Project Summary Concomitant treatment of HIV and tuberculosis (TB) is complicated by drug-drug interactions and high rates of drug toxicity and discontinuation. The optimal duration of TB treatment is characterized by low rates of TB treatment failure and relapse. Remaining sputum culture-positive after two months of treatment is a traditional marker of subsequent TB relapse risk. Standard TB treatment is a 6-month isoniazid and rifampin-based regimen; efavirenz-based antiretroviral therapy is routinely used to treat HIV, particularly in low- and middle- income countries. These treatment regimens are hepatotoxic and neurotoxic, respectively. Single nucleotide polymorphisms (SNPs) in genes that affect metabolism of these drugs may affect pharmacokinetics and susceptibility to drug toxicity, as well as other treatment outcomes. This includes variants of NAT2 (slow vs. rapid acetylation of isoniazid), CYP2B6 (slow vs. rapid metabolism of efavirenz), CYP2A6 (metabolism of both efavirenz and isoniazid), UGT2B7 (metabolism of efavirenz), SLCO1B1 (rifampin), and UTG1A1 (dolutegravir). The relationships between SNP, drug level, and outcomes such as toxicity, two-month sputum culture- positivity, and TB treatment failure/relapse are not well-understood, particularly given drug interactions of TB and HIV drugs. Differences in human ancestry may also influence the effect of SNPs on drug metabolism. In this proposal we seek to utilize the newly-established Regional Prospective Observational Research on Tuberculosis (RePORT)-Brazil cohort that will enroll and follow 800 participants (approximately 40% of whom will be HIV-infected) with culture-confirmed drug-susceptible pulmonary TB for two years after TB treatment initiation. We will also utilize state-of-the-art mass spectrometry capacity at Vanderbilt to determine plasma concentrations of TB and HIV drugs, and pharmacogenomics expertise in the United States and Brazil to determine the relationships between SNP and treatment outcome after accounting for ancestry and other potentially confounding variables, including host immune factors and M. tuberculosis pathogen characteristics. The over-arching goal of this project is to optimize the treatment of HIV-related tuberculosis in a large, genetically diverse cohort in Brazil. We will characterize the relationship between human genetic SNPs, TB and HIV drug levels, and three key TB treatment outcomes: drug discontinuation due to toxicity (Aim 1), two- month sputum culture-positivity, as well as TB treatment failure and reIapse (Aim 2). These results will lay the groundwork for drug dosing and regimens that improve outcomes and treatment effectiveness of HIV-related TB.

Narrative The over-arching goal of this project is to optimize the treatment of HIV-related tuberculosis in a large, genetically diverse cohort in Brazil. We will characterize the relationship between human genetic single nucleotide polymorphisms (SNPs), tuberculosis and HIV drug levels, and three key tuberculosis treatment outcomes: drug toxicity, 2-month sputum culture-positivity, and tuberculosis treatment failure/reIapse. These results will lay the groundwork for drug dosing and regimens that improve outcomes and treatment effectiveness of HIV-related tuberculosis.