Elsevier

The Lancet

Volume 369, Issue 9562, 24 February–2 March 2007, Pages 643-656
The Lancet

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Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(07)60312-2Get rights and content

Summary

Background

Male circumcision could provide substantial protection against acquisition of HIV-1 infection. Our aim was to determine whether male circumcision had a protective effect against HIV infection, and to assess safety and changes in sexual behaviour related to this intervention.

Methods

We did a randomised controlled trial of 2784 men aged 18–24 years in Kisumu, Kenya. Men were randomly assigned to an intervention group (circumcision; n=1391) or a control group (delayed circumcision, 1393), and assessed by HIV testing, medical examinations, and behavioural interviews during follow-ups at 1, 3, 6, 12, 18, and 24 months. HIV seroincidence was estimated in an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, with the number NCT00059371.

Findings

The trial was stopped early on December 12, 2006, after a third interim analysis reviewed by the data and safety monitoring board. The median length of follow-up was 24 months. Follow-up for HIV status was incomplete for 240 (8·6%) participants. 22 men in the intervention group and 47 in the control group had tested positive for HIV when the study was stopped. The 2-year HIV incidence was 2·1% (95% CI 1·2–3·0) in the circumcision group and 4·2% (3·0–5·4) in the control group (p=0·0065); the relative risk of HIV infection in circumcised men was 0·47 (0·28–0·78), which corresponds to a reduction in the risk of acquiring an HIV infection of 53% (22–72). Adjusting for non-adherence to treatment and excluding four men found to be seropositive at enrolment, the protective effect of circumcision was 60% (32–77). Adverse events related to the intervention (21 events in 1·5% of those circumcised) resolved quickly. No behavioural risk compensation after circumcision was observed.

Interpretation

Male circumcision significantly reduces the risk of HIV acquisition in young men in Africa. Where appropriate, voluntary, safe, and affordable circumcision services should be integrated with other HIV preventive interventions and provided as expeditiously as possible.

Introduction

Although the availability of antiretroviral therapy for individuals infected with HIV is increasing worldwide, many more new infections are occurring for every additional person started on such treatment.1 Prevention of new infections is the only realistic hope for stemming the HIV pandemic, yet currently available prevention measures have often been unsuccessful in restricting the spread of HIV, and there is little promise that an effective vaccine will be available within the next 15 years.2 Effective new HIV preventive interventions are needed.

That male circumcision might reduce risk of HIV acquisition was first proposed in 1986.3, 4 Ecological studies have shown that, in regions where HIV transmission is predominantly heterosexual, the prevalence of HIV and of male circumcision are inversely correlated.5, 6, 7, 8 More than 30 cross-sectional studies have found the prevalence of HIV to be significantly higher in uncircumcised men than in those who are circumcised,9 and 14 prospective studies all show a protective effect, ranging from 48% to 88%.9, 10, 11, 12, 13 A systematic review and meta-analysis of studies from sub-Saharan Africa reported an adjusted relative risk of 0·42 (95% CI 0·34–0·54) in all circumcised men, with a stronger adjusted relative risk of 0·29 (0·20–0·41) in circumcised men who were at higher risk of acquiring HIV.14 In a cohort study of Ugandan discordant couples in which the female was HIV infected and the male partner was initially HIV seronegative, 37 of 134 uncircumcised men versus none of 50 circumcised men became seropositive after about 2 years of follow-up.15

Biological studies suggest a plausible mechanism for this protection. The inner mucosal surface of the human foreskin, exposed upon erection, has nine times higher density of HIV target cells (Langerhans' cells, CD4+ T cells, and macrophages) than does cervical tissue.16 The number of preputial target cells is increased in men with a history of recent sexually transmitted infections.17 By contrast with the foreskin's inner surface, HIV target cells on the outer surface and the glans are protected by a layer of squamous epithelial cells.16, 18 In explant culture, several times more HIV-1 is taken up by Langerhans' cells and CD4+ T cells in foreskin than in cervical tissue; the virus does not infiltrate cells on the outer surface of the foreskin.16 Other possible mechanisms by which the presence of the foreskin could lead to greater risk for HIV infection include poor hygiene,19 greater incidence of ulcerative sexually transmitted infections,20 and susceptibility of the foreskin to abrasions.9

Recently, a randomised controlled trial of male circumcision in 18–24-year-old men in Orange Farm, South Africa, was stopped by the data and safety monitoring board when an interim analysis showed a 60% protective effect of circumcision in an intention-to-treat analysis, and a 76% protective effect in a per-protocol analysis that adjusted for crossovers. There were 20 HIV infections (incidence rate 0·85 per 100 person-years) in the circumcision group and 49 (2·1 per 100 person-years) in the uncircumcised group. Controlling for behavioural factors—eg, condom use, health-seeking behaviour, and sexual behaviour—the protective effect was much the same (61%).21

Upon announcement of the Orange Farm results in July, 2005,22 the WHO and UN agencies issued a statement indicating that the evidence available up to that time for male circumcision having a protective effect against HIV infection was very promising, but that circumcision should not be promoted as a prevention strategy until results from this study, and a third trial in Rakai, Uganda, became available.23 A Cochrane review had also cautioned against implementation of male circumcision as a preventive strategy in the absence of more data from clinical trials.24

Here we report the results of a randomised controlled trial of male circumcision in 18–24-year-old men in Kisumu, Kenya. Our aim was to determine the relative risk of HIV incidence in men randomly assigned to receive circumcision versus those who did not receive such treatment.

Section snippets

Participants

This trial was done in Kisumu district, Kenya. Kisumu is the capital city of Nyanza Province in western Kenya and has a population of about 500 000 residents.25 Most residents self-identify as Luo, an ethnic group that does not traditionally practice circumcision. About 10% of Luo adult men in Kisumu are circumcised.26 In 2003, HIV prevalence was about 25% in Luo women and 18% in Luo men.27

Participants were recruited via local newspapers, radio, fliers, and street shows by drama and musical

Results

Figure 1 shows the trial profile. 6686 men initially came to the study clinic; 6159 (92%) met preliminary criteria. Of these, 478 (8%) were HIV seropositive, 59 (1%) were of indeterminate HIV status, and 5622 (91%) were seronegative. Of the seronegative individuals, 1133 (20%) were excluded for other reasons. Thus 4489 individuals were eligible for randomisation. Of these, 1407 were undecided or did not return for randomisation, 53 declined further participation, 201 were considered to have

Discussion

Our results confirm that male circumcision substantially reduces the risk of acquiring an HIV infection. Circumcision provided a 53% (95% CI 22–72) protective effect against HIV acquisition compared with the control group and a 60% (32–77) protective effect after adjustments for non-adherence and for those individuals who were found to be HIV positive at baseline. These findings are much the same as those from the Orange Farm trial in South Africa (60% [32–76] protection against HIV infection,

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