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Injectable contraception and HIV-1 risk in women in HIV-1 serodiscordant partnerships: persistence of effect in multiple sensitivity analyses.

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  1. Injectable contraception and HIV-1 risk in women in HIV-1 serodiscordant partnerships: persistence of effect in multiple sensitivity analyses Renee Heffron1, Deborah Donnell2, Helen Rees3, Connie Celum1, Nelly Mugo4, Edwin Were5, Guy de Bruyn3, Edith Nakku-Joloba6, Kenneth Ngure5, James Kiarie5, Robert Coombs1 and Jared Baeten1 for the Partners in Prevention HSV/HIV Transmission Team from 1University of Washington, Seattle, WA, USA; 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3University of the Witswatersrand, Johannesburg, South Africa; 4Kenyatta National Hospital, Nairobi, Kenya; 5Moi University, Eldoret, Kenya; 6Makere University College of Health Sciences, Kampala, Uganda

  2. Background • Hormonal contraceptives are widely used • Some epidemiologic and laboratory studies have suggested that hormonal contraceptives may alter HIV-1 susceptibility in women • Results across studies have been inconsistent

  3. Background • In October 2011, we published an analysis from a prospective cohort study of African HIV-1 serodiscordant couples where injectable contraceptives were associated with a doubling of the risk for HIV-1 acquisition (adjusted hazard ratio 2.05, p=0.04) • WHO has recently recommended that women using injectable contraceptives be especially counseled to use condoms for dual protection • Results from observational studies of hormonal contraception and HIV-1 risk can be challenging to interpret; associations could be explained by behavioral and/or biological factors

  4. Objective • Perform sensitivity analyses to explore the effect of analytic assumptions on our primary results • Analyses include: • Adjusting for sexual behavior using alternative and additional factors • Reduce possible exposure misclassification • Isolate effect of DMPA injectable contraception from other injectable contraceptives

  5. Study population • Prospective cohort study of 3790 HIV-1 serodiscordant 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) 1Celum et al. NEJM 2010

  6. Methods • 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 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

  7. Primary statistical model Multivariate Cox proportional hazards model Adjusted for • Age • Plasma viral load • Sex without a condom (time dependent) • Pregnancy (time dependent)

  8. Primary analysis resultsLancet Infectious Diseases, 2012

  9. Sensitivity analyses Minimize confounding by sexual behavior • Include additional sexual behavior covariate – sexual frequency • Include alternate sexual behavior covariate – male report of unprotected sex • Restrict to periods with unprotected sex Reduce misclassification among women who switched hormonal contraception during follow up • Restrict to periods prior to a hormonal contraceptive switch Isolate the effect of DMPA from other injectable contraceptives • Restrict to consistent non-South African injectable users (consistent DMPA users)

  10. Sensitivity analysis results

  11. Adjusting for additional sexual behavior factors – number of sex acts

  12. Adjusting for alternative sexual behavior factors – male report of unprotected sex

  13. In the subgroup of women who reported unprotected sex

  14. Restricting to periods prior to hormonal contraceptive method switch

  15. Restrict to consistent non-South African injectable users (consistent DMPA users)

  16. Summary • An approximate 2-fold HIV-1 risk with injectable contraceptive use persists in multiple sensitivity analyses • Some analyses had diminished power for precision due to decreased sample size but the adjusted HR always indicated a trend towards increased risk

  17. Conclusions • The benefits of injectable contraceptives are unequivocal and must be balanced with the potential risk for HIV-1 infection • More high quality studies of hormonal contraceptives and HIV-1 risk are needed • Integration of reproductive health and HIV-1 prevention programs is extremely important

  18. Acknowledgements University of Washington Coordinating Center and Central Laboratories - Seattle, WA ConnieCelum,Anna Wald, JairamLingappa, Jared Baeten, Mary Campbell, Lawrence Corey, Robert Coombs, James Hughes, AmaliaMagaret, M.JulianaMcElrath, 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, KayitesiKayitenkore, Susan Allen South Africa: David Coetzee, Guy de Bruyn, Sinead Delany-Moretlwe, Glenda Gray, James McIntyre, Helen Rees Tanzania: Rachel Manongi, SaidiKapiga Uganda: EllyKatabira, Allan Ronald Zambia: MubianaInambao, William Kanweka, BellingtonVwalika, Susan Allen Partners in Prevention HSV/HIV Transmission Study Team • Study participants and staff • IAS 2012 International Scholarship Programme • NIH (R03 HD068143 and T32 AI007140) • Bill & Melinda Gates Foundation

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