# Quantifying Sex-and-Age-Related Differences in Antiretroviral Exposure and Adverse Effects in the MACS/WIHS Combined Cohort Study

> **NIH NIH R56** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $567,218

## Abstract

ABSTRACT
The long-term objective of the proposed work is to provide evidenced-based recommendations for minimizing
metabolic adverse events, particularly weight gain, in a diverse population of people living with HIV (PLWH) by
identifying and quantifying variability in drug exposure that may increase risk in patient subgroups. We will
consider a broad array of modifying factors of drug exposure, including demographic characteristics, prior
laboratory values, body anthropometrics, frailty phenotype, and pharmacogenomics. Our focus is on the
integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG) and bictegravir (BIC), as well as tenofovir
alafenamide (TAF). The MWCCS includes diverse PLWH underrepresented in Phase III clinical trials and thus,
in the sponsor-developed population pharmacokinetic models of the drug. In AIM 1, we will enroll diverse PLWH
from four MWCCS sites to collect pharmacokinetic data and further refine the knowledge of factors that influence
DTG, BIC, and TAF pharmacokinetics. Drug concentrations will be measured in blood plasma and peripheral
blood mononuclear cells (TAF only) in the UNC Center for AIDS Research Clinical Pharmacology and Analytical
Chemistry Laboratory (CFAR CPAC). Nonlinear mixed effects models will be used to develop a comprehensive
PK model for each drug of interest. Using these models, then, in AIM 2, we will retrospectively measure drug
concentrations in repository specimens (using the same methods and laboratory as AIM 1, and predict drug
clearance in men and women from initiation of DTG, BIC, and/or TAF. These drug clearances, predicted for
multiple visits per participant, will then be analyzed as the predictors of body weight gain, increased waist to hip
ratio, and increased insulin resistance (as measured by HOMA-IR) over the course of treatment on the drug of
interest, with multiple measures of drug exposure. The hypothesis is that those PLWH with higher drug exposure
(via slower drug clearance) will be more likely to experience the metabolic adverse events of these drugs. Upon
completion, we expect to have the underpinnings of a model-based risk estimator developed for further
prospective validation.

## Key facts

- **NIH application ID:** 10235106
- **Project number:** 1R56AI153007-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Julie Brumer Dumond
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $567,218
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-04-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235106

## Citation

> US National Institutes of Health, RePORTER application 10235106, Quantifying Sex-and-Age-Related Differences in Antiretroviral Exposure and Adverse Effects in the MACS/WIHS Combined Cohort Study (1R56AI153007-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10235106. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*