Influence of drug transporter gene polymorphisms on pharmacokinetics and treatment outcomes in African Mycobacterium tuberculosis Cohorts.

Abstract

Background: Tuberculosis (TB) remains a major health challenge in Africa, and achieving the United Nations Sustainable Development Goal of ending TB by 2030 may be hindered by limited understanding of how African populations respond to current therapies. Emerging evidence indicates that African patients metabolize anti-TB drugs differently due to unique genetic variants, particularly in drug-transporter genes. Many variants known to affect drug response in Asian and European populations occur at lower frequencies or are absent in African groups, while numerous African-specific or understudied variants remain unexplored. This study examined the role of drug-transporter genes and genome-wide variants with pharmacodynamics, HIV and TB-associated biomarkers among South African patients receiving anti-TB therapy or HAART. Specifically, this study: (1) reviewed the genetic diversity of transporter-gene variants in African individuals with TB; (2) assessed the effects of specific ABCB1 and SLCO1B1 mutations on moxifloxacin pharmacokinetics (PK); (3) investigated genome-wide markers associated with HIV/TB co-infection and TB recurrence; and (4) identified ATP-Binding Cassette (ABC), Solute Carriers (SC) and genome-wide variants influencing moxifloxacin pharmacokinetics (PK). Materials and Methods: A total of 1,407 black race South African participants from various clinical trials from rural and urban KwaZulu-Natal were included for this study across chapters, namely the TB Recurrence upon treatment with HAART study (TRUTH) n= 427, Improving Retreatment Success (IMPRESS) n=157, University of KwaZulu-Natal cohort (UKZN) n=778, Integrase Strand Trasnfer Inhibitors (INSTIs) for The Management of HIV-associated TB study (INSIGHT) n=32 and Individualized M(X) drug-resistant TB Treatment Strategy Study (InDEX), n= 13. TB diagnoses were confirmed through microscopy, PCR, and culture methods. Moxifloxacin pharmacokinetic measurements were obtained approximately 24 hours post-dose using mass spectrometry. ABCB1 and SLCO1B1 variants were genotyped by real-time PCR, and genome-wide Single Nucleotide Polymorphisms (SNPs) were genotyped by microarray technology.