David M. Margolis , MD Professor of Medicine

1. Towards an HIV cure: medical, social and ethical challenges in research and testing David M. Margolis, MD Professor of Medicine

2. 1997

3. - Latent HIV infection persists despite ART: Stable Resting CD4+Cell Infection 10000 Time to eradication > 73.4 years 1000 100 10 Frequency (per 106 cells) 1 0.1 0.01 0.001 0.0001 0.00001 0 1 2 3 4 5 6 7 Time on HAART (years) Siliciano JD, et al. Nature Med. 2003;9:727-728.

5. Predicted Survival if HIV+ at age 25 years Lohse 2007 ----------------------------------------------- US military cohort (n = 2327, mean age 35) who started ART after 2000, 5-year mortality 0.3% Marconi 2010

6. 2008

7. “Functional Cure”Infant: Standard HIV-1 Assays Undetectable to Age 41 Mos

8. Failure of Cure in a Newborn: Reported at Canadian HIV Research Network meeting: • Mother infected during pregnancy • HIV RNA never >10,000 • Treated and suppressed during pregnancy • Newborn initiated AZT, 3TC, nevirapine within hours of birth • Child treated for three years • Suppressed at every visit • Around age 3 “social issues” degraded ability to continue child’s therapy. Decision made to stop therapy. • Viral rebound within 2 – 3 weeks

10. Last public appearance of the entire AIDS Quilt, 1996

11. A second step to eliminate latent HIV infection? A first step to eliminate latent HIV infection Immunotherapy Anti-latency therapy • Other Challenges: • Clearance of infected cells • Clearance of virions • Complete block of new infection

13. Multiple Dose VOR testing single dose CA-RNA assay response (n=8) Five elect to enter multi-dose arm: Patients 1, 2, 3, 7, 8 VOR 400 mg Cycle 4 RC RNA assay @ dose 11 Tuesday VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T VOR 400 mg M, T Rest 4 days Rest 4 days Rest 4 days Rest 4 days Rest 4 days Rest 4 days Cycle 8 RC RNA assay and IUPM @ dose 22 Tuesday Archinet al. JID 2014

14. Challenges – Research • What is Cure? • Sustainable drug-free remission • VSOT (“Virologic Suppression Off Therapy”) • How to measure and monitor • Long development time to develop safety information for new drugs, or even those approved for other uses (eg. oncology) • Modality that does not impair immune system (no T cell activation) • Modality that does not interfere with ART • Low bar for acceptable toxicities • Need for appropriate animal models

15. Challenges – Research • How will we get there? • Latency disruption • Immune augmentation or modulation • Cellular or genetic therapies • Other approaches: directed cell killing • Multiple endpoints and biomarkers are likely to be required • Both virologic and immunological markers are likely to be needed • Virological markers include inducible cell-associated RNA or viral production from latently infected CD4+ T cells • Immunological markers include cytokine production, HIV antibody and activation markers (CD38/HLA DR) • Q-VOA is a minimal estimate of the size of the latent HIV-1 proviral reservoir or replication-competent proviral DNA

16. Ethical Challenges • Clear informed consent process • Fair enrollment of study participants • Analytical treatment interruption (ATI) or intensively monitored antiretroviral pause (IMAP) • Which HIV-1 cure research modality? Which patients? • After how much reduction of the “reservoir”? • Criteria for ART resumption • Frequency of viral load measurements? • Criteria for therapeutic success? • No validated biomarker to predict viral rebound or relapse after ATI • Safety monitoring, especially for novel mechanisms and combinations • Endpoint uncertainties and sensitivities of current assays • Cure “failures” may take time to become manifest

17. Social Challenges • Need to communicate thatHIV-1 cure research areclinical experiments ---calibrate expectations • Role of the patient in the funding and regulatory process • Acceptable risks vs. benefits ratios • Reproductive risks and enrollment of women into trials • Return of study results such as the size of the HIV-1 proviral reservoir • Risks of being ineligible for future research (?) • Capacity for research • Issues around HIV-1 cure research literacy

18. HIV Cure Research Curriculum

19. Proposed Modules • HIV/AIDS and Cure Basics • Role of Community in HIV Cure Research • Informed Consent and HIV Cure Research • Stem Cell Transplant • Gene Therapy • Shock and Kill and Latency-Reversing Agents • Concepts in Basic Sciences and Translational Research • Therapeutic Vaccines and Immune-Based Therapies • Measuring the Latent HIV Reservoir • Treatment Interruption • Participation in HIV Cure Trials • Regulatory Issues in HIV Cure Trials • Early ART • Pediatric HIV Cure Research • Ethics of HIV Cure Research • Animal Models in HIV Cure Research • Combination Approaches---The Science Looking Forward

20. Concept • Each module will be developed by a community and scientific lead • The modules will be stand-along learning tools but can be taught as a larger course • Clear metrics will measure the learners pre and post module knowledge • Additional participatory activities will be included for trainers to use this information • Launch: Spring 2015

21. KarineDube, UNC Volunteers in cure research for their altruism

22. Questions and Discussion