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Dual vs. Triple ART: What to start?

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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!