Circumcision: HIV/STIs and behaviors in a RCT and post-RCT surveillance; Rakai

描述（由申请人提供）：三个随机试验，其中一个是本提案的基础，以及许多观察性研究表明，男性包皮环切术可以减少男性艾滋病毒感染。我们在乌干达Rakai农村开展了一项由美国国立卫生研究院资助的男性包皮环切预防艾滋病毒的试验，5000名年龄在15-49岁的HIV阴性男性VCT受体随机分为立即包皮环切（干预）和延迟包皮环切（对照）两组。该试验于2006年12月12日被DSMB终止，当时一项中期分析表明，包皮环切术降低了HIV感染（IRR= 0.52, Cl 0.31-0.86, p = 0.012），降低了GUD （RR=0.44, Cl 0.33-0.58, p<0.001）。由于艾滋病是艾滋病毒的一个危险因素，因此减少导致艾滋病的性传播感染可能有助于包皮环切术对艾滋病毒的保护作用。在基线和随访6、12和24个月时收集血清和阴茎拭子，但试验资金不包括性传播感染分析。本提案的具体目的是：1)对试验中储存的样本进行性传播感染检测，以确定包皮环切术在预防选定性传播感染方面的功效。我们假设梅毒和HSV-2风险的降低将解释对GUD的保护，这将有助于艾滋病毒的保护。包皮环切术也会减少阴茎携带HPV病毒；2)通过对参加NIH试验的男性进行额外5年的年度随访，评估包皮环切术预防HIV/STI的长期有效性，以及对性风险行为的影响。我们假设，与未割包皮的男性相比，割包皮的男性HIV/STI发病率将持续下降，并且性风险行为不会增加。试验后随访的未行包皮环切术的男性将包括干预组交叉组和在试验结束时拒绝行包皮环切术的对照组参与者（N~380），以及在单独资助下，来自Rakai社区队列研究（RCCS）的约1600名未行包皮环切术的男性，RCCS是一项正在进行的艾滋病毒/性传播感染监测研究，从包皮环切术试验参与者中招募。由于我们的nih资助的试验和拟议的试验后随访与RCCS同时进行，Rakai的设置提供了独特的机会——在其他两个包皮环切试验中没有——来比较包皮环切试验参与者与未包皮环切男性的危险行为。评估包皮环切术的可接受性及其对一般人群中艾滋病毒发病率的影响，并估计包皮环切术的数量和避免每例艾滋病毒感染的费用。关于nih试验和RCCS参与者的详细流行病学/行为数据有助于对可能的选择偏差进行调整。还将进行定性研究，以加强对调查结果的解释。因此，我们建议评估包皮环切术对个人和社区的长期影响。在本提案中，我们请求资助NIH试验参与者的随访。RCCS参与者将得到其他资金的支持。

DESCRIPTION (provided by applicant): Three randomized trials, including one which is the basis for this proposal, and numerous observational studies demonstrate that male circumcision reduces male HIV acquisition. We conducted an NIH-funded trial of male circumcision for HIV prevention in rural Rakai, Uganda. 5000 HIV-negative male VCT acceptors aged 15-49 were randomized to either immediate circumcision (intervention) or delayed circumcision (controls). The trial was stopped by the DSMB on Dec 12, 2006, when an interim analysis demonstrated reduced HIV acquisition (IRR= 0.52, Cl 0.31-0.86, p = 0.012) and reduced GUD (RR=0.44, Cl 0.33-0.58, p<0.001) in circumcised men. Since GUD is a risk factor for HIV, it is possible that a reduction in STIs which cause GUD contributes to the HIV protective effect of circumcision. Serum and penile swabs were collected at baseline and at 6, 12 and 24 months of follow up, but trial funding did not cover STI assays. The specific aims of this proposal are: 1) To conduct STI assays on stored samples from the trial to determine the efficacy of circumcision in preventing selected STIs. We hypothesize that reduced risks of syphilis and HSV-2 will account for the protection against GUD, and this will contribute to HIV protection. Also circumcision will reduce penile HPV carriage; 2) To assess the long-term effectiveness of circumcision for HIV/STI prevention, and effects on sexual risk behaviors, by conducting an additional 5 years of annual follow up among men who had enrolled in the NIH trial. We hypothesize that circumcised men will have sustained reductions in HIV/STI incidence, and no increase in sexual risk behaviors, both over time and compared to uncircumcised men. Uncircumcised men in the post-trial follow up will include intervention arm crossovers and control arm participants who decline circumcision at the end of the trial (N~380) and, with separate funding, ~1,600 uncircumcised men from the Rakai Community Cohort Study (RCCS), an ongoing HIV/STI surveillance study conducted in villages from which circumcision trial participants were recruited. Because our NIH-funded trial and the proposed post-trial follow up are conducted in parallel to the RCCS, the Rakai setting provides unique opportunities- not available in the other two circumcision trials - to compare risk behaviors in circumcised trial participants with that of uncircumcised men. Assess circumcision acceptability and its effects on HIV incidence in the general population, and to estimate the number of circumcisions and the cost per HIV infection averted. Detailed epidemiological/ behavioral data available on NIH-trial and RCCS participants facilitate adjustment for possible selection bias. Qualitative research will also be conducted to enhance interpretation of findings. We thus propose to assess the long term individual and community effects of circumcision. In this proposal, we request funds for follow-up of NIH trial participants. RCCS participants will be supported by other funding.