenz; FTC = emtricitabine; INSTI = integrase strand transfer

inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse

transcriptase inhibitor; PI = protease inhibitor; qd = once daily; RAL = raltegravir; RPV =

rilpivirine; TDF = tenofovir disoproxil fumarate

Data from EACS Guidelines.[2]


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The DHHS guidelines are the most recently updated; they were revised in May 2014 .[4]These

guidelines continue to recommend several regimens for ARV-naive patients (Table 4): 1

NNRTI-based regimen comprising efavirenz/tenofovir disoproxil fumarate/emtricitabine; 2 PI-

based regimens comprising ritonavir-boosted atazanavir + tenofovir disoproxil

fumarate/emtricitabine or ritonavir-boosted darunavir + tenofovir disoproxil

fumarate/emtricitabine; and the INSTI-based regimen of raltegravir 400 mg twice daily plus

tenofovir 300 mg/emtricitabine 200 mg once daily. As part of the update, these regimens were

changed from preferred to recommended, and an additional 3 INSTI-based regimens have

been included, bringing the total to 4 (Table 4): elvitegravir 150 mg/cobicistat 150 mg/tenofovir

300 mg/emtricitabine 200 mg once daily in patients with estimated creatinine clearance (CrCl)

70 mL/min (EVG/COBI/TDF/FTC). This regimen was previously considered an alternative

regimen. Two dolutegravir-based regimens are now also recommended: dolutegravir 50 mg

once daily plus abacavir 600 mg/lamivudine 300 mg once daily in patients who are HLA

B*5701 negative; and dolutegravir 50 mg once daily plus tenofovir 300 mg/emtricitabine 200

mg once daily. A number of alternative regimens are also provided (Table 4).

Table 4. DHHS Guidelines Recommended First-line Regimens in Treatment-Naive

Patients

Recommended Regimens for ART-Naive patients Regardless of Baseline Viral Load orCD4 Count

NNRTI-Based Regimen

EFV/TDF/FTCa

PI-Based Regimens

ATV/r + TDF/FTCa DRV/r + TDF/FTCa

INSTI-Based Regimens

RAL + TDF/FTCa

EVG +COBI+TDF +FTC DTG +ABC/3TCa DTG +TDF/FTC

Recommended Regimens for Patients With Pre-ART Plasma HIV RNA


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EFV + ABC/3TCa-- only for patients who are HLA-B*5701 negative RPV +TDF/FTCa-- only for patients with CD4 cell count >200 cells/mm3

PI-Based Regimen

ATV/r + ABC/3TCa-- only for patients who are HLA-B*5701 negative

Alternative Initial ART Regimen Options

These are regimens that are effective and tolerable but have potential disadvantages whencompared with the recommended regimens or have less data from randomized clinical trials.

An alternative regimen may be the preferred regimen for some patients.

PI-Based Regimens

DRV/r + ABC/3TCa-- only for patients who are HLA-B*5701 negative

LPV/r (once

b

or twice daily) + ABC/3TC

a

-- only for patients who are HLA-B*5701negative LPV/r (onceb or twice daily) + TDF/FTCa

INSTI-Based Regimen

RAL + ABC/3TC -- only for patients who are HLA-B*5701 negative

Data from DHHS.[4]

a3TC can be substituted for FTC or vice versa. The following combinations in the

recommended list above are available as coformulated fixed-dose combinations: ABC/3TC,

EFV/TDF/FTC, EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, and TDF/FTC.

bOnce-daily LPV/r is not recommended for pregnant patients.

3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ATV/r = atazanavir/ritonavir;

COBI = cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG =

elvitegravir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; LPV/r

lopinavir/ritonavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside

reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; TDF

= tenofovir disoproxil fumarate

When selecting the most appropriate regimen for a patient, clinicians should take into

consideration any drug-related, disease-related, and patient-related factors. Selection of a

regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing

frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions.

Some of the older regimens are effective but have large pill burdens, and a high pill burden has

been shown to be a predictor of nonadherence.[27,28]


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INSTIs Offer New Options

The 3 new INSTIs offer new options for treatment-naive patients. Each regimen has different

characteristics, including dosing frequency, number of tablets per day, and whether medication

needs to be taken with a meal (Table 5).

Table 5.Comparison of 4 INSTI-Based Regimens

RAL +TDF/FTC

EVG/COBI/TDF/FTC DTG +ABC/3TC

DTG +TDF/FTC

Dosing frequency Twice daily Once daily Once daily Once daily

Numbers of tabletsper day

3 1 2 2

Meal consideration None Take with a meal None None

Data from http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf

3TC = lamivudine; ABC = abacavir; COBI = cobicistat; DTG = dolutegravir; EVG = elvitegravir;

FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; RAL = raltegravir; TDF =

tenofovir disoproxil fumarate

Effectiveness of INSTIs

For the most part, INSTIs were approved after being shown to be noninferior to other preferred

ART regimens in treatment-naive patients. The noninferiority double-blind STARTMRK trial

enrolled 566 patients who had a viral load of >5000 copies/mL and susceptibility to

efavirenz.[29,30]At baseline, 53% of patients had a viral load of


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to elvitegravir or coformulated efavirenz 600 mg, emtricitabine 200 mg, and tenofovir 300 mg.

The study showed noninferiority, with 87.6% of patients in the elvitegravir arm and 84.1% of

patients in the control arm having HIV RNA concentrations


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concluded that once-daily dosing without requirement for a pharmacokinetic booster made

dolutegravir-based therapy a very promising therapeutic option.

Adverse Events With INSTIs

Overall, INSTIs are well-tolerated and have very few side effects;

[34]

however, all 3 areassociated with an increased risk for nausea and diarrhea. Raltegravir is associated with a risk

for skin rash with fever (rare), creatine phosphokinase elevation, muscle weakness,

rhabdomyolysis (very rare), transient elevation of serum transaminase levels, hypersensitive

reactions, and hepatitis.[4,29,30]Elvitegravir has been shown to increase the risk for headache,

insomnia, and estimated glomerular filtration rate (GFR) decreases when it is combined with

cobicistat.[4,19]Patients taking dolutegravir or cobicistat experience only benign elevations in

serum creatinine because these drugs inhibit tubular creatinine secretion without influencing

the actual GFR.[35]

Discontinuation of INSTI treatment because of adverse events is a rare occurrence. In the

STARTMRK trial, the discontinuation rate was 5% in patients taking raltegravir.[29,30]In the

SINGLE trial, the rate was 2% in the dolutegravir arm.[21]In GS-US-236-0102, the rate for

discontinuation of elvitegravir was 4% in patients receiving the single quad pill.[19]

Special Considerations for Choosing an ART Regimen

Special considerations are advised for patients with certain comorbidities and characteristics

when choosing an ART regimen for HIV-infected patients (Table 6, Table 7, Table 8). For

example, tenofovir should be used with caution in patients with renal

insufficiency.[4]EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl


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Results from some studies suggest that certain patients might benefit from first-line use of

INSTIs. For example, INSTIs are a good option for patients with cardiovascular disease

because of their small impact on lipid levels. Patients with multiple comorbidities requiring

multiple medications are also good candidates for raltegravir and dolutegravir. The 2 newer

INSTIs are not substrates for CYP3A; therefore, the risk for drug-drug interactions is low.[38]On

the other hand, cobicistat is a potent CYP3A4 inhibitor and may therefore interact with various

drugs, so EVG/COBI/TDF/FTC is not a good option for patients with multiple comorbidities and

polypharmacy.[4]Viral resistance to elvitegravir may develop if the drug is coadministered with

drugs that interact with elvitegravir and cobicistat via induction of CYP3A activity.[25]

Other special considerations include the presence of HLA-B*5701 and the rate of creatinine

clearance (Table 6, Table 7).

Table 6. Special Characteristics to Consider When Selecting an INSTI Regimen

RAL +TDF/FTC

EVG/COBI/TDF/FTC DTG +ABC/3TC

DTG +TDF/FTC

CY 3A4interactions

No Yes

COBI-potent CYP3A4inhibitor

EVG-CYP3A4 substrate

No

DTG-minorCYP3A4substrate

No

DTG-minorCYP3A4substrate

CrCl anddosing

Dosageadjustment forTDF and FTCif CrCl


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clearance; DTG = dolutegravir; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase

strand transfer inhibitor; RAL = raltegravir; TDF = tenofovir disoproxil fumarate

Table 7. Special Characteristics to Consider When Selecting Recommended Non-INSTI

Regimens

NNRTI-Based Regimen Comments

EFV/TDF/FTC* EFV is teratogenic in nonhuman primates. A non-EFVregimen should be strongly considered in women whomight become or are planning to become pregnant.

PI-Based Regimens

ATV/r + TDF/FTC* DRV/r (once daily) +

TDF/FTC*

TDF should be used with caution in patients with renalinsufficiency.

ATV/r should not be used in patients who require >20 mgomeprazole equivalent per day.

Source: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

*3TC may substitute for FTC or vice versa. The following combinations in the recommended

list above are available as coformulated fixed-dose combinations: ABC/3TC, EFV/TDF/FTC,

EVG/COBI/TDF/FTC, LPV/r, RPV/TDF/FTC, TDF/FTC, and ZDV/3TC.

3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; COBI = cobicistat; DRV/r =

darunavir/ritonavir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase

strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse

transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; TDF = tenofovir disoproxil

fumarate; ZDV = zidovudine

In summary, all 3 INSTIs are recommended for HIV treatment-naive patients in the DHHS

guidelines. EVG/COBI/TDF/FTC is only approved for patients with a creatinine clearance >70

mL/min, and cobicistat is a potent CYP3A4 inhibitor. Dolutegravir has been shown to be

noninferior to raltegravir and can be given once daily with or without food; however,

postmarketing experience with the drug is limited

SIMPLIFICATION THERAPY

Overview


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In some cases, patients may request simplification of therapy to improve their quality of life. A

recent study reported that 48% of patients wished to simplify their regimen, 20% were

concerned about long-term side effects of their current regimen, 14% had trouble tolerating the

current regimen due to side effects, and 5% had trouble taking their current regimen on a

regular basis.[39]In other cases, clinicians may suggest simplification to minimize drug side

effects, maintain long-term adherence, and reduce the risk for virologic failure.

Clinicians might consider simplifying regimens for patients who are taking older drugs that are

associated with more severe side effects and that often come with a high pill burden and/or

frequent dosing requirements.[4]In one study, a pill burden of more vs less than 10 pills per day

was associated with a much higher risk for nonadherence than twice- vs once-daily dosing or

small differences in the number of types of ARV treatments in a regimen .[27]

Adherence to anti-HIV medications has been shown to increase with reduced dosing

frequency. A meta-analysis of 11 randomized clinical trials involving 3029 patients revealed

that the adherence rate was improved in patients who received once-daily regimens vs with

twice-daily regimens (+2.9%; 95% CI, 1.0%-4.8%; P < .003).[40]Treatments currently available

in once-daily dosing include efavirenz, didanosine, tenofovir, lamivudine, atazanavir,

emtricitabine, elvitegravir, and dolutegravir. Caution is needed when choosing a simplified

regimen, as not all simplification efforts will result in the maintenance of virologic suppression.

Clinicians can choose to simplify therapy with drugs from the currently used class of drugs or

from a different class. The randomized Nevirapine, Efavirenz and Abacavir Resistance Team

trial compared nevirapine, efavirenz, or abacavir as substitutes for protease inhibitors in 460

HIV-1-infected patients successfully treated with ARV regimens containing protease inhibitors -

- patients had viral load


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the activity of the 2 NRTIs when contemplating the potential risks and benefits of

simplification.[42]

High lipid value is a common reason for simplification. The phase 3 SPIRIT trial evaluated

simplifying a regimen of a protease inhibitor/ritonavir plus 2 NRTIs to a regimen of

rilpivirine/emtricitabine/tenofovir in 317 patients who were switched compared with 159 patients

who were not switched.[43]Patients who switched continued to have an undetectable viral load

and an improved lipid profile associated with lower cardiovascular risk (low-density lipoprotein

cholesterol, -16 vs 0 mg/dL; triglycerides, -53 vs +3 mg/dL).

Simplification With INSTIs

Good tolerability and fewer drug interactions than with other ARTs make simplifying therapy

with INSTIs an attractive option. Rates of diarrhea are low with dolutegravir, raltegravir,

elvitegravir, and rilpivirine/tenofovir/emtricitabine.[19,21,29,30,43]

In some cases, switching to INSTIs can result in lower lipid levels. Early results from the

STRATEGY-PI study have demonstrated that regimen simplification from a PI-based regimen

(PI+ RTV +FTC/TDF) to the single tablet containing elvitegravir maintains HIV suppression and

is well-tolerated.[44, 45]

To be included in the study, patients had to be receiving their first or second ARV regimen and

have a viral load of


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lipoprotein (0 vs -3; P = .008). Only 8% of patients taking EVG/COBI/TDF/FTC regimen had

diarrhea.

The SWITCHMRK-1 and 2 double-blind, randomized trials included 707 eligible patients who

were randomly assigned to switch from lopinavir-ritonavir to raltegravir (n=353) or to remain on

lopinavir-ritonavir (n=354), while continuing background therapy consisting of at least 2 NRTIs

or NtRTIs.[42]To be included, patients had to have documented viral RNA concentration below

the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based

regimen. Although switching to raltegravir was associated with greater reductions in serum lipid

concentrations, efficacy data did not establish noninferiority of raltegravir to lopinavir-ritonavir.

No patients receiving raltegravir had moderate to severe diarrhea. Failures in patients taking

raltegravir were concentrated in patients who had experienced prior virologic failures, and the

researchers suggested that these patients probably had partially active nucleosides. To date,

there are no clinical trials testing dolutegravir in patients wishing to simplify therapy.

RESCUE TREATMENT

Overview

It is estimated that up to one quarter of patients receiving ART are not virologically suppressed

and are therefore not achieving target plasma HIV RNA levels.[47]Some patients may have

minimal or no drug resistance, whereas others may have extensive resistance, depending on

their treatment history. Management of virologic failure and extensive resistance is a complex

process, but strategies are available to manage such cases. Assessing and managing failureof ART is complex. The DHHS guidelines make several recommendations for rescue

treatment.[4]A new regimen should include at least 2 (preferably 3) fully active agents, whose

expected activity is based on the patient's treatment history, drug-resistance testing, and/or the

drug's novel mechanism of action. The guidelines do not recommend adding a single, fully

active ARV drug to a virologically failing regimen because of the risk for rapid development of

resistance to all drugs in the regimen. However, in certain cases, the combination of a fully

active ritonavir-boosted PI and a single active drug may result in a regimen that is as effective

as a regimen with more active agents. Such active ARV agents include etravirine, darunavir,

tipranavir, and dolutegravir, as well as drugs with a unique mechanism of action, such as the

CCR5 antagonist maraviroc. Some ARVs such as darunavir and dolutegravir may need to be

administered twice rather than once daily in order to achieve higher drug concentrations for

patients with preexistent protease or integrase mutations. The DHHS guidelines make several

other recommendations for rescue treatment (Table 8).


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Table 8. DHHS Recommendations for Rescue Treatment

Assessing and managing an HIV patient experiencing treatment failure is complex.Clinicians should seek expert advice.

Evaluation of virologic failure should include an assessment of adherence, drug-drug ordrug-food interactions, drug tolerability, ART history, use of concomitant medications withconsideration of adverse drug interactions with ARV agents, HIV RNA and CD4 T-cellcount trends over time, and prior and current drug-resistance testing results.

Drug-resistance testing should be performed while the patient is taking the failing ARVregimen or within 4 weeks of treatment discontinuation. Even if more than 4 weeks haveelapsed since the ARVs were discontinued, resistance testing can still provide usefulinformation to guide therapy, though it may not detect previously selected resistancemutations.

The goal of treatment for ARV-experienced patients with drug resistance who areexperiencing virologic failure is to establish virologic suppression

A new regimen should include at least 2, preferably 3, fully active agents. A fully activeagent is one that is expected to have ARV activity on the basis of a patient's treatmenthistory and drug-resistance testing results and/or the drug's novel mechanism of action.

In general, adding a single fully active ARV agent to a virologically failing regimen is not

recommended because of the risk for development of resistance to all drugs in theregimen.

For some highly ART-experienced patients, maximal virologic suppression is notpossible. In this case, ART should be continued with regimens designed to minimizetoxicity, preserve CD4 cell counts, and at least delay clinical progression.

When no viable suppressive regimen can be constructed for a patient with multidrug-resistant HIV, the clinician should consider enrolling the patient in a clinical trial ofinvestigational agents or contacting pharmaceutical sponsors that may haveinvestigational agents available.

Discontinuing or briefly interrupting therapy in a patient may lead to a rapid increase inHIV RNA and a decrease in CD4 cell count and increases the risk for clinicalprogression. Therefore, this strategy is not recommended.

Data from http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

ART = antiretroviral therapy; ARV = antiretroviral

INSTIs in Rescue Treatment

Good tolerability and fewer drug interactions make INSTIs an attractive choice when switching

treatment regimens due to virologic failure. Several clinical trials have tested INSTIs in HIV

rescue therapy.

Raltegravir has achieved positive results as a second-line therapy in clinical trials. The

BENCHMARK study enrolled triple-class resistant HIV patients who were not responding to

therapy and who were INSTI-naive.[48]Patients received either placebo (n=237) or raltegravir

(n=462). At week 240, the viral load was


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during the open-label phase. The phase 2 TRIO trial enrolled 103 patients with HIV RNA levels

>1000 copies/mL who did not respond to therapy on NNRTIs, had 3 or more PPI and NRTI

mutations, and had 3 or more darunavir and NNRTI mutations.[49]Patients received raltegravir

plus etravirine and darunavir/ritonavir. At week 48, a total of 86% of patients had an HIV RNA

level 1000 copies/mL at

screening), resistance to 2 or more classes of ARV drugs, and 1-2 fully active drugs for

background therapy.[53]Patients were randomly assigned to receive once-daily dolutegravir 50

mg (n=354) or twice-daily raltegravir 400 mg (n=361), with investigator-selected background

therapy. At 48 weeks, more patients receiving dolutegravir had a viral load


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In the single-arm VIKING trial, dolutegravir twice daily was given to patients who were resistant

to raltegravir and/or elvitegravir as well as multiple other drug classes.[24,54]At week 24, a total

of 69% of the 183 patients who received raltegravir had achieved a viral load

Hiv Update Arv Treatment Medscape Jun 2014

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