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.

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

We are conducting two cohort 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 are whether the drug 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 Alcohol Use Disorders Identification Test - Consumption (AUDIT-C)) and/or a reduction in substance use disorder (SUD)-related outcomes (e.g., opioid use, incident opioid use disorder (OUD) diagnoses, and all cause hospitalization). We have started to conduct high-quality pharmacoepidemiological studies using state-of-the-art methods leveraging high-quality, longitudinal electronic health record data. We are applying approaches consistent with the emerging role of data science in biomedical research and with cutting-edge pharmacoepidemiological 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 drug under investigation, for any indication, to generate clinically-relevant novel information for outcomes of interest. Our team and collaborators have published and developed expertise in pharmacoepidemiology studies, with the objective of identifying early efficacy signals that may guide prospective randomized controlled trials with novel treatments for PLWH and comorbid ASUDs (for example, see: Farokhnia, Rentsch, Chuong, McGinn, et. al., Mol Psychiatry 2022; Farokhnia et. al., JCI 2025). 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 OUD. Similar to baclofen, there is strong rationale for studying spironolactone in PLWH. Spironolactone is an FDA-approved non-selective 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. In a third unpublished pharmacoepidemiological study using data from the TriNetX platform, we took a target trial emulation approach and found that spironolactone prescription was associated with higher rates of AUD remission and lower rates of alcohol intoxication compared with other classes of antihypertensive drugs such as angiotensin-converting-enzyme inhibitors, calcium channel blockers, and beta blockers. 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 ASUDs 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. The cohorts for these studies have been identified, data has been cleaned, and propensity-score matching is in progress.