Genetic susceptibility to aminoglycoside cochleotoxicity in South African multidrug-resistant and rifampicin-resistant tuberculosis patients

Abstract

BACKGROUND: South Africa has a high burden of multidrug-resistant tuberculosis (MDR-TB) and rifampicin-resistant tuberculosis (RR-TB). At the time of this study, kanamycin formed part of the South African MDR/RR-TB treatment regimen. Although treatment has shifted towards shorter all-oral regimens, aminoglycoside-related ototoxicity remains clinically relevant. OBJECTIVES: This study investigated the association between two mitochondrial variants, m.15312TC (I189T in MT-CYB [mitochondrially encoded cytochrome b]) and m.10114TC (I19T in MT-ND3 [mitochondrially encoded NADH]), and susceptibility to cochleotoxicity in South African patients receiving kanamycin-based MDR/RR-TB treatment. METHOD: A prospective cohort study was conducted in Cape Town, South Africa. Hearing thresholds from 0.25 kHz to 16 kHz were monitored at baseline and at 4 weeks, 8 weeks and 12 weeks after treatment initiation. Cochleotoxicity was defined using the American Speech-Language-Hearing Association's significant threshold shift criteria. Mitochondrial variants were identified using polymerase chain reaction and Sanger sequencing. Fisher's exact tests were used to explore associations between variants and cochleotoxicity. RESULTS: Hearing data were analysed for 102 participants. Cochleotoxicity developed in 84 participants (82.4%). The m.15312TC variant was detected in three of 78 successfully sequenced participants, and m.10114TC in four of 80. All variant carriers had cochleotoxicity. Statistically significant associations were not demonstrated for m.15312TC (p = 1.000) or m.10114TC (p = 1.000). CONCLUSION: The variants were observed only among participants who developed cochleotoxicity, but no statistically significant associations were observed. The findings are exploratory and require validation before clinical screening.Contribution: This study supports future genetic-susceptibility research in African aminoglycoside-exposed populations.