Three randomized trials indicate that male circumcision lowers men's HIV risk [1–3]. The subsequent influence of male circumcision on HIV risk in their female sex partners has not been well characterized. The few existing studies on this topic have yielded mixed results. Compared with women with uncircumcised partners, those with circumcised partners have been found to have lower [4–10], higher , and approximately equal  HIV risk. A prospective study of urban Tanzanian women from family planning clinics  and prospective couples' studies in rural Uganda [5,9,10] found that women with circumcised partners had reduced HIV risk. Three cross-sectional studies also report lower HIV prevalence among women with circumcised partners, conducted among Kenyan patients at family planning clinics , urban Ugandan couples seeking HIV counseling and testing , and Brazilian serodiscordant couples . Conversely, a cross-sectional study among child-bearing Rwandan women found that male circumcision was not associated with women's HIV prevalence , and HIV prevalence among pregnant Rwandan women seeking antenatal care was higher among women with circumcised partners . Many of these studies presented only crude estimates of the effect of male circumcision [8,9,11,12].
Several biological mechanisms have been proposed through which male circumcision may alter women's HIV risk. Uncircumcised men may have a higher efficiency of transmitting HIV, because the foreskin is a repository for shed cells and a hospitable environment for microorganism growth . The foreskin may be more susceptible to HIV infection because of increased concentrations of HIV target cells: one study found that adult foreskin mucosa had higher mean proportions of CD4 T cells, macrophages, and Langerhans cells than pediatric foreskin or cervical mucosa. The same authors quantitatively compared HIV infectivity by tissue type following ex vivo HIV infection of adult and pediatric foreskin biopsies and cervical biopsies. Adult foreskin mucosa had more rapid uptake of HIV than either cervical mucosa or the external surface of the foreskin tissue . Several studies indicate that uncircumcised men have substantially increased rates of genital ulcer disease , and presence of ulcers is a known cofactor increasing HIV transmissibility [16,17]. It may be that male circumcision has no direct effect on the transmissibility of HIV from infected men to susceptible women, but if circumcision reduces men's HIV risk, women partnered with circumcised men may be less likely to be exposed to HIV.
The effect of male circumcision on women's HIV risk was examined through secondary data analysis of the Hormonal Contraception and the Risk of HIV Acquisition (HC-HIV) study, a multisite prospective cohort study assessing the effect of hormonal contraception on HIV acquisition among women. Detailed methods have been published previously .
Study setting and population
The HC-HIV study recruited women from 1999 to 2002 in Uganda, Zimbabwe, and Thailand. Thai women were excluded from this analysis because of very low HIV incidence.
Eligible women were 18–35 years of age; HIV seronegative; sexually active (three or more acts in the past 3 months); and using either combined oral contraceptive pills (COC), injectable depot medroxyprogesterone acetate (DMPA), or a nonhormonal/no contraceptive method. All Zimbabwean and most Ugandan participants were recruited from family planning and mother–child health clinics. Owing to low initial HIV incidence among Ugandan participants, recruitment in Uganda was expanded to include referrals from ‘high-risk’ populations, such as patients at sexually transmitted disease clinics, sex workers and military wives.
All participants provided written informed consent prior to study entry. The HC-HIV study was approved by ethics committees at collaborating institutions.
This analysis was restricted to women in Zimbabwe and Uganda who completed at least one follow-up visit with valid HIV results and provided information about their primary partner's circumcision status (see below). Follow-up officially ended at the first visit following 24 months. Follow-up time was censored after 28 months for a small number of women with extended follow-up.
At enrollment and each follow-up visit, women received structured interviews about their reproductive, contraceptive, and sexual behavior and physical examinations with specimen collection. Visits were conducted approximately every 12 weeks.
At enrollment, participants answered several questions about their primary partner, including his circumcision status. At subsequent visits, women were asked whether their primary partner had changed. Participants with new primary partners were asked if that partner was circumcised, and, therefore, male circumcision was time varying in this analysis. For a woman reporting a new primary partner with a different circumcision status than the previous partner, the switch in exposure status was assumed to have occurred at the start of the interval about which she was reporting. Male circumcision data were not collected for nonprimary partners.
Women were considered HIV infected if positive on a combination of two enzyme-linked immunosorbent assays [Recombigen HIV-1/HIV-2 (Cambridge Biotech, Cambridge, UK), Organon Vironostika (Organon Teknika, Boxtel, the Netherlands), Abbott Murex (Abbott, Dartford, UK), or Sanofi (Sanofi Diagnostics Pasteur, Redmond, DC, USA)] or rapid tests [HIV SAV1 or SAV2 (Savyon Diagnostics, Ashdod, Israel), Capillus HIV-1/HIV-2 (Trinity Biotech, Carlsbad, California, USA) or Determine (Abbott)]. Positive results were confirmed by Western blot (BioRad, Hercules, California, USA) or HIV polymerase chain reaction (PCR) (Amplicor HIV-1 DNA test, version 1.5; Roche Diagnostics, Branchburg, New Jersey, USA). Serial testing was conducted on stored specimens using PCR to date incident HIV infections accurately.
Statistical analyses were performed using SAS (version 9.1.3, SAS Institute, Cary, North Carolina, USA).
Using extended Cox proportional hazards models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated to describe the effect of primary partner's circumcision status on women's time to HIV infection. Person-time was calculated as time from enrollment to either the visit date at which HIV was detected or the last visit date for women remaining uninfected.
To evaluate heterogeneity of the male circumcision effect among population subgroups (women recruited from family planning clinics in Uganda versus higher-risk settings in Uganda versus family planning clinics in Zimbabwe), the significance of a product-interaction term between male circumcision and population was examined; an interaction term with P < 0.10 led to inclusion in multivariable models . Participants' demographic characteristics, reproductive factors, and sexual behavior were also examined for their confounding influence on the male circumcision effect measure. Those variables were included in preliminary multivariate models that were associated with male circumcision or HIV acquisition in simple Cox models.
A manual, backward elimination, change-in-estimate strategy was used to remove, one at a time, those variables that did not confound the association between male circumcision and women's HIV risk . Covariates were not retained if removal changed the male circumcision association by less than 10% overall or in any stratum of population [21,22]. Women who did not know their partner's circumcision status were excluded from multivariable models.
To achieve the best characterization of the relationship between male circumcision and women's HIV risk, the results present both the overall association between male circumcision and women's HIV risk in the full cohort and the associations in each population subgroup.
The robustness of the observed association between male circumcision and women's HIV risk was examined using sensitivity analysis (comparable to the methods of Lash and Silliman ). Specifically, because male circumcision status was reported by women, the influence of misclassification of men's circumcision status on the observed HR values was assessed.
The estimates of the association between male circumcision and women's HIV risk were corrected using three reports of the sensitivity and specificity with which women classify male circumcision [94% sensitivity with 89% specificity , 95% sensitivity with 92% specificity , and 92% sensitivity with 97% specificity (Ron Gray, unpublished data)]. Women who did not know their partners' circumcision status were excluded.
The corrections were carried out in two steps, separately for each sensitivity–specificity pair. First, the two probabilities that a participant's report about her partner was inaccurate were computed: that a man was truly circumcised, although his partner reported he was uncircumcised, or that he was truly uncircumcised, although his partner reported he was circumcised. Using these probabilities, the circumcision status of participants' partners was randomly reclassified 2500 times to create 2500 corrected datasets. From each reclassified dataset, corrected unadjusted and adjusted HR values were calculated. The median HR from the 2500 simulations was interpreted as the corrected HR and the 2.5th and 97.5th percentiles as the corrected 95% CI.
The HC-HIV study enrolled 4531 participants from Uganda and Zimbabwe; 114 were excluded: 80 did not return for follow-up; 14 first returned 28 months or longer after enrollment, and were therefore censored; 12 used exclusively nonstudy contraceptive methods, and 8 were missing male circumcision data at every follow-up visit. [Thirteen women were missing male circumcision status of their primary partner at baseline but had valid male circumcision data later in follow-up; these participants were excluded from characteristics of baseline characteristics (Tables 1 and 2) but included in longitudinal analyses. All 13 women reported an uncircumcised partner later in follow-up.] This analysis included 4417 women: 393 high-risk Ugandans (9%), 1793 low-risk Ugandans (41%), and 2231 Zimbabweans (50%).
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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