Risk factors for treatment failure in isoniazid resistant tuberculosis

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There were 8.6 million cases and 1.3 million deaths from tuberculosis (TB) globally in 2012. Among the major challenges to global TB control and the ultimate goal of TB elimination is the increasing prevalence of drug resistant strains of Mycobacterium tuberculosis worldwide, coupled with an extremely limited pipeline of novel drug development. In 2012 there were an estimated 450,000 cases of muti- drug resistant TB (resistant to at least rifampicin and isoniazid) and 170,000 deaths due to multi-drug resistant (MDR) TB worldwide. The prevalence of resistance to isoniazid is extrememly high In some regions of the world, including Vietnam, where 25% of new smear positive patients and 54% of re treatment patients are infected with strains resistant to isoniazid. Treatment outcomes are known to be worse for patients with undiagnosed isoniazid resistant (INHR) TB treated with standard regimens but the majority of patients have successful outcomes. This thesis investigated risk factors for treatment failure among patients with isoniazid resistant TB in Ho Chi Minh City, Vietnam. Chapter one provides. an -introduction to tuberculosis and isoniazid resistant TB and chapter two describes the methodology of the studies decribed in the thesis. In chapter three, I investigate the treatment outcomes among a cohort of patients with isoniazid resistant tuberculosis treated according to National TB guidelines. The data show that unfavourable treatment outcomes are unacceptably high, at 19% among patients with INHR TB. In chapter four, I investigate three bacterial factors associated with unfavourable treatment outcomes among patients with isoniazid resistant TB, bacterial lineage, MIC to isoniazid and mutations responsible for isoniazid resistance. I show that the Beijing genotype is associated with young age, isoniazid resistance and multi-drug resistance, and unfavourable outcome. In chapter five, I determine the prevalence of viral hepatitis co-infection among patients with INHR TB. Infection with hepatitis B is 9.8% and hepatitis C 4.6% among patients with INHR TB and is a risk factor for the development of anti TB drug-induced hepatitis (ATDIH) but not for unfavourable outcome. In chapter six, I determine the distribution of acetylator types for isoniazid among Vietnamese TB patients and show that acetylator status is not a risk factor for unfavourable outcome in patients with INHR TB. Overall, these studies show that INHR TB is a serious challenge to TB control efforts in Vietnam, with unacceptably high rates of treatment failure. In the final chapter, I discuss the implication of my findings and propose priorities for further research to address these issues.