Chemoprophylaxis for HIV Prevention in Men

描述(由申请者提供)：联合国艾滋病规划署估计，全世界每天有14,000人新感染艾滋病毒，其中一半人年龄在15岁至24岁之间。尽管人们普遍认识到艾滋病毒-1的传播方式以及使用避孕套提供的保护，但仍出现了新的感染病例。迫切需要预防艾滋病毒-1病毒的新概念。我们建议在秘鲁有极高感染艾滋病毒风险的男性中进行一项随机、盲法试验，每天口服替诺福韦300毫克与安慰剂，以评估预防艾滋病毒的化学预防的安全性和有效性。选择每天口服替诺福韦300毫克进行评估，因为它是FDA许可的人类使用，允许每天一次给药，耐受性良好，对许多抗药性HIV-1病毒株有效，并被证明在非人类灵长类动物模型中预防有效。我们建议招募2100名男性，他们将以1：1的随机比例每天服用替诺福韦300毫克与安慰剂，并对HIV-1血清转换(目标1)、不良事件(目标2)、血清转换后的病毒载量、耐药性和CD4T细胞计数(目标3)进行13个月的跟踪观察。之所以在秘鲁选择研究地点，是因为那里有完善的预防研究基础设施，而且有能力招募艾滋病毒感染的高风险男子，而且留校率很高。招募将来自秘鲁的3个城市，这些城市在最近的两次调查中艾滋病毒-1感染率最高，拥有支持密切监测的临床试验所需的基础设施，并具有巨大的遗传和地球物理多样性。样本量足以检测艾滋病毒-1预防的成本效益水平。该试验还旨在评估该制剂在未感染艾滋病毒的人群中的安全性，包括轻度肾功能不全和肝脏炎症的发生率。化学预防也可能带来持久的好处或风险，可能会由于早期抑制病毒复制或耐药性而导致感染病程缩短。这项拟议的研究直接解决了重要的知识空白，包括直肠暴露后暴露于艾滋病毒的男性每天口服替诺福韦化学预防的安全性和有效性。这一独特和重要的信息直接与美洲的艾滋病毒预防有关，在美国、亚洲和非洲计划的其他研究完成后将无法获得。由于生殖生物学、通常暴露于艾滋病毒的粘膜表面、行为差异和药代动力学的不同，化学预防的安全性和有效性在男性和女性中可能有所不同。这项研究最终旨在通过保护有艾滋病毒风险的男性来打破艾滋病毒-1的流行循环，并可能放过他们的性伴侣和他们未来的孩子。

DESCRIPTION (provided by applicant): UNAIDS estimates that 14,000 persons are newly infected with HIV every day throughout the world, of which one half are between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV-1 transmission, and the protection afforded by condom use. Novel concepts for HIV-1 prevention are urgently needed. We propose to evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in a randomized and blinded trial of daily oral tenofovir 300 mg versus placebo among men in Peru, who have extremely high risk of acquiring HIV infection. Daily oral tenofovir 300 mg is selected for evaluation because it is FDA-licensed for human use, allows once a-day dosing, is well-tolerated, is active against many drug resistant HIV-1 strains, and was demonstrated to be effective for prevention in non-human primate models. We propose to enroll 2100 men who will be randomized 1:1 to receive daily oral tenofovir 300 mg versus placebo and followed for 13 months for HIV-1 seroconversion (aim 1), adverse events (aim 2), and viral load, drug resistance and CD4 T cell count after seroconversion (aim 3). Study sites are selected in Peru because of their well-developed prevention research infrastructure and their demonstrated ability to recruit men at high risk for HIV infection with outstanding rates of retention. Recruitment will be derived from 3 cities in Peru that had the highest incidence of HIV-1 infection in two recent surveys, have the required infrastructure to support a closely monitored clinical trial, and represent enormous genetic and geophysical diversity. The sample size is sufficient to detect cost-effective levels of HIV-1 prevention. The trial also aims to evaluate the safety of this agent in HIV uninfected persons, including the incidence of mild renal insufficiency and liver inflammation. Chemoprophylaxis may involve durable benefits or risks as well, possibly leading to an attenuated course of infection due to early inhibition of viral replication or drug resistance. The proposed research addresses important gaps of knowledge directly, including the safety and efficacy of daily oral tenofovir chemoprophylaxis among men exposed to HIV after rectal exposure. This unique and essential information bears directly on HIV prevention in the Americas and will not be available after the completion of other studies planned for the United States, Asia and Africa. The safety and efficacy of chemoprophylaxis may differ in men and women due to differences in reproductive biology, the mucosal surfaces that are typically exposed to HIV, behavioral differences, and pharmacokinetics. This research ultimately aims to break the epidemic cycle of HIV-1 by protecting men at risk for HIV, and may spare their sexual partners and their future children.