Data mixed on increased risk of HIV in women using contraceptive shots
Researchers plan randomized controlled trial in 2015 to clarify issue
Injectable contraceptives are among the world’s most popular family planning options. In Eastern Africa and Southern Africa, injectables account for more than 40% of contraceptive use. About 2.4% of contracepting women in the United States choose the method.1,2
EXECUTIVE SUMMARY
Presentations at the AIDS 2014 conference offer differing outlooks on increased risk of HIV in women using contraceptive injections.
- In a meta-analysis that included individual-level data on 37,000 women, results indicate use of depot medroxyprogesterone acetate (DMPA) is linked with a higher rate of new HIV infections. However, findings from a separate longitudinal study of serodiscordant couples suggest no link between hormonal contraceptives and a woman's risk for HIV.
- A large randomized controlled trial in which participants will be openly randomized to use DMPA, the levonorgestrel implant, or the copper intrauterine device might offer a more definitive answer.
Use of progestin-only contraceptive injectables, particularly depot medroxyprogesterone acetate (DMPA), has come under question after findings from some studies suggest that use might be associated with an increased risk of acquiring HIV from an infected partner.3-4
Two presentations at the recent AIDS 2014 conference in Melbourne, Australia, offer differing outlooks on increased risk of HIV in women using contraceptive injections. In a meta-analysis that included individual-level data on 37,000 women, results indicate use of DMPA is linked with a higher rate of new HIV infections in women.5 However, findings from a separate longitudinal study of serodiscordant couples suggest no link between hormonal contraceptives and a woman’s risk for HIV.6
To get more definitive answers on the subject, a large randomized controlled trial is being planned by the Evidence for Contraceptive Options and HIV Outcomes (ECHO) consortium. Members of the consortium include FHI 360 in Durham, NC, the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa, the University of Washington in Seattle, and the World Health Organization (WHO) in Geneva, Switzerland.
The trial plans to enroll approximately 8,600 HIV-negative women from 14 sites in east and southern Africa who desire contraception. Study participants will be openly randomized to use DMPA, the levonorgestrel implant, or the copper intrauterine device, and they will be followed for an average of 15 months. Researchers will look at the rates of HIV acquisition among the three groups of women, Rates of pregnancy, contraceptive method continuation, and contraceptive method-related adverse events also will be examined. The trial will take approximately four years to complete, with enrollment expected to begin in early 2015.
While the timeline might be somewhat delayed by funding challenges, researchers hope to move forward in examining this issue, says Charles Morrison, PhD, director of clinical sciences at FHI 360. "We feel by doing a randomized trial, which has not been done before, that we will get the most definitive answer that we can get to this question," says Morrison. "Women, policymakers, and clinicians really need this information, especially in sub-Saharan Africa."
Look at meta-analysis
Morrison presented results of FHI 360’s and collaborators’ meta-analysis of individual participant data on hormonal contraception and HIV acquisition from 18 prospective studies and HIV prevention trials in sub-Saharan Africa at the recent AIDS 2014 conference.5 By using data from individual participants, the research team aimed to help overcome some of the methodological challenges of simply combining estimates of the effects from multiple studies.
In looking at contraceptive methods, 28% of the cohort reported DMPA use, 19% of women used oral contraceptives, 8% used norethisterone enanthate, and 43% used nonhormonal methods. Of the individual data on 37,124 women that were pooled, there were 1,830 incident HIV infections. In the primary analysis, researchers estimated the hazard ratio (HR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. The team conducted sensitivity analyses to assess whether results were influenced by risk of methodological bias in component studies, HIV incidence, pregnancy status, or limiting person-time to periods with no condom use.
Relative to non-users, the pooled adjusted HR for HIV acquisition was 1.50 (95% confidence interval [CI]:1.24-1.83) for DMPA, 1.24 (95% CI:0.84-1.82) for norethisterone enanthate, and 1.03 (95% CI:0.88-1.20) for combined oral contraceptives. Studies at lower risk of bias showed lower hazard ratios [DMPA (1.22; 95% CI:0.99-1.50), norethisterone enanthate (0.67; 95% CI:0.47-0.96), combined oral contraceptives (0.91; 95% CI:0.73-1.14)] than those at higher risk of bias: [DMPA (HR 1.73; 95% CI:1.39-2.16), norethisterone enanthate (HR 1.50; 95% CI:1.14-1.96) and combined pills (HR 1.16; 95% CI:0.93-1.45)].5
Researchers found evidence that DMPA, but not norethisterone enanthate or combined oral contraceptive use, increased women’s risk of HIV. However, the estimated risks associated with hormonal contraceptive use were substantially lower in studies at less risk of methodological bias, which highlights the limitations of observational data, researchers concluded.
Check Zambian results
To look at the relationship between HIV risk and use of hormonal contraception, a separate group of investigators looked at longitudinal data gathered by the Rwanda Zambia HIV Research Group, with headquarters at the Rollins School of Public Health at Emory University in Atlanta. The research group has maintained one of the longest-standing and largest discordant cohorts in the world, notes Kristin Wall, PhD, research assistant professor in the Rollins School. Wall presented 17 years of follow-up data on the cohort at the AIDS 2014 conference.6
"Understanding HIV risk among discordant couples is advantageous due to their relatively homogenous level of HIV exposure," explains Wall. "We also collect multiple measures of unprotected sex, an important confounder, and provided contraceptive methods on site with high frequency: every three months."
Researchers hoped that by using such rigorously collected and robust data, they could add important findings to the controversial evidence surrounding this issue, said Wall. "We felt an obligation to explore this potential association as findings indicating increased HIV acquisition risk for hormonal contraception users could directly effect the health of women in the communities we work where unintended pregnancy and HIV are epidemic," she notes.
To perform the study, researchers looked at 1,393 couples, each with an HIV-positive man and HIV-negative woman. A total of 252 women acquired HIV. Incidence of HIV infection was 11.5% for women using oral contraceptives, 10.7% for women using injectable contraceptives, 8.4% for women who used condoms or no contraception, and 7.3% for women using a contraceptive implant. After thorough consideration of confounding, misclassification, effect measure modification, interaction, and mediation, researchers found no association between hormonal contraception and HIV acquisition risk among women over 17 years of follow-up.6
What does the WHO say?
WHO presented its latest recommendations at the AIDS 2014 conference. The guidance recommends no restrictions on the use of combined hormonal contraceptives (pills, patch, vaginal ring, or injectable) or progestin-only contraceptives (pills, injectable, or implants) for women with or vulnerable to HIV. Women taking antiretroviral therapy now are generally eligible for all hormonal contraceptive methods, although special consideration might be necessary, the guidance notes.7
"Because any risk of HIV acquisition associated with progestogen-only injectable use remains on open question, women and couples at high risk of HIV infection should be informed about (and have access to) HIV preventative measures, including male and female condoms," the guidance states. "WHO is committed to continually review its recommendations in light of the accumulating evidence, and strongly supports the need for further research to identify definitive answers that address concerns around increased biological vulnerability to HIV among women using progestogen-only injectables."
Four systematic reviews of epidemiological, clinical, and pharmacological evidence available through January 2014 were conducted to inform the guidance. Results of the two studies presented at the July 2014 AIDS conference were not available for inclusion in the reviews.
REFERENCES
- United Nations. World Contraceptive Patterns 2013. Accessed at http://bit.ly/1cqDlE2.
- Guttmacher Institute. Contraceptive Use in the United States.
- Accessed at http://bit.ly/1iwK7wB.
- Heffron R, Donnell D, Rees H, et al; Partners in Prevention HSV/HIV Transmission Study Team. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis 2012; 12(1):19-26.
- Morrison CS, Chen PL, Kwok C, et al. Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling. AIDS 2010; 24(11):1,778-1,781.
- Morrison C, Chen PL, Kwok C, et al. Hormonal contraception and HIV infection: results from a large individual participant data meta-analysis. Presented at the 20th International AIDS Conference. Melbourne; July 2014.
- Wall K, Kilembe W, Naw HK, et al. Weighing 17 years of evidence: Does hormonal contraception increase HIV acquisition risk among Zambian women in discordant couples? Presented at the 20th International AIDS Conference. Melbourne; July 2014.
- Gaffield ME, Phillips SJ, Baggaley RC, et al. HIV and contraception complex issues for safe choice: the latest recommendations from the World Health Organization (WHO). Presented at the 20th International AIDS Conference. Melbourne; July 2014.
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