# Defining the impact of injection drug use on antiretroviral therapy and HIV treatment outcomes: an (epi)genomic approach

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $517,732

## Abstract

Although uptake of combination antiretroviral therapy (cART) in people who inject drugs (PWID) infected with
HIV has increased dramatically in the past decade, poor health outcomes including non-AIDS-related
comorbidity and mortality in HIV-infected PWID on cART remains a significant public health problem. A crucial
knowledge gap is a lack of the understanding about how injection drug use (IDU) impacts the course of HIV
disease. Differences in gene regulation affected by IDU and non-adherence to cART are likely to affect the
pharmacokinetics and pharmacodynamics of these treatments that may result in poor outcomes. Thus, there is
an urgent need to identify genomic signatures for PWID and to link PWID-associated genomic signals to HIV
outcomes in the context of cART exposure (i.e., levels in plasma). Our overall hypothesis is that PWID
accrue DNA methylation (DNAm) and transcriptome variations that impact on health outcomes, and which may
be explained in part by variability in cART exposure. This hypothesis is built on our previous findings showing
that IDU significantly altered the blood DNA methylome in HIV-infected individuals. Furthermore, DNAm
signatures associated with IDU differentiated less and greater HIV disease frailty. To test this hypothesis, our
approach will first perform epigenome-wide DNAm association analysis and transcriptome-wide association
analysis in HIV-infected PWID as compared to HIV-infected non-PWID who are treated with cART in two
independent cohorts. Second, we will test the relationship between PWID-associated differentially methylated
positions (DMP) or regions (DMR) and differential gene expression (DGE) on cART variability in plasma and
also their relationships with HIV frailty and mortality. Last, we propose to integrate genetic variation (single
nucleotide polymorphism [SNP]), DNAm, and gene expression that differs by HIV-infected PWID/non-PWID
status. Our goal is to identify DMP or DMR and DGE between HIV-infected PWID and non-PWID in the
context of cART and to apply epigenetic and transcriptomic signatures as biomarkers to predict HIV frailty and
mortality.
The application proposes the first integrative pharmacogenomic approach of genetic variants, epigenomic and
transcriptomic associations for HIV-infected PWID in the context of cART. We expect to identify PWID-
associated genes that can predict HIV cART treatment outcomes. The predictive model resulting from this
project can inform biomarker identification for HIV outcomes. The proposal is the first step towards the
understanding of pharmacogenomics and pharamcoepigenomics in PWID with HIV infection. The results will fill
the knowledge gap of the biological basis of IDU effects on HIV outcomes and provide evidence to prioritize
genes for future research of their functions in HIV progression.

## Key facts

- **NIH application ID:** 9976483
- **Project number:** 5R01DA047063-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Bradley E Aouizerat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,732
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976483

## Citation

> US National Institutes of Health, RePORTER application 9976483, Defining the impact of injection drug use on antiretroviral therapy and HIV treatment outcomes: an (epi)genomic approach (5R01DA047063-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976483. Licensed CC0.

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