Impact of rpoB gene mutations and Rifampicin-resistance levels on treatment outcomes in Rifampicin-resistant tuberculosis

BACKGROUND: Although many studies have examined the connection between mutations in the rpoB gene and drug resistance, the impact of common mutations on treatment outcomes for RR-TB is not yet fully understood. OBJECTIVES: This study explores the relationship between rpoB gene mutations and drug-resistant phenotypes, assesses their role in predicting RR-TB prognosis, and investigates the impact of disputed rpoB mutations in M. tuberculosis on treatment outcomes. METHODS: 192 rifampicin-resistant isolates were retested for drug susceptibility and gene sequencing. Minimum inhibitory concentrations (MICs) were determined for 98 isolates with disputed rpoB gene mutations. These mutations can cause low-level resistance to rifampicin, leading to inconsistencies in drug susceptibility testing and impacting medication therapy decisions. RESULTS: Of 192 cases, 116 (60.4%) achieved successful outcomes, while 76 (39.6%) were unsuccessful. Among the 98 isolates tested for phenotypic drug susceptibility testing (DST) based on minimum inhibitory concentration (MIC), 67 (68.4%) showed high-level resistance with a MIC of ≥ 1 µg/mL. In contrast, 31 (31.6%) drug-susceptible tuberculosis isolates exhibited low-level resistance with a MIC of < 1.0 µg/mL. Of the 31 isolates with low-level resistance, 14 (45.2%) had successful treatment outcomes, while 17 (54.8%) did not. Among the 67 isolates with high-level resistance, 41 (61.2%) achieved successful outcomes, whereas 26 (38.8%) did not. In analysing the 14 codons of the Rifampicin Resistance Determining Region (RRDR) of the rpoB gene, the Leu430Pro codon showed the highest odds ratio (OR) of 2.98 (95% CI: 0.96-9.27) with a p-value of 0.0591, indicating statistically not significant. However, this suggests a potential association with rifampicin resistance that requires further investigation, particularly in areas with high drug-resistant tuberculosis prevalence. Other reported variants had lower odds ratios: Asp435Val with 1.23 (95% CI: 0.32-4.75), Asp435Tyr with 1.86 (95% CI: 0.60-5.76), His445Tyr with 1.16 (95% CI: 0.47-2.91), and Ser450Leu with 1.44 (95% CI: 0.81-2.58). CONCLUSIONS: This study indicates that low-level rifampicin mono-resistance in tuberculosis (TB) patients is associated with poor clinical outcomes. A mutation at the Leu430Pro codon showed the highest odds ratio of 2.98 (p-value 0.0591), suggesting a potential association with rifampicin resistance that warrants further research, especially in areas with high drug-resistant TB. It highlights the need for more aggressive treatment strategies for patients with low-level rifampicin resistance, even if they seem solely mono-resistant.