Bacterial risk factors for treatment failure and relapse among patients with isoniazid resistant tuberculosis.

BACKGROUND: Drug resistant tuberculosis (TB) is increasing in prevalence worldwide. Treatment failure and relapse is known to be high for patients with isoniazid resistant TB treated with standard first line regimens. However, risk factors for unfavourable outcomes and the optimal treatment regimen for isoniazid resistant TB are unknown. This cohort study was conducted when Vietnam used the eight month first line treatment regimen and examined risk factors for failure/relapse among patients with isoniazid resistant TB. METHODS: Between December 2008 and June 2011 2090 consecutive HIV-negative adults (≥18 years of age) with new smear positive pulmonary TB presenting at participating district TB units in Ho Chi Minh City were recruited. Participants with isoniazid resistant TB identified by Microscopic Observation Drug Susceptibility (MODS) had extended follow-up for 2 years with mycobacterial culture to test for relapse. MGIT drug susceptibility testing confirmed 239 participants with isoniazid resistant, rifampicin susceptible TB. Bacterial and demographic factors were analysed for association with treatment failure and relapse. RESULTS: Using only routine programmatic sputum smear microscopy for assessment, (months 2, 5 and 8) 30/239 (12.6%) had an unfavourable outcome by WHO criteria. Thirty-nine patients were additionally detected with unfavourable outcomes during 2 year follow up, giving a total of 69/239 (28.9%) of isoniazid (INH) resistant cases with unfavourable outcome by 2 years of follow-up. Beijing lineage was the only factor significantly associated with unfavourable outcome among INH-resistant TB cases during 2 years of follow-up. (adjusted OR = 3.16 [1.54-6.47], P = 0.002). CONCLUSION: One third of isoniazid resistant TB cases suffered failure/relapse within 2 years under the old eight month regimen. Over half of these cases were not identified by standard WHO recommended treatment monitoring. Intensified research on early identification and optimal regimens for isoniazid resistant TB is needed. Infection with Beijing genotype of TB is a significant risk factor for bacterial persistence on treatment resulting in failure/relapse within 2 years. The underlying mechanism of increased tolerance for standard drug regimens in Beijing genotype strains remains unknown.

Common polymorphisms in the CD43 gene region are associated with tuberculosis disease and mortality.

CD43, a surface glycoprotein, regulates Mycobacterium tuberculosis macrophage binding, replication, and proinflammatory cytokine induction in a murine model. We hypothesized that single-nucleotide polymorphisms (SNPs) in the CD43 gene region are associated with human tuberculosis (TB) susceptibility. We performed a case-population study in discovery (352 TB cases and 382 control subjects) and validation cohorts (339 TB cases and 376 control subjects). We examined whether 11 haplotype-tagging SNPs in the CD43 gene region were associated with tuberculous meningitis (TBM) and pulmonary TB (PTB) in Vietnam. Three SNPs from the CD43 gene region were associated with TB susceptibility with a genotypic model. The association fit a recessive genetic model and was greater for TBM than for PTB (for TBM: rs4788172, odds ratio [OR], 1.64; 95% confidence interval [CI], 1.04-2.59, rs17842268 [OR, 2.20; 95% CI, 1.29-3.76, and rs12596308 [OR, 2.38; 95% CI, 1.47-3.89]). Among TBM cases, rs17842268 was associated with decreased survival (hazard ratio, 2.7; 95% CI, 1.1-6.5; P = 0.011). In addition, rs12596308 and rs17842268 were associated with focal neurologic deficit at TBM presentation. Our data suggest that CD43 polymorphisms are associated with TB susceptibility, disease manifestations, and worse outcomes. To our knowledge, this is the first report that links CD43 genetic variants with susceptibility and outcome from a disease.

A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis.

BACKGROUND: Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB). METHODS: We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB. RESULTS: The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response. CONCLUSIONS: These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.