Chemoprophylaxis for HIV Prevention in Men

说明（由申请人提供）：艾滋病规划署估计，全世界每天有14 000人新感染艾滋病毒，其中一半年龄在15至24岁之间。尽管人们普遍认识到艾滋病毒-1的传播方式，并使用避孕套提供保护，但仍有新的感染发生。迫切需要新的HIV-1预防概念。我们建议在秘鲁的HIV感染风险极高的男性中，通过每日口服替诺福韦300mg与安慰剂的随机盲法试验来评估化学预防预防HIV的安全性和有效性。选择每日口服替诺福韦300毫克进行评估，因为它已获得fda批准用于人类使用，允许每天一次给药，耐受性良好，对许多耐药HIV-1毒株有活性，并且在非人类灵长类动物模型中被证明对预防有效。我们建议招募2100名男性，他们将以1:1的比例随机分配，每天口服替诺福韦300 mg与安慰剂，并随访13个月，观察HIV-1血清转化（目标1）、不良事件（目标2）、血清转化后的病毒载量、耐药性和CD4 T细胞计数（目标3）。研究地点选择在秘鲁，是因为秘鲁有发达的预防研究基础设施，而且有能力招募艾滋病毒感染高风险的男性，保留率很高。招募人员将来自秘鲁的三个城市，这些城市在最近的两次调查中艾滋病毒-1感染发生率最高，具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。样本量足以发现具有成本效益的HIV-1预防水平。该试验还旨在评估该药物在未感染HIV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。化学预防也可能涉及持久的益处或风险，由于早期抑制病毒复制或耐药性，可能导致感染过程的减弱。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日口服替诺福韦化学预防的安全性和有效性。这一独特而重要的信息直接关系到美洲的艾滋病毒预防工作，在为美国、亚洲和非洲计划进行的其他研究完成后将无法提供。化学预防的安全性和有效性在男性和女性中可能存在差异，这是由于生殖生物学、通常暴露于HIV的粘膜表面、行为差异和药代动力学的差异。这项研究的最终目的是通过保护有感染艾滋病毒风险的男性来打破艾滋病毒-1的流行循环，并可能使他们的性伴侣和未来的孩子免受伤害。

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.