SOW_HIV_GLP-1.pdf

STATEMENT OF WORK

(SOW)

GENERAL INFORMATION

Title of Project:

Role of Glucagon-like Peptide-1 (GLP-1) receptor agonists versus DPP-4 inhibitors for alcohol and substance use disorders in improving HIV-related outcomes and providing health benefits in people living with HIV

Statement of Need and Purpose:

The goal of this study is to examine Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP- 1RAs) and their potential health benefits for PLWH, in addition to alcohol and substance use disorders outcomes, using extensive pharmacoepidemiologic data. This approach is consistent with the overall goal of our lab, and the NIDA IRP at large, to identifying new pharmacological targets and develop an effective treatment for patients afflicted with drug addiction.

Background Information:

Dr. Leggio's NIDA Clinical Psychoneuroendocrinology (CPN) laboratory, jointly with NIAAA, conducts clinical and translational inpatient and outpatient studies to identify possible novel medications for addiction. His group uses a combination of state-of-the-art, innovative biobehavioral and pharmacological procedures performed under well-controlled human laboratory conditions. Dr. Leggio and his team are particularly interested in the role of neuroendocrine pathways in alcohol- and drug-seeking behaviors and identifying novel effective pharmacotherapies in this regard. Previous literature supports the overall hypothesis that GLP- 1RAs may have beneficial effects on HIV-related outcomes in PLWH and comorbid alcohol and substance use disorders (ASUDs) by decreasing HIV RNA levels, increasing CD4 count, improving retention on antiretroviral therapy (ART), and improving liver function.

GLP-1RAs’ roles extend beyond their potential effects in reducing food-, alcohol-, and drug-seeking and intake; for example, growing research demonstrates significant anti-inflammatory effects of GLP-1RAs both peripherally and centrally. These mechanisms make GLP-1RAs uniquely positioned to be effective and beneficial in PLWH and comorbid ASUDs. If proven effective in improving HIV-related outcomes and providing health benefits in PLWH, these medications could be rapidly implemented in clinical practice. Of special note, liver damage is often present in PLWH and GLP-1RAs are proven to be effective in reducing liver inflammation, further supporting their safety and potential efficacy in PLWH.

The co-primary aims will be whether GLP-1RAs, as compared to untreated matched controls and/or matched controls treated with other GLP-1 therapies (i.e., DPP-4 inhibitors) lead 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 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 assess relevant secondary aims in each study.

Attachment 1

We will conduct high-quality pharmacoepidemiological studies using state-of-the-art methods leveraging 20+ years of high-quality, longitudinal electronic health record data the Veterans Aging Cohort Study (VACS). 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. Of note, our collaborator (Dr. Rentsch) recently published an online textbook that aims to promote careful design and methodological approaches supporting causal inferences on drug safety and effectiveness that guide clinical and regulatory decisions.

Period of Performance:

Base Period: August 7, 2026 through August 6, 2027 Option Period 1: August 7, 2027 through August 6, 2028 Option Period 2: August 7, 2028 through August 6, 2029 Option Period 3: August 7, 2029 through August 6, 2030

SCOPE OF WORK

General Requirements:

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the work below:

Data extraction, management, analysis, and report of a propensity-score matched pharmacoepidemiological study of GLP-1RAs, prescribed for any indication, on HIV- and ASUD-related outcomes in a general patient population and a naturalistic setting.

Specific Requirements:

The objective of the proposed project is to examine GLP-1RAs and their potential health benefits for PLWH, in addition to alcohol and substance use disorders outcomes. Using electronic health record data from the Department of Veterans Affairs (VA), the largest integrated healthcare system in the US, we will investigate the association between GLP-1RAs (prescribed for any indication) and HIV- and ASUD-related outcomes in adults. Individuals exposed to GLP-1RAs will be propensity-score matched to up to five unexposed individuals.

Multivariable linear regression models will estimate changes in HIV- and ASUD-related outcomes before and after exposure.

Pharmacy records will be extracted to identify patients who did and did not receive the medication under investigation dispensed at VA pharmacies. We will identify the first prescription for the medication during the study period and will require a washout period for new episodes of medication exposure. Exposure to the medication is defined as receipt of two or more fills for a minimum number of continuous days (determined as part of the analysis), for any indication, from VA outpatient clinics. For unexposed comparators, we will select patients who attended at least one of the same clinics, but never received the medication, ensuring that unexposed patients came from the same source population, were exposed to an overall similar medical care, and had equal opportunities to receive the same medication. We will create an “index date” (also referred to as “baseline”), defined as the first fill date for exposed patients and a randomly selected outpatient visit date for unexposed patients. We will exclude patients with no outpatient care in the year prior to their index date due to the inability to capture baseline characteristics.

To balance the distribution of all potential confounders across treatment groups, we will perform propensity score approaches (e.g., matching, weighting). This is done by first modelling the probability (i.e., propensity) of receiving the medication as a function of measured covariates associated with the exposure and outcome using a multivariable logistic regression model.

Variables included in the propensity score model will be guided largely by our previous work.

We have >100 variables cleaned and ready for analyses in VACS, including demographics, comorbidities, labs, vital signs, and other health behaviors. Covariates will be summarized using descriptive statistics, stratified by treatment group. To assess balance, we will calculate absolute standardized mean differences (SMD) between AUDIT-C categories and consider 0.1 or less as balanced. For a detailed description of an applied propensity score analysis in VACS data, please see e.g., Farokhnia et al. Molecular Psychiatry 2022 and JCI 2025.

Contract staff will be responsible for pulling, organizing and cleaning the specific datasets. Dr.

Rentsch will lead study data analyses and will also aid in resulting abstract and manuscript development (NIDA IRP will lead the development and preparation of the manuscript). The data are generated via the VA Birth Cohort Study and housed at the VA Connect Medical Center in West Haven, CT. Dr. Rentsch has full access to the data.

The contractor will be completing data management and analysis for this project. Dr. Rentsch is perfectly suited to manage the data and run these analyses, given his profound knowledge and skillset in the field and with this specific dataset. We will regularly meet with the research team to brainstorm about and outline the specifics of the project. Dr. Rentsch will run the analyses and will send us a final report of the methods and results, which will only include aggregate data (no raw data or personally identifiable information).

Level of Effort:

Dr. Rentsch will lead this project and will provide service at 20% effort to carry out the proposed studies. He is an Assistant Professor Adjunct of Medicine at Yale School of Medicine and has been a VA Investigator for the Veterans Aging Cohort Study (VACS) since 2011 resulting in >100 peer-reviewed papers (h-index=33). Dr. Amy Justice (Consortium PI for VACS) will act as Co-I on this project at a service of 5% effort. Dr. Justice will also aid in resulting manuscript development. Ms. Angela Consorte (VACS Program Manager) will serve as the coordinator of the project at a service of 10% effort.

GOVERNMENT RESPONSIBILITIES

There are no specific responsibilities to the government. NIDA IRP will lead the development and preparation of the manuscript after they receive the aggregate data (i.e., a summary of the methods and results).

DELIVERY OR DELIVERABLES

Deliverables include a comprehensive and detailed summary of the method and results. The deliverables will be used by NIDA IRP to develop (in collaboration with the Yale/VA team) conference abstracts and peer-reviewed publications to disseminate the findings to the scientific community.

REPORTING REQUIREMENTS

There are no specific reporting requirements for this project. We will regularly meet and discuss the progress. We will not receive any raw data or personally identifiable information. Only aggregate information will be received.

TRAVEL

N/A

KEY PERSONNEL

Dr. Rentsch is responsible for the data analysis on this project. He will contribute to abstract and manuscript submission as well.

OTHER CONSIDERATIONS

Information System Security Plan:

N/A

Data Rights:

All identifiable data will remain on VA secure servers. The Yale/VA team will abide by outlined standards of only sharing De-identified data if and when necessary. Sharing requires approval of the research proposal. Only aggregate information and data will be shared with the NIDA IRP investigators. No personal identifiable information or raw data will be shared with the NIDA IRP investigators.

Section 508—Electronic and Information Technology Standards:

N/A

Publications and Publicity:

The contractor will produce abstracts and manuscripts as a result of this project. NIDA IRP will lead the development and preparation of the final manuscript for publication.

Confidentiality of Information:

The government will not be providing any confidential information to the contractor. All data and results are confidential until reported to the public in resulting manuscript. Aggregate results will be reported and no person-level data will be identifiable.