Monotherapy or Dual Therapy in Switch Studies: Which is the Best Regimen? Dr. Jose R Arribas @jrarribas

Conflict of Interest Speaker’s Bureau, Member/Advisory Panel Only triple* Triple and Dual Triple, Dual and Mono Gilead ViiV Janssen MSD *so far Monotherapy or Dual Therapy

Monotherapy or Dual Therapy or Triple Therapy in Switch Studies: Which is the Best Regimen? Dr. Jose R Arribas @jrarribas

HOW TO EVALUATE AN ART REGIMEN? GUIDANCE FOR INDUSTRY The goal of antiretroviral treatment is to indefinitely maintain suppression of plasma HIV- ribonucleic acid (RNA) levels (also called viral load) below the level of detection of sensitive HIV-RNA assays ALL ABOUT VIRAL LOAD Sourhttps://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm355128.pdf Monotherapy or Dual Therapy

Monotherapy or Dual Therapy REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) DRV/r vs DRV/r + 2NRTis (PROTEA) -8.7% PI MONOTHERAPY bPI vs 2 NRTIs + 3rd drug (PIVOT) -1.4%* … … … 2015 2005 2008 2010 2014 2016 LPV/r vs LPV/r + 2 NRTIs (OK Pilot) LPV/r vs LPV/r + 2 NRTIs (OK 04) -5.7% DRV/r vs DRV/r + 2NRTis (MONET) -1.6% ATV/r vs ATV/r + 2 NRTIs (MODAT) -12% bPI monotherapy *(loss of future treatment options) Source: Arribas JR et al. JAIDS 2009; 51:147–152. Pulido F et al. AIDS 2008; 22:F1–9. Arribas JR et al. AIDS 2010; 24:223–230. Castagna A et al. AIDS 2014; 28:2269–2279. Antinori A et al. AIDS 2015; 29:1811–1820. Paton NI et al. The Lancet HIV 2015; 2:e417–26 Monotherapy or Dual Therapy

Monotherapy or Dual Therapy REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) DUAL THERAPY PI + MVC PI + ISTI … … … 2015 2005 2008 2010 2014 2016 bPI+CCR5I bPI + MVC vs bPI + 2NRTIs (MARCH) -17.4% ↑R ATV/r + RAL vs ATV/r + TDF/FTC (HARNESS) -17.1% ↑R bPI+ISTI Source: van Lunzen et al. J Acquir Immune Defic Syndr 2016; 71:538–543. Pett SL et al. Clin Infect Dis 2016; 63:122–132. Monotherapy or Dual Therapy

Monotherapy or Dual Therapy REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) ATV/r + 3TC vs ATV/r + 2 NRTIs (SALT, ATLAS) +1%, +9.8% DUAL THERAPY PI + 3TC LPV/r + 3TC vs LPV/r + 2NRTIs (OLE) +1% 2015 2016 DRV/r + 3TC Vs DRV/r + 2NRTIs (DUAL) -4% bPI+ 3TC (1051 patients in 4 RCT) Source: Di Giambenedetto et al. J Antimicrob Chemother. 2017 Jan 15. pii: dkw557. doi: 10.1093/jac/dkw557. Arribas JR, et al. The Lancet Infectious Diseases 2015;15(7):785–92. Pérez-Molina JA et al. The Lancet Infectious Diseases 2015; 15:775–784.Pulido F et al. HIV13, 2016 Glasgow, abstract O331 Monotherapy or Dual Therapy

DUAL THERAPY IN SWITCH STUDIES: FINDINGS MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI. 3TC, can substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI Monotherapy or Dual Therapy

DUAL THERAPY IN SWITCH STUDIES: FINDINGS MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI. 3TC, can substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI After 30 years of ART we still don’t know why only certain drug combinations control viral replication in the majority patients Monotherapy or Dual Therapy

1 BLIP IN 12 YEARS ON PI MONOTHERAPY (2005-2017) Monotherapy or Dual Therapy

ANTIRETROVIRAL DRUG HALF-LIFES Monotherapy or Dual Therapy

SWORD-1 AND SWORD-2 PHASE III STUDY DESIGN Screening Early switch phase Late switch phase Continuation phase 1:1 VL <50 c/mL on INI, NNRTI, or PI + 2 NRTIs DTG + RPV (N=513) DTG + RPV DTG + RPV CAR (N=511) Day 1 Week 52 Week 148 Inclusion criteria On stable CAR >6 months before screening 1st or 2nd ART with no change in prior regimen due to VF Confirmed HIV-1 RNA <50 c/mL during the 12 months before screening HBV negative Primary endpoint at 48 weeks: subjects with VL <50 c/mL (ITT-E snapshot)a Countries Argentina Australia Belgium Canada France Germany Italy Netherlands Russia Spain Taiwan United Kingdom United States a-8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies Source: Llibre et al. CROI 2017; Seattle, WA. Abstract 2421. Monotherapy or Dual Therapy

SWORD: SNAPSHOT OUTCOMES AT WEEK 48. ITT-E (POOLED) One subject on DTG + RPV meeting virologic withdrawal criteria had identified an NNRTI resistance–associated mutation (K101K/E) No INI resistance–associated mutations were identified Source: Llibre JM CROI 2017 #44LB Monotherapy or Dual Therapy

LATTE-2 Week 96 HIV-1 RNA <50 c/mL - ITT-ME (Snapshot) Virologic outcomes Treatment differences (95% CI) Oral IM Q8W IM TRIPLE DUAL − 0.6 20.5 −8.4 14.4 Q4W IM Source: Eron et al. IAS 2017 Paris, France. Abstract MOAX0205LB. Monotherapy or Dual Therapy

No INSTI resistance in 3 pts with virologic failure LAMIDOL INTERIM ANALYSIS: SWITCH TO DTG + 3TC EFFECTIVE IN MAINTAINING VIRAL SUPPRESSION 100 100 100 100 99 99 99 98 97 97% (101/104) pts maintained therapeutic success through 40 wks of dual therapy (study Wk 48) No INSTI resistance in 3 pts with virologic failure 7 pts with serious AEs; only 2 related to dual therapy 80 60 Pts With HIV-1 RNA < 50 copies/mL (%) 40 20 110/110 104/104 104/ 104 103/ 104 103/ 104 103/ 104 n/N = 102/ 104 101/ 104 Wk: 8 12 16 24 32 40 48 Wks 0-8: pts on baseline 3-drug ART switched to DTG + 2 NRTIs Wks 8-56: pts with HIV-1 RNA < 50 copies/mL switched to DTG + 3TC Source: Joly V, et al. CROI 2017. Abstract 458. Monotherapy or Dual Therapy

Monotherapy or Dual Therapy DOLUTEGRAVIR MONOTHERAPY. HIGHER RISK OF VIROLOGICAL FAILURE AND RESISTANCE DOMONO: 8/77 (10%) VF, 3 with ISTI resistance REDOMO: 11/122 (9%) VF, 9 with ISTI resistance Monotherapy or Dual Therapy

Monotherapy or Dual Therapy MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE BEST REGIMEN? Only two types of reduced drug regimes have matched the efficacy of 2NRTIs + 3rd drug in switch studies bPI + 3TC (vs bPI + 2 NRTIs) DTG + RPV These regimens contain a reverse transcriptase inhibitor with a long half life Confirmation pending: CAB LA & RPV LA, DTG-3TC Monotherapy or Dual Therapy

DO WE NEED TRIPLE THERAPY FOR EVERYONE FOR LIFE? MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE BEST REGIMEN? Dual DO WE NEED TRIPLE THERAPY FOR EVERYONE FOR LIFE? Do we Need a Reverse Transcriptase Inhibitor with a Long Half-life for Everyone for Life? Monotherapy or Dual Therapy

HOW TO EVALUATE AN ART REGIMEN? Residual viremia Persistent inflammation Immunoactivation Penetration in reservoirs Toxicity COST ONLY VIRAL LOAD? Monotherapy or Dual Therapy

Monotherapy or Dual Therapy AKNOWLEDGMENTS Babafemi Taiwo, Pedro Cahn, Federico Pulido, L Ciaffi, B.J.A. Rijnders, I.E.A. Wijting, José Luis Blanco, V Joly, E Martinez, JM Gatell. Jules Levin Joe Eron. José Luis Narro PARTICIPANTS IN CLINICAL TRIALS HIV Unit at La Paz Hospital Monotherapy or Dual Therapy