# Quantifying genomic and pharmacometabolomic differences in antiretroviral exposure in MACS/WIHS Combined Cohort Study

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $258,310

## Abstract

PROJECT SUMMARY/ABSTRACT
A key challenge in medicine is identifying individuals who will benefit the most from treatment. Despite the
effectiveness of combination antiretroviral therapy (cART), patients experience side effects that challenge
future treatment strategies. Since most drugs' therapeutic and toxic effects are directly related to drug
exposure, identifying predictors of exposure can help better predict variability in response to medication. For
the proposed project, we are leveraging the unprecedented time-series plasma samples collected during
ongoing (AI153007) intensive pharmacokinetic (iPK) studies of dolutegravir (DTG) and tenofovir alafenamide
fumarate (TAF), a prodrug of tenofovir (TFV), in representative and understudied HIV+ men and women in the
multi-ethnic cohort MACS/WIHS Combined Cohort Study (MWCCS). Given the recent development in the field
of pharmacometabolomic, where endogenous metabolite concentrations in plasma are shown to predict
response to sertraline, escitalopram, and aspirin, we plan to determine the plasma metabolome profile of
MWCSS participants treated with DTG and TAF. Our immediate objective is to identify, through correlations of
plasma drug concentrations with endogenous metabolite plasma levels. These genes control metabolic
pathways affecting DTG, TFV plasma, and tenofovir-diphosphate (TFV-dp) intracellular concentrations and
their associated metabolic adverse effects (i.e., weight gain and insulin resistance). To achieve our immediate
objective, we have three specific aims. In aim 1, we plan to identify endogenous metabolites associated with
concentrations of DTG (n=60), TFV, and TFV-dp (n~42) at nine different time points in virally suppressed HIV+
men and women under actual use conditions. Using these correlated metabolites as biomarkers of medication
concentration, in aim 2, we will identify, through genome-wide association analyses, novel genetic variants
impacting metabolite concentrations in 16,322 individuals from two independent population-based cohorts from
the United Kingdom (UK): The UK National Institute of Health Research and Twins UK. The extensive UK
sample size provides ample power to identify gene-metabolite associations reliably, offering a higher-resolution
picture of metabolism and elimination for DTG and TAF. In aim 3, the effect of identified novel genes on DTG,
TFV, and TFV-dp concentrations and their associated metabolic adverse effects (i.e., weight gain, insulin
resistance) will be further validated in 1157 MWCSS women and men treated with these medications. This
novel approach will help identify new genes impacting DTG and TFV plasma exposure and clinically significant
adverse effects. The deliverables from this study will positively impact future studies in the field of PGx of anti-
HIV medication and beyond in two ways: First, we will characterize for the first time and with much higher
resolution the primary and secondary metabolic and elimination pathways relevant to DT...

## Key facts

- **NIH application ID:** 11013709
- **Project number:** 1R21AI177219-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Pirro G Hysi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $258,310
- **Award type:** 1
- **Project period:** 2024-07-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11013709

## Citation

> US National Institutes of Health, RePORTER application 11013709, Quantifying genomic and pharmacometabolomic differences in antiretroviral exposure in MACS/WIHS Combined Cohort Study (1R21AI177219-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11013709. Licensed CC0.

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