Isoniazid resistance in Mycobacterium tuberculosis

Drug resistant tuberculosis (TB) is increasing worldwide and it is now estimated by the World Health Organisation (WHO) that 7% of TB cases globally are resistant to isoniazid (INH). INH is a key drug for the treatment of TB, alongside rifampicin (RIF). Understanding factors which influence the emergence and propagation of INH resistance and the influence of INH resistance on TB treatment success are vital in improving global TB control efforts. Vietnam is ranked 12th of 22 high burden countries for TB and has a high prevalence of INH resistance (25%) with a relatively modest prevalence of TB resistant to both INH and RIF (multi-drug resistant, MDR TB) (2.7%) The first study in this thesis developed rapid screening tests for both RIF and INH resistance in Mycobacterium tuberculosis isolates which showed high accuracy. The specificity and the sensitivity of the MAS-PCR test for INH resistance compared to the conventional phenotypic DST were 100% [95% CI 92.9-100%] and 90% [95% CI 82.4-95.1 %], respectively. The second study demonstrated that the minimum inhibitory concentration (MIC) for INH is influenced by both the mutation responsible for resistance to INH and the lineage backbone of the M.tuberculosis isolate. A two-way ANOVA of MIC including both strain lineage (p=0.003) and resistance mutation (p<0.001) showed highly significant independent effects of both factors on MIC level. MIC to INH of isolates with a katG315 mutation (2ug/ml) was significantly higher compared to MIC to INH of isolates with an inhA-15 mutation (0.25p.g/ml) and wild-type isolates (0- 0.lug/ml) (p