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.

我们将进行两项研究，以检查新兴药物疗法（巴氯芬和螺内酯）及其对艾滋病毒感染者（PLWH）的潜在健康益处，以及酒精和其他物质使用障碍（ASUD）的结果。对于每一项研究，共同的主要目标将是所研究的药物是否会导致1)直接与HIV相关的生物标志物的改善，即HIV RNA水平的降低和/或CD4计数的增加，2)改善抗逆转录病毒治疗（ART）的保留，3)通过肝损伤和功能的临床相关生物标志物（FIB-4、AST、ALT、GGT、胆红素、碱性磷酸酶、白蛋白、凝血酶原时间）来测量肝功能的改善；4)改善身体健康（详见下文）和生理虚弱（VAC指数）；5)减轻疼痛程度。我们还将检查每项研究中调查的药物是否导致饮酒减少（由AUDIT-C测量）和/或减少与sud相关的结果（例如，阿片类药物使用、事件OUD诊断和全因住院）。