Investigational Approaches to Antiretroviral Therapy Eric S. Daar, MD Professor of Medicine University of California Los Angeles Los Angeles, California FORMATTED: 04/26/17 Chicago, Illinois: May 10, 2017

Financial Relationships With Commercial Entities Dr Daar has received research and grant support from Gilead Sciences, Inc, Merck, and ViiV Healthcare. He has also received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Merck, Teva, and ViiV Healthcare. (Updated 04/26/17)

Learning Objectives After attending this presentation, learners will be able to: Summarize treatments being investigated for HIV-infected persons with viremia Describe treatments being investigated for those with virologic suppression on antiretroviral therapy

Investigational Treatment Strategies

PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) Cahn P, et al 21st International AIDS Conference 2016, Durban, South Africa, Abstract FRAB0104LB

ANRS 167 LamiDol Study: DTG/3TC Maintenance Inclusion Criteria CD4 nadir>200 cells/uL No h/o VF and suppressed >2 yrs Baseline Characteristics Time on ART (4.0 yrs) CD4 743 cells/uL Third agent: NNRTI (56%); PI (23%); INSTI (21%) Primary end-point: Proportion therapeutic success* at wk 56 of DTG + 3TC *no VF, interruption, LTFU or death Joly V, et al. 24th CROI 2017, Abst 458

Confirmed virologic withdrawal 2 per arm One DTG + RPV had K101K/E No INSTI resistance

Investigational Drugs/Formulations

Once-Daily Raltegravir Baseline Characteristics Median HIV RNA 4.6 log/mL (28% >100,000 c/mL) Median CD4 380/416 cells/uL Cahn P, et al 21st International AIDS Conference 2016, Durban, South Africa, Abstract FRAB0103LB.

AE

Bictegravir vs. Dolutegravir for First-Line Therapy Baseline Characteristics Median HIV RNA= 4.4-5 log10/mL (15-21% >100,000 c/mL) Median CD4= 441/455 cells/uL Sax PE, et al. 24th Conference on Retroviruses and Opportunistic Infections 2017; Seattle, WA. Abstract 41. Sax PE, et al. Lancet HIV. 2017; 4:e154-160.

Doravirine vs. Darunavir/ritonavir for First-Line Therapy Baseline Characteristics Median HIV RNA 4.4 log10 c/mL (19-22% >100,000 c/mL) Median CD4 412-433 cells/uL 87-88% TDF/FTC Molin J-M, et al. 24th CROI 2017, Abst 45LB

Virologic Failure and Resistance Non PDVF patients D/C with noncompliance at week 24: V106I, H221Y, F227C and M184V with high level DOR resistance Rash at week 2 with 2.8- fold increase (from 2.2 fold at baseline)

LATTE 2 Margolis D, et al. 21st International AIDS Conference 2016, Durban, South Africa, Abstract THAB0206LB

PDVF Q8wk (2); Q4wk (0); Daily (1) Only resistance in single Q8wk patient: NNRTI- K103N, E138G and K238T; INSTI- Q148R (5.8 FC to CAB)

TMB-301: Ibalizumab in Patients with Multidrug Resistance Baseline Characteristics Mean VL= 100,287 c/mL Mean CD4= 150 cells/uL Fostemsavir in OBR= 43% Resistance: NRTI (93%); NNRTI (93%); PI (88%); INSTI (68%) Ibalizumab: humanized mAb to CD4 receptor that blocks HIV entry into CD4+ T-cells FDA breakthrough and orphan drug designations Single-arm, open-label phase III trial Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14 53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance; 43% required investigational agent fostemsavir in OBR Pts with HIV-1 RNA > 1000 copies/mL; on ART ≥ 6 mos, on stable ART ≥ 8 wks; resistant to ≥ 1 ARV from 3 classes, sensitive to ≥ 1 ARV for OBR (N = 40) Wk 25 Ibalizumab 2000 mg IV Day 7 (loading dose) Continue Failing ART Days 0-14 800 mg IV Day 21, Q2W (maintenance dose) Switch to OBR Day 14 Primary Endpoint: Control Period: Day 0-7 Lewis S, et al. CROI 2017. Abstract 449LB.

9 pts reported 17 serious AEs Virologic Outcome[1] Ibalizumab + OBR Day 14 ≥ 0.5 log10 HIV-1 RNA decrease, % 83* ≥ 1.0 log10 HIV-1 RNA decrease, % 60 Mean HIV-1 RNA decrease, log10 1.1 Wk 24 55 ≥ 2.0 log10 HIV-1 RNA decrease, % 48 HIV-1 RNA < 50 copies/mL, % 43 HIV-1 RNA < 200 copies/mL, % 50 Mean HIV-1 RNA decrease from BL, log10 1.6 9 pts reported 17 serious AEs 1 drug-related SAE (IRIS) resulted in discontinuation 9 other pts discontinued Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma) Consent withdrawal (n = 3) Lost to follow-up (n = 2) No cases of anti-ibalizumab antibodies Phase III TMB-311 study ongoing; extension for pts from TMB-301; accepting new pts[2] *Primary endpoint; P < .0001 vs 3% at end of control period. 1. Lewis S, et al. CROI 2017. Abstract 449LB. 2. ClinicalTrials.gov. NCT02707861.

Randomized, active-controlled, phase IIb study, blinded to dose Fostemsavir: attachment inhibitor prodrug; proposed MOA: binding HIV-1 gp120 prevents viral attachment and entry into host CD4+ cells Randomized, active-controlled, phase IIb study, blinded to dose Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 Fostemsavir 600 mg QD* + RAL + TDF (n = 51) HIV-infected pts with exposure HIV-1 RNA ≥ 1000 c/mL; CD4+ ≥ 50 cells/mm3; virus susceptible to RAL, TDF, ATV, and fostemsavir IC50 < 100 nM (N = 254) Wk 48 Wk 24: 1̊ endpoint ATV/RTV 300/100 mg QD + RAL + TDF Fostemsavir 1200 mg QD + RAL + TDF (n = 50) Fostemsavir 400 mg BID* + RAL + TDF Fostemsavir 800 mg BID* + RAL + TDF (n = 49) Wk 96 Granados-Reyes ER, et al. HIV Glasgow 2016. Abstract O335A. Llamoso C, et al. HIV Glasgow 2016. Abstract O335B. *Fostemsavir dose changed to 1200 mg QD from Wk 48 to Wk 96.

At Wk 96, 90% of pts had HIV-1 RNA < 50 copies/mL in both fostemsavir and ATV/RTV arms in observed analysis[1] No significant differences in virologic efficacy regardless of race, sex, age, BL HIV-1 RNA, BL CD4+ cell count, or IC50 subgroups[1] Fostemsavir generally well tolerated, with higher rates of grade 2-4 TEAEs (37% vs 9%) and d/c for AEs (10% vs 3%) for ATV/RTV arm vs fostemsavir arm[2] Phase III trial of fostemsavir in heavily treatment–experienced pts ongoing[3] Wk 49 Placebo Pts with HIV-1 RNA ≥ 400 c/mL on current regimen; ≤ 2 classes of active approved ARVs left to compose OBR due to resistance, intolerance, or contraindications Fostemsavir + OBR Day 8* Fostemsavir As above but with no active approved ARV options remaining *1° endpoint: mean log10 HIV RNA change from BL. 1. Granados-Reyes ER, et al. HIV Glasgow 2016. Abstract O335A. 2. Llamoso C, et al. HIV Glasgow 2016. Abstract O335B. 3. ClinicalTrials.gov. NCT02362503.

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