1. Dual vs. Triple ART: What to start?
R.M. Gulick, MD, MPH
Professor of Medicine
Weill Cornell Medicine
New York City

2. Disclosures
none

3. Evolution of ART (123 drugs)
1994: 2-drug NRTI therapy superior to monotherapy
ACTG 175 (N=2467): Hammer NEJM 1996;335:
Delta (N=3308): Delta Study group Lancet 1996;348:283-91
CPCRA (N=1113): Saravolatz NEJM 1996;335:
NUCA 3001 (N=366): Eron NEJM 1995;333:1662-9
NUCB 3001 (N=223): Staszewski JAMA 1996;276:
1996: 3-drug therapy with 2 NRTI + PI (or NNRTI) superior to 2 NRTI
ACTG 320 (N=1156): Hammer NEJM 1997;337:725-33
MRK 035 (N=97): Gulick NEJM 1997;337:734-9
INCAS (N=153): Montaner JAMA JAMA 1998;279:930-7
↓ number of drugs: toxicity, complexity, class-sparing, cost

4. Maintenance ART: 2-Drug vs. 3-Drug
ACTG 343 (N=509) Havlir NEJM 1998;339:1261–1268
ZDV/3TC/IDV  ZDV/3TC or IDV or continue 3 drugs
Trilege (N=279) Flandre AIDS 2002;16:561-8
ZDV/3TC/IDV  ZDV/3TC or ZDV/IDV or continue 3 drugs (stopped early)
ADAM (N=62) Reijers Lancet 1998;352:185–190
d4T/3TC/SQV/NFV  d4T/NFV or SQV/NFV or continue 4 drugs (stopped early)
Cochrane Systematic Review: Loss of virologic suppression
Rutherford Cochrane Rvw 2003;4:CD002037

5. What to Start?: 2-Drug Regimens (1)
PI/r + NNRTI (NRTI-sparing)
ACTG 5142 (2 NRTIs with [EFV or LPV/r] vs. LPV/r + EFV)
Study population: treatment-naïve; HIV RNA >2000; resistance testing if HIV-infected <1 year (N=757)
89% 2 NRTIs + EFV
83% LPV/r + EFV
77% 2 NRTIs + LPV/r
LPV/r + EFV: ↑resistance at virologic failure and ↑lipids
Riddler NEJM 2008;358:2095

6. What to Start?: 2-Drug Regimens (2)
PI/r + TDF
KALEAD (N=152) Pinola J Antivir Antiretrovir 2010;2:56-62
LPV/r + TDF (vs. LPV/r + 2 NRTI)
 >40% discontinuation of study meds; TDF not non-inferior
PI + integrase inhibitor
SPARTAN (N=94) Kozal HIV Clin Trials 2012;13:
ATV + RAL (vs. TDF/FTC + ATV/r) – stopped early
 20% grade 4 hyperbilirubinemia; virologic failure + RAL resistance
ACTG 5262 (N=112) Taiwo AIDS 2011;25:2113
DRV/r + RAL single-arm study
 26% with virologic failure at week 48

7. What to Start?: 2-Drug Regimens (3)
PI/r + 3TC
GARDEL (LPV/r + 3TC vs. 2 NRTI + LPV/r)
Study population: Rx-naive, HIV RNA >1000, no chronic HBV infection, no resistance to NRTIs, LPV, RTV (N=426)
88% 2-drug ART
84% 3-drug ART (with more tox d/c)
(∆ +4.6%, % CI: –2.2%, +11.8%; p=0·171)
2-drugs non-inferior
54% on 3-drugs on ZDV
Cahn Lancet Infect Dis 2014;14:572

8. What to Start?: 2-Drug Regimens (4)
PI/r + integrase inhibitor
PROGRESS: (N=206) Reynes AIDS Res Hum Retro 2013;29:256
LPV/r + RAL (vs. TDF/FTC + LPV/r)
 <70% virologic suppression overall at week 96
NEAT-001: (N=805) Raffi Lancet 2014;384:1942
DRV/r + RAL (vs. TDF/FTC + DRV/r)
 Subgroup analysis: DRV/r + RAL inferior if CD4 <200, VL >100,000
PI/r + CCR5 antagonist
MODERN (N=797) Stellbrink AIDS 2016;30:1229
DRV/r + MVC (vs. TDF/FTC + DRV/r)
 DSMB stopped study early due to lack of efficacy in MVC arm

9. Meta-Analysis: 2-drug Initial ART Regimens (2008-15)
Outcome: Virologic Failure
(N=11)
For baseline HIV RNA >100,000: RR 1.24 (95% CI: 1.03, 1.49)
For resistance mutations:
RR 2.04 (95% CI: 1.23, 3.39)
Achhra Lancet HIV 2016;3:e351-e360.

10. What to Start?: 2-Drug Regimens (6)
DTG + 3TC
PADDLE Study Cahn JIAS 2017;20:1-7; Figueroa IAS 2017 #MOPEB0287
Treatment-naïve individuals with HIV RNA 5-100K (N=20)
Results: All suppressed VL <50 by week 8
18/20 (90%) remained suppressed through week 96
1 had VL 9924661 with no RT mutations, then resuppressed
1 had adverse event (suicide) between weeks 24 and 36
ACTG Taiwo CID 2018;66:1689
Treatment-naïve, HIV RNA up to 500K (N=120)
90% <50 copies/ml at week 24 (FDA snapshot analysis)
One pt with suboptimal adherence developed 2-class resistance

11. What to Start?: 2-Drug Regimens (7)
DTG + 3TC
GEMINI 1 and 2 (N=1441) Cahn Lancet 2019;393:
Randomized, double-blinded, international phase 3 study
Study population: Rx-naive, HIV RNA ,000, no chronic HBV infection, no major resistance mutations
93% TDF/FTC + DTG
91% DTG + 3TC
∆ -1.7 (95% CI: -4.4, +1.1)
2 drugs non-inferior
no resistance
April 2019
96 week results: Cahn IAS 2019 #WEAB0404LB

12. Emerging 2-drug ART Regimens
DRV/r + 3TC
ANDES (N=182): Figueroa CROI 2018 #489
DRV/r + 3TC (vs. TDF/3TC + DRV/r) open-label
 93% with HIV RNA <50 on 2-drug ART
 non-inferior to 3-drug ART
DRV/r + DTG clinicaltrials.gov #NCT
D2EFT (N=1010): second-line therapy regimens
DRV/r + DTG (vs. 2 NRTI + DRV/r vs. 2 NRTI + DTG)
islatravir (MK-8591) + DOR Molina IAS 2019 #WEAB0402LB

13. ART Guidelines: What to Start? 2-drug ART: Alternative or “Other”
2-drug ART scenario
regimens
US DHHS 2018
when ABC, TAF, and TDF cannot be used or are not optimal
DRV/r + RAL*
DRV/r + 3TC
DTG + 3TC
IAS-USA 2018
JAMA 2018;320:379
when individuals cannot take ABC, TAF, or TDF
DRV/c or /r +
RAL or DTG or 3TC or FTC
EACS 2018
society.org/
alternative
DRV/c or /r + RAL*
WHO 2018
none
* performs less well/not recommended for baseline HIV RNA >100,000 or CD4 <200

14. Switching: Maintenance 2-Drug ART Regimens (1)
PI/r + 3TC (vs. 2 NRTIs + PI/r)
OLE (LPV/r, N=250) Arribas Lancet Infect Dis 2015;15:785
ATLAS-M (ATV/r, N=266) Fabbiani JIAS 2014;17:19808
SALT (ATV/r, N=286) Perez-Molina Lancet ID 2015;15:775
DUAL (DRV/r, N=249) Pulido CID 2017;65;2112
DTG + 3TC
ASPIRE: (N=90) Taiwo Clin Infect Dis 2018;66:1794–7
LAMIDOL/ANRS 167: (N=110) Joly JAC 2019;74:
TANGO: (N=700) Van Wyk IAS 2019 #WEAB0403LB

15. Switching: Maintenance 2-Drug ART Regimens (2)
II + NNRTI
SWORD 1 and 2 (DTG/RPV; N=1028) Llibre Lancet 2018;391:839
LATTE 2 (CAB + RPV; N=309) Margolis Lancet 2017;390:1499
ATLAS (CAB + RPV; N=616) Swindells CROI 2019 #139
FLAIR (CAB + RPV; N=629) Orkin CROI 2019 #140
DRV/r + DTG
TIVISTA (Italian Cohort; N=113) Capetti Antivir Ther 2017;22:
Spanish Cohort (N=50) Navarro Pharmacother 2019;39:
DUALIS (N=263) Spinner IAS 2019 #MOPEB269
HIV RNA <50: 86% (2 drugs) vs. 88% (3 drugs)
November 2017
May 2018

16. 2-Drug Initial ART: Conclusions
2-drug ART regimens challenge current 3-drug ART regimens.
Optimal 2-drug ART regimens are potent, convenient, well-tolerated, have a high barrier to resistance, and are drug-sparing.
Strongest 2-drug initial ART data:
Boosted PI + 3TC
Caveats: baseline resistance testing, HBV co-infection, side effects/drug interactions
DTG + 3TC
Caveats: VL <500K, baseline resistance testing, HBV co-infection, pregnancy, class drug resistance (rare), durability
Mixed 2-drug initial ART data: Boosted PI + INSTI
Emerging 2-drug regimens: DRV/r + 3TC, DRV/r + DTG, others
Current guidelines recommend 2-drug regimens as alternative/other – this may change!

17. Acknowledgments Cornell HIV Clinical Trials Unit (CCTU)
Division of Infectious Diseases
Weill Cornell Medicine
AIDS Clinical Trials Group (ACTG)
HIV Prevention Trials Network (HPTN)
Division of AIDS, NIAID, NIH
Industry partners
The participant volunteers!