1. 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

2. 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

3. 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)

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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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)

12. 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

13. 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: )
0.83 (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 visits

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

15. 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

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

17. 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%.

18. 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

19. 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

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