How do people get multi-drug resistant tuberculosis? (360G-Wellcome-214560_Z_18_Z)

Recent data suggests that most isoniazid resistant strains have been circulating for decades. The global diagnostic focus on rifampicin resistance has meant that isoniazid mono-resistant strains are systematically being treated with first-line therapy. With MDR-TB incidence rising despite overall TB incidence falling, the concern is that we are selecting for rifampicin resistance. The alternative explanation, that MDR-TB is transmitting more successfully, seems unlikely, but possible. The hypothesis I will test is that most isoniazid resistance is acquired through transmission whereas most rifampicin resistance evolves de novoin patients with undiagnosed, pre-existing isoniazid resistance. I will investigate the following research questions in Vietnam: (i) What is the proportion of transmitted versus newly evolved MDR-TB? (ii) What is the prevalence of isoniazid resistance among patients never previously exposed to the drug, and what proportion of patients with unsuccessful treatment outcomes evolve isoniazid resistance? (iii) What is the risk of evolving rifampicin resistance by treating isoniazid resistant strains with first-line drugs? What proportion of patients who evolve rifampicin resistance after exposure to first-line drugs also evolved isoniazid resistance? (iv) Do host genotype and variable anti-tuberculosis drug pharmacokinetics contribute to evolving drug resistance? The findings will inform policy on diagnostics, treatment protocols and disease control.