Depo-Provera associated with increased HIV risk

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ProveraWEBBirth control pills and some types of injectable and implanted contraceptives were not associated with an increased risk of HIV acquisition found a Guttmacher Institute meta-analysis. However, evidence continues to suggest that use of depot medroxyprogesterone acetate (DMPA or Depo-Provera) raises the likelihood of HIV infection.

The World Health Organisation plans to meet soon to assess whether guidance needs to change in the light of the new findings.

Over the years studies have produced conflicting evidence about the link between hormonal contraception – especially DMPA, a long-acting progesterone-only injectable – and women’s risk of HIV infection. Chelsea Polis of the Guttmacher Institute and colleagues have conducted ongoing systematic reviews and meta-analyses of studies looking at the association between contraception and HIV.

At the 2012 International AIDS Conference, Polis reported that studies to date did not show a link between oral contraceptives and HIV infection after adjusting for confounding, nor did the less widely used progesterone-only injectable norethisterone enantate (NET-EN), but a couple of studies saw a significant association with DMPA.

At the 2014 conference, researchers with FHI 360 reported that an individual participant meta-analysis (analysing pooled data from all participants in multiple studies) yielded similar results.

For the latest updated meta-analysis, commissioned by the World Health Organisation, Polis and her team searched for articles published between January 2014 and January 2016. They identified ten new studies since the last review, five of which they deemed relevant to the primary question about the link between contraceptives and HIV infection.

They again found that “the preponderance of data” for oral contraceptive pills, injectable norethisterone enanthate and levonorgestrel implants “do not suggest an association with HIV acquisition.” A suggestion of increased risk with NET-EN seen in the previous review was no longer apparent. They stressed, however, that data for levonorgestrel implants are limited and there are no HIV infection data currently available for etonogestrel implants or for contraceptive patches, rings or hormonal IUDs.

They noted that the new, higher-quality studies on DMPA (or injectables considered together), which previously had mixed results in terms of statistical significance, now had hazard ratios between 1.2 and 1.7, or between a 20 and 70% increase in the risk of HIV acquisition. If the association is causal, the true magnitude of the effect is likely < 1.5, they said.

“While confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women,” the study authors concluded. “Data for other hormonal contraceptive methods, including NET-EN, are largely reassuring.”

“This is a critical area of research, given that hormonal contraceptives are highly effective methods for preventing unintended pregnancy and its health risks,” Polis stated. “Many places where HIV rates are high also have high levels of unmet need for contraception, unintended pregnancy, and maternal mortality. It is essential that we understand whether use of any particular hormonal contraceptive method could elevate women’s risk of HIV acquisition.”

“While definitively inferring causality with observational studies is challenging, it is worth noting that the methodological quality of studies looking at the association of DMPA use with HIV acquisition in women has improved dramatically over time,” she added. “This underscores the need to consider next steps on this issue carefully, in terms of clinical guidelines and further research.”

The WHO periodically reviews the latest data to support its global recommendations on contraceptive use. In 2014 the organisation concluded that the evidence available at that time did not support restrictions on the use of injectable contraceptives, given their ease of use and high level of effectiveness in preventing unwanted pregnancy, which can lead to poor health outcomes and increased mortality for women and children.

In response to the new findings, the WHO said it will convene an expert review group later this year to examine the links between the use of various hormonal contraceptive methods and women’s risk of HIV acquisition. The group will assess whether current WHO guidance needs to change in the light of the new data review. “These new data…do strengthen existing concerns about a possible increase in risk of HIV acquisition in women using injectable DMPA, although the statistical significance of these studies varies and they are observational in nature,” the WHO said.

To overcome some of the drawbacks of observational studies – which are not always able to control for all differences between groups using various interventions – a research consortium is now conducting a randomised trial to compare the risks of HIV acquisition among women using different contraceptive methods. But the results of this study will not be available for several years.

“WHO is concerned that access to preferred contraceptive methods for women, their partners, and for couples, is maximised, while protecting women’s health and that of their communities,” the WHO statement concluded. “Women have the right to the latest and best information and to access their preferred options when choosing a contraceptive method that is safe, effective and acceptable.”

Abstract
Objective and Design: Some studies suggest that specific hormonal contraceptive (HC) methods (particularly depot medroxyprogesterone acetate [DMPA]) may increase women’s HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.
Methods: We searched for articles published between 1/15/2014-1/15/2016, and hand-searched reference lists. We identified longitudinal studies comparing users of a specific HC method against either (1) non-users of HC, or (2) users of another specific HC method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus no HC.
Results: We identified ten new reports: five were considered “unlikely to inform the primary question”. We focus on the other five reports, along with 9 from the previous review, considered “informative but with important limitations”. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate (NET-EN), and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher-quality studies on DMPA (or non-disaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios (HR) between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher-quality studies of HR 1.4.
Conclusions: While confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely <=HR 1.5. Data for other hormonal contraceptive methods, including NET-EN, are largely reassuring.

Authors
Polis, Chelsea B; Curtis, Kathryn M; Hannaford, Philip C; Phillips, Sharon J; Chipato, Tsungai; Kiarie, James N; Westreich, Daniel J; Steyn, Petrus S

Aidsmap material
AIDS abstract
WHO material


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