Effects of pyrazinamide and/or ethambutol resistance on Tuberculosis treatment outcome by whole genome sequencing, South Africa 2020 – 2022

Abstract

Introduction: In South Africa, both pyrazinamide (PZA) and/or ethambutol (EMB) were included in the all- oral short-course regimen despite the high resistance rates to pyrazinamide (PZA) and/or ethambutol (EMB) reported among people with MDR-TB. The effect of resistance to these drugs on treatment outcomes are poorly understood. This study evaluated the effects of PZA and/or EMB resistance on treatment outcomes among MDR-TB cases treated with the all oral short course regimen in South Africa from 2020 to 2022. Methods: We conducted a retrospective cohort study of people with MDR-TB detected through routine TB diagnostics performed at Braamfontein and Greenpoint laboratories who were treated with the all-oral short-course regimen. Isolates from these laboratories were referred for whole genome sequencing (WGS) as part of a surveillance study. Drug susceptibility patterns for PZA and EMB were classified into four categories: susceptibility to both drugs (EMB-S & PZA-S), resistance to PZA only (EMB-S & PZA-R), resistance to EMB only (EMB-R & PZA-S), and resistance to both drugs (EMB-R & PZA-R). Treatment outcomes were categorized as either successful patient outcomes or unsuccessful patient outcomes. A directed acyclic graph guided the selection of variables for the generalized linear model. Adjusted incident rate ratio (aIRR) were calculated with 95% confidence intervals using modified Poisson regression with robust error variances. Results: Among the 598 people with MDR-TB included in the analysis, 60% (356/598) were resistant to one or both TB drugs. There was no evidence that resistance to PZA and/or EMB increased USPO or SPO: resistance to PZA (aIRR = 1.18, 95% CI: 0.86–1.63), resistance to EMB alone (aIRR = 0.94, 95% CI: 0.67–1.32), and resistance to both drugs (aIRR = 0.97, 95% CI: 0.73– 1.27). Conclusion: This study also highlights PZA or EMB does not affect treatment outcomes in patients with MDR-TB. This observation supports the rationale behind the 2023 adoption of the all-oral MDR-TB regimen. WGS is recommended to guide treatment regimens that include PZA and EMB.