A report by Deborah Cohan, MD, MPH, associate professor, Department of Obstetrics, Gynecology and Reproductive Sciences at UCSF:
HIV and unintended pregnancies are synergistic public health crises.
Some epidemiologic and laboratory studies suggest hormonal contraception, particularly depo medroxyprogesterone acetate (DMPA), may alter risk of HIV acquisition but data are conflicting.
Hormonal contraception is widely used globally. In sub-Saharan Africa, injectable contraceptive use is particularly common. This panel presented additional data to address this controversy.
Association between STI/RTI infections, altered cervical innate immunity and HIV-1 seroconversion among hormonal contraceptive users
Fichorova presented a secondary analysis to assess the association between sexually transmitted infections (STIs)/reproductive tract infections (RTIs) and the risk of altered innate immunity protein levels among hormonal contraceptive methods.
This study included 199 women who became HIV+ within 3 months compared to 633 matched controls (1/3 were non-hormonal contraceptive users; 1/3 used DMPA; 1/3 were using combined oral contraception (COC). Biomarkers measured included IL-1, Il-6, IL-8; MIP-3alpha, VEGF, RANTES, biodefensin2 (BD2) and SLPI. Those women who acquired HIV within 3 months were found to have increased RANTES and BD2 and decreased SLPI.
The researchers found that DMPA was associated with increased RANTES compared to non-hormonal contraceptive users. BD2 levels were increased among women with STIs who used DMPA. Increased RANTES, associated with increased risk of HIV acquisition, was seen among DMPA users regardless of the presence of STIs/RTIs. In contrast, this finding was only noted among COC users with herpes. The researchers concluded that a disturbed microbiome sensitized the cervical mucosa and STIs differentially sensitize cervical mucosa to adverse immune activation effects of DMPA compared to COC.
Overall, they found enhanced proinflammatory cytokines among COC users and reduced protective mediators among DMPA users. Overall, these data reinforce the biological basis for an association seen between DMPA use and HIV acquisition in some epidemiological studies.
Association of injectable contraception and risk of HIV-1 acquisition in women in HIV-1 serodiscordant partnerships: persistence of effect in multiple sensitivity analyses
Association of injectable contraception and HIV risk in women in HIV serodiscordant partnerships: persistence of effect in multiple sensitivity analyses
Renee Heffron reported on additional sensitivity analyses from their data published earlier this year in Lancet Infectious Diseases. The objective of these secondary sensitivity analyses was to explore the effect of analytic assumptions on primary results already published from the Partners in Prevention Study (n=3321) and the Couples Observation Study (n=469). The additional sensitivity analyses included 1) adjusting for sexual behavior, 2) reducinge misclassification among women who switched hormonal contraception during follow-up and 3) isolating the effect of DMPA from other injectable contraceptives by limiting the analysis to non-South African participants. These 2 studies enrolled a total of 3790 serodiscordant couples between 2004 and 2010.
HIV+ partners were not eligible for antiretrovirals according to in-country criteria at enrollment but were referred for care if reaching eligibility for treatment. HIV- partners received quarterly HIV testing and contraceptive use and sexual behavior were assessed quarterly. All analyses adjusted for age, plasma viral load, sex without condom (time dependent) and pregnancy (time dependent). The initial analysis published in Lancet ID found that DMPA use was associated with a 2 fold increased risk of HIV acquisition among HIV- women (adjusted hazard ratio (aHR) 2.05; 95% confidence interval [CI] 1.04-4.04).
In these subsequent analyses presented today, this aHR did not change substantially. In particular, when adjusting for the number of sex acts reported by women, the aHR was 2.06. When adjusting for the number of sex acts reported by the male partners, the aHR was 2.03. When the researchers restricted the period prior to hormonal contraception switch, the aHR was 2.62. Restricting the analysis to non-South African DMPA users, the aHR was 3.39 (95% CI 1.38-11.22). In sum, these additional sensitivity analyses reinforce the original findings of an association between DMPA use and HIV acquisition published earlier this year.
Hormonal contraception and HIV acquisition in women: a systematic review of the epidemiological evidence.
Chelsea Polis from USAID presented this meta-analysis that was performed in preparation for the WHO consultation in early 2012 to evaluate the association between hormonal contraception and HIV acquisition. The meta-analysis included data available through December 15, 2011. Eight studies met minimum quality criteria. Of the 7 studies evaluating COC, only Baeten et al. 2007 showed a statistically significant increased risk of COC and HIV acquisition. Of the 8 studies evaluating injectable hormonal contraception, 2 studies found an increased statistically significant increased risk (Baeten 2007 and Heffron 2012).
In sensitivity analyses, only those studies that specifically enrolled serodiscordant couples showed an association between hormonal contraception and HIV acquisition. This increased risk was also seen in the studies that had the shortest intervals between survey administration. While the authors concluded that the data linking DMPA and HIV acquisition are equivocal and inconclusive, the most robust studies have found an association.
Hormonal contraception and HIV disease progression: a systematic review of the epidemiological evidence
Sharon Phillips presented this meta-analysis of hormonal contraception and HIV disease progression that was also prepared for the WHO consultation in early 2012 including data available through December 15, 2011. The meta-analysis looked at multiple outcomes including 1) death or progression to AIDS (<200; initiation of ART; or clinical AIDS) and 2) change in CD4 count or viral load. Overall the researchers included 12 reports of 11 studies (one RCT analyzed twice and 10 observational studies).
Seven observational studies found no association between hormonal contraception and HIV disease progression.
One RCT that compared postpartum use of copper T IUD, DMPA and COC found an increased risk of CD4 count dropping below 200 or a composite outcome of CD4 <200 and mortality among those women randomized to receive DMPA. Both intention to treat and as-treated analyses showed consistent findings. Five observational studies found no adverse association between hormonal contraception and change in viral load or CD4 but these studies were small and did not adequately measure confounding variables.
While the RCT was the sole study to find an association between DMPA use and HIV disease progression, the high loss to follow-up and rate of switching to different contraceptive methods caused the researchers and the WHO consultants to give less weight this this otherwise robust study. As such, the researchers who conducted this meta-analysis and the WHO Consultation panel ultimately concluded that data are inconclusive and do not support any change in practice related to the provision of contraception to HIV-infected women.
The new laboratory and epidemiological data presented in this session point towards an association between DMPA use and increased risk of HIV acquisition. The 2 meta-analyses presented using data available up until December 15, 2011 suggest no overall increased risk of HIV acquisition or disease progression. There was a robust discussion about whether observational data should outweigh data from randomized controlled trial with high loss to follow-up. In my opinion, these data reinforce that more contraceptive options are needed. Moreover, HIV+ individuals should have universal access to antiretroviral therapy so that women can choose whatever contraceptive method works best for them without fear of HIV acquisition or progression.