Monotherapy or Dual Therapy in Switch Studies Which

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

Monotherapy or Dual Therapy in Switch Studies: Which is the Best Regimen? Dr. Jose R Arribas @jrarribas #IAS 2017 | @IAS_Conference

#IAS 2017 | @IAS_conference Conflict of Interest Speaker’s Bureau, Member/Advisory Panel Only triple* Triple

#IAS 2017 | @IAS_conference Conflict of Interest Speaker’s Bureau, Member/Advisory Panel Only triple* Triple and Dual Triple, Dual and Mono Gilead MSD Vii. V Janssen *so far Monotherapy or Dual Therapy

Monotherapy or Dual Therapy or Triple Therapy in Switch Studies: Which is the Best

Monotherapy or Dual Therapy or Triple Therapy in Switch Studies: Which is the Best Regimen? Dr. Jose R Arribas @jrarribas #IAS 2017 | @IAS_Conference

#IAS 2017 | @IAS_conference HOW TO EVALUATE AN ART REGIMEN? GUIDANCE FOR INDUSTRY The

#IAS 2017 | @IAS_conference 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/ucm 355128. pdf Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) DRV/r vs DRV/r + 2 NRTis (PROTEA) -8. 7% PI MONOTHERAPY b. PI vs 2 NRTIs + 3 rd drug (PIVOT) -1. 4%* … … … 2015 2008 2010 2014 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 + 2 NRTis (MONET) -1. 6% ATV/r vs ATV/r + 2 NRTIs (MODAT) -12% b. PI monotherapy 2016 *(loss of future treatment options) Source: Arribas JR et al. JAIDS 2009; 51: 147– 152. Pulido F et al. AIDS 2008; 22: F 1– 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: e 417– 26 Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) DUAL THERAPY PI + MVC PI + ISTI … 2005 … 2008 … 2010 2015 2014 2016 b. PI + MVC vs b. PI + 2 NRTIs (MARCH) -17. 4% ↑R ATV/r + RAL vs ATV/r + TDF/FTC (HARNESS) -17. 1% ↑R b. PI+CCR 5 I b. PI+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

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary

#IAS 2017 | @IAS_conference REDUCED DRUG REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen) DUAL THERAPY PI + 3 TC ATV/r + 3 TC vs ATV/r + 2 NRTIs (SALT, ATLAS) +1%, +9. 8% LPV/r + 3 TC vs LPV/r + 2 NRTIs (OLE) +1% 2015 2016 b. PI+ 3 TC (1051 patients in 4 RCT) DRV/r + 3 TC Vs DRV/r + 2 NRTIs (DUAL) -4% Source: Di Giambenedetto et al. J Antimicrob Chemother. 2017 Jan 15. pii: dkw 557. doi: 10. 1093/jac/dkw 557. 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. HIV 13, 2016 Glasgow, abstract O 331 Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference DUAL THERAPY IN SWITCH STUDIES: FINDINGS • MCV or RAL

#IAS 2017 | @IAS_conference DUAL THERAPY IN SWITCH STUDIES: FINDINGS • MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI. • 3 TC, can substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference DUAL THERAPY IN SWITCH STUDIES: FINDINGS • MCV or RAL

#IAS 2017 | @IAS_conference DUAL THERAPY IN SWITCH STUDIES: FINDINGS • MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI. • 3 TC, 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

#IAS 2017 | @IAS_conference 1 BLIP IN 12 YEARS ON PI MONOTHERAPY (2005 -2017)

#IAS 2017 | @IAS_conference 1 BLIP IN 12 YEARS ON PI MONOTHERAPY (2005 -2017) Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference ANTIRETROVIRAL DRUG HALF-LIFES Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference ANTIRETROVIRAL DRUG HALF-LIFES Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference SWORD-1 AND SWORD-2 PHASE III STUDY DESIGN Screening Early switch

#IAS 2017 | @IAS_conference SWORD-1 AND SWORD-2 PHASE III STUDY DESIGN Screening Early switch phase 1: 1 DTG + RPV CAR (N=511) Day 1 Inclusion criteria • On stable CAR >6 months before screening • 1 st or 2 nd ART with no change in prior regimen due to VF • Confirmed HIV-1 RNA <50 c/m. L during the 12 months before screening • HBV negative a-8% Continuation phase DTG + RPV (N=513) VL <50 c/m. L on INI, NNRTI, or PI + 2 NRTIs • Late switch phase Week 52 Primary endpoint at 48 weeks: subjects with VL <50 c/m. L (ITT-E snapshot)a Week 148 Countries Argentina Australia France Germany Russia Spain United States 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 Belgium Italy Taiwan Canada Netherlands United Kingdom

#IAS 2017 | @IAS_conference SWORD: SNAPSHOT OUTCOMES AT WEEK 48. ITT-E (POOLED) One subject

#IAS 2017 | @IAS_conference 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 (K 101 K/E) No INI resistance–associated mutations were identified Source: Llibre JM CROI 2017 #44 LB Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference LATTE-2 Week 96 HIV-1 RNA <50 c/m. L - ITT-ME

#IAS 2017 | @IAS_conference LATTE-2 Week 96 HIV-1 RNA <50 c/m. L - ITT-ME (Snapshot) Virologic outcomes Treatment differences (95% CI) DUAL 100 94 87 HIV-1 RNA <50 c/m. L, % Oral IM Q 8 W IM CAB + RPV LA Q 8 W (n=115) CAB + RPV LA Q 4 W (n=115) 84 CAB + NRTIs PO (n=56) 80 10. 0% − 0. 6 TRIPLE 60 40 20. 5 Q 4 W IM 13 14 20 4 0 Virologic success 0 2 Virologic non-response 3. 0% 2 No virologic data Source: Eron et al. IAS 2017 Paris, France. Abstract MOAX 0205 LB. 14. 4 − 8. 4 -12 -9 Monotherapy or Dual Therapy -6 -3 0 3 6 9 12 15

#IAS 2017 | @IAS_conference LAMIDOL INTERIM ANALYSIS: SWITCH TO DTG + 3 TC EFFECTIVE

#IAS 2017 | @IAS_conference LAMIDOL INTERIM ANALYSIS: SWITCH TO DTG + 3 TC EFFECTIVE IN MAINTAINING VIRAL SUPPRESSION Pts With HIV-1 RNA < 50 copies/m. L (%) 100 100 99 99 99 80 60 40 20 n/N = 0 Wk: 110/ 110 104/ 104 103/ 104 0 8 12 16 24 32 Wks 0 -8: pts on baseline 3 -drug ART switched to DTG + 2 NRTIs Source: Joly V, et al. CROI 2017. Abstract 458. 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 102/ 101/ failure 104 – 7 pts with 40 48 serious AEs; only 2 related Wks 8 -56: pts with HIV-1 RNA < 50 to dual copies/m. L switched to DTG + 3 TC therapy Monotherapy or Dual Therapy •

#IAS 2017 | @IAS_conference DOLUTEGRAVIR MONOTHERAPY. HIGHER RISK OF VIROLOGICAL FAILURE AND RESISTANCE •

#IAS 2017 | @IAS_conference 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

#IAS 2017 | @IAS_conference MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE

#IAS 2017 | @IAS_conference MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE BEST REGIMEN? • Only two types of reduced drug regimes have matched the efficacy of 2 NRTIs + 3 rd drug in switch studies – b. PI + 3 TC (vs b. PI + 2 NRTIs) – DTG + RPV – These regimens contain a reverse transcriptase inhibitor with a long half life • Confirmation pending: CAB LA & RPV LA, DTG-3 TC Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE

#IAS 2017 | @IAS_conference 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

#IAS 2017 | @IAS_conference HOW TO EVALUATE AN ART REGIMEN? • • • Residual

#IAS 2017 | @IAS_conference HOW TO EVALUATE AN ART REGIMEN? • • • Residual viremia Persistent inflammation Immunoactivation Penetration in reservoirs Toxicity COST ONLY VIRAL LOAD? Monotherapy or Dual Therapy

#IAS 2017 | @IAS_conference AKNOWLEDGMENTS Babafemi Taiwo, Pedro Cahn, Federico Pulido, L Ciaffi, B.

#IAS 2017 | @IAS_conference 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