Presented by Nancy S. Padian The diaphragm and lubricant gel for prevention of HIV acquisition in Southern African women: results of a randomized controlled trial Presented by Nancy S. Padian Women’s Global Health Imperative University of California, San Francisco 4th IAS Conference • July 25, 2007 BEFORE I BEGIN, I WOULD LIKE TO ACKNOWLEGE OUR FUNDER, THE BILL AND MELINDA GATES FOUNDATION

Co-authors Ariane van der Straten1, Gita Ramjee2, Tsungai Chipato3, Guy de Bruyn4, Kelly Blanchard5, Stephen Shiboski1, Elizabeth Montgomery1, Heidi Fancher1, Helen Cheng1, Michael Rosenblum6, Mark van der Laan6, Nicholas Jewell6, James McIntyre4, the MIRA Team UCSF, Women’s Global Health Imperative Medical Research Council, Durban, RSA University of Zimbabwe-UCSF Collaborative Research Programme in Women's Health, Harare, Zimbabwe Perinatal HIV Research Unit, Johannesburg, RSA Ibis Reproductive Health, USA & RSA University of California, Berkeley

MIRA Summary Primary Aim: Examine the effectiveness of the diaphragm and gel for preventing HIV acquisition in women Open label RCT Expected HIV incidence ~4% Powered to detect 33% reduction in HIV infection Expected adherence = 80% Study duration: 3 years (Sept 03 – Dec 06)

Study Design All women receive risk reduction counseling, free male condoms and diagnosis and treatment of curable STIs Women were followed quarterly for 12-24 months

MIRA Trial Sites Total n = 5045 UZ-UCSF Harare, Zimbabwe n=2502 PHRU Soweto, South Africa n=1028 MRC Durban, South Africa n=1515 THERE ARE 3 MIRA TRIAL SITES; ONE AT UZ-UCSF IN 2 PERIURBAN COMMUNITIES OUTSIDE OF HARARE ONE AT THE MEDICAL RESEARCH COUNCIL HIV PREVENTION UNIT IN DURBAN IN 2 SEMI-RURAL SURROUNDING COMMUNITIES ONE AT THE PERINATAL HIV RESEARCH UNIT IN SOWETO, OUTSIDE OF JOBURG

Study Products Male condoms Ortho All-Flex diaphragm Female controlled, may be used discreetly, reusable, available worldwide Replens lubricant Over-the-counter vaginal moisturizer Non-contraceptive Facilitates diaphragm insertion; lubricates vaginal walls Several types of diaphragms – point out in Outlook article – describe the ortho all-flex with arcing ring

Inclusion Criteria Age 18-49 years old Sexually active (≥4 acts per month) HIV-negative CT, NG and pregnancy test negative Willing to follow protocol/informed consent Healthy cervix Able to insert/remove diaphragm correctly

Recruitment & Retention Recruitment from well-baby clinics, community groups, word-of-mouth, community outreach Screening to Enrollment ratio = 2.2 to 1 Retention (% returned for closing visit): 93% completed scheduled closing visit 2% early withdrawals 5% lost to follow-up

Baseline Characteristics No significant differences found by group 77% aged 18-34 68% living together 59% married 56% earned income in past year 44% had at least high school education Current contraceptive use 36% Pill (COC or POP) 25% Injectable hormones 20% Barrier method 13% Other or none 6% Long term P Long term= (IUD, tubal ligation, vasectomy, implants) partner circumcised: 59% no; 22% yes; 20% don’t know.

Baseline sexual and risk history Mean lifetime # sexual partners: 2 Mean age at first sex: 18 years 16% tested positive for NG, CT, TV, or TP 59% tested positive for HSV-2 59% said that partner was not circumcised 29% had ≥ 1 indicator of high risk behavior 69% had ≥ 1 indicator of high partner risk High BEHAVIOR RISK defined as meeting AT LEAST ONE of the following conditions: Any exchange of sex for money/food/drugs/shelter 2 or more sexual partners within last 3 months Ever had vaginal sex under influence of drugs/alcohol in last 3 months Ever used needle for injectable drug use Ever had anal sex High PARTNER RISK defined as meeting AT LEAST ONE of the following conditions: Having any sexual partners test positive for HIV Suspect or know that regular partner had other sex partners in the last 3 months Ever had vaginal sex when partner was under influence of drugs/alcohol in last 3 months Regular partner was away from home for 1 or more months OTHER CATEGORIES NOT REPORTED IN SLIDE: <1% reported ever using a diaphragm 94% Christian (vs. other/none) 35% Coital freq of more than 3 times per week Language of screening form: 12% English 49% Shona 34% Zulu 5% Sotho

Results from ITT (n=4948) HIV Incidence rate Relative Hazard (95% CI) All Sites 4.0 1.05 (0.84 – 1.32) Harare 2.7 1.20 (0.83 – 1.74) Durban 6.8 0.95 (0.69 – 1.31) Johannesburg 3.4 1.05 (0.60 – 1.87)

Subgroup Analyses Relative hazard of HIV acquisition stable across all baseline sub-groups examined Age, education, coital frequency, circumcision of partner, STI positive, HSV-2 positive, behavioral risk, partner risk, contraceptive use, condom use

Per-protocol Results Women in intervention group reported average diaphragm use at last sex 73% of the time* Relative hazard of HIV incidence: 0.90 (95% CI: 0.68 - 1.17) 0.83 (95% CI: 0.61 – 1.14) (for adherence defined as all the time since last visit) Proportion who reported ALWAYS use of diaphragm Cumulatively? *corresponds to 9385 times reported out of 12868 visits

Pregnancy results Yearly incidence of first pregnancy: 13.1% intervention group 13.2% control group RT = reproductive tract

Adverse Events % women with RT related S/AEs did not differ between groups  N = 5039 AE SAE Total events 3052 (61%) 231 (5%) Bacterial vaginosis 258 (5%) Vaginal candidiasis 153 (3%) PID 130 (2.6%) 2 (<0.1%) Other RT events 1368 (27%) 23 (0.5%) UTI 103 (2%) 1 (<0.1%) Other UT events 378 (7.5%) Pregnancy-related events 108 (2.1%) 93 (1.8%) %’s represent proportions of women who had at least one of the specified types of event RT=reproductive tract UT=urinary tract

Differential condom use in MIRA Figure 3. Proportion of women reporting condom use at last sex, by visit

Effect of adherence + differential condom use Post-trial simulations, with levels of diaphragm and condom use equivalent to that observed in our study sample: 70% diaphragm use (in intervention arm) 50% condom use in the intervention arm 85% condom use in the control arm Power to detect a 33% reduction in incidence is < 25%.

Summary of results In the context of a comprehensive HIV prevention package offered to all participants, the trial found no additional protective benefit against HIV infection from providing the diaphragm plus lubricant in the intervention arm

What MIRA could not assess… Whether the cervix is most vulnerable Whether a diaphragm is as good as a condom Whether a diaphragm is better than nothing Whether other cervical barriers might have worked better Whether a barrier would be more effective with a microbicide

Next steps Secondary endpoint analyses Adherence Chlamydia, Gonorrhea HSV-2, Trichomoniasis Adherence Direct effect, causal inference models Acceptability