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

2. 1997

3. 0.0001 0.001 0.01 0.1 1 10 100 1000 10000 01234567 Time on HAART (years) Frequency (per 10 6 cells) Latent HIV infection persists despite ART: Stable Resting CD4 + Cell Infection Time to eradication > 73.4 years 0.00001 Siliciano JD, et al. Nature Med. 2003;9:727-728.

5. Lohse 2007 Predicted Survival if HIV+ at age 25 years 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. Prevention Diagnosis TreatmentCure Last public appearance of the entire AIDS Quilt, 1996Prevention Diagnosis Treatment

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

13. Multiple Dose VOR testing RC RNA assay @ dose 11 Tuesday Cycle 4 RC RNA assay and IUPM @ dose 22 Tuesday Cycle 8 VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T VOR 400 mg M, T, W Rest 4 days Rest 4 days Rest 4 days single dose CA-RNA assay response (n=8) Five elect to enter multi-dose arm: Patients 1, 2, 3, 7, 8 VOR 400 mg VOR 400 mg M, T, W VOR 400 mg M, T, W VOR 400 mg M, T VOR 400 mg M, T, W Rest 4 days Rest 4 days Rest 4 days Archin et 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 that HIV-1 cure research are clinical 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. Karine Dube, UNC Volunteers in cure research for their altruism

22. Questions and Discussion