# Novel next-generation sequencing assay for monitoring multidrug resistant tuberculosis treatment in the setting of HIV infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $736,217

## Abstract

PROJECT SUMMARY / ABSTRACT
Novel next-generation sequencing assay for monitoring multidrug resistant tuberculosis treatment in
the setting of HIV infection
Multidrug resistant tuberculosis (MDR-TB) is a worsening global public health crisis and critical barrier to
achieving TB elimination during our lifetimes. Current treatment of MDR-TB requires long treatment courses of
decades-old, toxic, and poorly efficacious second-line drugs. In the setting of HIV co-infection, in particular,
treatment of MDR-TB is complicated by extraordinary pill burden, overlapping drug toxicities, poor drug
absorption, and often results in high early mortality. The extent of second-line anti-TB drug resistance during
treatment is a strong predictor of poor outcome, but such resistance is only detected by existing molecular tests
when it is already well-established. Evidence from our preliminary studies and others’ suggest that small resistant
M. tuberculosis (M.tb) subpopulations may be common precursors to clinical resistance. Detection and
monitoring of micro-heteroresistance (<5% of total M.tb population, beneath the threshold for commonly used
TB molecular tests) could transform clinical management through individualized treatment regimens and prompt
reassessment of ineffective treatments (i.e., sub-therapeutic drug levels or inadequate regimens). Tremendous
financial and scientific resources are directed toward investigation of new drugs for MDR-TB, but efforts to
optimize and shorten treatment are hindered significantly by a poor understanding of exposure-response
relationships for each drug within multi-drug regimens and how to best identify those patients who will respond
inadequately to treatment. Our goal in proposing this work is to comprehensively characterize the pharmacologic
correlates of M.tb micro-heteroresistance, and to determine the extent to which detection of micro-
heteroresistance improves clinicians’ ability to predict those MDR-TB patients, with and without HIV co-infection,
who are at especially high likelihood for poor outcome. In order to achieve our Aims, we will leverage the
infrastructure established through two major MDR-TB clinical trials, an existing NIH/NIAID R01 award, and the
coordinated efforts of a large international non-profit organization whose mission is to enable development and
delivery of diagnostic tests for poverty-related diseases.

## Key facts

- **NIH application ID:** 10320408
- **Project number:** 5R01AI131939-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David M Engelthaler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $736,217
- **Award type:** 5
- **Project period:** 2018-01-19 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320408

## Citation

> US National Institutes of Health, RePORTER application 10320408, Novel next-generation sequencing assay for monitoring multidrug resistant tuberculosis treatment in the setting of HIV infection (5R01AI131939-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320408. Licensed CC0.

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