For the majority of the 3,790 HIV-1 serodiscordant couples, the HIV-1 infected partner was female (). Most couples were married with children. The median age was in the mid-30s, and 24.4% of uninfected women were aged <25 years. Among HIV-1 seropositive participants, the median CD4 count was 455 (interquartile range [IQR] 337–626) cells/mm3 and median plasma HIV-1 RNA concentration was 4.10 (IQR 3.37–4.73) log10 copies/mL. More than a quarter of women experienced a pregnancy during study follow-up.
Participant characteristics, prospective study of 3790 African heterosexual HIV-1 serodiscordant couples
Hormonal contraceptive use
At enrollment, 14.8% of HIV-1 seronegative and 17.4% of HIV-1 seropositive women used hormonal contraception; injectable contraception was more commonly used than oral pills (used by 12.5% and 3.9% of women, respectively). In total, 21.2% of HIV-1 seronegative and 33.3% of HIV-1 seropositive women used hormonal methods during study follow-up. Most (82.6% [n=1085] of HIV-1 seronegative and 77.1% [n=1909] of HIV-1 seropositive) women did not switch contraceptive methods during follow-up. However, among women who ever used hormonal contraception during the study, 48.0% (47.4% of HIV-1 seropositive and 49.5% of HIV-1 seronegative women) were not using such methods at some point during follow-up.
Follow-up and incident HIV-1 infection
Median follow-up for HIV-1 seronegative women and men was 18.0 (IQR 12.6–24.2) and 18.7 months (IQR 12.8–24.2), respectively. Retention at 12 and 24 months was 93.1% and 87.4% for HIV-1 seronegative women and 90.0% and 83.7% for HIV-1 seronegative men. HIV-1 seronegative partners accrued 5157.9 person-years of follow-up for assessment of HIV-1 seroincidence, during which 167 HIV-1 seroconversions occurred. Of the 73 infections in women, 62 (84.9%) were determined by viral sequencing to be genetically linked within the partnership, and of the 93 infections in men, 59 (63.4%) were determined to be linked.
During follow-up, hormonal contraceptives were used more frequently by couples with younger HIV-1 uninfected partners and couples who did not experience pregnancy (). Sexual behaviors did not differ for HIV-1 uninfected women during periods when they were using versus not using hormonal contraception. For HIV-1 uninfected men, unprotected sex was more likely and sex with an external partner was less likely during periods when their female partner was using hormonal contraception. Plasma HIV-1 RNA concentrations and CD4 counts were similar for hormonal contraception exposed versus unexposed periods.
Participant characteristics during quarterly follow up intervals with and without hormonal contraceptive use
Hormonal contraception and HIV-1 acquisition in women
HIV-1 acquisition rates were 6.61 and 3.78 per 100 person-years in women using and not using hormonal contraception (). In multivariate Cox proportional hazards analysis adjusted for age, pregnancy, unprotected sex and plasma HIV-1 levels in the HIV-1 infected partner, hormonal contraceptive use was associated with a 2-fold increased risk of HIV-1 acquisition (adjusted hazard ratio [AHR] 1.98, 95% confidence interval [CI] 1.06–3.68). Elevated risk was seen for both injectable (AHR=2.05, 95% CI 1.04–4.04) and oral contraceptive use (AHR=1.80, 95% CI 0.55–5.82), although the oral contraceptive use analysis included only 50.5 person-years and did not achieve statistical significance. The results from the marginal structural models were generally in agreement with the Cox regression models. We found no evidence that the effect of hormonal contraception on HIV-1 risk was different for HSV-2 seronegative (15.2% of women) versus seropositive women (AHR=1.56 versus 2.00, interaction p=0.82) or for women <25 (24.4% of women) versus ≥25 years of age (AHR=1.96 versus 2.21, interaction p=0.82).
Hormonal contraceptive use and risk of HIV-1 acquisition in women
Hormonal contraception and HIV-1 transmission from women to men
HIV-1 transmission rates from women to their male partners were 2.61 and 1.51 per 100 person-years from hormonal contraceptive users and nonusers, respectively (). In multivariate analysis adjusted for age, pregnancy, unprotected sex and plasma HIV-1 levels in the HIV-1 infected partner, men’s HIV-1 risk was increased 2-fold when their partners were using hormonal contraception (AHR=1.97, 95% CI 1.12–3.45). Both injectable (AHR=1.95, 95% CI 1.06–3.58) and oral contraceptive use by female partners (AHR=2.09, 95% CI 0.75–5.84) were associated with increased HIV-1 risk for men, although the effect was statistically significant only for injectable contraception. The marginal structural model analyses generated similar results to the Cox proportional hazards regression.
Hormonal contraceptive use and risk of HIV-1 transmission from women to men
In order to account for the potential persistent biologic effects of hormonal contraception on HIV-1 risk when women switched contraceptive methods, we assessed the effect of extending the exposure window for 3 months after last hormonal contraceptive use (thus, women could be exposed to >1 method during one study visit window). This affected 1.8% of person-years and one seroconversion event for the HIV-1 acquisition analysis and 2.1% of person-years and one event for the female-to-male transmission analysis. The results of these analyses were not substantially different than those presented in and (data not shown). When we limited the analysis of HIV-1 acquisition by women to those 62 outcomes that were genetically-linked to their male study partners, the effect estimates were not substantially changed (for any hormonal contraceptive use, Cox regression AHR=2.06, 95% CI 1.05–4.03 and marginal structural model odds ratio=2.01, 95% CI 1.02–3.95). In a third sensitivity analysis, we censored observations during pregnancy and adjusted our Cox model for age, unprotected sex and plasma HIV-1 levels in the HIV-1 infected partner. We did not see substantial differences in the effect estimates (Cox regression AHR=1.84, 95% CI 0.97–3.49 for the association of hormonal contraception and HIV-1 acquisition among women and AHR=1.86, 95% CI 1.04–3.32 for the association of hormonal contraception and HIV-1 transmission to men) for this approach compared with our primary study models.
Contraceptive use and genital HIV-1 RNA concentrations in HIV-1 seropositive women
We measured endocervical HIV-1 RNA concentrations from a single time-point in 1691 HIV-1 infected women (). Women using injectable contraception at the time of endocervical sample collection were more likely to have genital HIV-1 RNA detected than those not using hormonal contraception. Genital HIV-1 RNA concentrations were also higher in those using injectable contraception, by an average of 0.19 log10 copies/swab, after adjusting for plasma HIV-1 levels and CD4 count. There was no association between contraception and plasma HIV-1 RNA levels collected at the same time as the endocervical sample (median 3.91 versus 4.03 log10 copies/mL for injectable users versus non-users, p=0.10), suggesting a localized effect of hormonal contraception on increased levels of HIV-1 in the female genital tract.
Endocervical HIV-1 RNA concentrations in HIV-1 seropositive women (n=1691), by contraceptive method