Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China

描述（由申请人提供）：在美国，治疗的进展已经将HIV疾病转变为大多数人的慢性疾病。慢性HIV疾病最常见的中枢神经系统（CNS）并发症是HIV相关的神经认知障碍（HAND）。在美国，HAND患病率估计范围高达55%的治疗个体。HAND在美国以外也很常见。例如，我们目前在中国的项目发现，在安徽和云南省接受治疗的近150名HIV（+）患者中，有三分之一以上患有HAND。这些数据支持抗逆转录病毒治疗（ART）的好处可能是不完整的，许多患者没有恢复正常的神经认知功能，或者更糟的是，在服用ART时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HIV复制控制和较差的神经认知表现相关。然而，大多数报告都集中在治疗-而不是预防-手。与许多其他医疗条件一样，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的工作的基础上，进行一项关于ART安全性和有效性的IV期、随机、对照临床试验，该试验在250名神经认知功能正常的ART初治个体中进行，其渗透特征不同。主要目的是确定较好的穿透性（BP）ART（齐多夫定-拉米夫定-奈韦拉平）与较差的穿透性（WP）ART（替诺福韦-拉米夫定-依法韦仑）对预防HAND的效果。我们假设随机接受BP-ART的志愿者在96周的观察期内，神经认知功能下降的可能性低于随机接受WP-ART的志愿者。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。在一个探索性的目标，该项目还将评估一个简洁的小组的药物处置相关的遗传多态性的研究结果的影响。证明HAND可以通过使用BP-ART来预防应该会影响美国的HIV治疗指南，中国和其他地方，并最终导致受艾滋病毒/艾滋病折磨的人的正常神经认知功能的保留。

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.