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Hormonal Contraception Increases Risk of HIV Infection for Women and Men

Use of hormonal contraceptives, especially the injectable progesterone Depot Provera, was associated with nearly double the risk of acquiring HIV for both women and their male partners in a large African trial. While the absolute increase in new infections was small, these findings raise important questions about the underlying biological mechanisms, and may shed light on some of the puzzling outcomes of recent HIV prevention studies.

As described in the October 4, 2011, advance online edition of The Lancet Infectious Diseases, Renee Heffron, Jared Baeten, and fellow investigators with the Partners in Prevention HSV/HIV Transmission Study assessed the association between hormonal contraceptive use and risk of HIV-1 acquisition by women, as well as HIV transmission from infected women to their male partners.

Partners in Prevention was designed to test whether treatment of herpes simplex virus infection would help prevent transmission or acquisition of HIV, since it is known that concurrent sexually transmitted diseases can facilitate HIV infection. Investigators also looked at other known or potential HIV risk factors, including hormonal contraceptives.

Several smaller observational studies have seen a link between hormonal contraception and higher rates of HIV among women; monkey studies have also shown a similar association. But large, randomized controlled trials are needed to conclusively demonstrate a significant cause-and-effect relationship.

This prospective analysis included 3790 heterosexual HIV serodiscordant couples (1 positive, 1 negative) participating in 2 longitudinal studies of HIV incidence in 7 African countries (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia).

The analyses controlled for age, pregnancy, condom use, and the positive partner's viral load, as well as a variety of demographic, behavioral, and clinical factors. Follow-up continued for approximately 18.5 months.

About twice as many couples had an HIV positive woman as had an HIV negative man. Study participants were counseled to use condoms in addition to hormonal contraceptives. Depot medroxyprogesterone acetate (DMPA, better known as Depo Provera) -- an injection given once every 3 months -- was the most frequently used method.

Results

• Among 1314 couples in which the woman was initially HIV negative, the rate of HIV acquisition was significantly higher for those who used hormonal contraception (adjusted hazard ratio [HR] 1.98, or 98% increased risk; P=0.03):
  • 6.61 per 100 person-years (PY) for women using hormonal contraception;
  • 3.78 per 100 PY for women who did not.
• Among 2476 couples in which the man was initially HIV negative, the rate of HIV infection was again significantly higher when his female partner used hormonal contraceptives (adjusted HR 1.97, or 97% increased risk; P = 0.02):
  • 2.61 per 100 PY if the women used hormonal contraception;
  • 1.51 per 100 PY if she did not.
• Sub-group analyses showed significantly increased risk of HIV infection when looking only at injectable hormonal methods.
• Oral hormonal contraceptive use was associated with a non-significant increase in HIV risk, but the number of women using pills was too small to draw definitive conclusions.
• HIV RNA levels in cervical secretions were higher in HIV positive women using injectable methods compared with those who did not, though this was not the case for plasma viral load.

"Our findings provide new data that show that contraception might increase a woman's risk of acquiring HIV-1, and they are consistent with longitudinal studies of sex workers in Kenya and family planning attendees from Uganda and Zimbabwe," the investigators wrote in their discussion. "Moreover, to our knowledge, ours is the first prospective study to show increased HIV-1 risk in male partners of HIV-1-infected women using hormonal contraception."

"Clinical and laboratory studies have suggested possible mechanisms by which hormonal contraception could influence HIV-1 susceptibility and infectiousness including changes to vaginal structure, cytokine regulation, CCR5 expression, and cervicovaginal HIV-1 shedding." they elaborated.

With regard to study limitations, they noted that contraceptive use was determined by self-report, they did not gather data on contraceptive adherence (although the widespread use of injectable progesterone suggests it was likely good), and they did not compare specific brands containing different hormone formulations.

In this trial the investigators halted follow-up when HIV positive partners started antiretroviral therapy (ART). Future research should evaluate whether results are similar when positive partners are on treatment and achieve viral suppression; if so, this would provide further support for early ART. Studies should also look at other types of hormonal methods including patches and implants, as well as non-hormonal methods such as intrauterine devices, the researchers recommended.

"The benefits of effective hormonal contraceptive methods are unequivocal and must be balanced with the risk for HIV-1 infection," they concluded. "Our findings argue for policies to counsel women about the potential for increased HIV-1 risk with hormonal contraceptive use, especially injectable DMPA use, and the importance of dual protection with condoms to decrease HIV-1 risk." They also suggested that, "Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1."

Editorial

In an accompanying editorial, Charles Morrison and Kavita Nanda from the non-profit global development organization FHI 360 laid out some of the issues and unanswered questions raised by these findings.

While this was a prospective study, it was a secondary analysis of an HIV prevention trial, not one specifically designed to look at the relationship between hormonal contraception and HIV risk, they cautioned. A small proportion of the overall Partners study population used hormonal contraceptives -- accounting for about 11% of total person-years of follow-up -- and switching methods was common. Furthermore, there were few new HIV infections in this group (10 among DMPA users and 3 among oral contraceptive users).

"Use of effective contraception to prevent unintended pregnancies has unequivocal benefits" that must be weighed against the small observed increase in HIV risk, they stressed, including reduced maternal mortality and morbidity, increased socioeconomic status of women, and improved health of children spaced further apart. They also noted that a separate analysis by the same study team suggested that pregnancy also increases the risk of HIV transmission.

"The question of hormonal contraceptive use and risk of HIV acquisition remains unanswered after more than two decades," they concluded. "Active promotion of DMPA in areas with high HIV incidence could be contributing to the HIV epidemic in sub-Saharan Africa, which would be tragic. Conversely, limiting one of the most highly used effective methods of contraception in sub-Saharan Africa would probably contribute to increased maternal mortality and morbidity and more low birthweight babies and orphans -- an equally tragic result."

The World Health Organization (WHO) currently recommends that the benefits of hormonal contraceptives outweigh any potential harm for women at high risk for or living with HIV, but WHO will convene a meeting of experts in January to reconsider the issue.

"The time to provide a more definitive answer to this crucial public health question is now," Morrison and Nanda added, urging financial donors to support a randomized trial of hormonal contraception and HIV acquisition.

10/4/11

References

R Heffron, D Donnell, H Rees, J Baeten, et al (Partners in Prevention HSV/HIV Transmission Study Team). Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. The LancetInfectious Diseases (free with registration). October 4, 2011 (Epub ahead of print).

CS Morrison and K Nanda. Hormonal contraception and HIV: an unanswered question. The Lancet Infectious Diseases. October 4, 2011 (Epub ahead of print).