Next Steps: An update on the Step Study and HVTN 504

1. 1 Next Steps: An update on the Step Study and HVTN 504 Susan Buchbinder, MD San Francisco Department of Public Health University of California, San Francisco HIV Vaccine Trials Network

2. 2 Purpose of efficacy trials

3. 3 Questions Analysis of Step results Reasons for vaccine failure to lower viral load? Reasons for increased acquisition in subgroups? Exploring role of Ad5, male circumcision Questions raised about role of cofactors in HIV acquisition apart from vaccine effects? How do these characteristics alter the effects vaccine has on HIV acquisition?

4. 4 Ad5 immunity Raised questions about role of Ad5 immunity in HIV acquisition No association of Ad5 with HIV infection in placebo recipients in Step Evaluating association in other cohorts (HPTN 039, MACS) Emphasized the importance of understanding natural and vaccine-induced immunity to vector Limitation of NHP models Studies underway from Step, other trials to explore role of Ad5 immunity on vaccine-induced Ad5- and HIV-specific immune responses Implications of these results for other vectors, regimens

5. 5 Association of male circumcision (MC) with HIV acquisition risk Heterosexual men Observational studies and 3 RCTs demonstrate MC reduces HIV acquisition risk > 50% Men who have sex with men (MSM) Observational studies on association of MC with HIV mixed Likely depends on mix of insertive vs. receptive anal sex Insertive anal sex ~5x less risky than receptive anal sex Studies in US MSM, ~10% of infxns attributable to lack of MC Laboratory studies suggest role of foreskin in HIV acquisition Keratin layer thin in inner mucosa Target cells abundant in foreskin Possibilities for micro-abrasions Moist environment

6. 6 Keratin in outer and inner foreskinPatterson AJP 2002

7. 7 Likely locations of HIV acquisition in uncircumcised penis

8. 8 Role of baseline unprotected insertive anal sex

9. 9 Role of baseline unprotected insertive anal sex

10. 10 How might these associations of increased risk in uncircumcised men be explained? Potential confounders (being studied) HSV-2, host genetics, sexual risk over time Sexual networks Potential biological mechanism Example: if vaccination led to homing of activated target cells to mucosal surfaces Make �less risky� sexual practice (insertive anal sex) riskier Considerations for next steps: Evaluate cellular and mucosal specimens in Step/Phambili Additional studies with other vectors in men awaiting circumcision Further emphasis on reliable measures of mucosal immunity

11. 11 Proportion of STEP US pts circumcisedby race/ethnicity

12. 12 �Hazard� of HIV Infection: MITT population (males)Crude estimation method using 26 week intervals

13. 13 Additional data Step follow-up to date Retention ~89% for both vaccinees and placebo recipients Clinical course in infected pts: Holly Janes Additional infections analyzed within next several months Additional specimens for laboratory study Mucosal Leukopheresis Future follow-up: HVTN 504 Follow-up of Step volunteers for 4 years or through 2009, whichever comes first Visits q 3 months Additional specimens More detailed behavioral data (post-unblinding) Ongoing risk reduction counseling Assess social harms

14. 14 Summary Step results demonstrate unique role of test of concept trials in discovery process Relatively quick answer to primary study questions Generated new insights, questions not raised in any other way Keep separate questions clear Mechanisms for failure to control viral load may be different than those driving increased acquisition Insights about effects in placebo participants may be different than those explaining increased acquisition in subgroups Participants remain committed to study objectives, continue to provide rich source of data and specimens Staff at study sites have done remarkable job of explaining challenging study results to participants, communities

15. The Step and Phambili Study Volunteers For their dedication and commitment in the search for an HIV vaccine

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