Isoniazid resistance in Mycobacterium tuberculosis

Dau, Quang Tho (2012). Isoniazid resistance in Mycobacterium tuberculosis. PhD thesis The Open University.



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<0.00l). The independent effect of the strain lineage on INH MIC was predicted to correspond to a 2.68-fold (95% Cl 1.52-4.73, p<0.001) increase for Beijing lineage strains and a 1.40-fold (95% Cl 0.72-2.74, p=0.32) increase for EuroAmerican lineage strains in comparison with strains of the Indo-Oceanic lineage.

The third study investigated the impact of INH resistance on outcome in patients with HIV-associated TB meningitis (HIV/TBM) and showed that HIV/TBM patients infected with INH resistant M.tuberculosis which remains susceptible to RIF have significantly worse outcomes than patients infected with fully susceptible strains. The adjusted hazard ratio for MDR patients in comparison with fully susceptible or streptomycin (STR)-monoresistant isolates was 5.21 [95% Cl 2.38-11.42], p<0.0001 compared with HR= 1.78 [95% Cl 1.18-2.66], p=0.005 for patients with INH resistant isolates (+/-STR resistance).

The final study investigated the distribution of N-acetylator-2 (NAT2) phenotypes for INH metabolism in healthy volunteers from the Vietnamese Kinh population and correlated this with phenotypes using caffeine as a surrogate indicator for INH metabolism. This study showed that characterisation of 3 single nucleotide polymorphisms is sufficient to determine the acetylator status of individuals of Vietnamese Kinh ethnicity and that there is a predominance of fast acetylators (65%) in this popUlation. A simple PCR-RFLP test was developed to enable rapid determination of acetylator status for further studies.

Collectively, these results contribute to our understanding of INH resistance in M.tuberculosis and provide molecular tools for further studies of this crucial drug.

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