Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men.

4996 uncircumcised, HIV-negative men aged 15–49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984.

Findings

Baseline characteristics of the men in the intervention and control groups were much the same at enrolment. Retention rates were much the same in the two groups, with 90–92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0·66 cases per 100 person-years in the intervention group and 1·33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16–72; p=0·006). The as-treated efficacy was 55% (95% CI 22–75; p=0·002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30–77; p=0·003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3·6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up.

Interpretation
Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men.

Introduction

A number of ecological and observational studies, mainly from sub-Saharan Africa, have suggested that male circumcision reduces the risk of HIV infection in men. A meta-analysis of cross-sectional and prospective studies estimated that the adjusted summary rate ratio of male HIV acquisition associated with circumcision in general populations was 0·56 (95% CI 0·44–0·70); in high-risk populations the adjusted summary rate ratio was 0·29 (0·20–0·41). However, observational findings do not consistently show protective associations in all studies, and to exclude the possibility of confounding due to differences in sexual risk behaviours and cultural or religious practices associated with circumcision is difficult. Thus, the potential efficacy of circumcision for HIV prevention can be determined only by randomised trials. One randomised trial done in South Africa was ended early after an interim analysis showed that circumcision reduced HIV incidence by 60% (32–76). Two other randomised trials, one in Kisumu, Kenya and the other in Rakai, Uganda—the results of which we report here—were also stopped early on December 12, 2006, after interim analyses showed significant efficacy.

Statistical analysis

For incidence rate and Poisson regression calculations, HIV seroconversion was estimated assuming that infection occurred at the mid-time point between the last negative and first positive serological tests, or at the time of the first positive RT-PCR for those participants seen during the period before HIV antibody seroconversion. For participants who were positive by PCR but who were negative for HIV antibody, the date of the positive PCR was used as the date of infection. In both groups, time from enrolment was accumulated up to the 24 month follow-up visit and HIV incidence was estimated per 100 person-years.

Exploratory analyses assessed the comparability of the two study groups at enrolment. HIV incidence during the trial was assessed by fixed covariates such as age, marital status, and education at enrolment, and by time-varying covariates such as sexual risk behaviours (eg, number of partners, non-marital relationships, condom use, and alcohol use), and symptoms of sexually transmitted diseases reported at follow-up visits. Men who were originally allocated to circumcision but who did not present for surgery within 6 months of enrolment were assessed as crossovers, as were individuals in the control group who opted to have circumcisions done outside the study.

Prof Ronald H Gray MD, Godfrey Kigozi MBChB,  David Serwadda MBChB,  Frederick Makumbi PhD
The Lancet 2007; 369:657-666

DOI:10.1016/S0140-6736(07)60313-4
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