HIV IS NOT OVER. Update From the Conference on Retroviruses and Opportunistic Infections (CROI) Learning Objectives

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1 Update From the Conference on Retroviruses and Opportunistic Infections (CROI) Davey M. Smith, MD, MAS Professor of Medicine University of California San Diego San Diego, California Learning Objectives After attending this presentation, learners will be able to describe data presented at the 2018 CROI pertaining to: Investigational drugs being developed for the treatment of HIV and its complications New advances in prevention of HIV and cure efforts New data on the optimal use of antiretroviral therapy (ART) Slide 3 of 36 HIV IS NOT OVER Slide 7 of 36

2 Slide 8 of 36 NA-ACCORD Study: Life Expectancy in U.S. and Canada Among Specific Groups 55,858 ART initiators 248,931 person-years of follow-up 3123 deaths Estimated life expectancy (LE) in 3 time periods: , , Althoff CROI 2018 #903 ANTIRETROVIRAL THERAPY: New Stuff Slide 9 of 36 MK-8591: nucleoside reverse transcriptase translocation inhibitor Not a chain terminator; slows further polymerization; prevents translocation 3 hydroxyl Slide 10 of 36 Absorbed rapidly, 0.25 mg achieves target dose in 24 hr Achieves steady state in a week Matthews, Abstract 26

3 Slide 11 of 36 MK-8591: Dosing Drug levels stay within goal range for a month after discontinuation Drug targets achieved in rectal, vaginal, and tissue PBMC Matthews, Abstract 26 MK-8591 protects against rectal SHIV infection at very low dose Dose achievable with 250mcg weekly or 10 mcg daily in humans Slide 12 of 36 Oral dosing might be weekly and PrEP includes the potential for a small removable slow-release implant that would last a year. Markowitz, Abstract 89LB ANTIRETROVIRAL THERAPY: Strategies Slide 13 of 36

4 Slide 14 of 36 ANDES: DRV/r + 3TC vs DTV/r+3TC/TDF Phase 4, randomized, open-label, Rx-naïve, VL >1000, no drug resistance to study meds, HBsAg negative (N=145) Proportion of People with VL<50 c/ml Figueroa CROI 2018 #489 Switch from DTG/ABC/3TC to Bictegravir/F/TAF Slide 15 of 36 Molina, Abstract 22 Switch from DTG/ABC/3TC to Bictegravir/F/TAF B/F/TAF non-inferior to DTG/ABC/3TC No significant differences in bone density or adverse events Slight differences in renal function (2.8 ml/min) and triglycerides favoring B/F/TAF Slide 16 of 36 Molina, Abstract 22

5 Slide 17 of 36 REALITY: Addition of 12 weeks of RAL at ART initiation, CD4<100 There was also no difference in IRIS complications with or without RAL. Gibb, Abstract 23 RCT of naltrexone therapy in people who use opioids to improve viral suppression (NEW HOPE, n=93) Conclusions Extended naltrexone for opioid users released from prison improves viral suppression rates Similar results for heavy alcohol users released from prison. (data not shown) Slide 18 of 36 Springer, Abstract 96 HIV Cure: TLR-7 agonist + broadly neutralizing antibody Monkeys treated with ART for 96 weeks followed by 4 strategies TLR7 agonist activates HIV bnab target infected cells Slide 19 of 36 Barouch, Abstract 73LB

6 ANTIRETROVIRAL THERAPY: Preexposure Prophylaxis Slide 20 of 36 Long-acting cabotegravir protects against penile SHIV infection Infected animal had cabotegravir levels that fell below 4 x IC 90 Protected animals maintained levels above 4 x IC 90 Slide 21 of 36 Dobard, Abstract 83 Combination broadly neutralizing Abs for HIV prevention Slide 22 of 36 Garber, Abstract 82

7 Slide 23 of 36 Tri-specific monoclonal antibodies for HIV prevention and tx Pegu, Abstract 113LB Open label dapivirine rings: Comparison to historical placebo HIV-1 incidence = 4.1 (95% CI ) MTN-020/ASPIRE placebo EXPECTED 54% reduction P=0.01 HIV-1 incidence = 1.9 (95% CI ) MTN-025/HOPE OBSERVED Expected incidence derived from 10,000 samplings from MTN-020/ASPIRE placebo group. Across 10,000 samplings, there was none with an HIV-1 incidence of 1.9 per 100 person-years Observed incidence was during open-label ring use from MTN-020/ASPIRE participants In a second trial using similar methods, expected HIV-1 incidence was 3.9 per 100 PY (95% CI: ) vs. 1.8 per 100 PY (95% CI: ) in the open-label doravirine ring period Slide 24 of 36 Baeten, Abstract #143LB, Nel, Abstract #144LB TAF/FTC for protection of HIV by vaginal transmission Slide 25 of 36 Massud, Abstract 85

8 Slide 26 of 36 Klatt CROI 2018 Slide 27 of 36 Klatt CROI 2018 Slide 28 of 36 Klatt CROI 2018

9 THERAPY FOR METABOLIC COMPLICATIONS Slide 29 of 36 Low dose methotrexate for HIV-associated inflammation RCT in ART-treated HIV-infected individuals 40 years of age with or at increased risk for CVD and with CD4+ T- cells >400 cells/mm3. Participants received weekly LDMTX or placebo (+ folic acid) for 24 weeks and were followed for an additional 12 weeks. Slide 30 of 36 Hsue, Abstract 79 Effect of switch from TDF to TAF +/- bisphosphonates (BP) Pooled data from two prospective 144-week, Phase 3 studies of HIV-infected adults virologically suppressed on TDF-based regimens who switched to elvitegravir, cobicistat, emtricitabine and TAF. Slide 31 of 36 Brown, Abstract 724

10 THE IMPACT OF SYNBIOTICS IN ADVANCED HIV DISEASE: A RANDOMIZED CLINICAL TRIAL Intervention: 30g nutritional supplement (PMT25341) of prebiotics, probiotics, oligonutrients essential amino acids. Omega-3 fatty acids Slide 32 of 36 Serrano-Villar CROI 2018 Conclusions HIV Prevention: There are emerging PrEP strategies including injecting cabotegravir, TAF/FTC, MK-8591, combination bnabs. HIV Treatment: Switch from DTG to BIC was non-inferior. MK-8591 has long half-life. RAL intensification of ART does not reduce IRIS. HIV Adherence: Naltrexone can help people who use opioids and heavy alcohol with their ART adherence. HIV Cure: TLR7 agonist + bnabs resulted in sustained aviremia in a subset of monkeys. Complications: Switch from TDF to TAF improved bone density but low dose methotrexate, biphosphonates and nutrient supplement not impactful. Slide 33 of 36 Acknowledgements Dr. Timothy Wilkin Dr. Sergio Ita Dr. Aaron Christensen-Quick Dr. Martin Hoengil Dr. Raphael Landovitz Selected Readings Most of the material from this presentation can be found (in a much better form) at: Slide 34 of 36

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