Co-infection with HIV-1 accounts for about 15% of the global tuberculosis (TB) burden. Treatment of TB/HIV is complicated by drug-drug interactions and increased drug toxicity risk. Current guidelines recommend a standard 6-month rifampin-based regimen regardless of HIV status, but recent studies suggest that TB failure/relapse risk is increased in HIV-infected persons. Early predictors of TB failure/relapse are needed to optimize treatment.
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. 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.
The NIH and Brazilian Ministry of Health established the Regional Prospective Observational Research on TB (RePORT)-Brazil cohort and specimen repository to enroll 900 TB patients (~40% HIV-infected) from 3 ethnically diverse regions in Brazil. In this cohort, participants are followed for two years from TB treatment initiation to evaluate response to therapy and failure/relapse. This project will capitalize upon and strengthen RePORT-Brazil to identify pharmacogenomic predictors of drug toxicity, failure to convert to culture-negative by two months, and TB treatment failure/relapse. We will control for clinical confounders, including easily measured components of the host immune response, as well as the M. tuberculosis pathogen. We wish to build upon RePORT-Brazil infrastructure by obtaining data and specimens at additional time points, ensuring adherence to TB therapy, and performing mass spectrometry drug assays and genotyping.
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 tuberculosis treatment outcomes.
This study aims to:
- To identify pharmacogenomic predictors of TB/HIV plasma drug exposure and increased risk for toxicity during TB therapy.
- Determine the pharmacogenomic predictors of two month culture-positivity, and TB treatment failure and relapse, while accounting for host and M. tuberculosis pathogen factors.
The results from this project will lay the groundwork for drug dosing regimens that improve outcomes and treatment effectiveness of HIV-related tuberculosis.
Timothy Sterling, M.D., Professor of Medicine, Division of Infectious Diseases, will serve at the principal investigator of this project along with Valeria Rolla, Professor at the Instituto Nacional de Infectologia in Rio de Janeiro, Brazil. Key investigators at Vanderbilt include David Haas, M.D., Richard Caprioli, Ph.D., Digna Velez Edwards, Ph.D., Bryan Shepherd, Ph.D., and Stephany Duda, Ph.D. Additionally, Ed Acosta, Ph.D. from the University of Alabama at Birmingham, and Brazilian investigators in Rio de Janeiro, Salvador, and Manaus are involved in the project.
Dr. Sterling is the Director of the Vanderbilt Tuberculosis Center (VTC), a joint effort between the Division of Infectious Diseases within the Department of Medicine and the Vanderbilt Institute for Global Health. The VTC is a focal point for collaborative efforts and tuberculosis research with an emphasis on epidemiology, clinical trials, and translational research.
This project is supported by NIH R01AI120790.