The Hidden Epidemic of Isoniazid-Resistant Tuberculosis in South Africa.

Rationale: Isoniazid-resistant tuberculosis (Hr-TB) is often overlooked in diagnostic algorithms because of reliance on first-line molecular assays testing only for rifampicin resistance. Objectives: To determine the prevalence, outcomes, and molecular mechanisms associated with rifampin-susceptible, isoniazid-resistant TB (Hr-TB) in the Eastern Cape, South Africa. Methods: Between April 2016 and October 2017, sputum samples were collected from patients with rifampin-susceptible TB at baseline and at Weeks 7 and 23 of drug-susceptible TB treatment. We performed isoniazid phenotypic and genotypic drug susceptibility testing, including FluoroTypeMTBDR, Sanger sequencing, targeted next-generation sequencing, and whole-genome sequencing. Results: We analyzed baseline isolates from 766 patients with rifampin-susceptible TB. Of 89 patients (11.7%) who were found to have Hr-TB, 39 (44%) had canonical katG or inhA promoter mutations; 35 (39%) had noncanonical katG mutations (including 5 with underlying large deletions); 4 (5%) had mutations in other candidate genes associated with isoniazid resistance. For 11 (12.4%), no cause of resistance was found. Conclusions: Among patients with rifampin-susceptible TB who were diagnosed using first-line molecular TB assays, there is a high prevalence of Hr-TB. Phenotypic drug susceptibility testing remains the gold standard. To improve the performance of genetic-based phenotyping tests, all isoniazid resistance-associated regions should be included, and such tests should have the ability to identify underlying mutations.