HIVNET 015: The Explore Trial Susan Buchbinder, MD Director, HIV Research Section

1. HIVNET 015: The Explore Trial Susan Buchbinder, MD Director, HIV Research Section San Francisco Dept. of Public Health

4. Prevalence of HIV in US MSMNHBS: MMWR 2005;54:597-601

5. HIV Prevalence in South American CitiesS Montano, JAIDS 2005; 40:57-64

6. Estimated number of adults and childrennewly infected with HIV during 2004 Eastern Europe & Central Asia 210 000 [110 000 – 480 000] Western & Central Europe 21 000 [14 000 – 38 000] North America 44 000 [16 000 – 120 000] East Asia 290 000 [84 000 – 830 000] North Africa & Middle East 92 000 [34 000 – 350 000] Caribbean 53 000 [27 000 – 140 000] South & South-East Asia 890 000 [480 000 – 2.0 million] Sub-Saharan Africa 3.1 million [2.7 – 3.8 million] Latin America 240 000 [170 000 – 430 000] Oceania 5 000 [2 100 – 13 000] Total: 4.9 (4.3 – 6.4) million

7. Estimated US Cases HIV/AIDS by year of diagnosis33 areas with name-based HIV infection reporting MMWR 2004;53:1106-10

8. Background • HIV epidemic throughout Americas (except parts of Caribbean) most concentrated in MSM • HIV prevalence 10-30%; HIV seroincidence 2-4% despite ongoing risk reduction counseling • Biomedical interventions (vaccines, PREP, STD rx, microbicides) being developed, but still years away • Behavioral interventions needed both as stand-alone and to complement biomedical interventions

9. EXPLORE • First behavioral intervention powered to address impact of intensive intervention on HIV seroincidence • “Cadillac version” of behavioral intervention intended to maximize effects, likelihood for success • Use of ACASI to get most accurate measures of risk, correlate change in risk with change in seroincidence

10. Study Design • Multi-site “RCT” (randomized controlled trial) efficacy trial • Eligibility: (range of risk behaviors) • Male, > 16 yo • Any anal sex with man in last year • Not in mutually monogamous relationship > 2 yrs • Intervention • 10 individualized sessions w/ boosters q 3 mos • Control • Project Respect risk reduction counseling q 6 mos

11. Intervention modules

12. Measurements • HIV antibody q 6 months • Interviewer administered • Demographics • STD history • ACASI (audio computer-assisted self interview) • Sexual risk • Drug use

13. Outcomes • Primary endpoint: HIV infection rates • “Phase IIB” or screening efficacy trial • If efficacy < 10%, discard or reformulate • If 10-35%, plausibly efficacious, more study • If > 35%, efficacious & implement • Because Phase IIB are smaller than full efficacy trial, less precision in measure

14. Enrollment by site

15. Recruitment Sources

16. Baseline Demographics

17. Baseline Partners

18. Baseline Sexual Practices

19. Adherence to initial sessions No. of initial session-modules % completing 0 1 1-3 12 4-6 5 7-9 7 10+ 75

20. Retention

21. Retention Group Final visit retention (%) Race/ethnicity White 89.5 Af-Am/Latino/API/NAm/oth 83.9 Age (years) < 25 80.0 26+ 89.8 Female partners No 88.5 Yes 74.2 Unprotected anal No 89.0 Yes 86.7 Intervention sessions completed <9 63.6 9+ 92.2 P<0.05 for all comparisons

22. .931 .918 OR 0.67 0.61 0.83 1.17 0.73 1.32 0.75 1.05 HIV SeroincidenceOverall seroincidence = 2.1 (1.9, 2.4) per 100 py 1.00 Intervention Control Efficacy: 18.2%(-4.7,36.0) Adj Efficacy: 15.7%(-8.4,34.4) 0.98 0.96 Percent free of HIV 0.94 0.92 0.90 Months 6 12 18 24 30 36 42 48 OR 0.67 0.61 0.83 1.17 0.73 1.32 0.75 1.05

23. Pre-set cutpoints for efficacy • Efficacy 18.2% (95% CI: -4.7 to 36%) • Adjusted efficacy 15.7% (95% CI: -8.4 to 34.4%) • If lower bound 95% CI > 10%: declare efficacious • Didn’t meet this cutpoint • If upper bound 95% CI < 35%: no substantial efficacy • Meet cutpoint to say no efficacy?

24. Sexual behavior outcomes: UA, SDUA & SDURA

25. Time Surrogate True Clinical Endpoint Outcome Disease True Clinical Outcome Disease Surrogate Endpoint

26. Time Intervention Surrogate HIV Endpoint Infection Risk Intervention HIV Infection Risk Surrogate Endpoint

27. Time Intervention Self reported HIV 6 mo. UA effects Infection Risk • Potential Differences between • self reported risk behaviors and true risk behaviors • Alternative Pathways for risk of HIV infection • Durability of effect

28. Conclusions • First study of impact of behavioral intervention for MSM on HIV seroincidence • Recruitment of large cohort, excellent retention • Modest reduction in HIV seroincidence • Can rule out substantial efficacy • At cusp between discarding and pursuing further • Significant reduction in self-reported risk behaviors • Implications for using self-reported risk as endpoint in intervention trials?

29. Future directions • Rationale for further analysis and modification • Significant reduction in risk • Possibility of early effects • Likelihood that control condition exceeds usual care • Precautions • Problems retaining young, diverse, risky MSM • Unwieldy intervention • Plans for exploratory analyses • Subgroup analyses • Focus groups w/ men of color • Many other analyses (HSV2, HHV8, risk factors for infection)

30. Co-chairs: Margaret Chesney Thomas Coates Beryl Koblin Site Principal Investigators Susan Buchbinder/Grant Colfax Connie Celum Frank Judson Beryl Koblin Ken Mayer David McKirnan Explore Study Team