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Antimicrobial resistance

How common is isoniazid-resistant TB, and which mutations cause it?

Dean AS, Zignol M, Cabibbe AM, et al. · PLoS medicine · 2020

Open access · cc by · source: Europe PMC

About 7.4% of new TB patients worldwide have TB resistant to isoniazid but not rifampicin, a form that current rifampicin-based rapid tests miss, and most cases are explained by a single katG mutation.

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Study at a glance

Design
Cross-sectional — Pooled aggregated national drug-resistance surveillance and survey data reported to WHO (most recent year, 2002-2018) from 156 countries, weighted by notified cases; plus phenotypic testing and whole-genome or targeted sequencing of isolates from 7 high-burden countries.
N
N=211753 · 211,753 pulmonary TB patients with isoniazid results (aggregated country data); the molecular analysis used 4,559 patients with complete sequencing and phenotypic results, of whom 1,174 were isoniazid resistant.
Population
New and previously treated pulmonary TB patients in national surveillance systems and drug-resistance surveys worldwide.
Outcome
Prevalence of isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), co-resistance to levofloxacin and pyrazinamide, and frequency of isoniazid-resistance mutations.

Structured fields used in claim comparison tables when every cited study has a complete layer.

Key findings

Hr-TB was found in 7.4% of new and 11.4% of previously treated patients, and any isoniazid resistance in 10.7% and 27.2% respectively, with wide variation between countries in the same region. Co-resistance to levofloxacin or pyrazinamide among Hr-TB patients was generally low, except in Pakistan where 12.6% of new Hr-TB patients had resistance to at least one. Among 1,174 isoniazid-resistant isolates, 78.6% carried a katG codon 315 mutation, 6.8% had only the inhA promoter c-15t mutation (the low-level resistance for which higher-dose isoniazid may still work), and 9.3% carried mutations not yet graded as resistance-conferring.

Methodology

Using WHO surveillance and national survey data from 156 countries or territories covering 211,753 pulmonary TB patients, the authors estimated how often TB is resistant to isoniazid but still susceptible to rifampicin (Hr-TB), separately for new and previously treated patients. For 6 countries with detailed surveys they also measured resistance to levofloxacin and pyrazinamide among Hr-TB patients, the two drugs in WHO's recommended Hr-TB regimen. Sequenced isolates from 4,559 patients were examined for known isoniazid-resistance mutations.

Limitations

The prevalence estimates rest mostly on aggregated cross-sectional country data from two sources of differing quality, and countries without data were excluded. The resistance and mutation data were not linked to patients' treatments or outcomes, so the study cannot show how Hr-TB or specific mutations affect cure rates. Laboratory testing quality varied between countries, which could misclassify resistance, and co-resistance estimates in some countries rest on very small numbers (for example 19 new Hr-TB cases in Belarus). HIV status, a likely driver of variation, could not be examined.

How this study connects

Role on claims

Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.

  • SupportsAntimicrobial Resistanceconcept

    Isoniazid resistance is common, comes first, and is invisible to a rifampicin-only test.

    Tuberculosis resistance arises repeatedly and in a consistent order. Genome dating of an extensively drug-resistant clone placed founding katG S315T resistance around 1957, and in that collection multidrug resistance emerged 56 separate times with isoniazid resistance preceding rifampicin resistance 46 times to 2. Global surveillance of 211,753 patients found isoniazid-resistant, rifampicin-susceptible TB in 7.4% of new and 11.4% of previously treated patients, with katG 315 mutations in 78.6% of isoniazid-resistant isolates.

    Evidence for the claim as stated.

History

When this study was placed

Dated entries from the concept change log — when this paper was added or removed as support, challenge, or qualifier on a claim.

  1. 2026-09-24

    Placed as supporting evidence on Antimicrobial Resistance

    Tuberculosis resistance arises repeatedly and in a consistent order. Genome dating of an extensively drug-resistant clone placed founding katG S315T resistance around 1957, and in that collection multidrug resistance emerged 56 separate times with isoniazid resistance preceding rifampicin resistance 46 times to 2. Global surveillance of 211,753 patients found isoniazid-resistant, rifampicin-susceptible TB in 7.4% of new and 11.4% of previously treated patients, with katG 315 mutations in 78.6% of isoniazid-resistant isolates.

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