Hormonal contraceptive use and risk of HIV-1 transmission: a prospective cohort analysis Renee Heffron, Deborah Donnell, Helen Rees, Connie Celum, Edwin Were, Nelly Mugo, Guy de Bruyn, Edith Nakku-Joloba, Kenneth Ngure, James Kiarie and Jared Baeten for the Partners in Prevention HSV/HIV Transmission Team

Background Hormonal contraceptives are widely used Some epidemiologic and laboratory studies have suggested that hormonal contraceptives may alter HIV-1 susceptibility in women Few studies have looked at hormonal contraception and the risk of transmission from women to men Results across studies have been inconsistent WHO has called for high quality studies to assess the potential role for hormonal contraceptives to increase HIV-1 risk

Objectives Compare HIV-1 incidence rates among women using and not using hormonal contraceptives – HIV-1 acquisition among women – HIV-1 transmission from women to men

Study population Prospective cohort study of 3790 HIV-1 discordant couples from East and southern Africa Couples recruited as part of 2 studies conducted between 2004 and 2010 – Partners in Prevention HSV/HIV Transmission Study Randomized trial of acyclovir herpes suppression to reduce HIV-1 transmission (n=3321) 1 – Couples Observational Study Prospective cohort study of immune correlates of HIV-1 protection (n=469) 1 Celum et al. NEJM 2010

Study sites S. Africa Cape Town Orange Farm Soweto Botswana Gabarone Zambia Kitwe Ndola Lusaka Tanzania Moshi Kenya Nairobi Eldoret Kisumu Thika Rwanda Kigali Uganda Kampala

Participants ≥18 years old and sexually active HIV-1 infected partners not eligible, at enrollment, for ART, under national guidelines For HIV-1 negative partners, HIV-1 testing done quarterly; for HIV-1 positive partners, CD4 counts measured every 6 months and plasma and genital viral load measured at enrollment and 6 months later Contraceptive use and sexual behavior measured quarterly with standardized questionnaires – We did not collect data on adherence or brand of contraception used Methods

Analyses conducted 1.HIV-1 acquisition by women – Association between contraceptive use and HIV-1 seroconversion among initially-HIV-1 seronegative women 2.HIV-1 transmission from women to men – Association between female partner’s contraceptive use and HIV-1 seroconversion among initially-HIV-1 seronegative men – Analysis limited to infections determined – by viral genetic sequencing – to have been acquired from the study partner

Statistical Methods Primary analysis: multivariate Cox proportional hazards model Adjusted for Secondary analysis: marginal structural model Weights balance the distribution of time varying covariates (unprotected sex and pregnancy) within hormonal contraceptive use groups For all analyses, periods with hormonal contraceptive use were compared to periods without hormonal contraceptive use Because of small numbers, time periods with IUD and implant usage were censored All time periods after ART initiation were also censored Sex without a condom (time dependent) Pregnancy (time dependent) Age Plasma viral load

Couple characteristics HIV-1 acquisition among women N (%) or median (IQR) N=1314 HIV-1 transmission from women to men N (%) or median (IQR) N=2476 Married1081 (82.3)1846 (74.6) Partnership duration, years6.5 ( )4.9 ( ) Number of children together2.0 ( )1.0 ( ) Number of sex acts together, past month3.0 ( )4.0 ( ) Any unprotected sex together, past month312 (23.7)727 (29.4) Couple experienced a pregnancy during study390 (29.7)571 (23.1) Enrollment plasma viral load4.4 ( )4.0 ( )

Couple characteristics HIV-1 acquisition among women N (%) or median (IQR) N=1314 HIV-1 transmission from women to men N (%) or median (IQR) N=2476 Married1081 (82.3)1846 (74.6) Partnership duration, years6.5 ( )4.9 ( ) Number of children together2.0 ( )1.0 ( ) Number of sex acts together, past month3.0 ( )4.0 ( ) Any unprotected sex together, past month312 (23.7)727 (29.4) Couple experienced a pregnancy during study390 (29.7)571 (23.1) Enrollment plasma viral load4.4 ( )4.0 ( )

Contraception and HIV-1 acquisition among women Overall, 21.2% of HIV-1 seronegative women used hormonal contraception at least once during follow up – Injectable contraception used at least once by 16.0% of women – Oral contraception used at least once by 6.7% of women There were a total of 73 incident HIV-1 infections – HIV-1 incidence rate: 4.09 per 100 person years

Contraception and HIV-1 acquisition among women Adjusted Cox PH regression analysis Adjusted marginal structural model analysis Incidence rate* HR (95% CI)p-value OR (95% CI)p-value No hormonal contraception Any hormonal contraception ( ) ( ) 0.06 Injectable ( ) ( ) 0.05 Oral ( ) ( ) 0.44 *per 100 person years

Contraception and HIV-1 transmission from women to men Overall, 33.3% of HIV-1 seropositive female partners used hormonal contraception at least once during follow up – Injectable contraception used at least once by 26.8% of women – Oral contraception used at least once by 8.9% of women There were 59 HIV-1 seroconversions in initially-HIV-1 seronegative men that were genetically linked to their female study partner – HIV-1 incidence rate: 1.75 per 100 person years

Contraception and HIV-1 transmission from women to men Adjusted Cox PH regression analysis Adjusted marginal structural model analysis Incidence rate* HR (95% CI)p-value OR (95% CI)p-value No hormonal contraception Any hormonal contraception ( ) ( ) 0.02 Injectable ( ) ( ) Oral ( ) ( ) 0.12 *per 100 person years

Does genital HIV-1 RNA contribute to the increased transmission from women to men? Any genital HIV-1 RNA detected N=1691 Genital HIV-1 RNA quantity (log 10 copies/swab) N=1691 Adjusted odds ratio* (95% CI) p-value Adjusted regression coefficient* (95% CI) p-value No hormonal contraception1.00 Any hormonal contraception 1.51 ( ) (+0.04, +0.23) <0.01 Injectable 1.67 ( ) (+0.08, +0.30) <0.01 Oral 1.06 ( ) (-0.24, +0.14) 0.60 *Adjusted for plasma viral load and CD4 count

Hormonal contraception was associated with a 2-fold increase in risk of: – HIV-1 acquisition by women – HIV-1 transmission from women to men Increased HIV-1 risk was found among the subgroup using injectable methods – Risk was elevated among oral contraceptive users but the number of women using pills was small HIV-1 seropositive women using injectables had greater genital HIV-1 RNA levels which may be responsible for the increased rate of transmission to men Summary

Mounting evidence that hormonal contraceptives - particularly injectable methods - increase a woman’s risk of acquiring HIV-1 First study to demonstrate that hormonal contraceptives increase an HIV-1 infected woman’s risk of transmitting HIV-1 to her partner The benefits of effective hormonal contraceptive methods are unequivocal and must be balanced with the risk for HIV-1 infection Women and couples should be counseled about these possible risks and the importance of HIV prevention in conjunction with hormonal contraception Strategies to improve access to and usage of lower dose and non hormonal methods – IUDs, implants, patches or combination injectables – should be investigated Implications

Partners in Prevention HSV/HIV Transmission Study Team University of Washington Coordinating Center and Central Laboratories - Seattle, WA Connie Celum, Anna Wald, Jairam Lingappa, Jared Baeten, Mary Campbell, Lawrence Corey, Robert Coombs, James Hughes, Amalia Magaret, M.Juliana McElrath, Rhoda Morrow, James Mullins Site Principal Investigators Botswana : Max Essex, Joseph Makhema Kenya : Elizabeth Bukusi, Kenneth Fife, James Kiarie, Nelly Rwamba Mugo, Edwin Were, Craig Cohen, Carey Farquhar, Grace John-Stewart Rwanda : Etienne Karita, Kayitesi Kayitenkore, Susan Allen South Africa : David Coetzee, Guy de Bruyn, Sinead Delany- Moretlwe, Glenda Gray, James McIntyre, Helen Rees Tanzania : Rachel Manongi, Saidi Kapiga Uganda : Elly Katabira, Allan Ronald Zambia : Mubiana Inambao, William Kanweka, Bellington Vwalika, Susan Allen Study participants and staff University of Washington STD/AIDS Research Training Grant Program, T32 AI from the National Institutes of Health (NIH) and the Department of Epidemiology IAS 2011 International Scholarship Programme NIH R01 AI , P30 AI Acknowledgments