Novel Antiretroviral Studies and Strategies Bob Harrington, MD University of Washington Presentation prepared by: Presenter Last Updated: Date

Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study Randomized study to start ART immediately (when CD4 > 500) or defer until CD4 < 350 215 sites in 35 countries, opened enrollment March 2011 N = 4685 men and women > 18 (median age 36), all with CD4 > 500 Median age 36, M:F 63%:27%, median CD4 651, VL 12,759 Median follow-up: 2.8 years Countries include low, middle and high income Outcome: combination of serious AIDS events, serious non-AIDS events and death INSIGHT START Study Group, New Engl J Med, July, 2015

Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study DSMB analysis of data from March 2015: Early Rx group: 42 events Deferred group: 96 events 57% reduction in the primary endpoint in the early Rx group Benefit regardless of age, sex, race, country, CD4 count, smoking status and FRS INSIGHT START Study Group, New Engl J Med, July, 2015

Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study End Point Immediate Rx Deferred Rx HR P value # #/100 py Composite primary endpoint 42 0.60 96 1.38 0.43 < 0.001 Components of endpoint Serious AIDS event 14 0.20 50 0.72 0.28 Serious non-AIDS event 29 0.42 47 0.67 0.61 0.04 Death 12 0.17 21 0.30 0.58 0.13 Tuberculosis 6 0.09 20 0.29 0.008 Kaposi’s sarcoma 1 0.01 11 0.16 0.02 Lymphoma 3 10 0.14 0.07 Non-AIDS cancer 9 18 0.26 0.50 Cardiovascular disease 0.84 0.65 INSIGHT START Study Group, New Engl J Med, July, 2015

Early Vs Deferred HAART TEMPRANO ANRS 12136 STUDY Unblinded, multicenter, randomized, controlled, 2 X 2 factorial trial conducted in 9 care centers in the Ivory Coast N = 2056 men and women > 18, with CD4 < 800 who met no criteria for starting ART. Randomized to: Deferred ART (until meeting WHO criteria) Deferred ART + IPT Immediate ART Immediate ART + IPT Primary endpoint: composite of AIDS illness OR non-AIDS cancer OR non-AIDS invasive bacterial infection OR death at 30 months Median age 35, F 79%, median CD4 ~ 460 (40% > 500) TEMPRANO ANRS 12136 Study Group, New Engl J Med, July, 2015

Early Vs Deferred HAART TEMPRANO ANRS 12136 STUDY TB and invasive bacterial disease accounted for 42% and 27% of the primary endpoints No difference in grade 3,4 AEs between the groups All patients HR for death or severe HIV disease (Early Vs late ART) HR for death or severe HIV disease (IPT Vs no IPT) All patients 0.56 (0.41-0.76) 0.65 (0.48-0.88) Patients with CD4 > 500 0.56 (0.33-0.94) 0.61 (0.36-1.01) CD4 > 500 CD4 < 500 TEMPRANO ANRS 12136 Study Group, New Engl J Med, July, 2015

SALT Study r/ATZ + 3TC Vs r/ATZ + 2 nRTIs Randomized, open label study, N = 286, Spain No h/o drug failure or drug resistance No chronic HBV HIV RNA < 50 copies/mL for at least 6 months Randomized to: r/ATZ + 3TC r/ATZ + 2 nRTIs (chosen by investigators) Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks Perez-Molina, Lancet Infect Disease, 2015

SALT Study r/ATZ + 3TC Vs r/ATZ + 2 nRTIs Dual therapy not inferior to triple therapy Toxicity similar between regimens Fewer patients in the dual therapy arm discontinued treatment (3 [2%] Vs 10 [7%]) < 50 at 48 Weeks Perez-Molina, Lancet Infect Disease, 2015

GARDEL Study r/LPV + 3TC Vs r/LPV + 2 nRTIs Randomized, controlled, open label study, N = 426, Argentina, Chile, Mexico, Peru, Spain and the US >18 years, ART naïve, VL > 1000, no CD4 criteria No h/o drug failure or drug resistance No chronic HBV Baseline characteristics Median CD4 ~ 320 Median HIV RNA 4.87 logs (44% > 100,000 copies) Randomized to: r/LPV + 3TC r/LPV + 2 nRTIs (chosen by investigators FTC/3TC + ABC or TDF or AZT) Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks Cahn, Lancet Infect Disease, 2014

GARDEL Study r/LPV + 3TC Vs r/LPV + 2 nRTIs Results Dual Rx Triple Rx < 50: all patients 88.3% 83.7% < 50 (BL VL > 100,000) 87.2% 77.9% Toxicity - discontinuations 1 (0.4%) 10 (4.9%) AEs 65 88 All pts > 100,000 Cahn, Lancet Infect Disease, 2014

OLE Study r/LPV + 3TC Vs r/LPV + 2 nRTIs Randomized, open label study, N = 250, Spain and France No h/o drug failure or drug resistance No chronic HBV HIV RNA < 50 copies/mL for at least 6 months on r/LPV + 2 nRTIs Randomized to: r/LPV + 3TC r/LPV + 2 nRTIs (chosen by investigators) Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks Arribas, Lancet Infect Disease, 2015

OLE Study r/LPV + 3TC Vs r/LPV + 2 nRTIs 48 Weeks Arribas, Lancet Infect Disease, 2015

Notes from IAS 2015: TAF A. Mills: Switching from TDF to TAF based regimens: data from suppressed patients at 48 weeks ~1200 patients, < 50 for 96 weeks on Stribild, Atripla or r/ATZ + TRU Switched to TAF + FTC + c/ELV or stayed on original regimen VL < 50 at 48 weeks: 97% (TAF) Vs 93% (TDF) (TAF superior to TDF) Increased BMD and less renal effects in TAF treated patients S. Gupta: Subjects with renal impairment switching from TDF to TAF: improved renal and bone safety at 48 weeks Single arm, open label study N = 242, CrCl 30-69 At 48 weeks: No change in GFR, reduced urine RBP, B2MG and protein excretion Improved BMD Increased TG, TC and LDL IAS 2015 Vancouver

Notes from IAS 2015: Doravirine J Gatell: Efficacy and safety of Doravirine + TDF/FTC Vs Efavirenz + TDF/FTC in ART naïve patients (24 weeks) Doravirine – unique R profile, is metabolized by CYP3A4 but does not induce or inhibit the enzyme N = 216 patients, 24 week analysis DRV (100 mg) + TDF/FTC EFV (600 mg) + TDF/FTC < 200 < 40 All patients 90% 73% 88% 72% BL < 100,000 92% 95% BL > 100,000 60% 66% AEs 28% 56% IAS 2015 Vancouver