The HC-HIV study enrolled 4,531 participants from Uganda and Zimbabwe. We excluded 114 women: 80 did not return for follow-up; 14 first returned 28 months or longer after enrollment, and were therefore censored; 12 used exclusively non-study contraceptive methods, and 8 were missing MC data at every follow-up visit. (Thirteen women missing MC at baseline, but with valid MC data later in follow-up, were excluded from and but included in longitudinal analyses. All 13 women reported an uncircumcised partner later in follow-up). This analysis includes 4,417 women (393 “high-risk” Ugandans (9%), 1,793 “low-risk” Ugandans (41%), and 2,231 Zimbabweans (50%)).
Selected characteristics of participants at enrollment, by circumcision status of the primary partner, Uganda and Zimbabwe, 1999-2002.
Selected characteristics of participants at enrollment, by circumcision status of the primary partner and population subgroup, Uganda and Zimbabwe, 1999-2002.
Median follow-up time was 23 months and the median interval between visits was 3 months.
Baseline population characteristics ( and )
Among 4,404 women providing the MC status of their primary partner at baseline, most (n=3,249, 74%) had uncircumcised partners, whereas 22% (n= 989) had circumcised partners and 4% (n=166) did not know their partner's circumcision status (). 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 COCs, DMPA, and non-hormonal 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 (STIs), including clinician-identified GUD, 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 vs. 17.7 years, P<0.001), a higher mean number of lifetime sex partners (4.8 vs. 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 vs. 6.1 nights, P<0.001) ().
To further explore differences in participant characteristics by circumcision status of the primary partner, we also examined baseline factors by population subgroup (low-risk Uganda vs. high-risk Uganda vs. Zimbabwe) (). 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 three months, and to have a higher mean number of lifetime sex partners than women from either the low-risk Uganda or Zimbabwe strata ().
During follow-up, participants with partners who were circumcised, uncircumcised, and of unknown circumcision status contributed 1,674 PY, 5,636 PY, and 256 PY, 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. Women with circumcised partners were more likely to self-report an STI (6% vs. 4% of follow-up intervals, P<0.001) or STI symptoms (26% vs. 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% vs. 14% of follow-up intervals, P<0.001). Although more women with circumcised partners reported never using condoms since the last visit (64% vs. 50% of follow-up intervals, P<0.001), they had a lower mean number of unprotected acts (8.6 vs. 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) (). For the full cohort, unadjusted HIV incidence rates (IRs) were 2.03 per 100 PY (95% CI: 1.41-2.84) among those with circumcised partners, 2.96 per 100 PY (95% CI: 2.53-3.45) in women with uncircumcised partners, and 3.51 per 100 PY (95% CI: 1.61-6.67) in women who did not know their partner's circumcision status. When examining IRs 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 ().
Incident HIV infections, person-time and HIV incidence rates overall and by population subgroup, Uganda and Zimbabwe, HC-HIV Study, 1999-2004
Unadjusted and adjusted multivariate models
We first examined associations between MC and HIV risk among all women in the cohort. The unadjusted Cox proportional hazard model indicated that women with circumcised partners had reduced HIV risk compared to women with uncircumcised partners (HR: 0.69, 95% CI: 0.48-0.99) (). The Kaplan-Meier plot shows similar results (P=0.06, ).
Unadjusted and adjusted hazard ratios and 95% confidence intervals, comparing women with circumcised partners to women with uncircumcised partners, overall and by population subgroup, Uganda and Zimbabwe, HC-HIV Study, 1999-2004
Unadjusted Kaplan-Meier curve comparing HIV-free survival time for women partnered with circumcised men to women partnered with uncircumcised men, by population
After adjustment for age, age at coital debut, contraceptive method, husband's employment status, education level, and number of sex partners in the previous three months, the protective effect of MC weakened (HR: 0.78, 95% CI: 0.53-1.14 ()). After further adjustment for population subgroup, the association disappeared (HR: 1.03, 95% CI: 0.69, 1.53 ()).
We next examined the effect of MC on women's HIV risk within each population subgroup (). HIV-free survival time for women with circumcised and uncircumcised partners was similar for both the low-risk Ugandan and 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, MC status was not significantly associated with women's risk of HIV acquisition in any subgroup, although the point estimates varied widely (). 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 MC 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 ().
Some women acquired STIs (Chlamydia trachomatis
(Ct), Neisseria gonorrhoeae
(GC), Trichomonas vaginalis
(Tv), herpes simplex virus type 2, or GUD) during follow-up. In order to better understand the influence of STIs, in preliminary analyses we examined the effect of controlling for STI status in multivariable models in several ways. Neither inclusion of baseline STI status, STI at the last visit, nor STI at the current visit meaningfully changed our estimates of the effect of MC on women's HIV risk. In addition, depending on the timing of infection, women's STI status could be affected by MC (i.e
., may lie on the causal pathway between MC and women's HIV risk) [26
]. For these reasons we did not adjust for confounding by STI in the final multivariate models. 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 MC and women's HIV risk were generally robust to misclassification of MC status. In particular, misclassification of MC was not influential for low-risk Ugandans or Zimbabweans, for whom the original estimates fell within the 2.5th and 97.5th percentiles of the corrected HRs under all three misclassification scenarios. Possible misclassification of MC 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).