Risk factors associated with isoniazid resistance in tuberculosis

[摘要] Tuberculosis (TB) is one of the most serious infectious diseases known to mankind, withdevastating outcomes in the poorest countries in the world. Isoniazid is the cornerstoneof all first-line anti-TB regimens. Forty-eight percent of all drug resistant TB isolates inthe Western Cape are Isoniazid mono-resistant, and the majority of these isolates belongto the Beijing/W strain family. Currently, the known molecular mechanisms whichconfer Isoniazid resistance in these isolates are attributed to mutations within the katGgene and account for up to 70% of all drug resistant TB isolates. Risk factors for thedevelopment of Isoniazid resistance can be attributed to either pathogen or host relatedfactors and may partially account for the other 30% of Isoniazid resistant isolates.In this study, three aspects which may contribute to Isoniazid resistance wereinvestigated: DNA repair in the bacterium, host response to anti-TB treatment and socioeconomicfactors.A PCR based dot-blot strategy was used to screen for previously reported missensemutations in the mutT2, Rv3908 and ogt DNA repair genes of different strains of M.tuberculosis. All the Beijing isolates (drug resistant and susceptible), in contrast to theAtypical Beijing strains and other dominant strain families, exhibited missense mutationsin all three base excision repair genes. It is therefore speculated that defects in the DNArepair genes (mutator phenotypes) of the Beijing isolates may contribute to the development of drug resistance and hence, may account for the large proportion ofisolates that are Isoniazid mono-resistant.A novel method, based on primer extension, was initially developed to screen the NAT2gene and then used to type individuals into fast, intermediate and slow acetylators ofIsoniazid. The newly develop method, which is sensitive and accurate, improves thedetection of Single Nucleotide Polymorphisms within the NAT2 gene, in contrast to thetraditionally used methods. Utilising this method, it was found that the combination offast and intermediate acetylators was significantly associated with Isoniazid resistance inthe study community. This finding may have an important impact on TB controlprogrammes, since it may allow for the administration of higher dosages of Isoniazid tofast/intermediate acetylators and a lower dose for slow acetylators.Clinical factors (compliance and retreatment after cure) and socio-economic factors(education, employment and income) were found to be significantly associated with thedevelopment of INH resistance. Diagnostic delay was also found to be a risk factor,since it may allow for transmission of TB during this period. The HIV prevalence in thestudy population is low and subsequently HIV status was not associated with thedevelopment of INH resistance.This study indicates that a combination of risk factors, both pathogen and host related, areinvolved in the development of Isoniazid resistance.

[发布机构] Stellenbosch University