Median follow-up time was 23 months and the median interval between visits was 3 months.
Baseline population characteristics
Among 4404 women providing the male circumcision status of their primary partner at baseline, most [3249 (74%)] had uncircumcised partners; 989 (22%) had circumcised partners and 166 (4%) did not know their partner's circumcision status (Table 1). Circumcision was more common among partners of Ugandan (36%) than Zimbabwean women (9%). Zimbabwean women accounted for 98% of those who did not know whether their partner was circumcised.
Users of combined oral contraceptive pills, depot medroxyprogesterone acetate, and nonhormonal methods were roughly balanced among circumcised and uncircumcised groups. Ever use of male condoms was high: approximately four-fifths of women reported ever using male condoms, regardless of partner circumcision status (P = 0.62). Sexually transmitted infections (STI), including clinician-identified genital ulcer disease, were present in few women, with no substantial differences by circumcision status of the primary partner. Women with circumcised partners had a lower mean age at coital debut (16.8 versus 17.7 years; P < 0.001), a higher mean number of lifetime sex partners (4.8 versus 2.7 partners; P < 0.001), and a higher mean number of nights the primary partner was away from home in the last month (9.1 versus 6.1 nights; P < 0.001) (Table 1).
Differences in participant characteristics by baseline circumcision status of the primary partner were further explored within the population subgroups (low-risk Uganda versus high-risk Uganda versus Zimbabwe) (Table 2). Women from the high-risk Uganda stratum generally reported riskier behavior at baseline: these women were more likely to have ever engaged in sex work, to report two or more partners in the last 3 months, and to have a higher mean number of lifetime sex partners than women from either the low-risk Uganda or Zimbabwe strata (Table 2).
During follow-up, participants with partners who were circumcised, uncircumcised and of unknown circumcision status contributed 1674, 5636, and 256 person-years, respectively. Changes in partnerships where the new partner had a different circumcision status than the previous partner were reported by 243 women (6%) at some point during follow-up.
Similar to baseline findings, women partnered with circumcised men reported somewhat riskier sexual behavior during follow-up. Compared with women with uncircumcised partners, women with circumcised partners were more likely to self-report an STI (6% versus 4% of follow-up intervals; P < 0.001) or STI symptoms (26% versus 20% of follow-up intervals; P < 0.001), and to have a risky sexual partner (a man with STI symptoms, other sex partners, or who was HIV-positive; 23% versus 14% of follow-up intervals, P < 0.001). Although more women with circumcised partners reported never using condoms since the last visit (64% versus 50% of follow-up intervals, P < 0.001), they had a lower mean number of unprotected acts (8.6 versus 9.3 acts per month, P < 0.001) than women with uncircumcised partners.
HIV infection occurred in 210 women during follow-up (34, 167, and 9 HIV seroconversions in women with partners who were circumcised, uncircumcised, and of unknown circumcision status, respectively; Table 3). For the full cohort, unadjusted HIV incidence rates were 2.03/100 person-years (95% CI, 1.41–2.84) among those with circumcised partners, 2.96/100 person-years (95% CI, 2.53–3.45) in women with uncircumcised partners, and 3.51/100 person-years (95% CI, 1.61–6.67) in women who did not know their partner's circumcision status. When incidence rates were examined by population subgroup, Zimbabwean women had the highest unadjusted rates of HIV acquisition, both overall and in each category of partner circumcision status. High-risk Ugandans with circumcised partners had the lowest rate of HIV acquisition of any subgroup (Table 3).
Unadjusted and adjusted multivariate models
Initially, associations between male circumcision and HIV risk were examined among all women in the cohort. The unadjusted Cox proportional hazard model indicated that women with circumcised partners had reduced HIV risk compared with women with uncircumcised partners (HR, 0.69; 95% CI, 0.48–0.99; Table 4). The Kaplan–Meier plot shows similar results (P = 0.06; Fig. 1a).
After adjustment for age, age at coital debut, contraceptive method, husband's employment status, education level, and number of sex partners in the previous 3 months, the protective effect of male circumcision weakened (HR, 0.78, 95% CI, 0.53–1.14; Table 4). After further adjustment for population subgroup, the association disappeared (HR, 1.03; 95% CI, 0.69–1.53; Table 4).
The effect of male circumcision on women's HIV risk within each population subgroup is shown in Fig. 1b–d. HIV-free survival time for women with circumcised and uncircumcised partners was similar for both the low-risk Ugandan and the Zimbabwean subgroups (P = 0.39 and P = 0.62, respectively). For the high-risk Ugandan cohort, women with circumcised partners had longer HIV-free survival than women with uncircumcised partners (P = 0.05).
In both unadjusted and adjusted multivariable models, male circumcision status was not significantly associated with women's risk of HIV acquisition in any subgroup, although the point estimates varied widely (Table 4). The unadjusted estimate for high-risk Ugandans suggested protection but was not statistically significant (HR, 0.26; 95% CI, 0.06–1.16), whereas there was little to no effect of male circumcision on women's HIV risk among low-risk Ugandans (HR, 1.28; 95% CI, 0.69–2.35) or Zimbabweans (HR, 1.10; 95% CI, 0.64–1.87). Estimates were similar following adjustment (Table 4).
Some women acquired STI (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, herpes simplex virus type 2, or genital ulcer disease) during follow-up. To assess the influence of STI, preliminary analyses examined the effect of controlling for STI status in multivariable models in several ways. Inclusion of baseline STI status, STI at the last visit, or STI at the current visit did not have a meaningful effect on the estimates of the effect of male circumcision on women's HIV risk. Additionly, depending on the timing of infection, women's STI status could be affected by male circumcision (i.e., may lie on the causal pathway between male circumcision and women's HIV risk) . For these reasons, the final multivariate models were not adjusted for confounding by STI.
Removing from the analysis dataset those observations where women reported multiple partnerships also did not change the observed measures of effect (data not shown).
Under three sensitivity-specificity scenarios, associations between male circumcision and women's HIV risk were generally robust to misclassification of male circumcision status. In particular, misclassification of male circumcision was not influential for low-risk Ugandans or Zimbabweans, for whom the original estimates fell within the 2.5–97.5th percentile of the corrected HR values under all three misclassification scenarios. Possible misclassification of male circumcision was more influential among high-risk Ugandan women. Under all three sensitivity-specificity scenarios, the median corrected HR for this group weakened considerably (though remained protective) (table available upon request).
Recent findings [1–3] have indicated that male circumcision is protective against HIV in men. These analyses were undertaken to determine whether the protective effect of male circumcision also extended to women in our cohort.
Although our unadjusted analysis agreed with earlier prospective studies reporting a significant protective effect of male circumcision on women's HIV risk [4,5,10], after adjustment, we did not observe a significant protective effect of male circumcision overall or for any subgroup in our cohort. For a small group referred through high-risk settings, we found a suggestion of lower HIV risk for women with circumcised partners. The nonsignificant association in this subgroup is based on few HIV infections (19 total infections, and only two among women with circumcised partners, Table 3), and, therefore, the suggestion that male circumcision may be protective for these high-risk women must be interpreted very tentatively.
In these analyses, population (high-risk Ugandans versus low-risk Ugandans versus Zimbabweans) was very influential in characterizing the association between male circumcision and women's HIV risk, both as a confounder in overall analyses and as a modifier leading to subgroup estimates of the effect of male circumcision on women's HIV risk. We believe that population captured otherwise unmeasured differences in participants' risk of HIV. Population-level factors (e.g., prevalence of HIV and other STI, density and complexity of sexual networks, availability of antiretroviral medications, and many other factors) play essential contextual roles in individual-level risk of exposure to HIV. For example, the likelihood of exposure to an HIV-infected sex partner was probably quite different for women in the two countries: HIV prevalence among women screened for HC-HIV in Zimbabwe was 38%, compared with 16% in Uganda .
First, population had a strong confounding influence. The unadjusted model indicated that male circumcision was protective against women's acquisition of HIV; when population was included in the multivariate models, the protective effect of male circumcision disappeared. This is because Zimbabwean women, who formed the largest segment of the full cohort, were less likely to have circumcised partners but more likely to become HIV-infected during follow-up ; thus the apparent protective effect of male circumcision in the unadjusted estimate was actually caused by the confounding influence of population.
Second, we detected substantial heterogeneity of the male circumcision effect according to population. After adjustment for sexual behavior and demographic factors, the suggested protective effect of male circumcision was limited to the subgroup of women reporting riskier behavior (those in Uganda referred from higher risk settings), whereas women in both countries from family planning clinic populations saw no benefit from having a circumcised partner. Our finding of protection among the high-risk subgroup agrees with earlier observational studies among men, conducted prior to the recent randomized trials, suggesting that the protection granted by male circumcision to men is greater for those with riskier behavior [5,27–30].
Wawer et al. hypothesized that the greater protection for high-risk men is due to induction of a mucosal immune response in the presence of repeated exposure to HIV. Why might a protective effect of male circumcision be more apparent in high-risk women? Even if male circumcision reduces the per-act probability of transmission from infected men to susceptible women, it is still likely to be greater than 0. A woman with low-risk behavior who is nonetheless repeatedly exposed to the same infected man (for example, her husband) will probably ultimately seroconvert, regardless of his circumcision status. However the effect of male circumcision may be more readily seen in women with multiple partners or frequent new partners because the number of acts with a given partner over time would be fewer and any reduced probability of infection owing to male circumcision more directly apparent.
Our analysis has a number of limitations. The HC-HIV study was not designed to evaluate the role of male circumcision on women's HIV risk and, therefore, we did not have some information that could have strengthened the analysis. For example, we did not ask about the religion of either the women or their partners . Adjustment for ethnicity as a proxy for religion, however, had no substantial effect on the parameter estimates. In addition, because religion and ethnicity do not affect HIV risk directly but are themselves proxies for behavioral characteristics related to disease acquisition, and we measured these behaviors directly, we expect any bias to be minimal.
Women's sexual behavior, as well as male circumcision, were self-reported and may suffer from recall and courtesy biases. We attempted to account for misclassification of male circumcision using sensitivity analyses, and we found that errors in reporting partners' circumcision status were unlikely to have obscured the association between male circumcision and women's HIV risk. We note that our sensitivity analyses corrected the HR values only for male circumcision misclassification of the primary partner. Some women, particularly those referred from higher-risk settings, may have been exposed to other men with unknown circumcision status. However, women reported multiple sex partners at only 2% visits (3% of visits contributed by low-risk Ugandan women, 7% of visits by high-risk Ugandan women, and < 1% of visits from Zimbabwean women). If this is an accurate report, bias resulting from exposure to other partners is likely to be minimal; we also note that when we removed from the dataset those observations where women reported multiple partnerships, the observed measures of effect did not change. If 2% is a substantial underreport, however, the HR values may reflect a mixture of the effects of primary and nonprimary partners' circumcision status on women's HIV risk.
Male circumcision may permit a man to avoid initial infection, breaking a link in the disease transmission chain and thereby reducing or eliminating the risk of infection in his partners, or it may reduce the transmissibility of HIV from infected men to susceptible women (or both). Our analysis captures the summary effects of these pathways. Ultimately, a quantification of the distinct components of any effect of male circumcision on women's HIV risk is needed, and a prospective, HIV-serodiscordant couples study (HIV-positive men and HIV-negative women) is a superior design to parse these effects (such a study is currently underway in Rakai, Uganda). We asked women about the HIV status of their partners and attempted to conduct a subanalysis of the effect of male circumcision on women's HIV risk just among women with HIV-positive partners, but we had insufficient sample size to characterize this association.
Men appear to gain substantial protection from male circumcision [1–3]. However, we saw little influence of male circumcision on HIV risk for most women in our cohort. The suggestion of protection among women recruited from high-risk settings warrants further investigation.
We thank Daniel Westreich for his programming expertise in the sensitivity analyses and Ron Gray for sharing, through personal communications, unpublished data characterizing the accuracy with which female study participants in Rakai, Uganda characterize their main partner's circumcision status.
Sponsorship: This project received funds from the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, through a contract with Family Health International (Contract Number N01-HD-0-3310). ANT was supported by the Joseph Pogue Fellowship at the University of North Carolina at Chapel Hill.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
HIV; male circumcision; misclassification; Uganda; women; Zimbabwe