Neurocognitive Effects of Opiate Agonist Treatment in HIV Infected Drug Users

描述（由申请人提供）：尽管出现了HAART，但HIV相关神经认知（NC）障碍的发生率仍然很高。HIV感染的吸毒者表现出加速和更严重的NC功能障碍比任何HIV感染者没有吸毒史，或未感染的吸毒者。由于无论HIV状态如何，阿片类药物使用者的NC损伤风险也会升高，因此HIV感染的阿片类药物使用者存在NC损伤的附加风险。通常用于治疗阿片类药物依赖的药物如何影响NC功能障碍的进展尚不清楚。 美沙酮是阿片类药物成瘾治疗最常用的药物，一些研究表明，美沙酮，一个完整的μ阿片受体激动剂，可能与NC缺陷。然而，这些研究在很大程度上缺乏纵向随访，以评估长期美沙酮维持是否与NC功能障碍的进展相关。此外，尽管美沙酮具有治疗益处，但美沙酮的利用率不足，2005年仅有12%的阿片类药物依赖的美国人接受美沙酮。为了解决这个问题，丁丙诺啡在2002年被批准用于阿片类药物成瘾治疗。丁丙诺啡是一种部分μ阿片受体激动剂和κ阿片受体拮抗剂，与美沙酮相比可能具有有利的NC效应。然而，很少有研究检查丁丙诺啡的NC效果，没有一项研究包括纵向随访或关注HIV感染者。为了确保治疗提供者了解丁丙诺啡的全部效果， 评价丁丙诺啡和美沙酮在有和无HIV感染的阿片类药物使用者中的相对NC效应。 在这份修订后的申请中，我们建议使用随机临床试验（RCT）设计来检验以下假设：与美沙酮相比，丁丙诺啡治疗与阿片类药物依赖性吸毒者（有和无HIV）的NC功能显著改善相关。我们还将研究艾滋病毒感染是否缓和阿片类激动剂治疗对NC功能的影响。我们将入组并随机分配160例受试者，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相同的监督环境中提供。我们将根据HIV血清状态对随机分组进行分层，以确保每组中HIV感染受试者的数量相等。在随机分组和一周的导入期后，我们将使用最先进的NC组合测量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组合。我们的具体目标是：（1）在RCT中确定与美沙酮相比，丁丙诺啡是否与NC功能的显著改善相关;（2）评估丁丙诺啡治疗对NC功能随时间变化的影响;（3）评估美沙酮治疗对NC功能随时间变化的影响。 这将是第一个调查美沙酮和丁丙诺啡对神经认知结果影响的随机纵向试验。这项研究的结果有可能影响对有或没有艾滋病毒的吸毒者阿片类药物依赖的治疗建议，改善NC结果，并加深我们对脑-药物相互作用的理解。

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.