Undetected isoniazid resistance leads to rifampicin-resistant tuberculosis: a prospective observational study and transmission modelling analysis
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Background
Isoniazid resistance is the most common form of drug-resistant tuberculosis (TB) globally. However, WHO-recommended molecular tests available to most TB patients worldwide detect rifampicin resistance only, risking under-treatment of isoniazid-resistant, rifampicin-susceptible TB (HR-TB) and the subsequent emergence of rifampicin resistance.
Methods
This prospective study, conducted between March 2020 and July 20204, aimed to collect and archive sputum specimens from all adults diagnosed with rifampicin-susceptible pulmonary TB in Ho Chi Minh City, Vietnam. Cases were participants who developed rifampicin-resistant recurrence; controls had rifampicin-susceptible recurrence or no recurrence. Whole-genome sequencing of paired isolates distinguished acquired rifampicin resistance from reinfection. The effect of pre-existing isoniazid resistance on rifampicin resistance acquisition was estimated using inverse probability of treatment weighting, and the projected epidemiological impact of routine HR-TB testing on the incidence of rifampicin-resistant TB (RR-TB) was modelled.
Findings
42,843 people were diagnosed with TB during the study period, from whom we archived 33,843 sputum samples. We enrolled 1,241 participants, 873 (70·4%) of whom had analysable data. 51/873 (5·8%) acquired rifampicin resistance, of whom 49/51 (96·1%) had isoniazid resistance at their index TB episode that was not detected by routine diagnostics. The weighted risk of acquired rifampicin resistance was 2·98% (95% CI 2·08-4·50) in participants with programmatically undetected isoniazid resistance, versus 0·03% (0·00-0·08) in participants with isoniazid-susceptible TB (risk ratio 105·42 (33·43-309·69)). Modelling projected that universal HR-TB diagnosis and treatment would reduce RR-TB incidence by 46% (35-61) over 10 years in Vietnam, with reductions of 26% (12-43) projected even where HR-TB prevalence was as low as 5%.
Interpretation
Undetected, under-treated HR-TB confers a 100 fold increased risk of acquiring rifampicin resistance. Routine isoniazid susceptibility testing combined with effective HR-TB treatment could substantially reduce the burden of RR-TB.
Funding
Wellcome
