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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.

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’, ‘human papillomavirus’ 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.

In 2012, 7 years after the introduction of antiretroviral treatment (ART) in the South African township of Orange Farm, we measured the proportion of HIV-positive people who were virally suppressed, especially among high-risk groups (women 18-29 years and men 25-34 years).A community-based cross-sectional representative survey was conducted among 3293 men and 3473 women.Study procedures included a face-to-face interview and collection of blood samples that were tested for HIV, 11 antiretroviral drugs and HIV-viral load.HIV prevalence was 17.0% [95% confidence interval: 15.7-18.3%] among men and 30.1% [28.5-31.6%] among women. Overall, 59.1% [57.4-60.8%] of men and 79.5% [78.2-80.9%] of women had previously been tested for HIV. When controlling for age, circumcised men were more likely to have been tested compared with uncircumcised men (66.1 vs 53.6%; P 0.001). Among HIV+, 21.0% [17.7-24.6%] of men and 30.5% [27.7-33.3%] of women tested positive for one or more antiretroviral drugs. Using basic calculations, we estimated that, between 2005 and 2012, ART programs prevented between 46 and 63% of AIDS-related deaths in the community. Among antiretroviral-positive, 91.9% [88.7-94.3%] had viral suppression (viral load400 copies/ml). The proportion of viral suppression among HIV+ was 27.0% [24.3-29.9%] among women and 17.5% [14.4-20.9%] among men. These proportions were lower among the high-risk groups: 15.6% [12.1-19.7%] among women and 8.4% [5.0-13.1%] among men.In Orange Farm, between 2005 and 2012, ART programs were suboptimal and, among those living with HIV, the proportion with viral suppression was still low, especially among the young age groups. However, our study showed that, in reality, antiretroviral drugs are highly effective in viral suppression at an individual level.

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

La circoncision est pratiquée en Afrique depuis plus de 4 000 ans, et actuellement, deux tiers des hommes de ce continent sont circoncis. L’infection par le virus du SIDA – le virus de l’immunodéficience acquise ou VIH – est moins fréquente dans les pays où la circoncision est une norme sociale. Des études scientifiques, menées entre 2002 et 2007 dans trois pays d’Afrique, ont permis d’établir une relation de cause à effet entre la circoncision et la réduction du risque d’infection des hommes par le VIH. Depuis ces études princeps, et avec le soutien d’organismes internationaux tels que l’OMS et l’ONU-SIDA, la généralisation de la circoncision est en cours en Afrique australe et dans des régions d’Afrique de l’Est, là où vivent la plupart des hommes non circoncis. Les premiers résultats sont encourageants. Ils démontrent la faisabilité des programmes de circoncision de masse et prouvent que leur acceptation par les populations peut être forte. Cependant, malgré le soutien de la communauté internationale, ces programmes sont actuellement pénalisés par une mobilisation trop faible des gouvernements africains.

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.

OBJECTIVE: We previously developed a multiassay algorithm (MAA) to identify recent HIV infection that includes the BED-capture enzyme immunoassay an avidity assay based on the Genetic Systems HIV-1/HIV-2 + O enzyme immunoassay CD4 cell count and HIV viral load. We used this MAA to evaluate the association between recent maternal HIV infection and in-utero transmission of HIV. METHODS: Plasma samples were collected at delivery from 2561 HIV-infected women in the postexposure prophylaxis of infants-Malawi trial. The MAA described above was used to identify women with recent HIV infection. Logistic regression models assessed association between recent HIV infection and in-utero HIV transmission (defined as a positive infant HIV DNA test at birth). RESULTS: Seventy-three women were identified as recently infected using the MAA. Those women were younger and had lower parity than women who were identified as not recently infected using the MAA (P < 0.0001 for age and parity). The frequency of in-utero HIV transmission was 17.8% among women identified as recently infected compared with 6.7% among women identified as not recently infected (13/73 vs. 166/2488 P = 0.001). In a multivariate model three factors were independently associated with in-utero HIV transmission: recent infection [adjusted odds ratio (AOR): 2.49 95% confidence interval (CI): 1.30-4.78 P = 0.006] log(10) HIV viral load at delivery (AOR: 2.01 95% CI: 1.60-2.51 P < 0.0001) and younger age (per 10 year increase AOR: 0.66 95% CI: 0.43-0.93 P = 0.02). CONCLUSION: Results obtained using a MAA suggest that recent maternal HIV acquisition is strongly associated with in-utero HIV transmission independent of HIV viral load at delivery.

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.

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 P P 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 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.

Granich et al. [Lancet 373 (2009) 48–57] ont recemment suggere avec un modele mathematique simple qu'un test annuel pour le VIH dans la population, avec tous les individus seropositifs detectes immediatement traites avec des antiretroviraux , pouvait conduire au declin a long terme de l'epidemie en Afrique du Sud et pouvait sauver des millions de vies en quelques annees. Le modele suggerait cependant que ce declin ne pouvait etre atteint avec une moindre frequence des tests. De nombreux observateurs ont fait remarquer qu'un test annuel etait tres difficile en pratique. Des essais a petite echelle sont neanmoins en preparation. Dans cet article, on utilise un modele structure par âge plus realiste. Il suggere que les niveaux eleves recemment rapportes d'utilisation de preservatifs pourraient deja conduire a un declin a long terme du VIH en Afrique du Sud. Le modele suggere aussi que des essais avec par exemple 20% de la population testee chaque annee seraient egalement interessants. Ils auraient des avantages similaires, quoique moindres, en terme de reduction de la mortalite et de l'incidence ; ils seraient beaucoup plus facile a generaliser a des populations plus grandes ; ils ne conduiraient pas a la persistance a long terme du VIH. Nos simulations suggerent enfin que la distribution par âge de l'incidence a change considerablement au cours des vingt dernieres annees en Afrique du Sud. Ceci fait douter d'une hypothese actuellement utilisee par EPP/Spectrum, le logiciel qu'ONUSIDA utilise pour ses estimations.

International audience; OBJECTIVES: A synergy between HIV and herpes simplex virus type 2 (HSV-2) infections has been reported in observational studies. The objectives of this study were to estimate the per-sex-act female-to-male transmission probabilities (FtoMTPs) of HIV and HSV-2, the effect of each infection on the FtoMTP of the other and the effect of male circumcision on these FtoMTPs. DESIGN: We used longitudinal data collected during the male circumcision trial conducted in Orange Farm (South Africa). METHODS: Results were obtained by specific mathematical modeling of HIV and HSV-2 statuses of the men as functions of their sexual behavior and male circumcision status. The model took into account an estimation of the HIV and HSV-2 statuses of each of their female partners. Confidence intervals (CI) were estimated using a bootstrap resampling method. RESULTS: The HIV and HSV-2 FtoMTPs, during an unprotected sexual contact for an uncircumcised male in the absence of the other virus in both partners, were 0.0047 (95% CI: 0.0014-0.017) and 0.0067 (95% CI: 0.0028-0.014), respectively. HSV-2 in either partner increased HIV FtoMTP with a relative risk (RR) of 3.0 (95% CI: 1.01-7.3). Conversely, HIV in either partner increased HSV-2 FtoMTP (RR= 2.5; 95% CI: 1.1- 6.3). Male circumcision significantly decreased these probabilities with RRs of 0.24 (95% CI: 0.11-0.44) and 0.59 (95% CI: 0.36-0.91), respectively. CONCLUSION: This study gave the first estimates of HSV-2 per-sex-act FtoMTPs in Africa. It demonstrated a synergy between HIV and HSV-2 infections and a protective effect of male circumcision on HSV-2 acquisition by males.

International audience; BACKGROUND: A causal association links high-risk human papillomavirus (HR-HPV) and cervical cancer, which is a major public health problem. The objective of the present study was to investigate the association between male circumcision (MC) and the prevalence of HR-HPV among young men. METHODS: We used data from a MC trial conducted in Orange Farm, South Africa, among men aged 18-24 years. Urethral swab samples were collected during a period of 262 consecutive days from participants in the intervention (circumcised) and control (uncircumcised) groups who were reporting for a scheduled follow-up visit. Swab samples were analyzed using polymerase chain reaction. HR-HPV prevalence rate ratios (PRRs) were assessed using univariate and multivariate log Poisson regression. RESULTS: In an intention-to-treat analysis, the prevalences of HR-HPV among the intervention and control groups were 14.8% (94/637) and 22.3% (140/627), respectively, with a PRR of 0.66 (0.51-0.86) (P = .002). Controlling for propensity score and confounders (ethnic group, age, education, sexual behavior [including condom use], marital status, and human immunodeficiency virus status) had no effect on the results. CONCLUSIONS: This is the first randomized controlled trial to show a reduction in the prevalence of urethral HR-HPV infection after MC. This finding explains why women with circumcised partners are at a lower risk of cervical cancer than other women.

Objective: To assess the association between male circumcision and Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis using data from a male circumcision randomised controlled trial. Methods: We used data collected during the male circumcision trial conducted in Orange Farm (South Africa) among men aged 18–24 years. Altogether, 1767 urine samples collected during the final follow-up visit were analysed using PCR. Prevalence of N gonorrhoeae, C trachomatis and T vaginalis was assessed as a function of male circumcision using odds ratios (OR) given by univariate and multivariate logistic regression. Results: In an intention-to-treat analysis, prevalence of N gonorrhoeae, C trachomatis and T vaginalis among intervention and control groups were 10.0% versus 10.3% (OR 0.97; p = 0.84), 2.1% versus 3.6% (OR 0.58; p = 0.065) and 1.7% versus 3.1% (OR 0.54; p = 0.062), respectively. The association between T vaginalis and male circumcision remained borderline when controlling for age, ethnic group, number of lifetime partners, marital status, condom use and HIV status (AOR 0.48; p = 0.069). In the as-treated analysis, this association became significant (OR 0.49, p = 0.030; AOR 0.41, p = 0.030). Conclusions: This study demonstrates for the first time that male circumcision reduces T vaginalis infection among men. This finding explains why women with circumcised partners are less at risk for T vaginalis infection than other women. The protective effect on T vaginalis is an additional argument to recommend male circumcision in Africa where it is acceptable. Trial registration number: NCT00122525.

Face a l’ampleur de l’epidemie de VIH en Afrique sub-saharienne, le developpement de nouveaux moyens de prevention est necessaire. La circoncision reduit la transmission du virus de la femme a l’homme de 57 %. Sa generalisation a l’echelle de l’Afrique sub-saharienne permettrait d’eviter, parmi les hommes et les femmes, 1 a 4 millions de nouvelles infections dans les 10 prochaines annees. L’acceptabilite de ce nouveau moyen de prevention est grande dans les pays qui en beneficieraient le plus, c’est-a-dire les pays d’Afrique australe, region ou les hommes sont en majorite non circoncis et ou la prevalence du VIH est elevee. La circoncision est une intervention de prevention cout-efficace. Les moyens de prevention actuels (preservatif, abstinence, fidelite) ne sont pas utilises suffisamment pour endiguer l’epidemie. Les moyens de prevention a l’etude (vaccin, prophylaxie pre- et post-exposition, microbicides, diaphragme) tardent a montrer leur efficacite. Cependant, la generalisation de la circoncision en Afrique australe est a l’origine de controverses liees notamment au fait qu’elle n’assure qu’une protection partielle. De plus, a ce jour, seuls quelques pays ont integre la circoncision dans leur programme de prevention du VIH, malgre les recentes recommandations de l’OMS (Organisation Mondiale de la Sante) en faveur de la promotion de la circoncision comme moyen complementaire de lutte contre le VIH. Les importants financements disponibles devraient faire evoluer rapidement la situation. Parallelement, la recherche se poursuit afin de mieux cerner les consequences et de faciliter la generalisation de ce moyen de prevention du VIH, qui represente un reel espoir pour l’Afrique australe.

The study aims to investigate the potential for an intervention based on male circumcision in a South African town with a high level of HIV infection. It draws on two cross-sectional studies conducted in August 2000 among a sample of 606 male adults aged 13-59 years, and in August 1999 among a sample of 723 male youth aged 14-24 years. A qualitative study was further conducted on perceptions and attitudes towards male circumcision using focus group discussions and in-depth interview. Among men aged 25-59 years, 36% reported being circumcised. The median reported age at circumcision was 20. A total of 42% of 14-24-year-old circumcised men reported having been circumcised in a medical setting. Circumcised and uncircumcised men did not differ in their sexual behaviour or in sociodemographic characteristics, apart from their age and ethnic group. Among 467 uncircumcised adult men, 59% said that they would be circumcised if circumcision reduced the chances of getting HIV and STDs. Focus group discussions showed that circumcision is still important to many people, and is seen as an essential part of the transition into adulthood. Reluctance to be circumcised was mainly related to the possibility of adverse outcomes of circumcision performed in non-medical settings, although initiation schools remain attractive for education and transmission of cultural values. Some misconceptions remain, however, especially about the preventative nature of circumcision for STD transmission. The cultural importance of male circumcision has weakened over the last century and when it is done it is often by a medical practitioner. An intervention that would include male circumcision seems feasible in communities such as the one where this study was conducted but needs to be carefully planned in order to ensure that participants understand that circumcision probably reduces, but certainly does not eliminate, the risk of HIV infection.

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

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. Copyright © 2013 John Wiley & Sons, Ltd.

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.

OBJECTIVE: To identify factors that could explain differences in rate of spread of HIV between different regions in sub-Saharan Africa. DESIGN: Cross-sectional study. METHODS: The study took place in two cities with a relatively low HIV prevalence (Cotonou, Benin and Yaounde, Cameroon), and two cities with a high HIV prevalence (Kisumu, Kenya and Ndola, Zambia). In each of these cities, a representative sample was taken of about 1000 men and 1000 women aged 15-49 years. Consenting men and women were interviewed about their socio-demographic background and sexual behaviour; and were tested for HIV, herpes simplex virus type 2 (HSV-2), syphilis, Chlamydia trachomatis and Neisseria gonorrhoea infection, and (women only) Trichomonas vaginalis. Analysis of risk factors for HIV infection was carried out for each city and each sex separately. Adjusted odds ratios (aOR) were obtained by multivariate logistic regression. RESULTS: The prevalence of HIV infection in sexually active men was 3.9% in Cotonou, 4.4% in Yaounde, 21.1% in Kisumu, and 25.4% in Ndola. For women, the corresponding figures were 4.0, 8.4, 31.6 and 35.1%. High-risk sexual behaviour was not more common in the high HIV prevalence cities than in the low HIV prevalence cities, but HSV-2 infection and lack of circumcision were consistently more prevalent in the high HIV prevalence cities than in the low HIV prevalence cities. In multivariate analysis, the association between HIV infection and sexual behavioural factors was variable across the four cities. Syphilis was associated with HIV infection in Ndola in men [aOR = 2.7, 95% confidence interval (CI) = 1.5-4.91 and in women (aOR = 1.7, 95% CI = 1.1-2.6). HSV-2 infection was strongly associated with HIV infection in all four cities and in both sexes (aOR ranging between 4.4 and 8.0). Circumcision had a strong protective effect against the acquisition of HIV by men in Kisumu (aOR = 0.25, 95% CI = 0.12-0.52). In Ndola, no association was found between circumcision and HIV infection but sample sizes were too small to fully adjust for confounding. CONCLUSION: The strong association between HIV and HSV-2 and male circumcision, and the distribution of the risk factors, led us to conclude that differences in efficiency of HIV transmission as mediated by biological factors outweigh differences in sexual behaviour in explaining the variation in rate of spread of HIV between the four cities.

Objective: To estimate parameters of concurrent sexual partnerships in five urban populations in sub-Saharan Africa and to assess their association with levels of HIV infection and other sexually transmitted infections (STI). Methods: Data were obtained from a multicentre study of factors which determine the differences in rate of spread of HIV in five African cities. Consenting participants were interviewed on sexual behaviour and at four of the five sites also provided a blood and a urine sample for testing for HIV and other STI. Data on sexual behaviour included the number of partnerships in the 12 months preceding the interview as well as the dates of the start and end of each partnership. Summary indices of concurrent sexual partnerships - some of which were taken from the literature, while others were newly developed - were computed for each city and compared to HIV and STI prevalence rates. Results: A total of 1819 adults aged 15-49 years were interviewed in Dakar (Senegal), 2116 in Cotonou (Benin), 2089 in Yaounde (Cameroon), 1889 in Kisumu (Kenya) and 1730 in Ndola (Zambia). Prevalence rates of HIV infection were 3.4% for Cotonou, 5.9% for Yaounde, 25.9% for Kisumu and 28.4% for Ndola, and around 1% for Dakar. The estimated fraction of sexual partnerships that were concurrent at the time of interview (index k) was relatively high in Yaounde (0.98), intermediate in Kisumu (0.44) and Cotonou (0.33) and low in Ndola (0.26) and in Dakar (0.18). An individual indicator of concurrency (iic) was developed which depends neither on the number of partners nor on the length of the partnerships and estimates the individual propensity to keep (positive values) or to dissolve (negative values) on-going partnership before engaging in another one. This measure iic did not discriminate between cities with high HIV infection levels and cities with low HIV infection levels. In addition, iic did not differ significantly between HIV-infected and uninfected people in the four cities where data on HIV status were collected. Conclusion: We could not find evidence that concurrent sexual partnerships were a major determinant of the rate of spread of HIV in five cities in sub-Saharan Africa. HIV epidemics are the result of many factors, behavioural as well as biological, of which concurrent sexual partnerships are only one.

We showed herein the potent virucidal effect of soap and water solutions against both CCR5-tropic and CXCR4-tropic cell-free HIV-1 strains, and cytotoxicity for HIV-1-infected lymphocytes during short incubation durations, ranging from 30 seconds to 2 minutes. These observations indicate a rapid inhibitory effect of soap and water on viral infectivity.

The multistage theory of carcinogenesis allows models to be constructed that provide the individual probability of a diagnosed tumor at a given age as a function of the person's past exposure to carcinogenic agents (exposure level versus age), the time since exposure, and age. When exposure to a carcinogenic agent and its impact in terms of morbidity and mortality are modeled on the scale of the general population, individual exposures must often be estimated. If appropriate data do not already exist, this difficult task necessitates expensive and difficult investigations. We propose here a method that allows this global exposure to be modeled without needing to know the individual exposures. The method is used and illustrated in the context of modeling the asbestos exposure of the French male population and calculating its mortality rate from mesothelioma (a type of cancer for which asbestos is the only carcinogen and for which a risk function based on the multistage theory of carcinogenesis exists). This method assumes that the exposure functions (how exposure levels vary with age) for all individuals are the same, with the exception of one parameter. That is, it utilizes a hypothesis that we called the hypothesis of the Standard Exposure Window (SEW). We used two methods to calculate the probability of death from mesothelioma in a representative sample of the French male population for whom individual histories of asbestos exposure are known: we applied the risk function to all the individuals, and we applied the SEW hypothesis. The number of deaths obtained by the two methods are very close and fit the observed mortality data satisfactorily.

Background/Aims: The reported incidence of biliary atresia varies from 5 to 32/100 000 live births. The existence of seasonality and/or clustering is controversial. Based on a large population analysis, we examined the incidence of biliary atresia in France, and the space-time distribution of cases. Methods: All patients with biliary atresia living in France and born in the years 1986-96 were recorded. Geographic distribution, seasonality, time clustering and space-time clustering were analysed. Statistical analysis used the Chi square test, the Spearman nonparametric correlation test, the Walter and Elwood test for seasonality of events and Knox analysis for time and space-time clustering. Results: We identified 461 patients: 421 born in metropolitan France (incidence 5.12 [4.63-5.61]/100 000 live births), and 40 born in overseas territories. No significant regional variation in incidence was found in metropolitan France, while the incidence was higher in French Polynesia (incidence 29.4 [15.4-43.3]/100 000 live births) (p

The objective was to estimate the likely percentage of HIV infections that may be attributable to one-off partnerships (such as those between female sex workers and their clients) and longer-term partnerships in rural Uganda. This was addressed by the application of a microsimulation model (SimulAIDS) of the transmission dynamics of HIV infection, drawing on data from a population cohort of 10,000 in rural Uganda. For a scenario reproducing documented characteristics of the study population in 1990, when adult HIV prevalence was 9%, and during subsequent follow up (1990-1994), when adult HIV incidence was 8 per 1000 person-years, the percentage of HIV infections in men (women) attributed to one-off partnerships decreased from 96% (26%) during 1980 to 67% (8%) in 1989 and 22% (5%) in 1994. Reducing HIV transmission between one-off partners early in an HIV epidemic may substantially limit the potential for the spread of HIV infection. At a later phase, prevention must also focus on control of transmission between longer-term HIV-discordant partners.This paper presents results of a study using a simulation model in estimating the likely percentage of HIV infections that may be attributable to one-off partnerships (e.g., female sex workers and their clients) and longer-term partnerships among the rural population of Uganda. The study adopted SimulAIDS, an age-structured microsimulation model of the HIV infection dynamics along with ulcerative and non-ulcerative sexually transmitted diseases. Data obtained from the 10,000 cohort population reflected a decline in the incidence of HIV in adults between 1990 and 1994, a result which could be attributed to one-off sexual partnerships in 1980, 1984, 1989, 1994, and 1999. The study supports that minimizing transmission of HIV from short-term sexual partnerships during early stage of the disease could have a strong impact on the reduction in the spread of HIV infection.

Since the sequential treatment of Kasai operation with or without liver transplantation became available, the overall prognosis of biliary atresia remains unclear. This study examined the prognostic factors from diagnosis. All patients with biliary atresia living in France and born in the years 1986 to 1996 were reviewed. Actuarial survival rates were calculated for survival with native liver, survival after liver transplantation, and overall survival. Potential prognostic factors were analyzed using the logrank test and the Cox model. A total of 472 patients were identified. Ten-year overall survival was 68%. Independent prognostic factors for overall survival were (S = 10-year rates) performance of Kasai operation (performed: S = 69%; not performed: S = 50%), age at Kasai operation (/=45 days: S = 80%;45 days: S = 66%), anatomical pattern of extrahepatic bile ducts, polysplenia syndrome, experience of the center (/=2 new biliary atresia [BA] patients/year [24 centers]: S = 54%; 3 to 5 [2 centers]: S = 60%;/=20 [1 center]: S = 78%). Survival with native liver depended on the same independent prognostic factors. In conclusion (1) Kasai operation remains the first line treatment of BA, and (2) early performance of Kasai operation and treatment in an experienced center reduces the need for liver transplantation in infancy and childhood and provides children with the best chance of survival.

We compared three intervention strategies for preventing heterosexual transmission of the human immunodeficiency virus (HIV) using deterministic and stochastic models to simulate the epidemic of acquired immunodeficiency syndromes (AIDS). We estimated demographic, biological, and behavioral parameters for a severely affected east African city early in the epidemic, and used these parameter values in computing the spread of HIV under five scenarios: (1) a baseline scenario with no public health interventions; three single-intervention scenarios with strategies to (2) reduce the number and rate of change of sex partners, (3) increase condom use, or (4) improve treatment of sexually transmitted diseases (STD); and a (5) combined-intervention scenario. The rankings were the same in both models—decreasing partner change was most effective, followed by condom use and STD treatment. Combined interventions were more effective than single interventions. They interacted to produce impacts that varied with the trajectory of the epidemic at the onset of the interventions. Their timely, targeted, and sustained implementation appears critical to slow the epidemic significantly.

Unprotected heterosexual contact in the presence of other sexually transmitted diseases (STD) enhances the probability of HIV transmission. The objective of this study was to estimate the proportion of HIV infections attributable to STD in rural Uganda.Simulation modelling scenarios of the transmission dynamics of HIV infection and of ulcerative and non-ulcerative STD were employed to address this objective, drawing on data from a specific rural population cohort of 10,000 in south-west Uganda.In simulations of the initial 10-year period of the HIV epidemic (1980-1990), over 90% of HIV infections were attributed to STD. Even given conservative assumptions about the prevalence of STD and about their enhancing effects on HIV transmission, STD played a critical role in the rapid and extensive spread of HIV infection. The role of STD decreased with progression of the HIV epidemic.In developing countries, control of the spread of HIV infection may benefit substantially from successful STD intervention programmes, and particularly in areas where HIV infection is not already well established.Unprotected heterosexual contact in the presence of other sexually transmitted diseases (STDs) increases the likelihood of HIV transmission. A detailed simulation model of HIV transmission dynamics and of ulcerative and nonulcerative STDs was fit to a rural population in southwest Uganda in an attempt to estimate the proportion of HIV infections attributable to STDs in the area. The study population includes the total population of approximately 10,000 in a cluster of 15 villages in Masaka district where population surveys have been conducted annually since mid-1990. In simulations of the initial 10-year period of the HIV epidemic of 1980-90, more than 90% of HIV infections were attributed to STDs. Even making conservative assumptions about the prevalence of STDs and their enhancing effects upon HIV transmission, STDs played an important role in the rapid and extensive spread of HIV infection. The role of STDs decreased with the progression of the HIV epidemic.

Betran Auvert and colleagues report findings from the Bophelo Pele project, a community-based HIV prevention intervention offering free voluntary medical male circumcision (VMMC), that demonstrate an association between VMMC roll-out and a reduction in the incidence and prevalence of HIV in the community. Please see later in the article for the Editors' Summary, 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, Editors' Summary Background Every year about 2.2 million people (mostly in sub-Saharan Africa) become infected with HIV, the virus that causes AIDS. There is no cure for HIV/AIDS. Consequently, prevention of HIV transmission is extremely important. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of HIV infection by abstaining from sex, by having only one or a few sexual partners, and by always using a male or female condom. The results of three randomized controlled trials conducted in sub-Saharan Africa also suggest that voluntary medical male circumcision (VMMC)—the removal of the foreskin, a loose fold of skin that covers the head of the penis—can reduce the heterosexual acquisition of HIV in men by 50%–60%. In 2007, the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended that VMMC should be offered as part of comprehensive HIV risk reduction programs in settings with generalized HIV epidemics and low levels of male circumcision and prioritized 14 east and southern African countries for VMMC roll-out. Why Was This Study Done? To date, about 3 million VMMCs have been performed for HIV prevention but it is not known whether “real world” VMMC roll-out programs will replicate the promising results obtained in the earlier trials. Indeed, there are fears that “risk compensation” (an increase in risky sexual behaviors after VMMC) might lead to increased HIV transmission in regions where VMMC is rolled out. In this study, the researchers use sequential cross-sectional surveys (studies that collect data from a group of people at a single time point) to investigate HIV infection levels in men in Orange Farm, a township in South Africa where one of the randomized controlled trials of VMMC was undertaken. The surveys were conducted before and after implementation of the Bophelo Pele project, a community-based campaign against HIV that was initiated in 2008 and that includes free VMMC. What Did the Researchers Do and Find? The researchers asked a random sample of nearly 2,000 men aged 15–49 years about their sexual behavior (for example, how many non-spousal partners they had had over the past year), and their intention to become circumcised if uncircumcised in a baseline survey in 2007–2008. The study participants were also offered HIV counseling and testing (including a test that indicated whether the participant had recently become HIV positive) and were examined to see whether they were already circumcised. A similar follow-up survey was conducted in 2010–2011 in which more than 3,000 men were invited to take part. At baseline, 12% of the men surveyed had been circumcised (a prevalence of circumcision of 12%) whereas in the follow-up survey, the overall prevalence of circumcision and the prevalence of circumcision among 15–29 year-olds (an important target group for VMMC roll-out) were 53% and 58%, respectively. The overall HIV prevalence at follow-up was 12% and the researchers estimated that without the VMMCs performed during the Bophelo Pele project and the preceding randomized control trial the prevalence of HIV among men living in Orange Farm would have been 15% in 2011. Using various cut-off values and corrections for a laboratory-based test to measure recent HIV infections, the researchers reported a reduction in the rate of new HIV infections (incidence rate) ranging from 57% to 61% among circumcised men in comparison with uncircumcised men. Importantly, there was no evidence of an association between circumcision status and risky sexual behavior but circumcision was associated with a reduction in the number of men who had recently become HIV positive. What Do These Findings Mean? These findings suggest that VMMC roll out in Orange Farm is associated with a reduction in HIV infection levels in the community and that circumcision is not associated with changes in sexual behavior that might affect HIV infection rates. They also suggest that VMMC roll-out is associated with a rapid uptake of VMMC, especially among young men, in an African community where male circumcision is not a social norm. Because this study is not a randomized controlled trial, it cannot establish cause and effect. Thus, although the observed reduction in HIV prevalence among circumcised men compared to uncircumcised men suggests that circumcision provided protection against HIV acquisition within the study population, the results do not conclusively prove this. The findings of this study nevertheless support the continuation and acceleration of the roll-out of adult VMMC in Africa although further studies are needed to show whether VMMC roll-out is also associated with a reduction in HIV acquisition among women and among uncircumcised men. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001509. Information and resources on male circumcision for HIV prevention are available Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and information on male circumcision for the prevention of HIV transmission Information is available from WHO and UNAIDS on all aspects of HIV/AIDS; the Clearinghouse on Male Circumcision, a resource provided by WHO, UNAIDS and other international bodies, provides information and tools for VMMC policy development and program implementation; a report entitled Progress in scaling up voluntary medical male circumcision for HIV prevention in East and Southern Africa, January-December 2011 is available Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in South Africa, on HIV prevention, and on circumcision and HIV (in English and Spanish) A 2010 PLOS Medicine Research Article by Pascale Lissouba et al. provides more information about the Bophelo Pele project Personal stories about living with HIV/AIDS are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline; a personal story about circumcision in Zimbabwe is available

Despite over two decades of extensive research showing that male circumcision protects against heterosexual acquisition of HIV in men, and that includes findings from large randomized controlled trials leading to acceptance by the WHO/UNAIDS and the Cochrane Committee, opponents of circumcision continue to generate specious arguments to the contrary. In a recent issue of the Journal of Public Health in Africa, Van Howe and Storms claim that male circumcision will increase HIV infections in Africa. Here we review the statements they use in support of their thesis and show that there is no scientific basis to such an assertion. We also evaluate the statistics used and show that when these data are properly analyzed the results lead to a contrary conclusion affirming the major role of male circumcision in protecting against HIV infection in Africa. Researchers, policy makers and the wider community should rely on balanced scholarship when assessing scientific evidence. We trust that our assessment may help refute the claims by Van Howe and Storms, and provide reassurance on the importance of circumcision for HIV prevention.

First, we thank Dr Lacout et al for their interest in and comments concerning our report that described the prevalence, characteristics, and outcomes of patients presenting with cardiogenic unilateral pulmonary edema (UPE).1 As detailed in the Methods section, this was not a study that included all patients with acute respiratory failure referred to our hospital, but a retrospective study that included patients with a final diagnosis of acute cardiogenic pulmonary edema. Thus, patients who presented with pulmonary embolism could not be included in our study. We agree with …

Background Tako-Tsubo cardiomyopathy (TTC) is characterized by transient left ventricular (LV) dysfunction. Incidence of TTC has only been estimated by retrospective studies. In a previous retrospective study, we found that TTC prevalence was 0.7% of ACS. The aim of this study was to prospectively assess TTC incidence. Methods We performed a multicentric prospective study. All consecutive patients referred for coronary angiography were included in three catheterization laboratories. The institutional review board approved the study protocol, and each patient provided written informed consent. Patients were classified as having (or not) coronary artery stenosis defined as a lesion of at least 50% diameter narrowing. In all patients without significant coronary artery stenosis, a right and left anterior oblique left ventricular angiogram was systematically performed. All these left ventricular angiograms were anonymously randomized and were systematically reviewed by three experts. Finally, we used the CARDIO-ARIF (Agence Regionale d’Hospitalisation d’Ile-de-France) registry, for the assessment of TTC incidence in Ile-de-France. Results The study population consisted of 2973 patients (women: 30.6%). Mean age was 63.3 years. An acute coronary syndrome (ACS) was diagnosed in 33.2% of these patients referred for coronary angiography. Twenty TTC were diagnosed (19 women, mean age: 63 years (55–73)). Incidence of TTC was 2% of ACS and 6.6% of ACS in women. Each year, in Ile-de-France, the number of TTC is estimated at 344 cases (95% CI = 216–514) and at 29.7 per 1,000,000 inhabitants (95% CI = 18.7–44.4). Conclusion Our prospective study suggests that incidence of TTC is higher than incidence estimated by retrospective studies. Each year, 29.7 new cases of TTC per 1,000,000 inhabitants occur in Ile-de-France.

International audience; OBJECTIVE: Little is known about the interaction between human papillomavirus (HPV) and HIV. This study aimed to explore the association of oncogenic (high risk) and nononcogenic (low risk) HPV with HIV incidence. METHODS: We used 1683 urethral swabs collected at the last follow-up visit of a male circumcision trial conducted in Orange Farm (South Africa). Swabs analyses and HPV genotyping were performed by polymerase chain reaction. We estimated HIV adjusted incidence rate ratios (aIRRs) and 95% confidence intervals (CIs) using survival analysis. Background characteristics, male circumcision status, sexual behavior, HPV status, and other sexually transmitted infections were used as covariates. RESULTS: The prevalence of HR and LR HPV was 14.0% (95% CI: 12.4 to 15.7) and 17.3% (95% CI: 15.6 to 19.2), respectively. When controlling for HR-HPV status, LR-HPV status was not associated with HIV incidence (aIRR = 1.13, 95% CI: 0.40 to 3.16; P = 0.82). When controlling for all covariates, HIV incidence increased significantly with HR-HPV positivity (aIRR = 3.76, 95% CI: 1.83 to 7.73, P < 0.001) and with the number of HR-HPV genotypes (adjusted-P linear trend = 0.0074). CONCLUSIONS: Several explanations could account for our findings. One is that HR-HPV facilitates HIV acquisition. The association of HPV with HIV acquisition requires further investigations.