Women who use injectable hormonal contraceptives may be at increased risk for acquiring STIs, according to a pair of secondary analyses of data from randomized trials. In a prospective cohort study of HIV-negative couples in Rakai, Uganda, women who used depot medroxyprogesterone acetate (DMPA) consistently had an elevated risk of becoming infected with herpes simplex virus 2 (HSV-2) relative to nonpregnant peers not using hormonal contraceptives (hazard ratio, 2.3).¹ And in a prospective study among women in South Africa using one of two progestin-only injectables, the risk of acquiring HIV-1 was elevated among DMPA users relative to norethisterone enanthate (NET-EN) users (1.4), especially if they were HSV-2 positive (2.0).²

The first study was conducted among HIV- and HSV-2–negative women aged 15–49 who were in long-term sexual partnerships with HIV-negative men who had enrolled in a randomized trial of male circumcision between August 2003 and July 2006. Women were excluded if they or their partner became seropositive for HIV. At enrollment and two annual follow-up visits, women and men provided information about their sociodemographic characteristics, sexual risk behaviors and health status. Women were also asked whether they were pregnant and were using oral or injectable hormonal contraceptives. At each visit, women were classified as consistently using DMPA if they reported use at both the current and previous visit, as initiating use if they reported use at only the current visit, and as discontinuing use if they reported use at only the previous visit. Blood samples collected at each visit were tested for HSV-2 by an enzyme-linked immunosorbent assay, and positive results were confirmed by western blot. The investigators performed univariate analyses assessing the association of consistent DMPA use and HSV-2 seroconversion, and constructed multivariate regression models to identify characteristics independently associated with this outcome.

Analyses were based on 682 women who were about 24 years old, on average, at enrollment. Overall, 25% of women reported using a hormonal contraceptive at some time during the study, of whom roughly a third were consistent users of DMPA.

During an average follow-up of 1.7 person-years, 10% of women became HSV-2 seropositive, corresponding to an incidence of 5.8 per 100 person-years. By group, the incidence was 13.5 per 100 person-years among women who were consistently using DMPA, 4.3 per 100 person-years among pregnant women who were not using hormonal contraceptives and 6.6 per 100 person-years among women who were neither pregnant nor using hormonal contraceptives.

In a multivariate analysis, compared with peers who were neither pregnant nor using hormonal contraceptives, women who were consistent DMPA users had an elevated risk of HSV-2 seroconversion (hazard ratio, 2.3). In contrast, risk was not increased for those who initiated or discontinued use, or for oral contraceptive users or those who were pregnant. Women were more likely to become HSV-2 seropositive if they had had four or more lifetime sexual partners than if they had had one (3.5), and if their male partner had a secondary or postsecondary education as compared with a primary education (1.9–2.9).

One-fifth of women had a partner who was HSV-2 seropositive at baseline or became seropositive during follow-up. In this group, the incidence of seroconversion was 10.6 per 100 person-years overall, but it was 36.4 per 100 person-years among consistent DMPA users. In a multivariate analysis, women who had consistently used DMPA had a sharply elevated risk of HSV-2 seroconversion relative to nonpregnant peers who had not used any form of hormonal contraceptive (hazard ratio, 6.2). Again, no increase in risk was seen for those who had initiated or discontinued use, or for oral hormonal contraceptive users or those who had been pregnant.

The study is the first to prospectively show that DMPA use is associated with increased risk of HSV-2 infection among HIV-negative women. The investigators caution that relatively few women became infected during the study and that follow-up intervals were long; therefore, the research should be replicated in larger studies that have shorter follow-up intervals and assess other contraceptives as well. Moreover, any elevation of HSV-2 risk associated with DMPA use should be balanced against known benefits, such as reductions in unwanted pregnancy and maternal mortality, the investigators maintain. "Increased access to other forms of highly effective, long-acting, low-dose contraceptive methods, including intrauterine devices and implants, is needed in Sub-Saharan Africa," the authors conclude.

The second study was conducted among South African women who used progestin- only injectable contraceptives while participating in a randomized trial of tenofovir for HIV-1 prevention between September 2009 and August 2012. At monthly visits, women were asked about contraceptive use and behavioral factors, and were tested for HIV-1 infection and pregnancy. The women were screened annually (or more often when indicated) for chlamydia, gonorrhea and trichomonas infection, and at baseline and the end of the study for HSV-2. All women were given condoms and standard counseling about reducing the risk of STI acquisition. The investigators used Cox proportional hazards regression analyses to estimate the difference in incident HIV-1 infection between women using DMPA and women using NET-EN.

Analyses were based on 3,141 women who had a median age of 23 at baseline; a fifth were married or cohabiting, and more than four-fifths had children. Overall, 57% of the women solely used DMPA, 35% solely used NET-EN and 8% used both but at different times during follow-up.

After a median follow-up of 13 months, the incidence of HIV-1 infection was 7.6 per 100 person-years in the cohort as a whole. It was 8.6 per 100 person-years among DMPA users, compared with 5.7 per 100 person-years among NET-EN users. In a multivariate analysis, women using DMPA were significantly more likely to acquire HIV-1 than peers using NET-EN (hazard ratio, 1.4).

Overall, 47% of women were seropositive for HSV-2 at enrollment. These women had a significantly higher adjusted risk of HIV-1 infection when using DMPA as compared with NET-EN (hazard ratio, 2.0), whereas HSV-2–seronegative women did not.

In addition, women in several subgroups were more likely to acquire HIV-1 if they were using DMPA rather than NET-EN. In particular, risk was elevated among women who, at baseline, reported not using condoms for vaginal sex (hazard ratio, 3.9), were younger than 25 (1.4) or had chlamydia, gonorrhea or trichomonas infection (1.8). Among women who used both injectables but at different times, risk was sharply higher during periods of DMPA use than during periods of NET-EN use (4.8).

The findings suggest there may be important differences among progestin-only injectable contraceptives with regard to the risk of acquiring HIV-1, according to the investigators. They note that the findings concerning risk by HSV-2 infection status differ from those of other studies, and thus more data are needed in this area. Study limitations included possible bias and confounding, as well as the lack of comparison groups not using hormonal contraceptives or using injectables that contain hormone combinations, the investigators acknowledge. Nonetheless, "the present data suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA, and policy makers, clinician scientists, and community stakeholders should continue to assess emerging evidence to establish whether women who prefer an injectable, in consultation with providers, should consider switching from DMPA to NET-EN in high HIV incidence settings where NET-EN is available," they conclude.—S. London

REFERENCES

1. Grabowski MK et al., Use of injectable hormonal contraception and women’s risk of herpes simplex virus type 2 acquisition: a prospective study of couples in Rakai, Uganda, Lancet Global Health, 2015, 3(8):e478–e486, doi: 10.1016/S2214-109X(15)00086-8.

2. Noguchi LM et al., Risk of HIV-1 acquisition among women who use different types of injectable progestin contraception in South Africa: a prospective cohort study, Lancet HIV, 2015, 2(7):e279–e287, doi: 10.1016/S2352-3018(15)00058-2.