Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China

描述（由申请人提供）：治疗的进步已经将HIV疾病转化为美国大多数个体的慢性疾病。慢性HIV疾病最常见的中枢神经系统（CNS）并发症是HIV相关神经认知障碍（HAND）。在美国，HAND患病率估计高达55%的治疗个体。HAND在美国以外的地区也很常见。例如，我们目前在中国的项目发现，在安徽和云南两省近150名接受治疗的艾滋病毒感染者中，超过三分之一的人患有HAND。诸如此类的数据支持抗逆转录病毒疗法（ART）的益处可能是不完整的，许多患者在接受ART治疗时没有恢复正常的神经认知表现，或者更糟的是，出现新的神经认知障碍。对此的一种解释是一些抗逆转录病毒药物对神经系统的渗透有限。最近的报告已经确定，较差的抗逆转录病毒渗透特性与较差的艾滋病毒复制控制和较差的神经认知表现有关。然而，大多数报告都集中在治疗上，而不是预防上。与许多其他疾病一样，预防HAND可能是比治疗已经发生的疾病更具成本效益的公共卫生目标。我们建议在我们之前在中国开展的工作的基础上，对ART的安全性和有效性进行一项随机对照临床试验，该试验在250名神经认知表现正常的未接受ART治疗的个体中进行，其渗透特征不同。主要目的是确定较好的穿透性（BP）抗逆转录病毒治疗（齐多夫定-拉米夫定-奈韦拉平）与较差的穿透性（WP）抗逆转录病毒治疗（替诺福韦-拉米夫定-依非韦伦）在预防HAND方面的效果。我们假设随机接受BP-ART治疗的志愿者在96周的观察中比随机接受WP-ART治疗的志愿者更不容易出现神经认知能力下降。次要目的是评估两种情况对研究结果的影响：持续性免疫激活和病毒性肝炎。在一个探索性的目的，该项目还将评估对研究结果的影响，简明小组的药物处置相关的遗传多态性。证明使用BP-ART可以预防HAND应该会影响美国、中国和其他地方的HIV治疗指南，并最终导致HIV/AIDS患者保持正常的神经认知功能。

DESCRIPTION (provided by applicant): Advances in treatment have transformed HIV disease to a chronic illness in most individuals in the U.S. The most common central nervous system (CNS) complication of chronic HIV disease is HIV-associated neurocognitive disorder (HAND). In the U.S., HAND prevalence estimates range up to 55% of treated individuals. HAND is also common outside the U.S. For example, our current project in China identified that more than a third of nearly 150 treated HIV (+) individuals in Anhui and Yunnan provinces had HAND. Data such as these support that the benefits of antiretroviral therapy (ART) can be incomplete, with many patients not returning to normal neurocognitive performance or, worse, developing new neurocognitive impairment while taking ART. One explanation for this is the limited penetration of some antiretrovirals into the nervous system. Recent reports have identified that worse antiretroviral penetration characteristics are associated with worse control of HIV replication and worse neurocognitive performance. Most reports, however, have focused on treatment - rather than prevention - of HAND. Like many other medical conditions, prevention of HAND may be a more cost-effective public health goal than treating disease that has already occurred. We propose to build on our prior work in China by performing a phase IV, randomized, controlled clinical trial of the safety and effectiveness of ART that differs in its penetration characteristics in 250 ART-naive individuals who have normal neurocognitive performance. The primary objective will be to determine the effects of better penetrating (BP) ART (zidovudine-lamivudine-nevirapine) compared with worse penetrating (WP) ART (tenofovir-lamivudine-efavirenz) on the prevention of HAND. We hypothesize that volunteers who are randomized to BP-ART will be less likely to neurocognitively decline over 96 weeks of observation than those who are randomized to WP-ART. The secondary objective will be to assess the influence on study outcomes of two conditions: persistent immune activation and viral hepatitis. In an exploratory aim, the project will also assess the influence on study outcomes of a concise panel of drug disposition-associated genetic polymorphisms. Demonstrating that HAND can be prevented by using BP-ART should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS. PUBLIC HEALTH RELEVANCE: The project proposes to demonstrate that HAND can be prevented by using better penetrating antiretroviral therapy, which should influence HIV treatment guidelines in the U.S., China, and elsewhere and ultimately lead to preservation of normal neurocognitive functioning in people afflicted with HIV/AIDS.