Dual vs. Triple ART: What to start? R.M. Gulick, MD, MPH Professor of Medicine Weill Cornell Medicine New York City
Disclosures none
Evolution of ART (123 drugs) 1994: 2-drug NRTI therapy superior to monotherapy ACTG 175 (N=2467): Hammer NEJM 1996;335:1081-90 Delta (N=3308): Delta Study group Lancet 1996;348:283-91 CPCRA (N=1113): Saravolatz NEJM 1996;335:1099-106 NUCA 3001 (N=366): Eron NEJM 1995;333:1662-9 NUCB 3001 (N=223): Staszewski JAMA 1996;276:111-117 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
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
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
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;13:119-130 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
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%, 95% 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
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
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.
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 9924661 with no RT mutations, then resuppressed 1 had adverse event (suicide) between weeks 24 and 36 ACTG 5353 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
What to Start?: 2-Drug Regimens (7) DTG + 3TC GEMINI 1 and 2 (N=1441) Cahn Lancet 2019;393:143-155 Randomized, double-blinded, international phase 3 study Study population: Rx-naive, HIV RNA 1000-500,000, 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
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 #NCT03017872 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
ART Guidelines: What to Start? 2-drug ART: Alternative or “Other” 2-drug ART scenario regimens US DHHS 2018 www.aidsinfo.nih.gov 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 www.europeanaidsclinical society.org/ alternative DRV/c or /r + RAL* WHO 2018 http://www.who.int/hiv/pub/guidelines/en/ none * performs less well/not recommended for baseline HIV RNA >100,000 or CD4 <200
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;74:739-745 TANGO: (N=700) Van Wyk IAS 2019 #WEAB0403LB
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;22:257-262 Spanish Cohort (N=50) Navarro Pharmacother 2019;39:501-507 DUALIS (N=263) Spinner IAS 2019 #MOPEB269 HIV RNA <50: 86% (2 drugs) vs. 88% (3 drugs) November 2017 May 2018
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, 2-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!
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!