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Dual vs. Triple ART: What to start?

This article explores the evolution and effectiveness of dual and triple antiretroviral therapy regimens for HIV treatment. It provides an overview of various studies and clinical trials comparing different drug combinations and their outcomes. The article also discusses emerging 2-drug ART regimens and their potential as alternative treatment options.

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Dual vs. Triple ART: What to start?

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  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;335:1081-90 • 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

  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) FlandreAIDS 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 RutherfordCochrane 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 AntivirAntiretrovir 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

  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%, 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

  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 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

  11. What to Start?: 2-Drug Regimens (7) April 2019 • 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 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 #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

  13. ART Guidelines: What to Start? 2-drug ART: Alternative or “Other” * 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;74:739-745 • 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) CapettiAntivirTher 2017;22:257-262 • Spanish Cohort (N=50)Navarro Pharmacother2019;39:501-507 • 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, 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!

  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!

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