First-line anti-tuberculosis drugs revisited

Drug-resistant tuberculosis (DR-TB) continues to be a major challenge in the control of the worldwide TB epidemic. One of the strategies to oppose DR-TB has been to optimize the use of existing drugs, including first-line drugs. In this thesis, we investigated the association between genotypic and phenotypic Mycobacterium tuberculosis resistance levels, and the impact of resistance on treatment outcome and transmission of rifampicin-resistant or multidrug-resistant TB (RR/MDR-TB). We found that high-confidence mutations in katG, inhA, and the inhA promoter largely predict the level of phenotypic isoniazid resistance, with the combination of inhA promoter region and katG mutations being associated with the highest-level resistance (≥19.2 mg/L), exceeding peak level concentrations of the drug even at the highest doses in clinical use. Secondly, we found that in patients with initially fluoroquinolone-/second-line-injectable-susceptible RR/MDR-TB who were treated with the shorter MDR-TB treatment regimen, resistance to other drugs in the regimen (either ethambutol, ethionamide, or pyrazinamide) was not associated with having a clinically adverse outcome. High-level isoniazid resistance (vs any other level) predicted treatment failure in patients with high-level fluoroquinolone resistance. Thirdly, in a dataset of 394 whole genome sequenced MDR-TB isolates from Bangladesh, gathered over 6 years, we found a relatively low percentage of transmission clustering (34.8%) but no difference in clustering between isolates with borderline rpoB mutations and those with common rpoB mutations. Compensatory mutations in rpoA, rpoB, and rpoC were associated with higher levels of transmission clustering as were lineages 2, 3, and 4 relative to lineage 1. Young people as well as patients with high sputum smear positive TB were more likely to be in a transmission cluster. Lastly, we characterised a set of 50 phenotypically RR-TB isolates with wild type rpoB, of which 33 belonged to the same lineage (lineage 4.7). Several mutations in genes previously associated with rifampicin resistance potentially explained resistance in these isolates. Retesting the isolates on Löwenstein-Jensen medium yielded minimum inhibitory concentrations around the critical concentration, as did retesting of rifampicin-susceptible isolates of lineage 4.7. Our studies contributed to and stressed the importance of accurate detection of drug resistance, including to first-line drugs, in order to optimise treatment of RR/MDR-TB and minimise its transmission.