1. Hormonal contraception and HIV acquisition in women: a systematic review of the epidemiological evidence International AIDS Conference July 25, 2012 Chelsea B. Polis, PhD - USAID Kathryn M. Curtis, PhD - CDC

2. HIV and unintended pregnancy: two important public health concerns Factors that increase risk of HIV contribute to the spread and consequences of the epidemic Unintended pregnancies can increase: – maternal and infant morbidity and mortality – vertical HIV transmission – sexual HIV acquisition/transmission? 2

3. Four key issues - hormonal contraception and: HIV-negative women 1. HIV acquisition? Women living with HIV 2. HIV disease progression to AIDS or death? 3. HIV transmission to men? 4. Drug interactions with antiretroviral therapy? 3

4. Unclear which biological mechanisms might be relevant Unclear how existing animal data extrapolates to humans Findings are inconsistent with other studies in women Several potential biological mechanisms postulated Some possible mechanisms supported by animal data Some studies in women suggest increased risk 4 Does hormonal contraception biologically alter risk of HIV acquisition?

5. Study selection and abstraction Systematic search of published or in press literature – Any language, published through Dec 15, 2011 – Included RCT or cohort studies, excluded cross-sectional studies Studies compared HIV-negative women using HC against HIV-negative women not using HC Both authors systematically abstracted study information to assess various aspects of quality 5

6. Prospective, observational studies of OC pills & HIV acquisition (including studies that did not meet minimum quality criteria) Adjusted OR, IRR, or HR (log scale) and 95% CI 6 * includes MSM and Cox estimates

7. Prospective, observational studies of injectables & HIV acquisition (including studies that did not meet minimum quality criteria) Adjusted OR, IRR, or HR (log scale) and 95% CI 7 * includes MSM and Cox estimates

8. Studies failed to meet minimum quality criteria if: Study contained two or more of these three flaws: 1. Unclear definition of exposure to HC use 2. High loss to follow up (>20% at 12 months) 3. Lack of consideration of potential confounding - or - Study authors noted that data were unlikely to provide information on the biological effect of HC on HIV acquisition 8

9. Among studies that met minimum quality criteria, we considered factors including: Frequency and accuracy in measurement of exposure, outcome, and key variables Study size and number of endpoints Population studied Purpose of data collection Statistical approach Potential for uncontrolled or residual confounding 9

10. Causal associations vs. confounded associations: condom use example Hormonal contraceptive use (exposure) Higher risk of HIV acquisition (outcome) 10 Less consistent condom use (confounder) OBSERVED ASSOCIATION ISCAUSAL DUE TO CONFOUNDING

11. Oral contraceptive pills and HIV acquisition STUDIES MEETING MINIMUM QUALITY CRITERIA 11 * includes MSM and Cox estimates

12. 12 * includes MSM and Cox estimates Injectables and HIV acquisition STUDIES MEETING MINIMUM QUALITY CRITERIA Depicting estimates that combine DMPA and Net-En, if available

13. 13 NET-EN and HIV acquisition STUDIES MEETING MINIMUM QUALITY CRITERIA

14. Sensitivity analyses Multiple factors could contribute to variation in estimates on progestin-only injectables and HIV acquisition, particularly: – Analysis of serodiscordant couples – Length of inter-survey interval – Manner of handling condom use Additional data could help to elucidate reasons for variation 14

15. Limitations Body of evidence – Potential for confounding in observational data – Many studies had limited power – Limited data for methods other than OCPs or injectables Systematic review – Assessing study quality is complex and multifactorial; other reviewers may have used different criteria WHO expert group vigorously discussed interpretation of various study strengths and weaknesses, body of evidence 15

16. Conclusions For OCPs and NET-EN, data available at the time of this review do not appear to suggest an association with HIV acquisition – Data for NET-EN limited to three studies For DMPA, data available at the time of this review neither establish a clear causal association nor definitively rule out the possibility of an effect on risk of HIV acquisition 16

17. Acknowledgements Jared Baeten, Tim Farley, Ron Gray, Phil Hannaford, Renee Heffron, Charlie Morrison, Bert Petersen, and BMGF colleagues for comments on the review Participants of WHO HC-HIV consultation for discussion WHO colleagues, including Sharon Phillips, Mary Lyn Gaffield, Nathalie Kapp, and Michael Mbizvo Study investigators who generously responded to requests for information And many others for constructive input 17