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      Randomized, Controlled Intervention Trial of Male Circumcision for Reduction of HIV Infection Risk: The ANRS 1265 Trial

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          Abstract

          Background

          Observational studies suggest that male circumcision may provide protection against HIV-1 infection. A randomized, controlled intervention trial was conducted in a general population of South Africa to test this hypothesis.

          Methods and Findings

          A total of 3,274 uncircumcised men, aged 18–24 y, were randomized to a control or an intervention group with follow-up visits at months 3, 12, and 21. Male circumcision was offered to the intervention group immediately after randomization and to the control group at the end of the follow-up. The grouped censored data were analyzed in intention-to-treat, univariate and multivariate, analyses, using piecewise exponential, proportional hazards models. Rate ratios (RR) of HIV incidence were determined with 95% CI. Protection against HIV infection was calculated as 1 − RR. The trial was stopped at the interim analysis, and the mean (interquartile range) follow-up was 18.1 mo (13.0–21.0) when the data were analyzed. There were 20 HIV infections (incidence rate = 0.85 per 100 person-years) in the intervention group and 49 (2.1 per 100 person-years) in the control group, corresponding to an RR of 0.40 (95% CI: 0.24%–0.68%; p < 0.001). This RR corresponds to a protection of 60% (95% CI: 32%–76%). When controlling for behavioural factors, including sexual behaviour that increased slightly in the intervention group, condom use, and health-seeking behaviour, the protection was of 61% (95% CI: 34%–77%).

          Conclusion

          Male circumcision provides a degree of protection against acquiring HIV infection, equivalent to what a vaccine of high efficacy would have achieved. Male circumcision may provide an important way of reducing the spread of HIV infection in sub-Saharan Africa. (Preliminary and partial results were presented at the International AIDS Society 2005 Conference, on 26 July 2005, in Rio de Janeiro, Brazil.)

          Abstract

          The first trial of male circumcision for reducing the risk of HIV finds significantly lower new cases in the treatment group.

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          Most cited references 35

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          Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis.

          To systematically review studies of male circumcision and the risk of HIV-1 infection in men in sub-Saharan Africa, and to summarize the findings in a meta-analysis. A meta-analysis of observational studies. A systematic literature review was carried out of studies published up to April 1999 that included circumcision as a risk factor for HIV-1 infection among men in sub-Saharan Africa. A random effects meta-analysis was used to calculate a pooled relative risk (RR) and 95% confidence interval (CI) for all studies combined, and stratified by type of study population. Further analyses were conducted among those studies that adjusted for potential confounding factors. Twenty-seven studies were included. Of these, 21 showed a reduced risk of HIV among circumcised men, being approximately half that in uncircumcised men (crude RR = 0.52, CI 0.40-0.68). In 15 studies that adjusted for potential confounding factors, the association was even stronger (adjusted RR = 0.42, CI 0.34-0.54). The association was stronger among men at high risk of HIV (crude RR = 0.27; adjusted RR = 0.29, CI 0.20-0.41) than among men in general populations (crude RR = 0.93; adjusted RR = 0.56, CI 0.44-0.70). Male circumcision is associated with a significantly reduced risk of HIV infection among men in sub-Saharan Africa, particularly those at high risk of HIV. These results suggest that consideration should be given to the acceptability and feasibility of providing safe services for male circumcision as an additional HIV prevention strategy in areas of Africa where men are not traditionally circumcised.
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            Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men.

            To determine the frequency and risk factors for female to male sexual transmission of human immunodeficiency virus type 1 (HIV-1), a prospective study was carried out in 422 men who had acquired a sexually transmitted disease (STD) from a group of prostitutes with a prevalence of HIV-1 infection of 85%. The initial seroprevalence of HIV among the men was 12%. 24 of 293 (8.2%) initially seronegative men seroconverted to HIV-1. Newly acquired infection was independently associated with frequent prostitute contact (risk ratio 3.2, 95% confidence interval 1.2-8.1), with the acquisition of genital ulcer disease (risk ratio 4.7, 95% confidence interval 1.3-17.0), and with being uncircumcised (risk ratio 8.2, 95% confidence interval 3.0-23.0). 96% of documented seroconversions occurred in men with one or both of the latter two risk factors. In a subgroup of 73 seronegative men who reported a single prostitute sexual contact, the frequency of HIV-1 infection was 8.2% during 12 weeks of observation. No man without a genital ulcer seroconverted. A cumulative 43% of uncircumcised men who acquired an ulcer seroconverted to HIV-1 after a single sexual exposure. These data indicate an extremely high rate of female to male transmission of HIV-1 in the presence of STD and confirm a causal relation between lack of male circumcision, genital ulcer disease, and susceptibility to HIV-1 infection.
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              Susceptibility to human immunodeficiency virus-1 infection of human foreskin and cervical tissue grown in explant culture.

              Numerous studies have indicated a protective effect of male circumcision against acquisition of human immunodeficiency virus (HIV)-1. We investigated mechanisms responsible for the possible increased HIV-1 susceptibility of human foreskin. Foreskins from eight pediatric and six adult patients with (n = 3) and without (n = 11) histories of sexually transmitted disease were evaluated. Six cervical biopsies from HIV-1-seronegative women were included as controls. CD4(+) T cells, macrophages, and Langerhans' cells (LCs) were quantified using image analysis. Cells expressing HIV-1 co-receptors CCR5 and CXCR4 were quantified using immunofluorescence and image analysis. Foreskin biopsies were infected ex vivo in organotypic culture with HIV-1. HIV-1 DNA copies in foreskin and cervical mucosal tissue were compared and the infected cell phenotype was determined. Foreskin mucosa contained higher mean proportions of CD4(+) T cells (22.4%), macrophages (2.4%), and LCs (11.5%) in adults than in children (4.9%, 0.3%, and 6.2%, respectively) or in cervical mucosa (6.2%, 1.4%, and 1.5%, respectively). The highest proportions of CD4(+) T cells and LCs occurred in patients with a history of infection. Foreskin immune cells expressed predominantly the CCR5 HIV-1 co-receptor. Adult foreskin mucosa had greater susceptibility to infection with HIV(bal) than cervical mucosa or the external surface of foreskin tissue. Circumcision likely reduces risk of HIV-1 acquisition in men by decreasing HIV-1 target cells.
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                Author and article information

                Affiliations
                1Hôpital Ambroise-Paré, Assitance Publique—Hôpitaux de Paris, Boulogne, France,
                2INSERM U 687, Saint-Maurice, France,
                3University Versailles Saint-Quentin, Versailles, France,
                4IFR 69, Villejuif, France,
                5Progressus, Johannesburg, South Africa,
                6National Institute for Communicable Disease, Johannesburg, South Africa
                simpleSan Francisco General Hospital, San Francisco, California United States of America.
                Author notes
                * To whom correspondence should be addressed. E-mail: bertran.auvert@ 123456apr.aphp.fr

                Competing Interests: The authors have declared that no competing interests exist.

                Author Contributions: BA designed the study with DT, EL, and AP. DT and AP were responsible for operational aspects, including laboratory and field work and in-country administration of the study. BA monitored the study with input from EL and wrote the paper with input from all authors. BA analyzed the data with RS, with inputs from JST. RS conducted the interim analysis.

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                November 2005
                25 October 2005
                : 2
                : 11
                1262556
                16231970
                10.1371/journal.pmed.0020298
                (Academic Editor)
                Copyright: © 2005 Auvert et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Categories
                Research Article
                Infectious Diseases
                Epidemiology/Public Health
                Health Policy
                HIV/AIDS
                Sexual Health
                Urology
                Infectious Diseases
                HIV Infection/AIDS
                Sexually Transmitted Infections - Other than HIV/AIDS
                Medicine in Developing Countries

                Medicine

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