Molecular characterization of genetic mutations with fitness loss in pulmonary tuberculosis patients associated with HIV co-infection in Northwest Amhara, Ethiopia

Abstract

Objectives: Molecular approaches to identifying resistance-conferring mutations suggest a revolution in the field of tuberculosis. The aim of the study was to determine the association between resistance-conferring mutations with fitness loss in Mycobacterium tuberculosis clinical isolates and HIV co-infection in the Amhara region of Ethiopia. Methods: A laboratory-based cross-sectional study was conducted between September 2022 and June 2023. A line probe assay was performed on 146 culture-positive clinical isolates. Logistic regression analysis was used to measure the strength of the association between the drug-resistance-conferring mutations with fitness loss in M. tuberculosis isolates and tuberculosis/HIV co-infection. A p-value ⩽ 0.05 was considered statistically significant. Results: A total of 11 distinct mutations at four genetic loci among 19 resistant isolates were detected. The frequency of rifampicin, isoniazid, and fluoroquinolones resistance-conferring mutations was identified in 12 (8.2%), 17 (11.6%), and 2 (1.4%) of the isolates, respectively. The most prominent specific mutations were S450L (5/9, 55.6%), S315T (11/11, 100%), C-15T (4/4, 100%), and D94G (1/1, 100%). Double mutations were observed in 10 (52.6%) multidrug-resistant tuberculosis isolates; the most common were detected in both the rpoB and katG genes (8/10, 80.0%). The HIV-co-infected tuberculosis patients carried a higher proportion of low fitness of non- rpoB S450L variants than those tuberculosis patients without HIV (80.0% vs 14.3%) and showed a significant association (cOR = 0.042, 95% CI: 0.002–0.877, p = 0.041), but not with the low fitness of non- katG S315T variants (cOR = 3.00, 95% CI: 0.348–25.870, p = 0.318). Conclusion: This study provides valuable information on the genetic variants with fitness loss associated with HIV co-infection, but requires further whole-genome-based mutation analysis.

WITHDRAWN: Prevalence ofkatGandinhAmutations in genes associated with isoniazid resistance inMycobacterium tuberculosisclinical isolates in Cameroon

“…Drug-resistant TB can spread when undetected and treated inappropriately [27]. Notably, mutations outside of the katG and inhA genetic loci are present in approximately 10%–25% of INH-R strains with unclear alterations [40]. Based on the data we evaluated, INH-resistant isolates with no katG and inhA mutations were seen in 9.5% of INH-R isolates, increasing the likelihood that they may elude molecular detection, the patients treated inadequately and, in the event of INH-monoresistant strains will develop into MDR-TB.…”

Phenotypic and Genotypic Drug Resistance of Mycobacterium tuberculosis Strains Isolated from HIV-Infected Patients from a Third-Level Public Hospital in Mexico

“…A mutation in the katG gene and inhA promoter region is responsible for resistance to INH [ 43 ]. In this study, mutations conferring INH resistance occurred at a similar rate in the inhA promoter region and the katG gene.…”