Neurocognitive Effects of Opiate Agonist Treatment in HIV Infected Drug Users

描述(由申请人提供)：尽管HAART的出现，艾滋病毒相关神经认知(NC)障碍的比率仍然很高。感染HIV的吸毒者比无吸毒史的HIV感染者或未感染的吸毒者表现出更快和更严重的NC功能障碍。由于无论艾滋病毒状态如何，阿片类药物使用者的NC损害风险也会增加，因此艾滋病毒感染的阿片类药物使用者NC损害的风险是相加的。通常用于治疗阿片类药物依赖的药物如何影响NC功能障碍的进展还知之甚少。美沙酮是治疗阿片成瘾最常用的药物，一些研究表明，美沙酮作为一种完整的阿片受体激动剂，可能与NC缺陷有关。然而，这些研究在很大程度上缺乏纵向追踪来评估长期的美沙酮维持是否与NC功能障碍的进展有关。此外，尽管美沙酮有治疗上的好处，但它仍未得到充分利用，2005年只有12%的阿片依赖美国人接受美沙酮治疗。为了纠正这一点，丁丙诺芬于2002年被批准用于阿片成瘾治疗。丁丙诺啡是部分Mu阿片受体激动剂和kappa阿片受体拮抗剂，与美沙酮相比可能具有良好的NC作用。然而，很少有研究考察丁丙诺啡的NC效应，也没有一项研究包括纵向随访或专注于艾滋病毒感染者。为了确保治疗提供者了解丁丙诺啡的全部影响，至关重要的是 目的：评价丁丙诺啡和美沙酮对有无HIV感染的阿片类药物使用者的相对NC效应。在这个修订的应用中，我们建议使用随机临床试验(RCT)设计来检验这样的假设，即与美沙酮相比，丁丙诺啡治疗与有无HIV的阿片依赖药物使用者的NC功能的显著改善有关。我们还将研究HIV感染是否缓和阿片类激动剂治疗对NC功能的影响。我们将招募160名受试者并随机进行1：1至6个月的丁丙诺啡或美沙酮治疗，这两种治疗将由经验丰富的药物滥用治疗医生在同一监督环境中进行。我们将根据HIV血清状态进行随机分组，以确保每组患者中感染HIV的人数相等。在随机化和一周的磨合之后，我们将使用最先进的NC电池来测量NC功能。然后，我们将在阿片类激动剂治疗3个月和6个月后重复NC电池。我们的具体目标是：(1)在随机对照试验中，确定与美沙酮相比，丁丙诺啡是否与NC功能的显著改善有关；(2)评估丁丙诺啡治疗对NC功能随时间的变化的影响；以及(3)评估美沙酮治疗对NC功能随时间的变化的影响。这将是第一个研究美沙酮和丁丙诺啡对神经认知结果影响的随机纵向试验。这项研究的发现有可能影响对患有或不患有艾滋病毒的吸毒者的阿片依赖治疗建议，改善NC结果，并加深我们对脑-药物相互作用的理解。 公共卫生相关性：艾滋病毒仍然是神经认知功能障碍的重要原因，尽管在20世纪90年代中期S引入了HAART。与没有吸毒史的艾滋病毒感染者或未感染的吸毒者相比，大量艾滋病毒感染的吸毒者表现出更快和更严重的神经认知功能障碍。由于无论艾滋病毒状态如何，阿片类药物使用者的NC损害风险也会增加，因此在感染艾滋病毒的阿片类药物使用者中，NC损害的风险是额外的。为了了解包括美沙酮和丁丙诺啡在内的阿片激动剂疗法是否会恶化或改善NC功能和治疗结果，评估它们对感染和不感染HIV的阿片类药物使用者NC功能的相对影响至关重要。

DESCRIPTION (provided by applicant): Rates of HIV-associated neurocognitive (NC) disorders remain high, despite the emergence of HAART. HIV-infected drug users exhibit accelerated and more severe NC dysfunction than either HIV-infected persons without drug use histories, or uninfected drug users. Because the risk of NC impairment is also elevated in opioid users regardless of HIV-status, there is additive risk of NC impairment for HIV-infected opioid users. How medications commonly used to treat opioid dependence affect the progression NC dysfunction is poorly understood. Methadone is the most commonly used medication for opioid addiction treatment, and some studies suggest that methadone, a full mu opioid receptor agonist, may be associated with NC deficits. However, these studies have largely lacked longitudinal follow-up to assess whether long-term methadone maintenance is associated with progression of NC dysfunction. Further, despite its therapeutic benefits, methadone is under- utilized, with only 12% of opioid-dependent Americans receiving methadone in 2005. To remedy this, buprenrophine was approved for opioid addiction treatment in 2002. Buprenorphine, a partial mu opioid receptor agonist and kappa opioid receptor antagonist, may have favorable NC effects compared to methadone. However, few studies have examined buprenorphine's NC effects, and none have included longitudinal follow-up or focused on HIV-infected persons. To ensure that treatment providers understand the full range of buprenorphine's effects, it is crucial to evaluate the relative NC effects of buprenorphine and methadone in opioid users with and without HIV infection. In this revised application, we propose to use a randomized clinical trial (RCT) design to test the hypothesis that treatment with buprenorphine is associated with significant improvement in NC function in opioid-dependent drug users with- and with- out HIV, compared to methadone. We will also examine whether HIV-infection moderates the impact of opioid agonist therapies on NC function. We will enroll and randomize 160 subjects 1:1 to 6 months of buprenorphine or methadone treatment, both of which will be delivered in the same supervised setting by experienced substance abuse treatment physicians. We will stratify randomization by HIV-serostatus, to ensure equal numbers of HIV-infected subjects in each arm. Following randomization and a one week run-in, we will measure NC function with a state-of-the art NC battery. We will then repeat the NC battery after 3 and 6 months of opioid agonist treatment. Our specific aims are: (1) to determine, in an RCT, whether buprenorphine is associated with significant improvement in NC function compared to methadone; (2) to assess the impact of buprenorphine treatment on change in NC function over time; and (3) to assess the impact of methadone treatment on changes in NC function over time. This will be the first randomized longitudinal trial investigating the impact of methadone and buprenorphine on neurocognitive outcomes. Findings from this study have the potential to impact treatment recommendations for opioid dependence for drug users with or without HIV, to improve NC outcomes, and to deepen our understanding of brain-drug interactions. PUBLIC HEALTH RELEVANCE: HIV remains an important cause of neurocognitive (NC) dysfunction, despite the introduction of HAART in the mid-1990's. Significant numbers of HIV infected drug users exhibit accelerated and more severe NC dysfunction compared to either HIV infected persons without a history of drug use, or to uninfected drug users. Because the risk of NC impairment is also elevated in opioid users regardless of HIV status, among HIV- infected opioid users there is an additive risk of NC impairment. To understand whether opiate agonist therapies, including methadone and buprenorphine, worsen or improve NC function and treatment outcomes, it is crucial to evaluate their relative impact on NC function in opioid users with and without HIV infection.