Pharmacogenomic determinants of antituberculosis drug exposure and toxicity in African populations: a systematic review protocol

Tuberculosis (TB) remains a major global public health burden, with African countries disproportionately affected. Standard antituberculosis (anti-TB) therapy demonstrates substantial interindividual variability in pharmacokinetics and susceptibility to adverse drug reactions, particularly drug-induced liver injury. Pharmacogenomic (PGx) variants in genes such as NAT2 , CYP2E1 , CYP2B6 , SLCO1B1 , and ABCB1 are known determinants of drug metabolism and toxicity. African populations harbour the greatest human genetic diversity globally yet remain under-represented in PGx research. Understanding genotype-phenotype relationships in this context is essential for informing precision dosing and improving TB treatment safety and outcomes. This review aims to synthesize evidence on associations between PGx variants and anti-TB pharmacokinetic (PK) parameters, drug-related adverse drug reactions (including drug-induced liver injury), treatment interruption, and clinical outcomes among individuals treated for TB in African populations. It will also examine how co-morbidities, including human immuno-deficiency virus (HIV) co-infection, diabetes mellitus, and pregnancy, modify these genotype-phenotype associations. This review will follow the Joanna Briggs Institute (JBI) methodology for systematic reviews of etiology and risk. A comprehensive search will be conducted in MEDLINE (PubMed), Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, African Index Medicus, and African Journals Online (AJOL). Unpublished literature will be sought through WHO Global Index Medicus, ClinicalTrials.gov, and the Pan African Clinical Trial Registry. Eligible study designs include prospective and retrospective cohort studies, case-control studies, analytical cross-sectional studies, randomized and non-randomized PK trials, and nested genetic analyses. Studies must involve individuals receiving first- or second-line anti-TB treatment in African countries and report human genetic variants linked to pharmacokinetics, adverse drug reactions, or clinical outcomes. Two reviewers will independently screen titles and abstracts, appraise full texts using JBI critical appraisal tools, and extract data using standardized JBI forms. Disagreements will be resolved by discussion or a third reviewer. Where feasible, meta-analysis will be conducted using random-effects models within JBI SUMARI. Statistical heterogeneity will be quantified using the I 2 statistic and Cochran’s Q test. Subgroup analyses will explore sources of heterogeneity by geographic region, genetic variant, genetic model, and population subgroup (HIV, diabetes mellitus, pregnancy). Certainty of evidence will be assessed using the GRADE framework. PROSPERO CRD420261378485