Circumcision and HIV Vaccines: What are the connections?

1. Circumcision and HIV Vaccines: What are the connections? Susan Buchbinder, MD HIV Research Section San Francisco Department of Public Health International AIDS Society Meeting Mexico City August 4, 2008

2. MRKAd5 trivalent vaccine • Vaccine: 1:1:1 admixture of 3 Ad5 vectors • Encoded transgenes: codon-optimized, near-consensus clade B HIV-1 sequences • Placebo: vaccine dilution buffer without Ad5

3. Trial Design • 3000 high-risk HIV uninfected men and women • Initial study: 1500 pts w/ Ad5 NAb <200 (Dec 2004) • Modification: additional 1500 w/ Ad5 NAb >200 (July 2005) • Randomization stratified by Ad5 <18, 19-200, 201-1000, >1000 Primary hypotheses:Ad5 <200 subset • Decrease in HIV acquisitionand/or • Lower viral load setpoint (∼3 months post-diagnosis) Secondary hypotheses:Total population • Same as primary (Ad5 <200 and Ad5 >200 combined)

4. Step Study sites

5. Planned Interim Analysis Results: Ad5<200 MITTAnalysis HIV Acquisition Early viral RNA

6. Incidence (95% CI) of HIV Infection MITT population (males) 18 is the LOQ for the Ad5 titer assay; includes all HIV cases thru Oct 17, 2007

7. Baseline characteristics by Ad5 status p<.05 Baseline Ad5 not associated with HIV in multivariate analysis (p=0.3)

8. Variables included in univariate/multivariate analyses • Vaccine vs. placebo • Baseline Ad5 • Circumcision (self-report) • Age • Race • Region • Baseline risk factors (previous 6 months) • # male sex partners • Unprotected receptive anal sex • Unprotected insertive anal sex • Substance use • Self-reported sexually transmitted infection

9. Variables included in univariate/multivariate analyses • Vaccine vs. placebo • Baseline Ad5* • Circumcision (self-report)* • Age • Race • Region • Baseline risk factors (previous 6 months) • # male sex partners • Unprotected receptive anal sex • Unprotected insertive anal sex • Substance use • Self-reported sexually transmitted infection *significant interaction with vaccine vs. placebo

10. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI) * Circumcision status was unknown for 49 (2.7%) men. All univariate and multivariate analyses are based on the Cox proportional hazards regression model for time-to-event data.

11. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI) * Circumcision status was unknown for 49 (2.7%) men. All univariate and multivariate analyses are based on the Cox proportional hazards regression model for time-to-event data.

12. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI) * Circumcision status was unknown for 49 (2.7%) men. All univariate and multivariate analyses are based on the Cox proportional hazards regression model for time-to-event data.

13. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI) Men with unknown circumcision status (49, 2.7%) were excluded from analyses. All analyses are based on the Cox proportional hazards regression model for time-to-event data.

14. Association of male circumcision (MC) with HIV acquisition risk • Observational studies demonstrate association of MC with reduced HIV acquisition • Many studies confirm in heterosexual men • Mixed data on role of MC in MSM • 3 RCT demonstrate adult MC reduces HIV acquisition risk by >50% • Laboratory studies demonstrate role of foreskin in HIV acquisition • Keratin layer thin in inner mucosa • Target cells abundant in foreskin • Possibilities for micro-abrasions

15. Keratin in outer and inner foreskinPatterson AJP 2002 Outer foreskin Inner foreskin

16. Langerhans’ cells (LC) in foreskin • In the penis: • LC most superficial of all target cells • Foreskin has greatest concentration of LC • LC most superficial in the inner foreskin • Most other target cells also most superficial in the inner foreskin McCombe AIDS 2006

17. Likely locations of HIV acquisition in uncircumcised penis McCombe AIDS 2006

18. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI) Men with unknown circumcision status (49, 2.7%) were excluded from analyses. All analyses are based on the Cox proportional hazards regression model for time-to-event data.

19. Role of baseline unprotected insertive anal sexThe Step Study

20. Role of baseline unprotected insertive anal sex The Step Study

21. Role of baseline unprotected receptive anal sex The Step Study

22. Role of baseline unprotected receptive anal sex The Step Study

23. How might these associations of increased risk in uncircumcised men be explained? • (As yet) unmeasured confounders • HSV-2, host genetics • Sexual networks • Sexual risk over time • Hypothetical: targeting of activated target cells to mucosa in Ad5 seropositives • Make “less risky” sexual practice (insertive anal sex) riskier • Next steps: • Analyze potential confounders • Evaluate cellular and mucosal specimens to explore enhancement • Follow study volunteers to evaluate long-term effects

24. Acknowledgments The Study Volunteers For their dedication and commitment in the search for an HIV vaccine

25. Sarah Alexander Gail Broder Susan Buchbinder Lisa Bull Danny Casimiro Ann Duerr Cheryl Ewing Dan Fitzgerald Paula Frew Lori Gabryelski Peter Gilbert Tirzah Griffin Soyon Im Dale Lawrence Rosario Leon David Li Ellen MacLachlan Julie McElrath Devan Mehrotra Robin Mogg Dewayne Mullis Gabriela O’Neill Mary Pleier Michael Robertson Steve Self Rosario Leon Amanda Vettori Steve Wakefield Amy Zhou STEP Study Protocol Team

26. STEP Study Sites