Contraception & HIV Still searching for answers after >2 decades

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1 Contraception & HIV Still searching for answers after >2 decades R Scott McClelland, MD, MPH University of Washington Inter CFAR Symposium on HIV Research in Women September 20 th 2012

2 Overview Global use of contraception & unmet need Hormonal contraception & HIV acquisition Hormonal contraception & HIV transmission Hormonal contraception & progression of HIV disease Current guidelines Where do we go from here?

3 Global Use of Contraception An estimated 800 million women use modern methods of contraception 150 million use hormonal contraceptives Others use IUDs, barriers, tubal ligation Population Reference Bureau, 2008

4 Reported Contraceptive Use and Unmet Need in Married Women Unmet Region Need Asia 57% 67% 9% Latin 62% 72% 11% America Africa 17% 28% 22%

5 Unmet Contraceptive Needs Ref: Network Vol 23, number 3, Family Health International Globally, 200 million couples not using contraception despite wanting to space or limit child bearing (WHO)

6 Benefits of Contraception Avoid unplanned pregnancies Potential for obstetrical complications Spacing pregnancies benefits the health of women, infants, and children Family planning empowers women, reducing gender inequality HIV-positive women may wish to reduce risk of vertical transmission by preventing further pregnancies

7 J Infect Dis 1991 AOR 4.5 (95% CI ) Non-OC Users OC Users

8 Does hormonal contraceptive use increase the risk of HIV acquisition in women?

9 Bradford Hill Criteria for Causation Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Experiment Coherence Analogy

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13 1314 HIV-serodiscordant couples in which the female partner was HIV-negative Participants in Partners in Prevention trial from seven countries in Africa Used marginal structural modeling and Cox proportional hazards regression to assess effect of contraceptive use on HIV acquisition Lancet Infect Dis 2012

14 HC Use and HIV Acquisition Incidence per 100 p-y Cox Model AHR (95% CI) No HC 3.78 Reference Any HC ( ) Injectable ( ) Oral ( ) Heffron et al. Lancet Infect Dis 2012

15 5567 HIV-negative women Participants in the Carraguard Phase 3 Efficacy Trial in South Africa Used marginal structural models and Cox models to assess effect of contraceptive use on HIV acquisition Overall and in subset years old AIDS 2012

16 HC Use and HIV Acquisition Incidence per 100 p-y Marginal Structural Models All women AHR (95% CI) Women <24 y.o. AHR (95% CI) No HC 3.4 Reference Reference DMPA ( ) 1.68 ( ) Net-En ( ) 1.36 ( ) COC ( ) 1.02 ( ) Morrison et al. AIDS 2012

17 2236 HIV-negative women Participants screened for the PRO 2000/5 trial in South Africa Used Cox proportional hazards regression AIDS 2012

18 HC Use and HIV Acquisition Cox Model AHR (95% CI) No HC Reference Injectable 2.02 ( ) Oral 0.95 ( ) Wand and Ramjee. AIDS 2012

19 Unprotected Sex Hormonal Contraception HIV Acquisition

20 Sub-cutaneous progesterone implants enhanced SIV vaginal transmission in macaques 7-fold compared to placebo Thinning of vaginal epithelium Increased number of SIV DNA-positive cells in vaginal lamina propria Higher plasma SIV RNA in first 3 months Nature Med 1996

21 SIV Vaginal Transmission Marx et al. Nature Med 1996

22 Blish. Am J Reprod Immunol 2011

23 Bradford Hill Criteria for Causation Strength of association Consistency Specificity Temporal relationship Biological gradient Plausibility Coherence Experiment Analogy

24 Can we disentangle the relationships between HC and HIV Acquisition?

25 Experimental Design Is it possible to conduct a randomized trial of hormonal contraception versus some control?

26 To trial or not to trial Pros Potential for providing a clear answer Potential for clarifying the biological mechanisms Cons Difficult to identify a suitable control condition Frequent switching of contraceptive method Added complexity of HIV prevention trials in setting of proven interventions Cost: most effective use of resources?

27 BJOG 2012 Decision analysis modeling risk of HIV acquisition and maternal mortality Chad, Kenya, South Africa, Uganda Assumes injectable progesterone associated with 2.19-fold increased HIV risk Contraceptive methods (UN), failure rates (Trussel Contracept 2011), maternal mortality & pregnancy outcome (WHO)

28 If progesterone injectables removed without % of women switching to IUD or COC, there could be up to 9 additional maternal deaths per HIV infection averted Rodriguez et al. BJOG 2012

29 Contraception 2012 Modeled risks of unwanted births, maternal deaths, and HIV acquisition associated with different contraceptive methods Kenya, South Africa, Zimbabwe Method-specific HIV risk for family planning, sex workers, and discordant couples 1-4 Contraceptive methods (UN), failure rates (Trussel 2007), maternal mortality & pregnancy outcome (WHO) 1. Heffron Lancet ID 2011, 2. Baeten AIDS 2007, 3-4. Morrison AIDS 2007 & 2010

30 Additional unwanted births per 100 HIV infections averted Jain. Contraception 2012

31 Additional maternal deaths per 100 HIV infections averted Jain. Contraception 2012

32 Does hormonal contraceptive use increase the risk of HIV transmission from women to men?

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34 156 female index patients with 159 HIVnegative male partners 26/114 (23%) of women who reported on contraceptive use were using COCs 19 (12%) male partners infected Reported no association between hormonal contraceptive use and transmission to male partner BMJ 1992

35 2,476 HIV-serodiscordant couples in which the male partner was HIV-negative Participants in Partners in Prevention trial from seven countries in Africa Used marginal structural modeling and Cox regression to assess effect of contraceptive use on HIV transmission Genetically linked HIV transmission events Lancet Infect Dis 2012

36 HC Use and HIV Transmission Incidence per 100 p-y Cox Model AHR (95% CI) No HC 1.51 Reference Any HC ( ) Injectable ( ) Oral ( ) Heffron et al. Lancet Infect Dis 2012

37 HC Use and Genital HIV Shedding Log10 copies/swab Median* (IQR) Adjusted coefficient (95% CI) No HC 3.14 ( ) Reference Any HC 3.29 ( ) 0.14 (0.04 to 0.23) Injectable 3.38 ( ) 0.19 (0.08 to 0.30) Oral 2.96 ( ) (-0.24 to 0.14) * Log10 HIV RNA copies/swab Average difference in HIV RNA concentration Heffron et al. Lancet Infect Dis 2012

38 Female to Male HIV Transmission in Rakai, Uganda 224 male HIV-/female HIV+ couples Excluded intervals with condom use Incidence airr (95% CI) per 100 PY Non-HC 7.0 Reference Any HC ( ) OC ( ) Injectables ( ) Lutalo et al. CROI 2012

39 Does hormonal contraceptive use increase the rate of disease progression in HIV+ women?

40 Hormonal Contraception and HIV Progression Higher Risk 1. Lavreys JID Stringer AJOG Stringer AIDS 2009 Neutral Risk 1. Kilmarx JID Cejtin AIDS Wang AIDS Richardson AIDS Allen J Women s Health Stringer AIDS Morrison JAIDS 2011 Lower Risk 1. Polis AIDS Heffron CROI 2012

41 599 postpartum women in Lusaka, Zambia RCT IUD vs. hormonal contraception Followed for at least 2 years Primary endpoint: Safety and efficacy of intrauterine device vs. hormonal contraception Secondary endpoints: Time to CD4<200 Time to death Combined endpoint: time to CD4<200 or death Am J Obstet Gynecol 2007

42 HC vs. IUD in HIV-positive Women Only one episode of PID in IUD arm Higher rate of discontinuation in IUD arm Pregnancy higher in HC vs. IUD HR 2.2 (95% CI ) Mortality did not differ significantly HR 1.4 (95% CI ) Faster progression to CD4<200 with hormonal contraception compared to IUD HR 1.6 (95% CI )

43 HC vs. IUD in HIV-positive Women CD4 decline CD4 decline or death Death Time to CD4<200 or death faster in HC vs. IUD HR 1.6 (95% CI )

44 HC vs. IUD in HIV-positive Women IUD appeared safe and was more effective than HC at preventing pregnancy No difference in mortality Time to CD4<200 longer with IUD vs. HC Limitations ~30% withdrew or lost to follow-up ~30% discontinued allocated method Generalizability? (Post-natal population)

45 303 HIV infected women contributed 1408 person-years of observation Neither DMPA use nor COCs associated with HIV disease progression DMPA ahr 0.90, 95%CI COC ahr 1.07, 95%CI In this study, STI symptoms and older age associated with greater risk of progression JAIDS 2011

46 625 women in Uganda Followed from time of HIV seroconversion Evaluated effect of hormonal contraceptive use on time to AIDS and death AIDS 2010

47 Effect of Hormonal Contraception on Time to AIDS or Death in Rakai, Uganda HC not associated with increased hazard of death (ahr 0.76, 95%CI ) Polis et al. AIDS 2010

48 Effect of Hormonal Contraception on Time to AIDS or Death in Rakai, Uganda HC associated with lower risk of AIDS or death (ahr 0.70, 95%CI ) Polis et al. AIDS 2010

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53 Clinical Trials?

54 Women s Values and Preferences?

55 Thank you!