Cannabis Effects on Antiretroviral Therapy, Pharmacokinetics, and Neurotoxicity

项目概要/摘要 该项目将确定大麻使用对抗逆转录病毒疗法（ART）药代动力学（PK）的影响 艾滋病毒感染者（PLWH），包括可能影响抗逆转录病毒药物分配到中枢神经系统的机制和 功效和神经毒性，可能对 HIV 相关神经认知障碍产生重大影响 （手）和情绪障碍，例如抑郁症。吸食大麻在艾滋病病毒感染者中很常见，可能会改变抗逆转录病毒疗法 通过改变影响 PK 的多种生物机制来发挥功效。虽然吸食大麻可能会产生不利影响 ART 依从性，它似乎还可以减少炎症并抑制两种常见的 ART 药物代谢 途径（细胞色素 P450、CYP 和尿苷 5'-二磷酸葡萄糖醛酸基转移酶，UGT）。考虑到 HIV 神经行为研究计划 (HNRP) 的重点是中枢神经系统 (CNS) 和我们的研究 凭借脑脊液 (CSF) 药理学方面的专业知识，我们的项目将重点关注血脑屏障 (BBB) 通透性、CSF PK 和 ART 功效以及神经毒性。 HIV 和吸毒都会影响 BBB 通透性 并可能在艾滋病毒和抗逆转录病毒治疗如何影响中枢神经系统方面发挥关键作用。尽管如此，很少有研究考察过 大麻对 PLWH 的 BBB 以及认知和情绪障碍的影响。此外，之前的研究并未 收集有关大麻使用的详细信息，这些信息可能决定其后果，包括给药方式， 使用原因（医疗或娱乐）、含量（Δ9-四氢大麻酚、THC 或大麻二酚、CBD）以及 使用模式（相对于物质使用的 ART 给药时间）。 拟议项目的目标 1 将通过确定大麻使用的影响来解决这些知识差距 代表关键 CYP 和 UGT 途径的 ART 药物在脑脊液和血液中的 PK。参与者将 进行评估： 1) 基线访视，对慢性大麻使用进行量化，抗逆转录病毒治疗药物的剂量将 施用后，将测量 ART 和大麻素的浓度，以及认知和抑郁症 评估（N=120）； 2) 三次急性大麻管理局 (ACA) 就诊，其中安慰剂、高 THC 大麻或高 CBD 大麻将在交叉中向 40 名多替拉韦使用者组成的小组进行管理 随机双盲设计。在 ACA 访问时，探测 CYP（丁螺环酮）和 UGT 的底物 （对乙酰氨基酚）也将被施用。目标 2 将重点关注生物机制并评估其影响 急性大麻给药对 CYP 和 UGT 探针底物药物代谢的影响以及 血脑屏障完整性指标，例如脑脊液/血清白蛋白比率和分子药物转运蛋白的表达 P-糖蛋白。目标 3 将重点关注大麻如何改变 ART PK-药效 (PK-PD) 关系 与艾滋病毒疾病以及认知和抑郁结果有关。 拟议的项目将解决美国国立卫生研究院艾滋病研究办公室的几个优先事项，包括艾滋病毒- 相关的合并症（物质使用和手）和艾滋病毒发病机制（物质之间的相互作用） 使用和ART PK）。

PROJECT SUMMARY/ABSTRACT This project will determine the effects of cannabis use on antiretroviral therapy (ART) pharmacokinetics (PK) in persons living with HIV (PLWH), including mechanisms that may affect ART distribution into the CNS and efficacy and neurotoxicity, which may have a significant impact on HIV-associated neurocognitive disorders (HAND) and mood disorders such as depression. Cannabis use is common among PLWH and may modify ART efficacy by altering several biological mechanisms that influence PK. While cannabis use may adversely affect ART adherence, it also appears to reduce inflammation and inhibit two common ART drug metabolizing pathways (cytochrome P450, CYP and uridine 5'-diphospho-glucuronosyltransferase, UGT). Considering the emphasis of HIV Neurobehavioral Research Program (HNRP) on the central nervous system (CNS) and our expertise in cerebrospinal fluid (CSF) pharmacology, our project will focus on blood-brain barrier (BBB) permeability, CSF PK, and ART efficacy and neurotoxicity. HIV and drug use can each affect BBB permeability and could play a key role in how HIV and ART affect the CNS. Despite this, little research has examined the effects of cannabis on the BBB and cognitive and mood disorders in PLWH. In addition, prior studies have not collected details about cannabis use that may determine its consequences, including mode of administration, reason for use (medicinal or recreational), content (Δ9-tetrahydrocannabinol, THC or cannabidiol, CBD), and pattern of use (timing of ART administration relative to substance use). Aim 1 of the proposed project will address these knowledge gaps by determining the effects of cannabis use on PK in CSF and blood for ART drugs that are representative of key CYP and UGT pathways. Participants will be assessed at: 1) a baseline visit at which chronic cannabis use will be quantified, a dose of ART drugs will be administered, concentrations of ART and cannabinoids will be measured, and cognition and depression assessed (N=120); and 2) three Acute Cannabis Administration (ACA) visits at which either placebo, high THC cannabis, or high CBD cannabis will be administered to a subgroup of 40 dolutegravir users in a crossover randomized double-blind design. At the ACA visits, probe substrates for CYP (buspirone) and UGT (acetaminophen) will also be administered. Aim 2 will focus on biological mechanisms and will assess the impact of acute cannabis administration on metabolism of the CYP and UGT probe substrate drugs as well as on indicators of BBB integrity, such as CSF/serum albumin ratio and expression of the molecular drug transporter P-glycoprotein. Aim 3 will focus on how cannabis modifies ART PK-pharmacodynamic (PK-PD) relationships with HIV disease and cognitive and depression outcomes. The proposed project will address several priorities of the NIH Office of AIDS Research, including HIV- associated comorbidities (substance use and HAND), and HIV pathogenesis (interaction between substance use and ART PK).