Phase 1/2 trial of Pharmacological HIV-1 Prevention

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-1，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，并通过使用避孕套提供保护，但仍有新的传播发生。年轻妇女特别容易受到影响，因为她们协商性活动情况的能力有限，包括性伴侣的数量、性伴侣的类型以及是否使用避孕套。例如，我们发现，柬埔寨年轻女性性工作者在初次性行为后仅2至3年，HIV-1感染率就达到26%。迫切需要新的HIV-1预防概念。我们建议在一项双盲I/II期安慰剂对照随机试验中评估HIV-1化学预防药物在HIV-1未感染的高危妇女中的可接受性和安全性。卖啤酒的柬埔寨妇女或“啤酒女孩”是这项研究的目标，因为她们在公共场所很容易被认出，她们有稳定的工作，可以留在研究中，而且她们感染艾滋病毒-1的风险很高。由于最近HIV-1的爆炸性传播，柬埔寨目前是进行这项研究的理想地点。所选择的抗逆转录病毒药物已被FDA批准用于人类，允许每天一次的剂量，具有良好的耐受性数年，并且对大多数耐药HIV-1菌株有效。该研究还将获得有关HIV-1发病率和药物功效的初步信息，这些信息是规划第三期试验所需的。我们估计，200名妇女接受长达24个月的治疗足以评估安全性和可接受性，如果药物的预防作用和对照组HIV-1发病率证明与非人灵长类动物研究和柬埔寨血清监测的估计相当，则可能证明有效性。这种分阶段进行预防研究的方法经过优化，可以在建立长期队列之前，通过在HIV-1爆炸性传播的群体中使用试点随机研究，在短时间内获得疗效信息。证实高发病率和可接受的干预措施的试点研究将扩大为密切监测的疗效试验。这些研究的最终目的是通过保护年轻妇女来打破艾滋病毒-1的流行循环，这也可能使她们未来的孩子和性伴侣免受伤害。

DESCRIPTION (provided by applicant): UNAIDS estimates that 14,000 persons are newly infected with HIV-1 every day throughout the world, of which one half are between the ages of 15 and 24. New transmission occurs despite widespread awareness of the modes of HIV-1 transmission, and the protection afforded by condom use. Young women are especially susceptible, due to limited capacity to negotiate the circumstances of sexual activity, including the numbers of sexual partners, the types of sexual partners, and whether condoms are used. For example, we have found that HIV-1 infection in young Cambodian female sex workers reaches a prevalence of 26% only 2 to 3 years after sexual debut. Novel concepts for HIV-1 prevention are urgently needed. We propose to evaluate the acceptability and safety of HIV-1 chemoprophylaxis in a double blind phase I/II placebo controlled randomized trial of an antiretroviral drug among HIV-1 uninfected women at risk. Cambodian women who sell beer, or "beer girls," are targeted for this study because they are readily identified in public places, they have stable employment allowing retention in the study, and they are at high risk for HIV-1 infection. Cambodia is ideal for this study at this time because of the recent explosive spread of HIV-1. The selected antiretroviral agent is FDA approved for human use, allows once-a-day dosing, is well tolerated for several years, and is active against most drug resistant HIV-1 strains. The study will also obtain preliminary information regarding HIV-1 incidence and drug efficacy that are required for planning a phase III trial. We estimate that 200 women treated for up to 24 months are sufficient to evaluate safety and acceptability, and may demonstrate efficacy if the prophylactic effect of the drug and the control group HIV-1 incidence prove to be comparable to estimates from non-human primate studies and Cambodian serosurveillance. This staged approach to prevention research is optimized to generate efficacy information in short time frames through use of pilot randomized studies in groups who suffer explosive HIV-1 spread before long term cohorts can be established. Pilot studies that confirm high incidence and acceptable interventions will be expanded into closely monitored efficacy trials. These studies ultimately aim to break the epidemic cycle of HIV-1 by protecting young women, which may also spare their future children and sexual partners.