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Switching Therapy to Integrase Inhibitors in Patients with...
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Switching Therapy to Integrase Inhibitors in Patients with Virologic Suppression
Ian Frank, MD
Professor of Medicine
Perelman School of Medicine
University of Pennsylvania
Reasons for Switching Therapy
• Convenience – switch to single tablet regimen
• Improved tolerability
• Comorbidities• Increased risk for cardiovascular disease (avoid abacavir, lopinavir/r, darunavir)
• Hyperlipidemia (avoid boosted PIs, efavirenz)
• Low bone density (avoid tenofovir DF)
• Renal dysfunction (avoid atazanvir, tenofovir DF, lopinavir/r)
• Hepatitis B (use tenofovir)
• Hepatitis C (use tenofovir AF and integrase inhibitors; avoid boosters)
• Drug-drug interactions – there are many
• Proton pump inhibitors (avoid rilpivirine, atazanavir)
• Rifampin (use dolutegravir, efavirenz)
• Pregnancy• Avoid elvitegravir/cobi, dolutegravir (at the moment), bictegravir; use raltegravir
Comorbidities of Newly Diagnosed HIV Patients in the US: A Longitudinal Analysis of Prevalent HIV Patients
0
10
20
30
40
50
60
70
Pre
va
len
ce
(%
)
CV Events
3%
7%
Gallant J, et al. J Infect Dis. 2017;216:1525-1533.
≥1 outpatient claim, >6 months of continuous care, and contributed data for 2003-2013 (continuous enrollment during the entire year).Baseline Commercial/Medicaid/Medicare: mean age 42/41/71 years; male: 78%/51%/64%.
RenalImpairment
Fracture/Osteoporosis
Hypertension Diabetes Obesity Hyperlipidemia
5% 6%3%
6%
25%
48%
9%
19%
5%
14%
22%
27%
2013 Databases
Commercial (n=14,638)
Medicaid (n=4869)
Medicare (n=848)
16%
20%
65%
31%
6%
48%
11%
EuroSIDA: Age and Chronic Kidney Disease Among Persons With HIV on ART (2014)
• Cross-sectional analysis of a prospective cohort (2014; n=12,882)
• Chronic kidney disease (ie, eGFR <60 mL/min 2 measurements >3 months apart): 7%
• Other comorbidities: dyslipidemia (69%), hypertension (60%), diabetes (6%), CVD (5%)
• Prevalence of chronic kidney disease increased by age group
• ≥60 versus ≤60 years: 16% versus 1% to 7%
• D:A:D 5-year risk for chronic kidney disease increased with increasing age
Pelchen-Matthews A, et al. AIDS. 2018;32:2405-2416.
D:A:D 5-Year Risk Score
0
20
40
60
80
100
Pa
rtic
ipa
nts
(%
)
<30(n=491)
Age (years)
30-39(n=2534)
40-49(n=4123)
50-59(n=3797)
≥60(n=1837)
Risk: Low (<0) Moderate (1-4) High (≥5)
A case
• You are caring for a 52 yo woman with HIV infection who has been on suppressive therapy with TDF/3TC/EFV for the past 8 years. She has no history of virologic failure. She has hypertension.
• She is undergoing menopause
• Recent VL = <20 copies/mL, CD4+ count = 890 cells/mm3,
• Creatinine = 1.2 mg/dL (CrCl = 54 mL/min)
Question
• Do you recommend your patient switch her antiretroviral therapy?
A. Yes
B. No
Possible Reasons to Switch Your Patient’s Regimen off TDF/3TC/EFV
• Need to take medication on an empty stomach at bed time
• Her creatinine clearance is 54 mL/min, and she has hypertension
• She’s at increased risk for worsening renal function
• If her CrCl falls to <50 mL/min she will need to have TDF dose reduced
• She’s a woman >age 50, therefore at increased risk for osteopenia
• EFV increases cholesterol levels by approximately 20%
Efavirenz and Risk of Suicidality
• Association reported in analysis of ACTG A5095, A5142, A5175, A5202
• Efavirenz (n=3241) versus no efavirenz (n=2091)
• Suicidality was uncommon (8.08 per 1000 person-years)
• 2-fold increase in risk of suicidality with efavirenzamong patients beginning ART
• Hazard ratio: 2.28 (95% CI 1.27 to 4.10, P=0.006)
• Factors associated with higher risk of suicidality
• Efavirenz treatment, younger age, IDU history, and psychiatric history
• No association found in other analyses
• D:A:D cohort
• FDA Adverse Event Reporting System database
Mollan KR, et al. Ann Intern Med. 2Smith C, et al. J Int AIDS Soc. 2014;17(suppl 3):19512. Abstract O315.Napoli AA, et al. J Int AIDS Soc. 2014;17:19214.
Suicidal Ideation orAttempted or Completed Suicide
Cu
mu
lati
ve
In
cid
en
ce
Weeks to Suicidality0 48 96 144 192
EfavirenzEfavirenz free
ITT DSMBGray P=0.005
Switching from Efavirenz to RilpivirineImproves Symptoms, Even if “Asymptomatic”
• Improvements in QoL, sleep, anxiety score, composite CNS score and lipids observed
Vera. IAS 2017. Abstr WEPEB0536.
Point estimates are median change. Error bars are interquartile range.
P = .008
P = .004P = .009
Change in Total Sleep Score from Switch to RPV
Improvement
Deterioration
Study Visit Time Points
Wk 4 Wk 12 Wk 3612
10
8
6
4
2
0
-2
-4
Perc
ent
Ch
ange
in T
ota
l Sl
eep
Sco
re F
rom
Bas
elin
e
Change in Anxiety Score from Switch to RPV
Improvement
Deterioration
Study Visit Time Points
Wk 4 Wk 12 Wk 3640
35
30
25
20
15
10
5
0Perc
ent
Ch
ange
in
An
xiet
y Sc
ore
Fro
m B
asel
ine
-5
-10
P < .001P = .029
P = .053
Changes in Spine and Hip BMD Following Switch to F/TAF in Virologically Suppressed Patients
Hip BMD
Me
an
Ch
an
ge (
%)
Spine BMD
Me
an
Ch
an
ge
(%
)
Treatment Week
-3
-2
-1
0
1
2
3
0 48 96
-0.2
F/TAF (n=321)
F/TDF (n=320)
1.5
P<0.001
-0.2
2.2
P<0.001
-3
-2
-1
0
1
2
3
-0.2
F/TAF (n=321)
F/TDF (n=317)
1.1
0 48 96
P<0.001
Treatment Week
-0.3
1.9
P<0.001
Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.Raffi F, et al. JAIDS. 2017;75:226-231.
Next question
• You recommend to your patient that she switches her antiretroviral because her risk for renal insufficiency, loss of bone density, and to increase the flexibility of her medication schedule
• She tells you she doesn’t want to switch because: 1) TDF/3TC/EFV saved her life, and 2) “Se não estiver quebrado, não conserte.”
• You say:
A. No problem. Forget about it.
B. I will put you on something that will be just as effective, easier to take and safer
How I Talk to My Patients About Switching Therapy
Ian’s car: 2004 Volvo S60Phyllis’ new car (maybe): 2019 Mercedes GLC
• Whose car do you want to drive?
A. Ian’s car
B. Phyllis’ car
Considerations When Switching Regimens in Virologically Suppressed Patients
Comorbidity:▪ HBV coinfection
▪ Cardiovascular disease or risk
▪ Renal function
▪ Bone mineral density
▪ Pregnancy
▪ Other coinfections
Safety:
▪ Review ART history for intolerance
▪ Must be HLA-B*5701 negative if considering ABC
▪ Consider drug–drug interactions with comedications
Drug Resistance:
▪ Review ART history for possible VF
▪ Review all available resistance test results
▪ If earlier resistance uncertain, only consider switch if new regimen likely to maintain suppression of resistant virus
▪ Caution when switching from boosted PI to another class if full treatment/resistance history not known
▪ Consult an expert when switching if resistance to ≥ 1 class
▪ Within-class switches usually maintain virologic suppression if no resistance to drugs in that class are present
Switching From Suppressive ART to an STR: Key Studies With Contemporary Regimens
• Noninferior efficacy for all switch regimens vs baseline regimen; all FDA approved to treat virologically suppressed patients
Key Studies Switch From Switch to
380-1878[1]
380-1844[2]
Boosted PI + 2 NRTIs DTG/ABC/3TC
BIC/FTC/TAF
SWORD 1 & 2[3] Third agent + 2 NRTIs DTG/RPV
STRIIVING[4] Third agent + 2 NRTIs DTG/ABC/3TC
EMERALD[5] Boosted PI + FTC/TDF DRV/COBI/FTC/TAF
GS-109[6] TDF-based regimen EVG/COBI/FTC/TAF
GS-1216[7]
GS-1160[8]RPV/FTC/TDFEFV/FTC/TDF
RPV/FTC/TAF
▪ Most recent FDA approvals: for BIC/FTC/TAF and DTG/RPV, must have no history of treatment failure and no resistance to regimen components; for DRV/COBI/FTC/TAF, must have no resistance to DRV, TFV
1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Llibre. Lancet. 2018;391:839. 4. Trottier. Antivir Ther. 2017;22:295.
5. Orkin. Lancet HIV. 2018;5:e23. 6. Mills. Lancet Infect Dis. 2016;16:43. 7. Orkin. Lancet HIV. 2017;4:e195. 8. DeJesus. Lancet HIV. 2017;4:e205.
SWORD-1 and -2: Switch to Dolutegravir + Rilpivirinevs Continue Therapy in Patients on Stable ART
Aboud M, et al. J Int AIDS Soc. 2018;21(suppl 6). Abstract THPEB047.
Dolutegravir + Rilpivirine
(n=513)
Stable ART
(n=511)
Week 0 52 100 148
Randomization1:1
48
Dolutegravir + Rilpivirine
Late-SwitchPhase
Early-SwitchPhase
ContinuationPhase
Dolutegravir + Rilpivirine
PrimaryEndpoint
HIV RNA <50 copies/mL(ITT-E snapshot)
2 IdenticalPhase 3 StudiesOpen-labelOn stable ART ≥6 months
(INSTI, NNRTI, or PI + 2 NRTIs)
HIV RNA <50 copies/mLfor 12 months
HBV negative
CurrentAnalysis
SWORD-1 and -2: Pooled Outcomes After Switch to Dolutegravir + Rilpivirine in Patients on Stable ART
• Dolutegravir + rilpivirine
• Non-inferior to stable ART at week 48
• Durable efficacy maintained through 100 weeks
• Stable ART late switch to dolutegravir + rilpivirine
• Consistent outcomes with week-48 results
• Virologic failures in both arms (n=10)
• None with emergent INSTI mutations
• Emergent NNRTI mutations with dolutegravir + rilpivirine (0.3%)
• Minimal impact on future ART options
• Safety of dolutegravir + rilpivirine was consistent with full prescribing information of each drug
Aboud M, et al. J Int AIDS Soc. 2018;21(suppl 6). Abstract THPEB047.
HIV RNA <50 Copies/mL
0
20
40
60
80
100
Week 48(Primary Outcome)
(n=513/511)
Day 1 to Week 100
(n=512)
Pa
tie
nts
(%
)
Week 52 to 100(Late Switch From
Stable ART)(n=477)
95% 95% 93%89%
Dolutegravir + rilpivirine Stable ARTTreatment Difference-0.2 (-3.0, 2.58)
TANGO Phase III Study Design
van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB. 18
Randomized, open-label, multicenter, parallel-group, non-inferiority study
DTG/3TC (N=369)b
Day
1
Screening
TAF-based regimen (N=372)
DTG/3TC
Week
48
Early-switch phase Late-switch
phase
Continuation
phase
Week
144
Week
24
Week
96
•Adults, virologically
suppressed (HIV-1 RNA
<50 c/mL) for >6 months
•Stable TAF-based regimen
Randomizationa
1:1
Week
148
Week
196
DTG/3TC DTG/3TC
Primary endpointc:
participants with
virologic failure per
FDA Snapshot (ITT-E)d
Eligibility criteria• ≥2 documented HIV-1 RNA
measurements <50 c/mL
• No HBV infection or need for
HCV therapy
• No prior VF and no documented
NRTI or INSTI resistance
• TAF/FTC + PI or INI or NNRTI as
initial regimenc
Australia
Belgium
Canada
France
Germany
Japan
Netherlands
Spain
United
Kingdom
United States
Countries
• In the per-protocol population, 0/352 participants in the DTG/3TC group and 2/358
participants in the TAF-based regimen group had HIV-1 RNA ≥50 c/mL at Week 48
(adjusted difference, −0.6; 95% CI, −1.3 to 0.2)
DTG/3TC Is Non-inferior to TAF-Based 3-Drug Regimen at Week 48
van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB. 19
0
93.2
6.50.6
93.0
6.5
0
20
40
60
80
100
HIV-1 RNA ≥50 c/mL
HIV-1 RNA<50 c/mL
No virologicdata
Pro
po
rtio
n o
f p
art
icip
an
ts,
%
DTG/3TC(N=369)
TAF-basedregimen (N=372)
Virologic outcomes Adjusted treatment difference (95% CI)
-8 -6 -4 -2 0 2 4 6 8
-3.4 3.9
Difference, %
-8 -6 -4 -2 0 2 4 6 8
-1.2 0.7
TAF-based regimen Primary endpoint:
DTG/3TC non-inferior to
TAF-based regimen
(≥50 c/mL) at Week 48
Key secondary endpoint:
DTG/3TC non-inferior to
TAF-based regimen
(<50 c/mL) at Week 48
DTG/3TC
TAF-based regimen DTG/3TC
-8% non-inferiority margin
Change in Serum Lipids From Baseline at Week 48: Safety Population
van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.
TC, total cholesterol; TGL, triglycerides.an = number of participants with non-missing fasting lipid data at Week 48, removing participants with lipid-modifying agent administered at baseline (lipid data collected after a lipid-modifying agent are censored and uses last on-treatment pre-modifying agent LOCF method). bNCEP categories at Week 48 vs baseline. cPurple shading indicates High for LDL.
20
NA, NA, Borderline high, High, 4.4 to <5
High, Low, Very high, Very high, ≥5
Missing
Desirable, High, Optimal, Normal, <3.5
Borderline high, Normal, Near/Above optimal, Borderline high, 3.5 to <4.4
0
25
50
75
100
TCb
BL W48
Pa
rtic
ipa
nts
, %
TAF-based regimen (n=277)a
HDLb LDLb,c TGLb TC/HDL TCb HDLb LDLb,c TGLb TC/HDL
BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48
DTG/3TC (n=291)a
Change in Renal Biomarkers at Week 48
van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB. 21
-2.9
6.3
-2.7
1.6
6.7
-7.8
-20-15-10-505
101520
Ch
an
ge
fro
m b
ase
line
, %
b6.67
-7.8
0.12.19
-3.0-1.6
-10
-5
0
5
10
Ad
juste
d m
ea
n c
ha
ng
e
fro
m b
ase
line
a
eGFR from
creatinine,
CKD-EPI
(mL/min/1.73 m2)
Creatinine
(µmol/L)
Protein/
Creatinine
(g/mol)
Retinol-binding
protein/
Creatinine
(µg/mmol)
Beta-2
microglobulin/
Creatinine
(mg/mmol)
DTG/3TC (N=369) TAF-based regimen (N=371)
*P<0.001
*
*
Plasma/Serum markers Urine markers
eGFR from
cystatin C,
CKD-EPI
(mL/min/1.73 m2)
• All participants in the DTG/3TC group with pro-viral M184V/I at baseline maintained HIV-1 RNA <50 c/mL at Week 48
Virologic Response by Pro-Viral M184V/I Status:Post Hoc Analysis of Stored Baseline Samples
van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.22
Participants, n (%)DTG/3TC (N=318)a
TAF-based regimen(N=308)
Pro-viral M184V/I at baselineb 4 (1) 3 (1)
HIV-1 RNA <50 c/mL at Week 48 4 (100) 3 (100)
HIV-1 RNA ≥50 c/mL at Week 48 0 0
No pro-viral M184V/I at baseline 314 (99) 305 (99)
HIV-1 RNA <50 c/mL at Week 48 314 (100) 303 (99)
HIV-1 RNA ≥50 c/mL at Week 48 0 2 (1)
GS-4030: Switching to TAF/FTC/BIC from DTG Plus FTC/TAF or FTC/TDF
• Phase 3, randomized, double-blind, active-controlled study
• Documented or suspected NRTI, NNRTI and PI resistance permitted
• Randomization stratified by known or suspected NRTI resistance category at baseline
• 1) K65R or ≥3 TAMS; 2) other NRTI mutations; 3) no known NRTI resistance
• Primary endpoint: proportion with HIV-1 RNA ≥50 c/mL at Week 48
• Noninferiority margin of 4% based on FDA snapshot algorithm
Week 0 48
Adults with HIV on DTG + F/TAFor DTG + F/TDF
▪ HIV-1 RNA <50 c/mL for ≥3 or 6 mo
▪ eGFRCG ≥30 mL/min
▪ No known INSTI resistance
▪ No prior virologic failure on INSTI
DTG + F/TAF placebo qd
B/F/TAF qd
B/F/TAF Placebo qd
DTG + F/TAF qd
n=284
n=281
Primary Endpoint
1:1
N=565
Sax PE et al. IAS 2019; Mexico City, Mexico. Abs MOAB0105.
<1
93
61
91
8
0
20
40
60
80
100
HIV-1 RNA
<50 c/mL
HIV-1 RNA
≥50 c/mL
No Virologic
Data
1
284
3
281
265
284
256
281
22
281
18
284
GS-4030: Virologic Outcome at Week 48
• Switching to B/F/TAF was noninferior to remaining on DTG + F/TAF
• No participant with pre-existing NRTI resistance had HIV-1 RNA ≥50 c/mL in either group
Treatment Difference in % Participants With HIV-1 RNA ≥50 c/mL (95.001% CI)
-… 1.0
-0.7
-4 -2 0 2 4
FavorsB/F/TAF
Favors DTG + F/TAFDTG+ F/TAF (n=281)
B/F/TAF (n=284)
Virologic Outcome by FDA
Snapshot
Pa
rtic
ipan
ts, %
Sax PE et al. IAS 2019; Mexico City, Mexico. Slides MOAB0105.
GS-4030: Pre-existing NRTI Resistance
*20 participants stratified to categories 1 or 2 based on investigator-suspected NRTI resistance (19 participants category 2, and 1 participant category 1); †Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions; ‡Includes only M184V/I mutations confirmed by genotype.
Category NRTI Mutation, n (%)
Stratification at randomization*
n=565Final analysis
n=565B/F/TAFn=284
DTG + F/TAFn=281
1K65R/E/N or ≥3 TAMs† 15 (3) 30 (5) 16 (6) 14 (5)
2 Any other pattern 63 (11) 108 (19) 55 (19) 53 (19)
3 No NRTI mutation 487 (86) 427 (76) 213 (75) 214 (76)
M184V/I‡ ± other mutations (from category 1 or 2)
29 (5) 81 (14) 47 (17) 34 (12)
M184V/I‡ only 12 (2) 21 (4) 15 (5) 6 (2)
Sax PE et al. IAS 2019; Mexico City, Mexico. Abs MOAB0105.
91 9487 91 91 8786
9387 85 86 85
0
20
40
60
80
100
Overall
GS-4030: Sensitivity Analysis for Low-level Viremiaby Resistance Mutations
♦ Undetectable HIV-1 RNA (target not detected) by overall B/F/TAF 64.1% vs DTG +F/TAF 60.5%
*Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions.
26
Virologic Outcome HIV-1 RNA <20 c/mL by FDA Snapshot
Pa
rtic
ipan
ts, %
DTG+ F/TAF (n=281)
B/F/TAF (n=284)
K65R or
≥3 TAMs*
Other NRTI
resistance
No NRTI
resistance
15
16
13
14
194
213
182
214
48
55
46
53
M184V/I ±
other resistance
No M184V/I
216
237
212
247
41
47
29
34
257
284
241
281
Sax PE et al. IAS 2019; Mexico City, Mexico. Slides MOAB0105.
ATLAS: Phase 3 Trial, IM Cabotegravir + Rilpivirine vsOral Therapy in Patients with Virologic Suppression
Swindells S, et al. CROI 2019. Abs. 139.
CAB LA (400 mg) + RPV LA (600 mg)§
IM monthly n=303
Screening Phase Maintenance Phase Extension Phase
PI, NNRTI or INSTI†
Current daily oral ART n=308N=705PI-, NNRTI-, or INSTI-based regimen with 2 NRTI backbone* R
and
om
izat
ion
1:1
Extension Phase or transition to the ATLAS-2M study
Oral CAB + RPV n=308
Primary Endpoint
Day 1Baseline
Week 96
Week 48
Week 4‖
Week 52
ATLAS
Rate of Virologic Success
Swindells S, et al. CROI 2019. Abs. 139.
Virologic Outcomes
Adjusted Treatment Difference (95% CI)*
1.6
92.5
5.81.0
95.5
3.6
0
20
40
60
80
100
Pro
po
rtio
n o
f P
art
icip
an
ts (
%)
CAB LA +RPV LA(n=308)
Virologic nonresponse (≥50 c/mL)
Virologic success
(<50 c/mL)
No virologic data
-1.2 2.5
0.6
-10 -8 -6 -4 -2 0 2 4 6 8 10Difference (%)
-6.7
-3.0
-10 -8 -6 -4 -2 0 2 4 6 8 10
0.7
Key Secondary Endpoint(HIV-1 RNA < 50 copies/mL)LA CAB + LA RPV noninferior
to continued BL ART
Primary Endpoint(HIV-1 RNA ≥ 50 copies/mL)LA CAB + LA RPV noninferior
to continued BL ART
6% NImargin
*Adjusted for sex and BL third agent class.
Continued ARTLA CAB + LA RPV
Continued ART LA CAB + LA RPV
Take Home Messages
• Switching therapy in patients with virologic suppression to better tolerated drugs with less potential for toxicity is an essential ARV strategy
• We should be switching regimens when there is an opportunity
• Combinations with next generation integrase inhibitors offer the opportunity to use well tolerated 3-drug and 2-drug combinations as maintenance therapy