Depo-Provera Linked to Increased HIV Risk in Africa

Ricki Lewis, PhD

January 09, 2015

The injectable contraceptive depot medroxyprogesterone (Depo-Provera or DMPA) is associated with elevated risk for HIV infection among women in low-income or middle-income countries of sub-Saharan Africa, according to a study published online January 8 in Lancet Infectious Diseases.

"The context in which to interpret our findings is different in the US, where the [Centers for Disease Control and Prevention] estimates that there about 50,000 new HIV infections per year. Depo-Provera use is less common among women in the US but is one of the more popular contraceptive methods women use in sub-Saharan Africa," Lauren Ralph, MPH, a doctoral candidate in the Department of Epidemiology at the University of California, Berkeley, and lead author of the article, told Medscape Medical News. Nationwide risk is difficult to assess because HIV prevalence and incidence vary greatly in different population subgroups, she added.

Approximately 144 million women worldwide use hormonal contraception. About 41 million use injectable products and 103 million take contraceptive pills. Hormonal contraception frees women from unwanted pregnancy, yet may expose them to HIV if their partners do not use condoms.

Researchers have scrutinized a possible link between hormonal contraception and increased susceptibility to HIV infection for 3 decades. Because study results have been inconclusive, the World Health Organization's statement on Hormonal Contraception and HIV from 2012 advises women at high risk for HIV infection to use condoms if they are using progestin-only injectable contraception.

The new report builds on a systematic review from 2013 ( Lancet Infect Dis. 2013;13:797-808) by quantitatively considering the heterogeneity among the studied populations and assessing specific contraceptive methods.

The investigators searched PubMed for reports published since December 2011. They identified 26 relevant observational studies, 12 of which met their inclusion criteria, including use of hormonal contraceptives (one or more of DMPA, norethisterone enanthate, combined oral contraceptives, or progestin-only pills). In addition, all of the studies were prospective, excluded HIV-positive women, and adjusted for age and condom use to minimize confounders. The overall loss to follow-up was less than 30%. The researchers used random-effects models to minimize heterogeneity across studies.

The 12 studies included more than 39,500 women. Ten studies considered DMPA and found an increase in HIV risk (pooled hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.16 - 1.69), but it was lower in eight of those studies that surveyed women in the general population (pooled HR, 1.31, 95% CI, 1.10 - 1.57). The two DMPA studies done in women at high risk for HIV infection were too different from each other in design to provide meaningful data.

Ten studies of oral contraceptive pills found no increase in risk (pooled HR, 1.00; 95% CI, 0.86 - 1.16), nor did five studies of norethisterone enanthate (pooled HR, 1.10; 95% CI, 0.88 - 1.37).

The increase risk for HIV infection among women who use DMPA was 40% for all women and 31% for those at elevated risk for infection, such as sex workers, users of injectable drugs, and women in relationships with HIV-positive partners. "Within each specific population, some groups are affected more than others. DMPA users were 40% more likely to be infected than nonusers, even though the risk of HIV in both groups remains low," Ralph said.

The mechanism behind a link between DMPA and HIV infection is not known. Although some evidence indicates that women who use hormonal contraception use condoms less than other women, and the hormones could alter the female genital tract, vaginal flora, or immune response in ways that increase susceptibility to HIV, it is not clear why an injectable form would do so and not oral forms. Reports such as "Hormonal Contraception and HIV-1 Transmission" ( Am J Reprod Immunol. 2011;65:302-307) consider the two together and call for distinction, which the new quantitative meta-analysis accomplishes.

Ralph put the findings in perspective: "Whether the increased risk merits withdrawal of DMPA needs to be balanced against the known benefits of highly effective contraception in preventing unintended pregnancy and its associated morbidity and mortality. Withdrawal of DMPA would not be warranted in most countries for women in the general population. "

A limitation of the investigation is the inability of the reviewed observational studies to indicate causal relationships.

In an accompanying comment, Christopher Colvin, PhD, from the Division of Social and Behavioural Sciences, School of Public Health and Family Medicine, University of Cape Town, South Africa, and Abigail Harrison, PhD, from the Department of Behavioral and Social Sciences, Brown University School of Public, Providence, Rhode Island, address the ethics of conducting controlled clinical trials to better assess the contribution of specific hormonal contraceptives to increasing risk for HIV infection.

Randomized trials would offer more information but would have obvious risks, agreed Mary Rosser, MD, PhD, from the Department of Obstetrics & Gynecology & Women's Health at Montefiore Medical Center, Bronx, New York, as would prospective studies of the timing of contraception use to acute HIV infection. She applauded the new study. "It's helpful to have the data summarized in this manner and attention should focus on those women in the high risk category," Dr Rosser told Medscape Medical News.

The authors, commentators, and Dr Rosser have disclosed no relevant financial relationships.

Lancet Infect Dis. Published online January 8, 2015. Abstract

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