This study provides the first experimental evidence of the efficacy of MC in protecting men against HIV infection. It was conducted in a general population, and it is the first randomized control trial testing the impact on health of MC. The demonstration in this study of a causal association between HIV infection and MC is consistent with protection suggested by meta-analyses of observational studies [12
] but with a higher protective effect. This difference can be explained, at least partly, by the effect of bias and confounding factors associated with cross-sectional studies. High values ranging from 0.12 to 0.29 of protective effect of MC have been reported in prospective studies conducted in high-risk groups [6
]. Our study is also the first experimental study demonstrating that surgery can be used to prevent an infectious disease. In addition, this finding is an a posteriori proof of the use of MC to improve hygiene in the common meaning of not being infected.
This study has some limitations. It was conducted in one area in sub-Saharan Africa and, therefore, may not be generalizable to other places. Nevertheless, because of the similar route of transmission of HIV in sub-Saharan Africa and because observational studies from various areas of sub-Saharan Africa have shown an association between HIV status and MC [12
], the result of this trial is applicable to all of sub-Saharan Africa with some degree of confidence.
Even though some participants were lost during the follow-up, and the loss to follow-up rate was greater than the event rate, the impact of missing participants on the overall results of this study is likely to be small not only because the loss to follow-up was small for a cohort study conducted in a general population, but also because those who were late for at least one follow-up visit were protected by MC just as the other participants. The reason for this loss to follow-up was a result of participants moving from the area or being unreachable, and not a result of HIV infection.
Because the Data and Safety Monitoring Board recommended to stop the trial after the intermediate analysis, it was not possible to follow all the participants as initially planned, and, as a consequence, only those participants recruited at the beginning had a full follow-up. This potential bias was taken into account by adjusting the analysis for the recruitment period; such an adjustment cannot fully account for the confounding effect associated with partial follow-up. When restricting the analysis to those participants who had a full follow-up, the intervention had an effect that was similar in size and significance, suggesting that this potential bias had a negligible impact.
A specific survey was implemented after the end of the recruiting period in order to assess the satisfaction of the results of the randomization. Of the participants, 65.3% said they were happy. However, the results also showed that a limited number of participants (7.5%), strongly unhappy with their group of randomization, were allocated and recorded in the other group. They were analyzed in their randomization group in the intention-to-treat analysis. The findings were confirmed by the person in charge of randomization. This factor contributed to increase the cross-over, which remained low, and to dilute the measure of the effect of the intervention, which remained high.
Another limitation concerns the timescale of this study. Participants were followed up for a short period of time, and, therefore, this study did not explore the long-term protective effect of MC.
The protective effect of MC on HIV infection was unchanged when controlling for sexual behaviour, including condom use, which was taken into account when defining those at-risk behaviour, the period of abstinence in the intervention group following MC, and heath-seeking behaviour, which was considered because treatment of STIs can have an effect on HIV acquisition [24
]. This shows that these factors play a minor role in explaining the protective effect of MC on HIV infection. The reasons for this protective effect of MC on HIV acquisition have to be found elsewhere, and several direct or indirect factors may explain this [25
]. Direct factors may be keratinization of the glans when not protected by the foreskin, short drying after sexual contact, reducing the life expectancy of HIV on the penis after sexual contact with an HIV-positive partner, reduction of the total surface of the skin of the penis, and reduction of target cells, which are numerous on the foreskin [26
]. Indirect factors may be a reduction in acquisition of other STIs, which in turn will reduce the acquisition of HIV. Our study does not allow for identification of the mechanism(s) of the protective effect of MC on HIV acquisition.
The first and obvious consequence of this study is that MC should be recognized as an important means to reduce the risk of males becoming infected by HIV. As shown by our study, MC is useful and feasible even among sexually experienced men living in an area with high HIV prevalence. Indeed, in our study the intervention delivered by local general practitioners resulted in a limited and reasonable number of adverse events and did not lead to an increase in deaths. In addition to the protective role in men, MC will indirectly protect women and, therefore, children from HIV infection because if men are less susceptible to HIV acquisition, women will be less exposed. Moreover, MC may also be protective against male-to-female HIV transmission, but this will require further investigation [7
]. The role that women can play in promoting MC is potentially important. If women are aware of the protective effect of MC, this awareness could, in turn, have an impact on the prevalence of MC by encouraging males to become circumcised.
It was found that the protective effect of MC is high. MC provides a degree of protection against acquiring HIV infection equivalent to what a vaccine of high efficacy would have achieved. Consequently, the authors think that MC should be regarded as an important public health intervention for preventing the spread of HIV. MC could be incorporated rapidly into the national plans of countries where most males are not circumcised and where the spread of HIV is mainly heterosexual. This is even more important at a time when no vaccine or microbicides are currently available and when delivering antiretroviral treatments under WHO guidelines will have only a small impact on the spread of HIV [27
]. In addition, MC is an inexpensive means of prevention, performed only once, and men can be circumcised over a wide age range, from childhood to adulthood.
The potential impact of prevention programmes based on MC is difficult to assess at population level and requires modelling. From the results of this study and of the meta-analysis quoted above, it can be predicted that widespread MC could lead to a strong reduction of the spread of HIV. The availability of a simple and ancient practice with a high potential effect on the spread of HIV is remarkable and should encourage decision makers to take MC into consideration as policy. Because most of southern and East Africa is concerned, the number of HIV infections that could be avoided by the widespread implementation of MC is high.
There are potential risks in promoting MC as way of reducing the risk of HIV infection. MC can be performed under poor hygienic conditions, leading to not only infection, bleeding, and permanent injury, but also HIV infection from non-sterilized instruments, and possible death if appropriate treatment of sequelae is not provided. In the healing period, sexually active men are likely to be at a higher risk of HIV infection, and this risk should not be underestimated. MC does not provide full protection and, if perceived as full protection, could lead to reduction of protection of men who, for example, decrease their condom use or otherwise engage in riskier behaviour. It was found that the intervention group had significantly more sexual contacts. While the protective effect of circumcision remained despite this increased risk, this should be a concern when considering implementation of circumcision as a means of preventing HIV infection. Finally, there is the danger of confusing MC with female circumcision, and that promotion of MC could be used by defenders of female circumcision to defend this practice.
Acceptability studies of the use of MC as a prevention measure against the spread of HIV have been conducted in South Africa [16
], Kenya [29
], Zimbabwe [31
], and Botswana [32
]. These studies, in which most of the uncircumcised African men expressed interest in becoming circumcised if performed safely and affordably, highlighted the potential of MC as a population-level intervention to reduce HIV spread. MC is a not a universal cultural practice, and cultural practices can be barriers in policy considerations. However, there are examples showing that the prevalence of MC can be changed. For example, in South Korea 50 years ago, almost no men were circumcised; today some 85% of Korean men 16–29 y old are circumcised [33
The experimental demonstration of the protective effect of MC on the acquisition of HIV emphasizes the role of MC in explaining the heterogeneity of HIV prevalence in sub-Saharan Africa. From a multi-site study conducted in four African countries, MC, together with sexual behaviour, has been posited as an important factor in the heterogeneity of HIV prevalence in sub-Saharan Africa [34
]. This role is confirmed and reinforced by the findings of the present study.