Undetected isoniazid resistance leads to rifampin-resistant tuberculosis

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 rifampin resistance only, risking under-treatment of isoniazid-resistant, rifampin-susceptible TB (HR-TB) and subsequent emergence of rifampin resistance. Methods: This prospective study (2020-2024) aimed to collect and archive sputum specimens from all adults diagnosed with rifampin-susceptible pulmonary TB in Ho Chi Minh City, Vietnam. Cases were participants who developed rifampin-resistant recurrence; controls had rifampin-susceptible recurrence or no recurrence. Whole-genome sequencing of paired isolates distinguished acquired rifampin resistance from reinfection. The effect of pre-existing isoniazid resistance on rifampin resistance acquisition was estimated using inverse probability of treatment weighting, and the projected epidemiological impact of routine HR-TB testing was modelled. Results: 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 rifampin resistance, of whom 49/51 (96.1%) had undetected isoniazid resistance. The weighted risk of acquired rifampin resistance was 2.98% (95% CI 2.08-4.50) with undetected isoniazid resistance, versus 0.03% (0.00-0.08) without (risk ratio105.42 (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%. Conclusions: Undetected, under-treated HR-TB confers a 100 fold increased risk of acquiring rifampin resistance. Routine isoniazid susceptibility testing combined with effective HR-TB treatment could substantially reduce the burden of RR-TB.