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

描述(由申请人提供)：三项随机试验，其中一项是这项建议的基础，许多观察性研究表明，男性包皮环切术减少了男性艾滋病毒的感染。我们在乌干达的拉凯农村进行了一项由美国国立卫生研究院资助的男性包皮环切术预防艾滋病毒的试验。5000名年龄在15-49岁的HIV阴性男性VCT接受者被随机分为立即包皮环切术(干预组)和延期包皮环切术(对照组)。该试验于2006年12月12日被dsmb终止，当时一项中期分析显示，在接受包皮环切术的男性中，HIV感染减少(IRR=0.52Cl0.31-0.86p=0.012)，GUD减少(RR=0.44Cl0.33-0.58p&lt；0.001)。由于GUD是HIV的一个危险因素，减少导致GUD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6个月、12个月和24个月的随访时收集血清和阴茎拭子，但试验资金不包括STI分析。这项建议的具体目标是：1)对试验中储存的样本进行STI检测，以确定包皮环切术在预防选定的STI方面的效果。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HIV保护。此外，包皮环切术还将减少阴茎HPV携带者；2)通过对参加NIH试验的男性额外进行5年的年度跟踪，评估包皮环切术预防艾滋病毒/性传播感染的长期有效性，以及对于性危险行为的影响。我们假设，无论是随着时间的推移，还是与未割包皮的男性相比，割包皮的男性艾滋病毒/性传播感染发病率将持续下降，性危险行为不会增加。试验后随访中的未割包皮男性将包括在试验结束时拒绝割礼的干预性交叉手臂和对照手臂参与者(N~380)，以及来自Rakai社区队列研究(RCCS)的约1,600名未割包皮男性，RCCS是在招募割礼试验参与者的村庄中进行的一项正在进行的艾滋病毒/性传播感染监测研究。由于我们由NIH资助的试验和拟议的试验后跟进是与RCC并行进行的，Rakai设置提供了独特的机会--其他两个割礼试验中没有的--来比较割礼试验参与者和未割包皮男性的危险行为。评估包皮环切术在一般人群中的可接受性及其对艾滋病毒发病率的影响，并估计包皮环切术的数量和避免的每一次艾滋病毒感染的成本。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向进行调整。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。在这项提案中，我们要求为NIH试验参与者的后续行动提供资金。农村信用社的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.