Prevalence of isoniazid resistance-conferring mutations associated with multidrug-resistant tuberculosis in Free State Province, South Africa.

Background: Multidrug- and extensively drug-resistant tuberculosis (MDR-TB and XDR- TB) threaten local and global control of the disease. The molecular line-probe assay (LPA) provides rapid diagnosis and early management of MDR-TB. The LPA detects mutations of katG and inhA genes associated with isoniazid (INH) resistance in Mycobacterium tuberculosis isolates. The katG and inhA genes are associated with high- and low-level INH resistance, respectively, as well as cross-resistance to ethionamide in the case of inhA gene mutations. Patients with MDR-TB due to an inhA mutation could benefit from the use of high-dose INH - instead of ethionamide - in their MDR-TB regimen.

Objective: To determine the frequencies of katG and inhA mutations that conferred INH resistance among MDR-TB isolates during 2014 - 2016 in Free State (FS) Province of South Africa.

Methods: We retrospectively reviewed MDR-TB isolates assayed with GenoType MTBDRplus (Hain Lifescience, Germany) (LPA) at the central TB laboratory of Universitas Academic Hospital, Bloemfontein, FS, and calculated the frequencies of katG and inhA mutations.

Results: Among 918 MDR-TB isolates, the prevalence of katG, inhA and katG plus inhA mutations was 63.9%, 13.4% and 22.7%, respectively. Approximately 60% (n=536; 58.4%) of the isolates were obtained from male patients. The patients' ages ranged from 1 to 89 (median 37) years. The Xhariep district had the highest incidence of INH resistance-conferring mutations in the province.

Conclusions: katG-associated mutations are the predominant INH resistance-conferring mechanism among MDR-TB isolates in the FS. Patients infected with isolates that harbour the katG mutation are unlikely to benefit from high-dose INH therapy in the bedaquiline (BDQ)-containing modified short MDR-TB regimen. They may, however, benefit from the inclusion of ethionamide in the regimen. Dual katG and inhA gene mutations make these patients unlikely to respond to either high-dose INH or ethionamide and should now be considered for either the BDQ-containing long MDR-TB regimen or an individualised treatment regimen, depending on fluoroquinolone susceptibility. Clinicians should familiarise themselves with interpreting various INH resistance-conferring mutation results and their implications for management of MDR-TB treatment.