1. 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

2. 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)

3. 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

4. Investigational Treatment Strategies

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

7. 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

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

11. Investigational Drugs/Formulations

12. 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.

14. AE

15. Bictegravir vs. Dolutegravir for First-Line Therapy
Baseline Characteristics
Median HIV RNA= 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:e

18. 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 CD cells/uL
87-88% TDF/FTC
Molin J-M, et al. 24th CROI 2017, Abst 45LB

21. 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)

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

27. 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)

29. 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 Abstract 449LB.

30. 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 < vs 3% at end of control period.
1. Lewis S, et al. CROI Abstract 449LB.
2. ClinicalTrials.gov. NCT

31. 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 Abstract O335A.
Llamoso C, et al. HIV Glasgow Abstract O335B.
*Fostemsavir dose changed to 1200 mg QD from Wk 48 to Wk 96.

32. 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 Abstract O335A. 2. Llamoso C, et al. HIV Glasgow Abstract O335B. 3. ClinicalTrials.gov. NCT

33. Thank you for your Attention Questions?