# Pharmacogenomics and Systems Pharmacology Approaches to Toxicity, Tolerability, and Comorbidities Associated with Modern Antiretroviral Therapies

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $824,847

## Abstract

ABSTRACT
Antiretroviral therapy (ART) has resulted in people living with HIV (PLWH) now aging with prolonged survival,
yet high rates of complications and comorbid conditions. This is due to a complex interplay between HIV
infection, host genetics, and traditional risk factors leading to comorbidities. Understanding the role of genetic
modification of drug responses to specific ART combinations through pharmacogenetic (PGx) evaluation could
improve drug efficacy, mitigate ART-related side effects and reduce comorbidities. Discovering informative
ART-PGx variants could not only help identify PLWH at risk for ART-associated adverse events and
comorbidities, but also anticipate side effects of nascent ART combinations. However, despite lifelong need for
ART, no comprehensive analysis of the role of genetic variation among PLWH in clinical care on combination
ART regimens have been conducted to better understand the wide variety of adverse clinical outcomes they
experience. We will use CNICS (Centers for AIDS Research Network of Integrated Clinical Systems), a large
well-characterized prospective cohort of PLWH in care in the U.S with in-depth longitudinal clinical data
including medications, health behaviors, laboratory test results, and validated and adjudicated diagnoses. In
this largest genetic study in PLWH to date, we will characterize the genetic landscape of a variety of adverse
side effects associated with ART regimens using existing genome-wide array data and newly generated next
generation sequencing data from ethnically/racially diverse phenotypic extremes. We will also use the systems
pharmacology approach to identify specific ART-induced pathways that are involved in the pathogenesis of
adverse events using relevant cell model systems. We will test the hypothesis that the increased risk of
adverse effects and comorbidities associated with ART can be explained, at least in part, by a burden of
common and/or low frequency genetic variants that exacerbate ART effects. Aim 1: Conduct a genome-wide
screening of variants that modify ART efficacy, including change in CD4 and viral load; ART tolerability,
including renal and hepatic toxicity, and ART-associated adjudicated comorbidities in ~14,000 PLWH from the
CNICS cohort. The significant findings will be validated in independent cohorts; Aim 2: Identify biological
pathways and related key driver genes through which various ART regimens promote adverse events using a
systems pharmacology approach and validate the findings in clinical cohorts, and Aim 3: Using novel
technologies, determine individual PGx gene profiles associated with ART-induced diverse adverse clinical
phenotypes by sequencing PLWH with the most severe toxicities, poor efficacy and tolerability, and adverse
effects or comorbidities. The proposed studies promise to enhance our understanding of the biological
mechanisms of ART response, helping reduce HIV-related complications. Identification of genetic modifiers of
combination...

## Key facts

- **NIH application ID:** 10015325
- **Project number:** 5R01HG010649-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Heidi M. Crane
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $824,847
- **Award type:** 5
- **Project period:** 2019-09-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015325

## Citation

> US National Institutes of Health, RePORTER application 10015325, Pharmacogenomics and Systems Pharmacology Approaches to Toxicity, Tolerability, and Comorbidities Associated with Modern Antiretroviral Therapies (5R01HG010649-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10015325. Licensed CC0.

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