Within-host pathogen population diversity predicts treatment response in Tuberculosis.

Area of Science:

• Microbiology
• Genetics
• Infectious Diseases

Background:

• Tuberculosis (TB) treatment outcomes are often suboptimal.
• Standard diagnostics struggle to predict treatment failure or relapse.
• The clinical significance of within-host Mycobacterium tuberculosis genetic diversity is unknown.

Purpose of the Study:

• To investigate the prognostic value of baseline within-host Mycobacterium tuberculosis genetic diversity.
• To determine if pathogen genetic diversity predicts unfavorable TB treatment outcomes.

Main Methods:

• Prospective cohort study of 364 patients with newly diagnosed pulmonary TB in South Africa.
• Sequencing of Mycobacterium tuberculosis using matched short-read and long-read assemblies to detect low-frequency variants.
• Multivariable Cox proportional-hazards models to assess the association between genetic diversity and clinical outcomes.

Main Results:

• Unfixed genetic variants were enriched in genes related to pathogen adaptation and drug tolerance.
• Within-host bacterial genetic diversity was a strong, independent predictor of unfavorable TB treatment outcomes.
• Increased genetic diversity was associated with a significantly higher risk of treatment failure, death, or relapse.

Conclusions:

• Baseline within-host pathogen genetic diversity independently predicts unfavorable TB treatment outcomes.
• Quantifying unfixed variants offers an accessible method for risk-stratifying TB patients.
• This approach may guide individualized TB treatment regimens.