Risk factors associated with isoniazid resistance in tuberculosis

Barnard, Marinus (2005-12)

Thesis (MScMed (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2005.


Tuberculosis (TB) is one of the most serious infectious diseases known to mankind, with devastating outcomes in the poorest countries in the world. Isoniazid is the cornerstone of all first-line anti-TB regimens. Forty-eight percent of all drug resistant TB isolates in the Western Cape are Isoniazid mono-resistant, and the majority of these isolates belong to the Beijing/W strain family. Currently, the known molecular mechanisms which confer Isoniazid resistance in these isolates are attributed to mutations within the katG gene and account for up to 70% of all drug resistant TB isolates. Risk factors for the development of Isoniazid resistance can be attributed to either pathogen or host related factors and may partially account for the other 30% of Isoniazid resistant isolates. In this study, three aspects which may contribute to Isoniazid resistance were investigated: DNA repair in the bacterium, host response to anti-TB treatment and socioeconomic factors. A PCR based dot-blot strategy was used to screen for previously reported missense mutations 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 the Atypical Beijing strains and other dominant strain families, exhibited missense mutations in all three base excision repair genes. It is therefore speculated that defects in the DNA repair genes (mutator phenotypes) of the Beijing isolates may contribute to the development of drug resistance and hence, may account for the large proportion of isolates that are Isoniazid mono-resistant. A novel method, based on primer extension, was initially developed to screen the NAT2 gene and then used to type individuals into fast, intermediate and slow acetylators of Isoniazid. The newly develop method, which is sensitive and accurate, improves the detection of Single Nucleotide Polymorphisms within the NAT2 gene, in contrast to the traditionally used methods. Utilising this method, it was found that the combination of fast and intermediate acetylators was significantly associated with Isoniazid resistance in the study community. This finding may have an important impact on TB control programmes, since it may allow for the administration of higher dosages of Isoniazid to fast/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 the development 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 the study population is low and subsequently HIV status was not associated with the development of INH resistance. This study indicates that a combination of risk factors, both pathogen and host related, are involved in the development of Isoniazid resistance.

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