# Poor Treatment Response and Outcomes in Bedaquiline-Based Treatment Regimens for Drug-Resistant Tuberculosis in South Africa

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $627,360

## Abstract

Project Summary
Resistance to anti-tuberculosis drugs complicates the care and worsens the outcomes of individuals with
tuberculosis, the leading infectious cause of death worldwide. South Africa is using the new anti-tuberculosis
drug bedaquiline as part of both shorter and longer all-oral treatment regimens for patients with rifampicin-
resistant tuberculosis (RR-TB). While clinical trials and observational studies demonstrate improved treatment
outcomes with bedaquiline-based treatment, the predictors of poor treatment response (defined as positive
cultures two, four, or six months after diagnosis) and poor treatment outcomes are not well-characterized in
programmatic settings. Alarmingly, resistance to bedaquiline has been detected in clinical Mycobacterium
tuberculosis isolates. The background resistance to both new and old drugs that compose treatment regimens,
combined with observed variation in pretreatment phenotypic susceptibility to bedaquiline, raise concerns that
the risks of poor treatment response and outcomes may be higher than anticipated. To address these
concerns, we will use the robust infrastructure of the South African National Health Laboratory system and the
electronic drug-resistant tuberculosis register to assess programmatic poor treatment response among patients
with RR-TB in South Africa. We will perform minimum inhibitory concentration testing of bedaquiline and
companion drugs on routinely collected specimens in the Gauteng Province of South Africa to determine
whether elevated minimum inhibitory concentrations of bedaquiline in phenotypically bedaquiline-susceptible
pretreatment isolates are associated with poor treatment response or outcomes. Whole genome sequencing
on routinely collected specimens will allow simultaneous characterization of the underlying molecular
epidemiology of RR-TB. We will also use a novel approach of using the concentration of drugs with different
half-lives determined programmatically and pharmacokinetic modeling to evaluate association with time to
culture positivity and treatment outcomes. We will combine mycobacteriologic factors, drug concentration data,
and clinical data to develop a prediction model for poor treatment response and outcomes. Our findings will
guide targeted intervention strategies for individuals at high risk for poor treatment response, inform rapid drug
susceptibility tests that incorporate genotypic data for bedaquiline and companion drugs in new treatment
regimens of RR-TB, and explore the potential importance of measuring drug concentrations early in the course
of RR-TB treatment. The insights gained about genotypic and phenotypic variation in relation to treatment
outcomes of RR-TB will be highly valuable not only for South African tuberculosis programs, but also for high-
burden and under-resourced settings worldwide. Our study team includes globally recognized content experts
from South Africa and the US and will allow critical progress in drug-resistant TB r...

## Key facts

- **NIH application ID:** 10871677
- **Project number:** 5R01AI158605-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Yuri F. van der Heijden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,360
- **Award type:** 5
- **Project period:** 2021-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871677

## Citation

> US National Institutes of Health, RePORTER application 10871677, Poor Treatment Response and Outcomes in Bedaquiline-Based Treatment Regimens for Drug-Resistant Tuberculosis in South Africa (5R01AI158605-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871677. Licensed CC0.

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