Male Circumcision Trial for HIV Prevention, Rakai-Uganda

观察研究表明，男性包皮环切术可以预防艾滋病毒和性传播疾病的感染。在乌干达的拉凯，我们观察到割包皮的男性HIV发病率为0.9/100Py，未割包皮的男性为1.8/100Py(调整后RR=0.53)。这在生物学上是可行的：包皮内侧粘膜含有丰富的HIV靶细胞，在性交过程中会收缩，使女性生殖器分泌物暴露在很大的表面积上。包皮也容易受到创伤和溃疡的影响，潮湿的包皮下间隙可能会延长HIV或STD的存活期，推迟GUD的愈合。然而，观察到的保护也可能反映出行为混乱，因为包皮环切术是出于宗教/文化原因或医学适应症进行的。例如，在青春期前接受割礼的穆斯林感染艾滋病毒的风险可能会降低，这是因为风险较低的行为和文化习俗，如性交后的生殖器清洗仪式。相反，非穆斯林更有可能因医学指征而接受割礼，这可能是与更高风险行为相关的既往性传播疾病的后遗症。观察数据不足以决定政策，在推广包皮环切术计划之前，需要进行随机试验。我们建议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在乌干达拉凯艾滋病毒阴性男性中预防艾滋病毒的作用。在第一阶段，我们建议对HIV阴性男性进行男性包皮环切术安全可及性的初步研究。在DSMD批准后，我们将进行一项两组单独随机试验，以检验主要假设：(I)包皮环切术是安全和可接受的，(Ii)与未包皮环切术对照相比，包皮环切术降低男性艾滋病毒发病率。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。来自72个社区的15-49岁自愿HIV阴性男性将被登记，并被单独随机分成包皮环切术干预组和对照组(n=2,500)。对接受割礼的男性进行随机化将避免自我选择的偏见。参与者将进行为期两年的年度跟踪。这项研究的能力是检测男性艾滋病毒发病率的RR=0.53，并对交叉进行了调整。包皮环切组相对于对照组的HIV发病率将通过使用多变量泊松回归的意向治疗分析来评估。将提供检测和咨询(VCT)、避孕套、艾滋病毒/STD预防教育、STD治疗和选定的医疗服务。控制臂男子将在4-5年内作为一项服务提供包皮环切术，这取决于DSMB的批准。

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.