HIV Treatment Evolution. Kimberly Y. Smith MD MPH Vice President and Head, Global Research and Medical Strategy Viiv Healthcare

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1 HIV Treatment Evolution Kimberly Y. Smith MD MPH Vice President and Head, Global Research and Medical Strategy Viiv Healthcare

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3 Overview of the Evolution of Antiretroviral Therapy Early Treatment Mono/Dual Therapy HAART Evolves Boosted PIs, NNRTIs Current ART Era INSTIs, bpis, FDCs, STRs, TAF Moving Forward 2017 Key Considerations Viral Suppression Life Expectancy Incomplete viral suppression; drug toxicities; emergence of resistance 1 Viral load measurement emerges as prognosis tool % expected to survive at 1 year after diagnosis 13 Suppress viral load; restore immune function; manage treatmentlimiting toxicities 2 SQV/r: 68% <400 c/ml at 48 weeks 5 EFV/ZDV/3TC: 69% <50 c/ml 48 at weeks Simplify dosing; improve tolerability; preserve treatment options 1 LPV/r: 67% <50c/mL at 48 weeks 7 DRV/r: 84% <50 c/ml at 48 weeks Optimize efficacy outcomes, tolerability, convenience, and adherence 3 RAL: 86% <50 c/ml at 48 weeks EVG STR: 87.6% <50 c/ml at 48 weeks 10 DTG: 93% <50 c/ml at 48 weeks 11 TAF vs TDF-based regimen, 92% and 90% <50 c/ml at 48 weeks, respectively Treatment optimization Dosing/formulations Tolerability/adherence Improve QoL Two drug regimens Long-acting injectables New drug targets Longer-term goals Vaccine Cure # of Pills Daily Up to 22/day /day /day ,3 Hit hard, hit early 1 Wait to treat CD4 count <200 cells/mm 31 Wait Treat to early; treat <350 Test and cell/mm treat 3 ; Treat early; test and treat 1 3TC, lamivudine; ART, antiretroviral therapy; bpi, boosted protease inhibitor; CD4, cluster of differentiation 4; c/ml, copies per milliliter; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FDC, fixed dose combination; HAART, highly active antiretroviral therapy; INSTI, integrase strand transfer inhibitor; LPV, lopinavir; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; QoL, quality of life; r, ritonavir; RAL, raltegravir; SQV, saquinavir; STR, single tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ZDV, Zidovudine. 1. Tseng A, et al. Br J Clin Pharmacol. 2014;79(2): Panel on Clinical Practices for Treatment of HIV Infection. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Released May 5, Accessed October 29, Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Accessed October 18, Mellors JW, et al. Science. 1996;272(5265): INVIRASE. [Prescribing Information]. Roche Laboratories, Inc., Nutley, NJ; April SUSTIVA [Prescribing Information]. Bristol-Myers Squibb Company, Princeton, NJ; October Walmsley S, et al. N Engl J Med. 2002;346(26): Ortiz R, et al. AIDS Jul 31;22(12): Lennox JL, et al. Lancet. 2009;374(9692): ClinicalTrials.gov. Accessed October 17, Gallant J, et al. Lancet. 2017; dos: Sax PE, et al. Lancet. 2015;385(9987): Rothenberg R. N Engl J Med. 1987;317: Marcus JL. J Acquir Immune Defic Syndr. 2016;73(1):39-46.

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9 HIV Prevention PREP

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11 Clinical Trial Evidence for HIV Prevention Options (February 2016) Prevention of sexual transmission PROUD daily oral TDF/FTC (MSM United Kingdom) IPERGAY event driven TDF/FTC (MSM Canada, France) Partners PrEP daily oral TDF/FTC (Serodiscordant couples Kenya, Uganda) Partners PrEP daily oral TDF (Serodiscordant couples Kenya, Uganda) TDF2 daily TDF/FTC (Heterosexual men and women Botswana) iprex daily oral TDF/FTC (MSM North and South America, South Africa, Thailand) Effect size (CI) 86% (58; 97) 86% (44; 99) 75% (55; 87) 67% (44; 81) 62% (22; 84) 44% (15; 63) CAPRISA 004 BAT 24 dosing vaginal tenofovir gel (Women South Africa) RV 144 six injectable ALVAC/AIDSVAX (Heterosexual men and women Thailand) The Ring Study monthly vaginal ring containing dapivirine (Women South Africa, Uganda) ASPIRE monthly vaginal ring containing dapivirine (Women Malawi, South Africa, Uganda, Zimbabwe) MTN 003/VOICE daily dosing vaginal tenofovir gel (Women South Africa, Uganda, Zimbabwe) FEM PrEP daily oral TDF/FTC (Women Kenya, South Africa, Tanzania) FACTS 001 event driven vaginal tenofovir gel (Women South Africa) MTN 003/VOICE daily oral TDF/FTC (Women South Africa, Uganda, Zimbabwe) MTN 003/VOICE daily oral TDF (Women South Africa, Uganda, Zimbabwe) R R R 39% (6; 60) 31% (1; 51) 31% (1; 51) 27% (1; 46) 15% (-21; 40) 6% (-21; 40) 0% (-40; 30) -4% (-49; 27) -49% (-129; 3) Prevention in people who inject drugs DELIVERY SYSTEM Bangkok Tenofovir Study daily oral TDF (PWID Thailand) ACTIVE DRUG % (10; 72) Vaccine Vaginal gel Oral pills Vaginal ring ALVAC/AIDSVAX Tenofovir Tenofovir/ emtricitabine (TDF/FTC) Dapivirin e Tenofovir disoproxil fumarate (TDF) Effectiveness (%) Adapted from: Salim S. Abdool Karim, CAPRISA

12 Relationship Between Effectiveness and Adherence in Microbicide & PrEP Trials Effectiveness (%) Pearson correlation = 0.86, p= CAPRISA 004 iprex TDF2 PartnersPrep PrEP (TDF) PartnersPreP PrEP (Truvada) (FTC) FemPrEP VOICE (TDF) VOICE (Truvada) VOICE (TFV gel) IPERGAY(Truvada) PROUD(Truvada) -60 Percentage of Participants Samples with detectable drug levels SS Abdool Karim, personal communication

13 The Ring Study 31% (1; 52) ASPIRE 27% (1; 46)

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16 Clinical Infect Dis, Sept 2015 Slide 24 of 34

17 What s Next? Slide 31 of 34 PrEP works, when taken consistently, and is the most effective tool for preventing sexual HIV transmission we have so far Only one ARV (TFV) available; data for women still limited Newer Investigational Agents Intravaginal dapivirine ring HPTN studies of long-acting ARV (cabotegravir, broadly neutralizing antibodies) Microbicide development Combination product development Antiretroviral + hormonal contraceptive

18 Thank You