# Rifabutin pharmacokinetics and safety among HIV/TB coinfected infants receiving lopinavir

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $152,745

## Abstract

PROJECT SUMMARY
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Tuberculosis is the leading cause of death among children with HIV, yet optimal cotreatment regimens are
lacking, particularly for the youngest and most vulnerable children. As a result, the World Health
Organization (WHO) has designated evaluation of newer treatment options for HIV/TB coinfected children a
research priority. To address this issue, we will carry out a prospective pharmacokinetic (PK) and safety
study to evaluate a novel pediatric cotreatment strategy. For children <3 years of age, lopinavir/ritonavir
(LPV/r)-based antiretroviral therapy (ART) is the current WHO-preferred first-line regimen to treat HIV
infection. However, potent drug interactions prohibit use of LPV/r along with standard TB treatment in
coinfected children, as rifampin lowers LPV concentrations by over 75%. For adults who require protease
inhibitors such as LPV/r, the WHO recommends substituting rifabutin, which has minimal effect on LPV
concentrations. This strategy has not been adequately studied in children, and so is generally unavailable
as a pediatric treatment regimen.
The Harvard/APIN pediatric ART program has supported rifabutin access for adults and children in Nigeria
since 2008. Our group previously reported favorable programmatic experience with rifabutin in children, and
are currently studying rifabutin PK and safety in older pediatric cohorts requiring LPV/r-based ART. At
interim analysis, we found that most patients achieved rifabutin concentrations well above the target value,
and severe neutropenia, the most concerning potential serious adverse event, was uncommon (5%).
However, because the liver enzymes that metabolize rifabutin do not reach adult activity until at least 12
months of age, it is expected that higher rifabutin mg/kg dosing is necessary in infants. Thus, we will
evaluate rifabutin concentrations among HIV/TB coinfected infants 2 weeks to <12 months of age. We
hypothesize that rifabutin dosed 5 mg/kg daily in this cohort will achieve adequate rifabutin concentrations,
equivalent to that observed with 2.5 mg/kg daily in the older cohort. Further, since variability in drug
concentrations among children remains a barrier to achieving safe and effective dosing recommendations,
we will utilize population PK modeling to quantify variability, evaluating patient factors such as malnutrition
and advanced immunocompromise to predict optimal rifabutin dosing by weight. Finally, given the challenge
of TB diagnosis among the youngest children, we will also evaluate newer urine-based TB diagnostics in
this cohort. The goal of this study is to influence WHO treatment guidelines by providing essential
knowledge of the efficacy and safety of this treatment strategy so that we may curb TB’s devastating toll
among this highly vulnerable population.

## Key facts

- **NIH application ID:** 10124281
- **Project number:** 5R21AI150347-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Holly Elizabeth Rawizza
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $152,745
- **Award type:** 5
- **Project period:** 2020-03-09 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124281

## Citation

> US National Institutes of Health, RePORTER application 10124281, Rifabutin pharmacokinetics and safety among HIV/TB coinfected infants receiving lopinavir (5R21AI150347-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10124281. Licensed CC0.

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