1. www.aids2014.org Weighing 17 years of evidence: Does hormonal contraception increase HIV acquisition risk among Zambian women in discordant couples? Kristin M. Wall, PhD kmwall@emory.edu Department of Epidemiology Rwanda Zambia HIV Research Group Emory University, Atlanta, GA, USA

2. www.aids2014.org Conflict of Interest Disclosure The authors have no conflicts of interest due to financial or personal relationships that might be perceived to cause bias.

3. www.aids2014.org Background Hormonal contraception Prevents unintended pregnancy 1 –Prong 2 PMTCT for HIV+ women 1 Is widely used in high HIV prevalence areas 2 Use among married women in Zambia 3 : 11% OCP9% Injectable0.4% Implant

4. www.aids2014.org Background Extant evidence is conflicting 1 2012 World Health Organization technical meeting Medical Eligibility Criteria (MEC) Category 1 Emphasized dual method use for high-risk women using progestogen-only injectables 1

5. www.aids2014.org

6. Study population M+F- serodiscordant couples Identified from couples’ voluntary HIV counseling and testing services in Lusaka from 1994-2012 >16 years of age Male partner was not on ART Followed 3-monthly at the research site –Contraception methods provided –HIV testing of negative partners

7. www.aids2014.org Contraceptive exposures Hormonal methods: –Implant (Norplant, Jadelle) –Injectable (150 mg IM DMPA) –Combined oral contraceptive pills (OCPs) Non-hormonal control: –No method –Condoms –Copper intrauterine device (IUD) –Permanent methods

8. www.aids2014.org HIV infection outcomes Time to any HIV infection –Genetically linked or unlinked to the study partner Time to linked HIV infections

9. www.aids2014.org Analyses Multivariate Cox models Potential effect-measure modifiers: –Genital ulceration, inflammation, VL, fertility intentions, age

10. www.aids2014.org Analyses Multivariate Cox models Potential effect-measure modifiers: –Genital ulceration, inflammation, VL, fertility intentions, age Sensitivity analyses explored effects of: Method exposure/control categorizations Cumulative exposure Misclassification of unprotected sex Time-dependent confounding –Marginal structural models

11. www.aids2014.org Non- seroconverting couples (N = 1141) Seroconverting couples (N=207 linked & 45 unlinked) Total (N = 1393 M+F- couples) 82%18%

12. www.aids2014.org Non- seroconverting couples (N = 1141) Seroconverting couples (N=207 linked & 45 unlinked) Total (N = 1393 M+F- couples) 82%18% Baseline contraceptive method None/condoms alone 72%74% OCPs 11%12% Injectables 10% Implant 3% IUD 2%1% Permanent method 1%0%

13. www.aids2014.org Seroconversion rates among HIV-women in discordant relationships by method of contraception METHOD # infections CY Incidence /100 CY 95%CI p-value (2-tail) None/condoms 15017968.47.19.8ref OCPs 4942511.58.615.10.06

14. www.aids2014.org Seroconversion rates among HIV-women in discordant relationships by method of contraception METHOD # infections CY Incidence /100 CY 95%CI p-value (2-tail) None/condoms 15017968.47.19.8ref OCPs 4942511.58.615.10.06 Injectables 4239210.77.814.30.16

15. www.aids2014.org Seroconversion rates among HIV-women in discordant relationships by method of contraception METHOD # infections CY Incidence /100 CY 95%CI p-value (2-tail) None/condoms 15017968.47.19.8ref OCPs 4942511.58.615.10.06 Injectables 4239210.77.814.30.16 Implant 91247.33.613.40.72

16. www.aids2014.org Multivariate models of time to ANY HIV seroconversion METHOD aHR*95%CIp-value (2-tail) Non- hormonal ref Implant0.90.42.00.86 Injectables1.20.81.80.32 OCPs1.30.91.90.14 *Controlling for: Woman's age (per year increase) Woman's literacy in Nyanja Sperm present on a wet prep during interval Genital ulceration of woman in past 3 months Genital inflammation of woman in the past 3 months

17. www.aids2014.org Multivariate models of time to ANY HIV seroconversion METHOD aHR*95%CIp-value (2-tail) Non- hormonal ref Implant0.90.42.00.86 Injectables1.20.81.80.32 OCPs1.30.91.90.14 *Controlling for: Woman's age (per year increase) Woman's literacy in Nyanja Sperm present on a wet prep during interval Genital ulceration of woman in past 3 months Genital inflammation of woman in the past 3 months  Findings remained the same when controlling for pregnancy and/or fertility intentions

18. www.aids2014.org Results Similarly, the results of: Multivariate models of linked infections only –Additionally controlling for baseline pregnancy, couples’ unprotected sex in past 3 months, genital ulceration and inflammation of male partner in past 3 months, and VL All sensitivity analyses Marginal structural models did not indicate any significant increase in HIV risk for hormonal contraception users.

19. www.aids2014.org Measures of unprotected sex by method of contraception 3-monthly measure of: Non- hormonal % OCPs % p-value (2- tailed)* Incident pregnancy 3%5% ^ Unprotected sex29%37%^ Sperm on wet prep 6%8%^ ^p-value <0.05 OCP vs. non-HC #p-value <0.001 injectables vs. non-HC &p-value <0.001 non-HC vs. implant

20. www.aids2014.org Measures of unprotected sex by method of contraception 3-monthly measure of: Non- hormonal % OCPs % Injectable % p-value (2- tailed)* Incident pregnancy 3%5%1% # Unprotected sex29%37%34%# Sperm on wet prep 6%8%6% ^p-value <0.05 OCP vs. non-HC #p-value <0.001 injectables vs. non-HC &p-value <0.001 non-HC vs. implant

21. www.aids2014.org Measures of unprotected sex by method of contraception 3-monthly measure of: Non- hormonal % OCPs % Injectable % Implant % p-value (2- tailed)* Incident pregnancy 3%5%1%0% & Unprotected sex 29%37%34%18%& Sperm on wet prep 6%8%6%2%& ^p-value <0.05 OCP vs. non-HC #p-value <0.001 injectables vs. non-HC &p-value <0.001 non-HC vs. implant

22. www.aids2014.org Measures of unprotected sex by pregnancy status 3-monthly measure of: Not pregnant % Pregnant % p-value (2-tailed)* No. times unprotected sex (mean) 26^ Any unprotected sex 28%54%^ Sperm on wet prep 6%10%^ ^p-value <0.001 pregnant vs. not pregnant

23. www.aids2014.org Conclusions & Recommendations We found no association between hormonal contraception and HIV acquisition risk in women Reinforced condom counseling is needed during: Oral contraceptive pill use Injectable use Pregnancy These findings: Add to a controversial literature Are important when evaluating MEC Categories

24. www.aids2014.org Acknowledgements Rwanda Zambia HIV Research Group (RZHRG) Contributors William Kilembe Htee Khu Naw Ilene Brill Bellington Vwalika Elwyn Chomba Brent Johnson Lisa Haddad Amanda Tichacek Susan Allen Zambian Ministry of Health & District Health Management Team Study Participants & Clinic Staff

25. www.aids2014.org Funding National Institutes of Child Health and Development (NICHD RO1 HD40125) National Institute of Mental Health (NIMH R01 66,767) AIDS International Training and Research Program Fogarty International Center (D43 TW001042) Emory Center for AIDS Research (P30 AI050409) National Institute of Allergy and Infectious Diseases (NIAID R01 AI51231; NIAID R01 AI040951; NIAID R01 AI023980; NIAID R01 AI64060; NIAID R37 AI51231) US Centers for Disease Control and Prevention (5U2GPS000758) International AIDS Vaccine Initiative This study was made possible by the generous support of the American people through the United States Agency for International Development (USAID). The contents are the responsibility of the International AIDS Vaccine Initiative and do not necessarily reflect the views of USAID or the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

26. www.aids2014.org Seroconversion rates among HIV-negative women in discordant relationships by method of contraception METHOD # infections CY Incidence /100 CY 95%CI p-value (2-tail) Total 25228398.97.810.0 None/condoms 15017968.47.19.8ref OCPs 4942511.58.615.10.06 Injectables 4239210.77.814.30.16 IUD 1581.70.18.50.06 Implant 91247.33.613.40.72 Permanent 1432.30.111.40.15