How common is isoniazid-resistant TB, and which mutations cause it?
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.
Source
Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data
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.
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What they did
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.
What they found
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.
The limits
What it doesn't show
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.
Key terms
- Hr-TB
- Tuberculosis resistant to isoniazid but susceptible to rifampicin; it is missed by tests that only check rifampicin resistance.
- MDR-TB
- Multidrug-resistant TB, resistant to both rifampicin and isoniazid, the two key first-line drugs.
- katG codon 315 mutation
- A change in the catalase-peroxidase gene that prevents activation of isoniazid and gives moderate to high-level resistance.
- inhA promoter mutation
- A mutation that increases production of isoniazid's target enzyme, typically giving low-level resistance that higher isoniazid doses may overcome.
- Whole-genome sequencing
- Reading the complete DNA of a bacterial isolate to detect resistance-associated mutations.
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Quiz yourself
What does Hr-TB refer to?
Common questions
Why are Hr-TB patients often missed?
Many countries screen with GeneXpert, which detects TB and rifampicin resistance only, so a patient with isoniazid resistance but rifampicin susceptibility looks like ordinary drug-susceptible TB and receives the standard regimen.
Why does the specific mutation matter for treatment?
Isolates with only an inhA promoter mutation usually have low-level resistance, so a higher isoniazid dose may still be effective, whereas katG 315 mutations give higher-level resistance where raising the dose is unlikely to help.
Why check levofloxacin and pyrazinamide resistance?
WHO's recommended Hr-TB regimen relies on these drugs with rifampicin and ethambutol, so low co-resistance supports using that regimen widely.
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