Male Circumcision Trial for HIV Prevention, Rakai-Uganda

观察性研究表明，男性包皮环切术可以预防艾滋病毒和性病的感染。在乌干达Rakai，我们观察到包皮环切男性的HIV感染率为0.9/100 Py，未包皮环切男性为1.8/100 Py（校正RR=0.53）。这在生物学上是合理的：包皮内粘膜富含HIV靶细胞，在性交时收缩，使大面积暴露于女性生殖器液体中。包皮也容易受到创伤和溃疡，而潮湿的包皮下空间可能会延长艾滋病毒或性病的生存时间，并延迟性病的愈合。然而，观察到的保护也可能反映出行为上的混淆，因为割礼是出于宗教/文化原因或医学指征进行的。例如，在青春期前做过包皮环切术的穆斯林感染艾滋病毒的风险可能会降低，因为他们有较低的风险行为和文化习俗，如性交后的仪式性生殖器清洗。相反，非穆斯林更有可能因医学适应症而行包皮环切术，这可能是先前与高风险行为相关的性传播疾病的后遗症。观察性数据不足以确定政策，在推广包皮环切项目之前需要进行随机试验。我们建议在乌干达Rakai进行一项两阶段随机对照试验，以评估成年男性包皮环切术对艾滋病毒阴性男性的预防作用。在第一阶段，我们提出了一个试点研究男性包皮环切安全-可及性在艾滋病毒阴性男性。在获得DSMD批准后，我们将进行一项两组随机试验，以验证主要假设：(i)包皮环切术是安全且可接受的，（ii）与未包皮环切术的对照组相比，包皮环切术降低了男性艾滋病毒的发病率。次要终点包括包皮环切术对男性性病和危险行为的影响，以及先前存在的病理对包皮环切术安全性的影响。将招募居住在72个社区的15-49岁艾滋病毒阴性男性，并将其随机分为包皮环切干预组和对照组（每个组2500人）。接受包皮环切术的男性的随机化将避免自我选择偏差。参与者将被随访两年，每年一次。该研究检测出男性艾滋病毒发病率的RR=0.53，调整了交叉。包皮环切术组相对于对照组的HIV发病率将通过使用多变量泊松回归的意向治疗分析进行评估。将提供检测和咨询（VCT）、避孕套、艾滋病毒/性病预防教育、性病治疗和选定的医疗服务。控制组的男性将在4-5年提供包皮环切术，视DSMB的批准而定。

Observational studies suggest that male circumcision is protective against HIV and STD acquisition. In Rakai, Uganda, we observed an HIV incidence of 0.9/100 Py in circumcised and 1.8/100 py in uncircumcised men (adjusted RR=0.53). This is biologically plausible: the inner preputial mucosa is rich in HIV target cells and is retracted during intercourse, exposing a large surface area to female genital fluids. The foreskin is also vulnerable to trauma and ulceration, and the moist subpreputial space may prolong survival of HIV or STDs and delay healing of GUD. However, the observed protection may also reflect behavioral confounding since circumcision is performed for religious/cultural reasons or for medical indications. For example, Muslims who are circumcised before puberty may be at reduced risk of HIV due to lower risk behaviors and cultural practices such as ritual post-coital genital washing. Conversely, non-Muslims are more likely to be circumcised for medical indications which may be sequelae of prior STDs associated with higher risk behaviors. Observational data are inadequate to determine policy and randomized trials are needed before circumcision programs can be promoted. We propose to conduct a two stage randomized controlled trial to evaluate adult male circumcision for HIV prevention among HIV-negative men in Rakai, Uganda. In the first stage, we propose a pilot study of male circumcision safety-accessibility in HIV-neg men. Following DSMD approval, we will conduct a two arm individually randomized trial to test the primary hypothesis that: (i) circumcision is safe and acceptable, and (ii) circumcision reduces male HIV incidence compared to uncircumcised controls. Secondary endpoints include the effects of circumcision on male STDs and risk behaviors, and the effects of pre-existing pathology on circumcision safety. Consenting HIV-negative men aged 15-49, resident in 72 communities, will be enrolled, and individually randomized into a Circumcision Intervention Arm aqnd a Control Arm (n=2,500 per arm). Randomization of men who accept circumcision will avoid self-selection bias. Participants will be followed annually for 2 years. The study is powered to detect a RR=0.53 for male HIV incidence, adjusting for cross-over. HIV incidence in the circumcision arm relative to the control arm will be assessed by an intent-to-treat analysis using multivariate Poisson regression. Testing and counseling (VCT), condoms, HIV/STD prevention education, STD treatment and selected medical care will be provided. Control arm men will be offered circumcision as a service in Years 4-5, contingent on DSMB approval.