Influence of trial duration on the bias of the estimated treatment effect in clinical trials when individual heterogeneity is ignored.

In randomized clinical trials where the times to event of two treatment groups are compared under a proportional hazards assumption, it has been established that omitting prognostic factors from the model entails an underestimation of the hazards ratio. Heterogeneity due to unobserved covariates in cancer patient populations is a concern since genomic investigations have revealed molecular and clinical heterogeneity in these populations. In HIV prevention trials, heterogeneity is unavoidable and has been shown to decrease the treatment effect over time. This article assesses the influence of trial duration on the bias of the estimated hazards ratio resulting from omitting covariates from the Cox analysis. The true model is defined by including an unobserved random frailty term in the individual hazard that reflects the omitted covariate. Three frailty distributions are investigated: gamma, log-normal, and binary, and the asymptotic bias of the hazards ratio estimator is calculated. We show that the attenuation of the treatment effect resulting from unobserved heterogeneity strongly increases with trial duration, especially for continuous frailties that are likely to reflect omitted covariates, as they are often encountered in practice. The possibility of interpreting the long-term decrease in treatment effects as a bias induced by heterogeneity and trial duration is illustrated by a trial in oncology where adjuvant chemotherapy in stage 1B NSCLC was investigated.

Mixture models for calibrating the BED for HIV incidence testing.

A number of antibody biomarkers have been developed to distinguish between recent and established Human Immunodeficiency Virus (HIV) infection and used for HIV incidence estimation from cross-sectional specimens. In general, a cut-off value is specified, and estimates of the following parameters are needed: (i) the mean time interval .w/ between seroconversion and reaching that cut-off; (ii) the probability of correctly identifying individuals who became infected in the last w years (sensitivity); and (iii) the probability of correctly identifying individuals who have been infected for more than w years (specificity). We develop two statistical methods to study the distribution of a biomarker and derive a formula for estimating HIV incidence from a cross-sectional survey. Both methods allow handling interval censored data and basically consist of using a generalized mixture model to model the growth of the biomarker as a function of time since infection. The first uses data from all followed-up individuals and allows incidence estimation in the cohort, whereas the second only uses data from seroconverters. We illustrate our methods using repeated measures of the IgG capture BED enzyme immunoassay. Estimates of calibration parameters, that is, mean window period, mean recency period, sensitivity, and specificities obtained from both models are comparable. The formula derived for incidence estimation gives the maximum likelihood estimate of incidence which, for a given window period, depends only on sensitivity and specificity. The optimal choice of the window period is discussed. Numerical simulations suggest that data from seroconverters can provide reasonable estimates of the calibration parameters.

Association of the ANRS-12126 male circumcision project with HIV levels among men in a South African township: evaluation of effectiveness using cross-sectional surveys.

BACKGROUND: Randomized controlled trials have shown that voluntary medical male circumcision (VMMC) reduces HIV infection by 50% to 60% in sub-Saharan African populations; however, little is known about the population-level effect of adult male circumcision (MC) as an HIV prevention method. We assessed the effectiveness of VMMC roll-out on the levels of HIV in the South African township of Orange Farm where the first randomized controlled trial (RCT) to test the effect of VMMC on HIV acquisition was conducted in 2002-2005. METHODS AND FINDINGS: The Bophelo Pele project is a community-based campaign against HIV, which includes the roll-out of free VMMC. A baseline cross-sectional biomedical survey was conducted in 2007-2008 among a random sample of 1,998 men aged 15 to 49 (survey response rate 80.7%). In 2010-2011, we conducted a follow-up random survey among 3,338 men aged 15 to 49 (survey response rate 79.6%) to evaluate the project. Participants were interviewed, blood samples were collected and tested for HIV and recent HIV infection (using the BED HIV incidence assay), and MC status was assessed through a clinical examination. Data were analyzed using multivariate and propensity statistical methods. Owing to the VMMCs performed in the context of the RCT and the Bophelo Pele project, the prevalence rate of adult MC increased from 0.12 (95% CI 0.10-0.14) to 0.53 (95% CI 0.51-0.55). Without these VMMCs, the HIV prevalence rate in 2010-2011 would have been 19% (95% CI 12%-26%) higher (0.147 instead of 0.123). When comparing circumcised and uncircumcised men, no association of MC status with sexual behavior was detected. Among circumcised and uncircumcised men, the proportion consistently using condoms with non-spousal partners in the past 12 months was 44.0% (95% CI 41.7%-46.5%) versus 45.4% (95% CI 42.2%-48.6%) with weighted prevalence rate ratio (wPRR) = 0.94 (95% CI 0.85-1.03). The proportion having two or more non-spousal partners was 50.4% (95% CI 47.9%-52.9%) versus 44.2% (95% CI 41.3%-46.9%) with wPRR = 1.03 (95% CI 0.95-1.10). We found a reduction of BED-estimated HIV incidence rate ranging from 57% (95% CI 29%-76%) to 61% (95% CI 14%-83%) among circumcised men in comparison with uncircumcised men. CONCLUSIONS: Findings suggest that the roll-out of VMMC in Orange Farm is associated with a significant reduction of HIV levels in the community. The main limitation of the study is that it was not randomized and cannot prove a causal association. The roll-out of VMMC among adults in sub-Saharan Africa should be an international priority and needs to be accelerated to effectively combat the spread of HIV. Please see later in the article for the Editors' Summary.

Association of genital human papillomavirus infection with HIV acquisition: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review and a meta-analysis of epidemiological studies investigating the association of genital human papillomavirus (HPV) infection and HIV acquisition. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Scientific databases and conference abstracts were systematically searched to identify all relevant studies published up to 31 January 2012. Search terms included 'HIV', 'HPV', 'humanpapillomavirus' and 'papillomaviridae' as keywords or text, in the title or abstract. METHODS: To be eligible for inclusion, a study had to be conducted among humans, report data on HIV incidence, and assess genital HPV infection. Summary ORs and 95% CIs were estimated from the extracted data using random-effect meta-analysis. Subgroup analyses were conducted for high-risk (HR) and low-risk(LR) HPV oncogenic risk groups. Between-study heterogeneity and publication bias were assessed. RESULTS: Of 2601 identified abstracts, six observational studies, comprising 6567 participants were retained for the systematic review and the meta-analysis. HIV acquisition was significantly associated with HPV infection (summary OR=1.96; 95% CI 1.55 to 2.49). HIV incident infection was significantly associated with HR-HPV in five of six studies and with LR-HPV in two out of five. The association was significant for HR-HPV(summary OR=1.92; 95% CI 1.49 to 2.46) and borderline for LR-HPV. No between-study heterogeneity was detected. There was a borderline indication of publication bias. CONCLUSIONS: Further research is needed to elucidate the biological mechanisms involved, and assess the effect of HPV vaccination on HIV acquisition, using vaccines with broad coverage of HPV genotypes. Such research could have important public health implications for HIV prevention.

Prevalence, characteristics, and outcomes of patients presenting with cardiogenic unilateral pulmonary edema.

BACKGROUND: Cardiogenic unilateral pulmonary edema (UPE) is a rare entity, frequently leading to initial misdiagnosis. We sought to assess the prevalence of UPE and to determine its impact on prognosis compared with bilateral pulmonary edema. METHODS AND RESULTS: We studied the characteristics and outcomes of patients admitted to our institution for cardiogenic pulmonary edema during an 8-year period. The study population included 869 consecutive patients. The prevalence of UPE was 2.1%: 16 right-sided UPE (89%) and 2 left-sided UPE (11%). In patients with UPE, blood pressure was significantly lower (P≤0.01), whereas noninvasive or invasive ventilation and catecholamines were used more frequently (P=0.0004 and P<0.0001, respectively). The prevalence of severe mitral regurgitation in patients with bilateral pulmonary edema and UPE was 6% and 100%, respectively (P<0.0001). In patients with UPE, use of antibiotic therapy and delay in treatment were significantly higher (P<0.0001 and P=0.003, respectively). In-hospital mortality was 9%: 39% for UPE versus 8% for bilateral pulmonary edema (odds ratio, 6.9; 95% confidence interval, 2.6 to 18; P<0.001). In multivariate analysis, unilateral location of pulmonary edema was independently related to death whatever the model used (adjusted odds ratio, 6.5; 95% confidence interval, 1.3 to 32; P=0.021 for model A; and adjusted odds ratio, 6.8; 95% confidence interval, 1.1 to 41; P=0.037 for model B). CONCLUSIONS: Unilateral pulmonary edema represented 2.1% of cardiogenic pulmonary edema in our study, usually appeared as an opacity involving the right lung, and was always associated with severe mitral regurgitation. Unilateral pulmonary edema is related to an independent increased risk of mortality and should be promptly recognized to avoid delays in treatment.

Partial inactivation of CCR5- and CXCR4- tropic HIV-1 by human urine.

Human urine has been poorly investigated with regard to infection with human immunodeficiency virus (HIV). Here, we have studied the anti-infective functional properties of human urine against HIV. The effect of fresh urine pools on CCR5- and CXCR4-tropic HIV-1 was evaluated by using four in vitro mucosal models: reduction of infectivity of urine-treated HIV-1 particles, HIV-1 attachment to immature monocyte-derived dendritic cells (iMDDC), transfer of HIV-1 particles from iMDDC to autologous CD4 T cells, and HIV-1 transcytosis through epithelial cells. Human urine partially disrupted both CCR5- and CXCR4-tropic HIV-1 particles, moderately decreased the adsorption of HIV-1 on dendritic cells, and partially decreased the transfer of HIV-1 particles from dendritic cells to autologous T cells. These findings demonstrate partial inactivation of HIV infectivity and suggest that voiding urine after coitus could play a potential role in reducing the risk of HIV infection by both mechanically flushing out and neutralizing the infectivity of HIV-1 particles present in the genital tract.

Adult male circumcision as an intervention against HIV: an operational study of uptake in a South African community (ANRS 12126).

BACKGROUND: To evaluate the knowledge, attitudes and beliefs about adult male circumcision (AMC), assess the association of AMC with HIV incidence and prevalence, and estimate AMC uptake in a Southern African community. METHODS: A cross-sectional biomedical survey (ANRS-12126) conducted in 2007-2008 among a random sample of 1198 men aged 15 to 49 from Orange Farm (South Africa). Face-to-face interviews were conducted by structured questionnaire. Recent HIV infections were evaluated using the BED incidence assay. Circumcision status was self-reported and clinically assessed. Adjusted HIV incidence rate ratios (aIRR) and prevalence ratios (aPR) were calculated using Poisson regression. RESULTS: The response rate was 73.9%. Most respondents agreed that circumcised men could become HIV infected and needed to use condoms, although 19.3% (95%CI: 17.1% to 21.6%) asserted that AMC protected fully against HIV. Among self-reported circumcised men, 44.9% (95%CI: 39.6% to 50.3%) had intact foreskins. Men without foreskins had lower HIV incidence and prevalence than men with foreskins (aIRR = 0.35; 95%CI: 0.14 to 0.88; aPR = 0.45, 95%CI: 0.26 to 0.79). No significant difference was found between self-reported circumcised men with foreskins and other uncircumcised men. Intention to undergo AMC was associated with ethnic group and partner and family support of AMC. Uptake of AMC was 58.8% (95%CI: 55.4% to 62.0%). CONCLUSIONS: AMC uptake in this community is high but communication and counseling should emphasize what clinical AMC is and its effect on HIV acquisition. These findings suggest that AMC roll-out is promising but requires careful implementation strategies to be successful against the African HIV epidemic.

The effect of heterogeneity on HIV prevention trials.

BACKGROUND: Randomized controlled trials (RCTs) for the prevention of HIV heterosexual acquisition are usually conducted among adult African populations with high heterogeneity in individual risk of infection. PURPOSE: The objectives were to (a) review how this heterogeneity has been considered when designing and interpreting such RCTs, (b) evaluate its effect on the findings and the statistical power of these trials, and (c) assess the potential advantages of using the crossover design with single failure-time endpoint. METHODS: Individual-level HIV prevention RCTs conducted in Africa and published in the period 1998-2008 were reviewed. Using Monte Carlo simulations and statistical calculations, we assessed the effect of heterogeneity on the findings and the statistical power of HIV prevention RCTs. RESULTS: All reviewed RCTs used the parallel design. The heterogeneity in individual risk of infection within study sites was not used for stratification nor generally considered in the design and interpretation of RCTs. Simulations showed that in the context of high HIV incidence, high heterogeneity can lead to a substantial underestimation of the impact of an intervention and reduced statistical power. Calculations demonstrated that the crossover design allowed for similar or better estimation and statistical power. The crossover design has the ethical advantage of sharing the potential benefits and risks of the intervention between participants. LIMITATIONS: Only trials with two treatment arms and two follow-up periods were modeled. The baseline risk of infection of each participant was assumed to be constant over time and HIV status was assessed at the end of each follow-up period. CONCLUSIONS: The heterogeneity in individual risk of HIV infection is an underestimated problem which should be taken into account when designing and interpreting RCTs that test prevention methods of HIV heterosexual acquisition in adult African populations with high HIV incidence. When the effects of tested interventions are rapidly reversible, the use of the crossover design should be considered.

Association of low-risk human papillomavirus infection with male circumcision in young men: results from a longitudinal study conducted in Orange Farm (South Africa).

BACKGROUND: Low-Risk Human Papillomavirus (LR-HPV) genotypes 6 and 11 cause genital warts. This study investigated the association of LR-HPV infection with male circumcision (MC). METHODS: We used data from the South African MC trial conducted among young men. Urethral swabs, collected among intervention (circumcised) and control (uncircumcised) groups, were analyzed using HPV linear array. Adjusted LR-HPV prevalence rate ratio (aPPR) and Poisson mean ratio (aPMR) of number of LR-HPV genotypes were estimated using log-Poisson regression, controlling for background characteristics, sexual behaviour, and HIV and HSV-2 statuses. RESULTS: Compared to controls, LR-HPV prevalence and mean number of genotypes were significantly lower among the intervention group ((8.5% versus 15.8%; aPRR: 0.54, P < .001) and (0.33 versus 0.18; aPMR: 0.54, P < .001), resp.). Mean number of LR-HPV genotypes increased with number of lifetime sexual partners and decreased with education level and consistent condom use. CONCLUSIONS: This study shows a reduction in LR-HPV infection among circumcised men.

High-risk human papillomavirus is associated with HIV acquisition among South African female sex workers.

BACKGROUND: Mounting evidence suggests an association between human papillomavirus (HPV) and HIV acquisition. This study aimed to explore this association among South African female sex workers (FSWs). METHODS: We used data from 88 HIV-negative FSWs who participated in a vaginal gel (COL-1492) trial. Cervicovaginal rinse samples, obtained before HIV-seroconversion, were genotyped into high-risk (HR-) and low-risk (LR-) HPV. HIV-adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were estimated using Cox survival analysis. RESULTS: HR- and LR-HPV prevalences were 70.5% (95% CI:60.5-79.2) and 60.2% (95% CI:49.9-70.0), respectively. Twenty-five women HIV seroconverted. Controlling for background characteristics and other sexually transmitted infections, HIV aHR increased by a factor of 1.7 (95% CI:1.01-2.7, P(linear trend) = 0.045) for an increase of one unit of the number of HR-HPV genotypes. CONCLUSIONS: HIV seroconversion among FSWs is associated with genital HR-HPV infection. Further investigation is warranted, including testing the possible protective effect of available HPV vaccines on HIV acquisition.

A model for the roll-out of comprehensive adult male circumcision services in African low-income settings of high HIV incidence: the ANRS 12126 Bophelo Pele Project.

BACKGROUND: World Health Organization (WHO)/Joint United Nations Programme on AIDS (UNAIDS) has recommended adult male circumcision (AMC) for the prevention of heterosexually acquired HIV infection in men from communities where HIV is hyperendemic and AMC prevalence is low. The objective of this study was to investigate the feasibility of the roll-out of medicalized AMC according to UNAIDS/WHO operational guidelines in a targeted African setting. METHODS AND FINDINGS: The ANRS 12126 "Bophelo Pele" project was implemented in 2008 in the township of Orange Farm (South Africa). It became functional in 5 mo once local and ethical authorizations were obtained. Project activities involved community mobilization and outreach, as well as communication approaches aimed at both men and women incorporating broader HIV prevention strategies and promoting sexual health. Free medicalized AMC was offered to male residents aged 15 y and over at the project's main center, which had been designed for low-income settings. Through the establishment of an innovative surgical organization, up to 150 AMCs under local anesthesia, with sterilized circumcision disposable kits and electrocautery, could be performed per day by three task-sharing teams of one medical circumciser and five nurses. Community support for the project was high. As of November 2009, 14,011 men had been circumcised, averaging 740 per month in the past 12 mo, and 27.5% of project participants agreed to be tested for HIV. The rate of adverse events, none of which resulted in permanent damage or death, was 1.8%. Most of the men surveyed (92%) rated the services provided positively. An estimated 39.1% of adult uncircumcised male residents have undergone surgery and uptake is steadily increasing. CONCLUSION: This study demonstrates that a quality AMC roll-out adapted to African low-income settings is feasible and can be implemented quickly and safely according to international guidelines. The project can be a model for the scale-up of comprehensive AMC services, which could be tailored for other rural and urban communities of high HIV prevalence and low AMC rates in Eastern and Southern Africa. Please see later in the article for the Editors' Summary.

Can HIV incidence testing be used for evaluating HIV intervention programs? A reanalysis of the Orange Farm male circumcision trial (ANRS-1265).

BACKGROUND: The objective of this study was to estimate the effect of male circumcision (MC) on HIV acquisition estimated using HIV incidence assays and to compare it to the effect measured by survival analysis. METHODS: We used samples collected during the MC randomized controlled trial (ANRS-1265) conducted in Orange Farm (South Africa) among men aged 18 to 24. Among the 2946 samples collected at the last follow-up visit, 194 HIV-positive samples were tested using two incidence assays: Calypte HIV-EIA (BED) and an avidity assay based on the BioRad HIV1/2+O EIA (AI). The results of the assays were also combined (BED-AI). The samples included the 124 participants (4.2% of total) who were HIV-positive at randomization. The protective effect was calculated as one minus the intention-to-treat incidence rate ratio in an uncorrected manner and with correction for misclassifications, with simple theoretical formulae. Theoretical calculations showed that the uncorrected intention-to-treat effect was approximately independent of the value of the incidence assay window period and was the ratio of the number tested recent seroconverters divided by the number tested HIV-negative between the randomization groups. We used cut-off values ranging from 0.325 to 2.27 for BED, 31.6 to 96 for AI and 0.325-31.6 to 1.89-96 for BED-AI. Effects were corrected for long-term specificity using a previously published formula. 95% Confidence intervals (CI) were estimated by bootstrap resampling. RESULTS: With the highest cut-off values, the uncorrected protective effects evaluated by BED, AI and BED-AI were 50% (95%CI: 27% to 66%), 50% (21% to 69%) and 63% (36% to 81%). The corrections for misclassifications were lower than 50% of the number of tested recent. The corrected effects were 53% (30% to 70%), 55% (25% to 77%) and 67% (38% to 86%), slightly higher than the corresponding uncorrected values. These values were consistent with the previously reported protective effect of 60% (34% to 76%) obtained with survival analysis. CONCLUSIONS: HIV incidence assays may be employed to assess the effect of interventions using cross-sectional data.

An age-structured model for the potential impact of generalized access to antiretrovirals on the South African HIV epidemic.

A simple mathematical model (Granich et al., Lancet 373:48-57, 2009) suggested recently that annual HIV testing of the population, with all detected HIV(+) individuals immediately treated with antiretrovirals, could lead to the long-term decline of HIV in South Africa and could save millions of lives in the next few years. However, the model suggested that the long-term decline of HIV could not be achieved with less frequent HIV testing. Many observers argued that an annual testing rate was very difficult in practice. Small scale trials are nevertheless in preparation. In this paper, we use a more realistic age-structured model, which suggests that the recent high levels of reported condom use could already lead to a long-term decline of HIV in South Africa. The model therefore suggests that trials with for example 20% of the population tested each year would also be interesting. They would have similar (though smaller) advantages in terms of reduction of mortality and incidence, would be much easier to generalize to larger populations, and would not lead to long term persistence of HIV. Our model simulations also suggest that the age distribution of incidence has changed considerably over the past 20 years in South Africa. This raises some concern about an assumption presently used in EPP/Spectrum, the software used by UNAIDS for its estimates.

[Male circumcision: hope for HIV infection decrease in southern Africa]. / La circoncision: un espoir de réduction de l'infection à VIH en Afrique australe.

Given the magnitude of the HIV pandemic, development of new prevention means is necessary. Male circumcision reduces HIV transmission from female to male by 57 % [95 % Confident Interval (CI): 42-68 %]. Its generalization in sub-Saharan Africa could avert, among men and women, from 1 to 4 millions new HIV infections over the next ten years. Acceptability of this new prevention mean is high in countries which could benefit the most from male circumcision, that means located in southern Africa, a region where in majority men are uncircumcised and where HIV prevalence is high. Male circumcision is a cost-effective prevention strategy. Actual prevention means (condoms, sexual abstinence and fidelity) are not used enough to curb the HIV epidemic. Research is ongoing on other prevention means (vaccine, pre- and post-exposition prophylaxis, microbicides, diaphragm) but their efficiency has not been demonstrated yet. Nevertheless, generalization of circumcision in southern Africa is responsible for contestations in part due to the fact that this prevention mean protects only partially from HIV infection. Moreover, for now, only a few countries integrated circumcision in their HIV prevention program in spite of WHO (World Health Organization) recommendations supporting male circumcision acknowledgement as an additional, important strategy for the prevention of heterosexually acquired HIV infection in men. Significant available funding should allow the situation to evolve quickly. At the same time, research goes on in order to know more about the effects and to facilitate the generalization of this prevention mean which is a great hope for southern Africa.

The HIV/AIDS epidemic in Cuba: description and tentative explanation of its low HIV prevalence.

BACKGROUND: The Cuban HIV/AIDS epidemic has the lowest prevalence rate of the Caribbean region. The objective of this paper is to give an overview of the HIV/AIDS epidemic in Cuba and to explore the reasons for this low prevalence. METHODS: Data were obtained from the Cuban HIV/AIDS programme established in 1983. This programme has an extensive adult HIV testing policy, including testing of all pregnant women. HIV and AIDS cases have been recorded since 1986. Persons found to be HIV-positive are interviewed on their sexual behaviour and partners. Tracing and voluntary testing of these partners are organised. Epidemiological description of this epidemic was obtained from analysis of this data set. Using elementary mathematical analyses, we estimated the coverage of the detection system (percentage of HIV-positive adults detected) and the average period between HIV infection and detection. Estimated HIV prevalence rates were corrected to account for the coverage. RESULTS: HIV prevalence has increased since 1996. In 2005, the prevalence among pregnant women was 1.2 per 10,000 (16/137000). Estimated HIV prevalence among 15- to 49-year-olds was 8.1 per 10,000 (4913/6065000; 95%CI: 7.9 per 10,000 - 8.3 per 10,000). Most (77%) of the HIV-positive adults were men, most (85.1%) of the detected HIV-positive men were reported as having sex with men (MSM), and most of the HIV-positive women reported having had sex with MSM. The average period between HIV infection and detection was estimated to be 2.1 years (IQR = 1.7 - 2.2 years). We estimated that, for the year 2005, 79.6% (IQR: 77.3 - 81.4%) of the HIV-positive persons were detected. CONCLUSION: MSM drive the HIV epidemic in Cuba. The extensive HIV testing policy may be an important factor in explaining the low HIV prevalence. To reduce the HIV epidemic in Cuba, the epidemic among MSM should be addressed. To understand this epidemic further, data on sexual behaviour should be collected. Now that antiretroviral therapy is more widely available, the Cuban policy, based on intensive HIV testing and tracing of partners, may be considered as a possible policy to control HIV/AIDS epidemics in other countries.

Women's knowledge and perception of male circumcision before and after its roll-out in the South African township of Orange Farm from community-based cross-sectional surveys.

The roll-out of medical male circumcision (MC) is progressing in Southern and Eastern Africa. Little is known about the effect of this roll-out on women. The objective of this study was to assess the knowledge and perceptions of women regarding MC in a setting before and after the roll-out. This study was conducted in the South African township of Orange Farm where MC prevalence among men increased from 17% to 53% in the period 2008-2010. Data from three community-based cross sectional surveys conducted in 2007, 2010 and 2012 among 1258, 1197 and 2583 adult women, respectively were studied. In 2012, among 2583 women, 73.7% reported a preference for circumcised partners, and 87.9% knew that circumcised men could become infected with HIV. A total of 95.8% preferred to have their male children circumcised. These three proportions increased significantly during the roll-out. In 2007, the corresponding values were 64.4%, 82.9% and 80.4%, respectively. Among 2581 women having had sexual intercourse with circumcised and uncircumcised men, a majority (55.8%, 1440/2581) agreed that it was easier for a circumcised man to use a condom, 20.5% (530/2581) disagreed; and 23.07 (611/2581) did not know. However, some women incorrectly stated that they were fully (32/2579; 1.2%; 95%CI: 0.9% to 1.7%) or partially (233/2579; 9.0%; 95%CI: 8.0% to 10.2%) protected when having unprotected sex with a circumcised HIV-positive partner. This study shows that the favorable perception of women and relatively correct knowledge regarding VMMC had increased during the roll-out of VMMC. When possible, women should participate in the promotion of VMMC although further effort should be made to improve their knowledge.

Obtaining a male circumcision prevalence rate of 80% among adults in a short time: An observational prospective intervention study in the Orange Farm township of South Africa.

World Health Organization recommends a target for the male circumcision prevalence rate of 80%. This rate will have a substantial impact on the human immunodeficiency virus-acquired immunodeficiency syndrome epidemic in Eastern and Southern Africa. The objective of the study was to assess whether an innovative intervention can lead to an increased voluntary male medical circumcision (VMMC) uptake among adults in a short time. This prospective observational study of a demand generation intervention was conducted in the township of Orange Farm (South Africa) in August to November 2015. In this community male circumcision prevalence rate among adults was stable between 2010 and 2015 at 55% and 57%, despite regular VMMC campaigns at community level and the presence of a VMMC clinic that offered free VMMC. The intervention took place in a random sample of 981 households where 522 men aged 18 to 49 years accepted to participate in the study. Among the 226 uncircumcised men, 212 accepted to be enrolled in the intervention study. A personal male circumcision adviser trained in interpersonal communication skills was assigned to each uncircumcised participant. The male circumcision advisers were trained to explain the risks and benefits of VMMC, and to discuss 24 possible reasons given by men for not being circumcised. Participants were then followed for 9 weeks. Each participant had a maximum of 3 motivational interviews at home. Participants who decided to be circumcised received financial compensation for their time equivalent to 2.5 days of work at the minimum South African salary rate. Among the 212 uncircumcised men enrolled in the intervention, 69.8% (148/212; 95% confidence interval [CI]; 63.4%-75.7%) agreed to be circumcised, which defines the uptake of the intervention. The male circumcision prevalence rate of the sample increased from 56.7% (296/522) to 81.4% (425/522; 77.9%-84.6%), P < 0.001, corresponding to a relative increase of 43.6% (95% CI: 35.4%-53.7%). The reported reasons for accepting circumcision were motivational interviews with the male circumcision adviser (83.1%), and time compensation (39.4%).Increased uptake of VMMC uptake can be obtained in a short time among adult males but requires an intense intervention centered on uncircumcised men at an individual level and time compensation.

Cost-effectiveness of male circumcision for HIV prevention in a South African setting.

BACKGROUND: Consistent with observational studies, a randomized controlled intervention trial of adult male circumcision (MC) conducted in the general population in Orange Farm (OF) (Gauteng Province, South Africa) demonstrated a protective effect against HIV acquisition of 60%. The objective of this study is to present the first cost-effectiveness analysis of the use of MC as an intervention to reduce the spread of HIV in sub-Saharan Africa. METHODS AND FINDINGS: Cost-effectiveness was modeled for 1,000 MCs done within a general adult male population. Intervention costs included performing MC and treatment of adverse events. HIV prevalence was estimated from published estimates and incidence among susceptible subjects calculated assuming a steady-state epidemic. Effectiveness was defined as the number of HIV infections averted (HIA), which was estimated by dynamically projecting over 20 years the reduction in HIV incidence observed in the OF trial, including secondary transmission to women. Net savings were calculated with adjustment for the averted lifetime duration cost of HIV treatment. Sensitivity analyses examined the effects of input uncertainty and program coverage. All results were discounted to the present at 3% per year. For Gauteng Province, assuming full coverage of the MC intervention, with a 2005 adult male prevalence of 25.6%, 1,000 circumcisions would avert an estimated 308 (80% CI 189-428) infections over 20 years. The cost is 181 dollars (80% CI 117-306 dollars) per HIA, and net savings are 2.4 million dollars (80% CI 1.3 million to 3.6 million dollars). Cost-effectiveness is sensitive to the costs of MC and of averted HIV treatment, the protective effect of MC, and HIV prevalence. With an HIV prevalence of 8.4%, the cost per HIA is 551 dollars (80% CI 344-1,071 dollars) and net savings are 753,000 (80% CI 0.3 million to 1.2 million dollars). Cost-effectiveness improves by less than 10% when MC intervention coverage is 50% of full coverage. CONCLUSIONS: In settings in sub-Saharan Africa with high or moderate HIV prevalence among the general population, adult MC is likely to be a cost-effective HIV prevention strategy, even when it has a low coverage. MC generates large net savings after adjustment for averted HIV medical costs.

The potential impact of male circumcision on HIV in Sub-Saharan Africa.

BACKGROUND: A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60% (32%-76%; 95% CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. METHODS AND FINDINGS: Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC, we estimate the impact of increasing MC coverage on HIV incidence, HIV prevalence, and HIV-related deaths over the next ten, twenty, and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years, we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95% confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1-3.8) million new HIV infections and 0.3 (0.1-0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that, it could avert a further 3.7 (1.9-7.5) million new HIV infections and 2.7 (1.5-5.3) million deaths, with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52% to 58%; b) where there is homogenous mixing but not all men are circumcised, the prevalence of infection in circumcised men is likely to be about 80% of that in uncircumcised men; c) MC is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%. CONCLUSIONS: This analysis is based on the result of just one RCT, but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa, especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate, the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years.

Sequential Cross-Sectional Surveys in Orange Farm, a Township of South Africa, Revealed a Constant Low Voluntary Medical Male Circumcision Uptake among Adults despite Demand Creation Campaigns and High Acceptability.

BACKGROUND: WHO recommends a male circumcision (MC) prevalence rate higher than 80% to have a substantial impact on the HIV-AIDS epidemic in Eastern and Southern Africa. Orange Farm, a township in South Africa, has a free-for-service voluntary medical male circumcision (VMMC) clinic in operation since 2008. Following an intense campaign from 2008 to 2010, MC prevalence rate increased to 55.4% (ANRS-12126). Ongoing and past VMMC campaigns focused on youths, through school talks, and adults at a community level. The main objective of the study was to assess the change in MC prevalence rate among adults aged 18-19 and 18-49 years in the past 5 years. METHODS: A cross-sectional survey (ANRS-12285) was conducted among a random sample of 522 adult men in 2015. MC status and characteristics of participants were collected through a genital examination and a face-to-face questionnaire. RESULTS: MC prevalence rate among young adult men aged 18-19 years increased markedly from 61.2% (95%CI: 57.4% to 65.0%) in 2010 to 87.5% (76.0% to 94.6%) in 2015 (p<0.001). In the same period, among men aged 18-49 years, MC prevalence rate varied slightly from 55.4% (53.6% to 57.1%) to 56.7% (52.4% to 60.9%). In 2015, 84.9% (79.2% to 89.5%) of uncircumcised adult men reported that they were willing to be circumcised. However, we estimated that only 4.6% (11/237; 2.5% to 7.9%) of the uncircumcised men underwent circumcision in 2015, despite 117/185 (63.2%; 95%CI: 56.1% to 69.9%) who reported that they were definitely willing to become circumcised. CONCLUSIONS: In Orange Farm, VMMC campaigns were successful among the youth and led to a sufficiently high MC prevalence rate to have a substantial impact in the future on the HIV-AIDS epidemic. However, despite high acceptability and a free VMMC service, VMMC campaigns since 2010 have failed to increase MC prevalence rate among adults to above 80%. These campaigns should be revisited.