# Mind the gaps: Pharmacokinetic research to advance pediatric HIV/TB cotreatment and TB prevention

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $322,814

## Abstract

PROJECT SUMMARY
Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available
on the pharmacokinetics (PK) of newer HIV/TB cotreatment and TB prevention strategies in children. Global
expansion of dolutegravir use for young children has the potential to significantly improve HIV treatment
outcomes, but there are no PK data to inform use of double-dose dolutegravir during rifampicin-containing
HIV/TB cotreatment for children under 6 years of age. Further, multiple studies have shown that current
WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose
rifampicin may improve outcomes and shorten treatment duration in adults and children. Yet the impact of
high-dose rifampicin on dolutegravir exposures has not been examined. Finally, it is well-established that
treatment of latent TB infection (LTBI) significantly reduces incident TB among HIV-infected persons, yet
this strategy is vastly underused in endemic settings. Short-course LTBI treatment regimens increase
completion rates, but have not been studied among HIV-infected children receiving dolutegravir. To address
these gaps in knowledge and provide needed PK and safety data to extend use of these promising
strategies from adults to children, we will carry out two prospective PK studies to examine: (1) twice daily
dolutegravir during both standard- and high-dose rifampicin, and (2) PK of dolutegravir during weekly
rifapentine/isoniazid for TB prevention/LTBI treatment.
To advance our understanding of underlying mechanisms of drug action we will also examine the impact of
standard- and high-dose daily rifampicin and weekly rifapentine on the 4β-hydroxy-cholesterol to cholesterol
ratio, an endogenous biomarker of CYP3A4 activity. This will provide critical pharmacodynamic (PD) data
for use in population PK/PD models to quantify variability and inform optimal drug dosing in this vulnerable
population of children.
Nigeria is home to more children living with HIV than any other country in the world, and also bears one of
the greatest burdens of incident TB. Since 2004, APIN Public Health Initiatives has provided HIV care and
treatment to over 20,000 children in Nigeria and thus is uniquely positioned to support this vital PK research.
This combination of studies addresses critical gaps in knowledge regarding PK and safety of newer drug
combinations for HIV/TB cotreatment and TB prevention, findings that may inform WHO guidance on use in
children, toward the goal of curbing TB’s devastating toll in this vulnerable population.

## Key facts

- **NIH application ID:** 10390005
- **Project number:** 1R01HD107726-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Holly Elizabeth Rawizza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $322,814
- **Award type:** 1
- **Project period:** 2022-04-07 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390005

## Citation

> US National Institutes of Health, RePORTER application 10390005, Mind the gaps: Pharmacokinetic research to advance pediatric HIV/TB cotreatment and TB prevention (1R01HD107726-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10390005. Licensed CC0.

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