Investigating the effects of novel medications for alcohol and substance use disorders in improving HIV-related outcomes and providing health benefits in people living with HIV.

研究治疗酒精和物质使用障碍的新型药物在改善艾滋病毒相关结果并为艾滋病毒感染者提供健康益处方面的效果。

• 批准号: 10928592
• 负责人: Lorenzo Leggio
• 金额: $ 38.85万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10928592
• 关键词: Address; Aging; Agonist; Albumins; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Aldosterone; Alkaline Phosphatase; Anxiety; Area; Baclofen; Behavioral Sciences; Bilirubin; Biological Markers; Biomedical Research; Blood; CD4 Lymphocyte Count; Cardiovascular system; Chronic Disease; Clinical; Clinical Research; Consensus; Country; Data; Data Science; Decision Making; Diagnosis; Dose; Drug Prescriptions; Drug usage; Early identification; Edema; Electronic Health Record; Environmental Risk Factor; Essential Hypertension; FDA approved; Female; Fentanyl; France; GABA-B Receptor; Goals; HIV; Health Benefit; Heart failure; Hepatitis C co-infection; Hepatology; Hepatotoxicity; Hospitalization; Human; Hypokalemia; Impairment; Individual; Intake; International; Investigation; Literature; Liver Cirrhosis; Liver diseases; Measures; Medical; Mental disorders; Meta-Analysis; Methods; Mineralocorticoid Receptor; Morbidity - disease rate; Motivation; Mus; Neurologic; Opioid; Outcome; Pain; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacotherapy; Physiological; Polypharmacy; Population; Primary Hyperaldosteronism; Prothrombin time assay; Psychiatry; Psychological reinforcement; Public Health; Publishing; RNA; Randomized, Controlled Trials; Rattus; Regulation; Reinforcement Schedule; Research; Research Priority; Risk; Risk Factors; Role; Safety; Self Administration; Series; Severities; Signal Transduction; Social Sciences; Spironolactone; Substance Use Disorder; Symptoms; Testing; Traction; United States National Institutes of Health; Work; Workload; addiction; alcohol comorbidity; alcohol craving; alcohol effect; alcohol seeking behavior; alcohol use disorder; antagonist; antiretroviral therapy; clinical practice; clinically relevant; co-infection; comorbidity; cost; cost effective; experience; experimental study; frailty; health disparity; high risk sexual behavior; improved; indexing; interest; liver function; liver injury; male; mortality; novel; off-label use; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; physical conditioning; preclinical study; prospective; randomized, clinical trials; social factors; substance use; therapy adherence; transmission process; vapor

We will conduct two studies to examine emerging pharmacotherapies (baclofen and spironolactone) and their potential health benefits for people living with HIV (PLWH), in addition to alcohol and other substance use disorder (ASUD) outcomes. For each study, the co-primary aims will be whether the medication under investigation leads to 1) improvements in direct HIV-related biomarkers, i.e. decrease in HIV RNA levels and/or increase in CD4 count, 2) improved retention on antiretroviral therapy (ART), 3) improvement in liver function as measured by clinically relevant biomarkers of liver damage and function (FIB-4, AST, ALT, GGT, bilirubin, alkaline phosphatase, albumin, prothrombin time); 4) improvement in physical health (details below) and physiological frailty (VAC index); and 5) reduction in pain level. We will also examine whether the medication under investigation in each study leads to a reduction in alcohol drinking (as measured by the AUDIT-C) and/or a reduction in SUD-related outcomes (e.g., opioid use, incident OUD diagnoses and all cause hospitalization) We will conduct high-quality pharmacoepidemiologic studies using state-of-the-art methods leveraging high-quality, longitudinal electronic health record data. We will apply approaches consistent with the emerging role of data science in biomedical research and with cutting-edge pharmacoepidemiologic approaches, which have been used in other fields and recently gained traction in the addiction field. Robust pharmacoepidemiology analyses have the potential of expanding our real-world understanding about the relationship between ASUD and HIV-related outcomes and identifying early efficacy signals with medications that can then be tested in prospective randomized controlled trials. This approach is not only cost-effective but also represents a translational bridge that takes advantage of existing detailed real-world data on people who already received the medication under investigation, for any indication, to generate clinically-relevant novel information for outcomes of interest. Our team and collaborators have recently published and developed expertise in pharmacoepidemiology studies, with the objective of identifying early efficacy signals that may guide prospective randomized controlled trials with novel medications for PLWH and comorbid ASUD (for example, see: Farokhnia, Rentsch, Chuong, McGinn et al., Mol Psychiatry 2022). Preclinical and human studies suggest that baclofen, a GABA-B receptor agonist, might be an effective pharmacotherapy for patients with moderate to severe alcohol use disorder (AUD). Although not all randomized controlled trials (RCTs) have been consistent in showing its efficacy, several studies provide compelling evidence that baclofen may be effective in patients with more severe AUD, especially those with comorbid alcohol-associated liver disease (ALD). Indeed, baclofen has been used off-label to treat AUD, especially in hepatology settings, and in 2018, the French drugs regulatory agency approved baclofen use for AUD. However, there is significant variability in baclofen use for clinical research and in medical practice, due to differences in treatment provision for AUD, clinical experience, and country-specific regulations and culture. Furthermore, most meta-analyses and an international consensus statement led by experts in the field concluded that baclofen is a promising pharmacotherapy for AUD, its effect may be dose-dependent, and patients with AUD/ALD may respond best to baclofen. Of note, patients with AUD and HIV are more likely to have liver disease due to the co-presence of at least three risk factors, i.e., alcohol, HCV co-infection, and ART-related liver toxicity. Accordingly, PLWH will likely benefit from baclofen. Furthermore, PLWH with AUD are also more likely to misuse opioids, and previous work shows that baclofen may be beneficial in reducing opioid withdrawal and other symptoms related to opioid use disorder (OUD). Similar to baclofen, there is strong rationale for studying spironolactone in PLWH. Spironolactone is an FDA-approved nonselective mineralocorticoid receptor (MR) antagonist medication used to treat essential hypertension, heart failure, edema due to liver cirrhosis, primary hyperaldosteronism, and hypokalemia. As such, spironolactone has been extensively used in patients with significant chronic diseases, including advanced liver damage. Recent translational work by our team supports a beneficial role of spironolactone for AUD. Preliminary clinical and preclinical studies suggest that aldosterone and the MR play a role in alcohol seeking and consumption. Blood aldosterone concentrations are significantly decreased in individuals with AUD who consume alcohol and correlate with self-reported alcohol craving and anxiety. In a study led by our team, spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice and reduced operant alcohol self-administration in dependent and nondependent male and female rats. In two pharmacoepidemiologic studies, we provided independent and convergent evidence supporting the role of spironolactone in AUD in human populations. Both pharmacoepidemiologic studies showed that the effects of spironolactone on alcohol outcomes were dose-dependent and stronger in those people with higher severity of AUD. Unpublished data from our team further extend the potential role of spironolactone to OUD. Specifically, in a series of mice experiments, we employed a fixed-ratio 1 schedule of reinforcement (low workload to obtain fentanyl) and showed that spironolactone decreased fentanyl vapor self-administration in mice tested under 1-h short-access (ShA; nondependent) conditions, but not in mice tested under 6-h long-access (LgA; dependent) conditions. Using a progressive ratio schedule of reinforcement (high workload to obtain fentanyl), spironolactone also decreased the motivation for fentanyl in mice tested under both ShA and LgA conditions. These results support a potential functional involvement of MRs in opioid reinforcement, motivation for opioids and pain Taken together, the previous literature supports the overall hypothesis that both baclofen and spironolactone may have beneficial effects on HIV-related outcomes in PLWH and comorbid ASUD by decreasing HIV RNA levels, increasing CD4 count, improving retention on ART, and improving liver function. We further hypothesize that baclofen and spironolactone may improve physical health, physiological frailty, and pain in PLWH.

除酒精和其他药物使用障碍（ASUD）外，我们还将进行两项研究，以检查新兴药物疗法（巴氯芬和螺内酯）及其对HIV（PLWH）患者的潜在健康益处。 For each study, the co-primary aims will be whether the medication under investigation leads to 1) improvements in direct HIV-related biomarkers, i.e. decrease in HIV RNA levels and/or increase in CD4 count, 2) improved retention on antiretroviral therapy (ART), 3) improvement in liver function as measured by clinically relevant biomarkers of liver damage and function (FIB-4, AST, ALT, GGT，胆红素，碱性磷酸酶，白蛋白，凝血酶原时间）； 4）改善身体健康（下面的详细信息）和生理脆弱（VAC指数）； 5）疼痛水平降低。我们还将检查每项研究中正在调查的药物是否导致饮酒降低（通过审计-C衡量）和/或与SUD相关的结果降低（例如，阿片类药物使用，发生OUD诊断和所有导致住院） 我们将使用利用高质量，纵向电子健康记录数据的最先进方法进行高质量的药物ePidemiologic研究。我们将采用与数据科学在生物医学研究中的新兴作用以及最先进的药物ePidemiologic方法一致的方法，这些方法已在其他领域使用，最近在成瘾领域中获得了吸引力。强大的药物ePidemiology分析具有扩展我们对ASUD和HIV相关结果之间关系的现实了解，并使用药物识别早期疗效信号，然后在前瞻性随机对照试验中进行测试。这种方法不仅具有成本效益，而且代表了一座转化桥，它利用现有的详细现实世界数据，这些数据已经接受了已经接受的药物（以表明任何迹象），以生成临床上与临床相关的新颖信息以获得感兴趣的结果。我们的团队和合作者最近发表并开发了药物ePidemiology研究的专业知识，目的是确定早期功效信号，可以指导前瞻性随机对照试验，并使用新颖的PLWH和Comorbid ASUD进行新颖的药物（例如，请参见：Farokhnia，Farokhn，Rentsch，Rentsch，Chuong，McGinn，McGinn，Molcinn等，Mol Psychiatry 20222222222.）。 临床前和人类研究表明，Baclofen是一种GABA-B受体激动剂，可能是中度至重度饮酒障碍（AUD）患者的有效药物疗法。尽管并非所有随机对照试验（RCT）在显示出疗效方面一直保持一致，但一些研究提供了令人信服的证据，表明巴氯芬可能对更严重的AUD患者有效，尤其是与酒精相关的肝病（ALD）有效。的确，巴氯芬已被使用非标签来治疗AUD，尤其是在肝病学环境中，2018年，法国药物监管机构批准了Baclofen用于AUD的使用。但是，由于aud，临床经验以及特定国家特定的法规和文化的治疗方案差异，巴氯芬用于临床研究和医学实践的使用差异很大。此外，大多数荟萃分析和该领域专家领导的国际共识声明得出结论认为，巴氯芬是一种有前途的AUD药物治疗，其作用可能是剂量依赖性的，并且AUD/ALD的患者可能对Baclofen反应最佳。值得注意的是，由于至少三个危险因素（即酒精，HCV共同感染和与ART相关的肝毒性）的共同存在，AUD和HIV患者更可能患有肝病。因此，PLWH可能会受益于巴氯芬。此外，带有AUD的PLWH也更有可能滥用阿片类药物，并且先前的工作表明，巴氯芬可能有益于减少阿片类药物的戒断和其他与阿片类药物使用障碍（OUD）有关的症状。 与Baclofen相似，在PLWH中研究螺内酯有很强的理由。螺内酯是一种由FDA批准的非选择性矿物皮质激素受体（MR）拮抗剂药物，用于治疗基本高血压，心力衰竭，肝硬化引起的水肿，原发性高醛酸和低血压。因此，螺内酯已广泛用于严重慢性疾病的患者，包括晚期肝损伤。我们的团队的最新翻译工作支持螺内酯在AUD中的有益作用。初步的临床和临床前研究表明，醛固酮和MR在寻求和消费中发挥了作用。 AUD患者的血液醛固酮浓度显着降低，他们食用酒精并与自我报告的酒精渴望和焦虑相关。在我们的团队领导的一项研究中，螺内酯剂量依赖性地降低了雄性和雌性小鼠中甜或未加糖的酒精溶液的摄入，并减少了依赖和非依赖性男性和女性大鼠的手术饮酒自我给药。在两项药物ePIDEMIologic研究中，我们提供了独立和收敛的证据，这些证据支持螺内酯在人群中AUD中的作用。两项药物ePIDEMIologic研究都表明，螺内酯对酒精结果的影响在较高严重程度的人中是剂量依赖性和更强的。我们团队未发表的数据进一步扩展了螺内酮的潜在作用。具体而言，在一系列小鼠实验中，我们采用了固定比例1的加固时间表（减少工作量以获得芬太尼），并表明在1-H短路下测试的小鼠中，螺内酯降低了芬太尼蒸气自加入（sha; nong; nong; nong; nong; nong; nong; nonge），但在小鼠中未经过6-Hongeccess（lonevent）（longe）（longe）（longe）（lone）6-Hongeccess（l）。使用渐进式增强比例时间表（高工作负荷以获得芬太尼），螺内酯也降低了在SHA和LGA条件下测试的小鼠中芬太尼的动机。这些结果支持MRS在阿片类药物增强中的潜在功能参与，阿片类药物的动机和疼痛的动机 综上所述，先前的文献支持了总体假设，即巴氯芬和螺内乳酸酮均通过降低HIV RNA水平，提高CD4计数，改善对ART的保留率并改善肝功能，对PLWH和合并症的与HIV相关的结果都有有益的影响。我们进一步假设巴氯芬和螺内乳酮可以改善PLWH的身体健康，生理脆弱和疼痛。