
What is this project about?
Adverse events caused by tuberculosis (TB) treatment exact a high cost due to the related morbidity and mortality, cause delays to urgently required TB treatment and create difficulty in accessing alternative therapies in resource-challenged environments. This is specifically relevant in Africa, a continent disproportionately affected by TB. A frequently observed but poorly understood adverse event is anti-TB drug induced liver injury (ATDILI). Interindividual and interpopulation variability in ATDILI risk points to the role of patient genetic factors. ATDILI studies on isoniazid, an anti-TB drug, demonstrated the role of genetic variation in drug metabolising enzymes such as NAT-2, CYP2E1, CYP3A4 and human leukocyte antigen (HLA) related factors. We therefore hypothesize that genetic variation in genes involved in drugabsorption, transport, distribution, metabolism and excretion(ADME) could be biomarkers for ATDILI. In addition, pharmacokinetic studies have also shown that anti-TB drug exposure levels are associated with ATDILI. In this proposal we will combine pharmacogenomic sequence data on ADME genes with clinical and pharmacokinetic data on ATDILI patients of African ancestry receiving anti-TB treatment to explore drug-gene interactions, understandTB treatment adverse events and guide biomarkerdevelopment.
Gene-drug interactions that increase risk for ATDILI, will be identifiedfrom patients with ADTLI and verified controls within study cohorts. The TB RePORT cohort of patients will be recruited on first line drug-sensitive regimens composed of isoniazid, rifampicin, ethambutol and pyrazinamide; the BPaL cohort of patients started on drug- resistant TB treatment regimen composed of bedaquiline, pretomanid and linezolid, and identifying and recruiting extreme phenotype of ATDILI patients admitted to and investigated in hospital. We will add to these cohorts using two additional studies that have already completed follow up of drug sensitive (DS) and drug resistant (DR) TB patients aftertreatment.
All patients will be initially screened for elevated alaninetransaminase (ALT) at baseline, month 1 month 2 and month 3 ofTB treatment for elevated alanine transaminase (ALT). In this study ATDILI is defined as alanine transaminase (ALT) level >120 IU/L and symptomatic (nausea, vomiting, abdominal pain, jaundice); or ALT level >200 IU/L and asymptomatic; or Total serum bilirubin (TBIL) concentration >40 μmol/L (Jong et al., 2013). The normal ranges for ALT are 7-35 IU/L and for TBil 5-21 μmol/L in South Africa. This translates to ATDILI being approximately 3xULN for ALT and 2xULN for TBil.
We estimate 80 patients with ATDILI will be identified and their specimens included. From the prospective cohorts, we will identify 240 controls who did not have ATDILI by the end of their TBtreatment. Anti-TB drug pharmacokinetic data will be determined by measurements of parent compounds and their major metabolites at steady state to infer patient drug exposure levels. Genomic data on all 320 patients will be generated using targeted DNA sequencing that includes 280 ADME genes (including part of the HLA region) and their regulatory and flanking sequences with all laboratory staff blinded to whether they were case or control patients. Associationsbetween ATDILI with drug exposure levels and genetic variants in the ADME genes will provide information to direct the developmentof biomarkers to inform risk for ATDILI.
This study will therefore result in a well characterized ATDILI phenotype dataset with associated ADME gene DNA sequence and anti-TB drug plasma exposure data in patients with DILI and matched controls without DILI. This will be a valuablepharmacogenomic resource in ongoing efforts to understandgenomic risk factors for ATDILI made available to the research community (e.g. in databases such as the EGA, H3ABioNet Precision Medicine Portal). Innovations anticipated from this workinclude identification of genomic biomarkers to predict the likelihoodof developing ATDILI, which could be further validated for clinicalutility in managing ATDILI. In this study we will collect liver tissuebiopsies from patients with severe ATDILI.
Funder
GSK
Novartis
SAMRC
PI & Team Members
Collen Masimirembwa (PI)
Neil Martison (Co-PI)
Ananyo Choudhury (Co-PI)
Vincent Aketch Nyangwara (Student)
Collaborators
None
Period
2022 - 2024
Pharmacogenomics of anti-TB Drug induced liver injury
Pharmacogenomics of hepatotoxicity in the treatment of drug sensitive and resistant TB in Africans (Pgx@DILI Study)

Project Media
Publications
None
The Aim
To combine pharmacogenomic sequence data on ADME genes with clinical and pharmacokinetic data on ATDILI patients of African ancestry receiving anti-TB treatment to explore drug-gene interactions, understand TB treatment adverse events and guide biomarker development.
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Objectives
To identify 80 TB DILI cases and their matched 240 controls from various cohorts on tb treatment
To determine the anti-tb drug exposure levels in participants
To conduct targeted sequencing of 280 ADME pharmacogenes in all participants
To investigate correlations of clinical phenotypes, drug exposure and gene sequence variation with risk for TB DILI