# Sputum Transcriptomic Expression Profiling in Study 31: Express 31

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $887,447

## Abstract

PROJECT SUMMARY/ ABSTRACT
Developing shorter, safer, more effective drug regimens for active tuberculosis (TB) is a critical public health
priority. However, a lack of reliable intermediate clinical trial endpoints constrains accurate regimen selection
for Phase 3 trials. Moreover, current surrogate markers cannot explain the root causes of poor outcomes,
namely the functional adaptations that enable survival of genetically-susceptible, drug-tolerant M. tuberculosis
(Mtb) subpopulations. Our objective is to evaluate sputum Mtb transcriptional profiling as a novel biomarker for
predicting relapse and as a surrogate endpoint for clinical trials. Our central hypothesis is that TB treatment
outcomes are driven by Mtb physiologic changes measurable via pathogen-targeted transcriptional profiling.
Our long-term objective is to develop novel surrogate markers and provide new biologic insights into drug
tolerance through direct, in vivo molecular monitoring of Mtb populations during treatment. Our scientific
approach will be to perform sputum Mtb transcriptional profiling in culture-confirmed, drug-susceptible
pulmonary TB patients co-enrolled in a large, Phase 3, open-label, randomized clinical trial led by the CDC TB
Trials Consortium (TBTC) and the NIAID/DAIDS AIDS Clinical Trials Group (ACTG). Study 31/ACTG 5349 will
compare two 4-month, high-dose rifapentine-based regimens (one including a fluoroquinolone) with standard
6-month TB treatment. At sites in Kenya, Peru, Uganda, and Vietnam, we will collect RNA-preserved sputum at
baseline and throughout treatment from patients at high risk of relapse, including HIV-infected patients, and
HIV-uninfected patients with cavitation on baseline chest radiograph. In Aim 1, we will perform genome-wide
Mtb transcriptional profiling in protocol-correct patients in each treatment arm to provide a comprehensive
roadmap of physiologic and pharmacodynamic effects of TB treatment on the Mtb transcriptome, with
biological interpretations of key drug-tolerance pathways. Specifically, we will test hypotheses that
transcriptional changes specific to drug mechanism of action can serve as pharmacodynamic markers, as well
as distinct hypotheses related to rifamycin and moxifloxacin exposure levels. In Aim 2, we will perform Mtb
transcriptional profiling in all culture-/genotype-confirmed relapses and matched controls with relapse-free
cure. We will build advanced pharmacokinetic models to select Mtb transcripts that can accurately predict
relapse and serve as surrogate endpoints for clinical trials. Aim 2 will also produce an integrative systems
pharmacology model to explain between-patient differences in treatment outcomes. Our research program has
the potential to inaugurate a new era in which drug-development is based not on culture-based surrogates but
on precise, in vivo molecular markers of pathogen physiologic state during TB treatment.

## Key facts

- **NIH application ID:** 10245036
- **Project number:** 5R01AI127300-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John Lucian Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $887,447
- **Award type:** 5
- **Project period:** 2017-08-03 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245036

## Citation

> US National Institutes of Health, RePORTER application 10245036, Sputum Transcriptomic Expression Profiling in Study 31: Express 31 (5R01AI127300-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245036. Licensed CC0.

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