# A Comparative Analysis of Resistance Patterns in Rifampin-Resistant Tuberculosis: Mutations Within and Outside the Rifampicin Resistance-Determining Region

## TL;DR

The study compares drug resistance patterns in tuberculosis patients with mutations in or outside a specific gene region linked to rifampicin resistance.

## Contribution

The study identifies distinct resistance patterns associated with mutations outside the known rifampicin resistance-determining region in tuberculosis.

## Key findings

- Isoniazid resistance was higher in patients with mutations within the RRDR.
- Amikacin resistance was only observed in patients with mutations outside the RRDR.
- Most MDR-TB cases had missing probes in molecular tests, but a few had no missing probes.

## Abstract

Background

Rifampicin resistance in tuberculosis (TB), often linked with isoniazid resistance, defines multidrug-resistant TB. The rifampicin resistance-determining region (RRDR) of the rpoB gene is a recognized hotspot, yet mutations outside the RRDR and their clinical relevance remain underexplored. This study aimed to compare drug resistance patterns associated with rpoB gene mutations occurring within and outside RRDR in patients with rifampicin-resistant pulmonary tuberculosis (RR-TB).

Methodology

This cross-sectional analytical study included 170 GeneXpert-confirmed RR-TB cases from Mayo Hospital/ King Edward Medical University, Lahore, from August 2020 to July 2022. Probe-missing patterns were recorded, and phenotypic drug susceptibility testing using the proportion method on Lowenstein-Jensen medium was performed. Chi-square test and logistic regression analysis were performed to compare resistance patterns between groups, with p-values ≤0.05 considered significant.

Results

Among 170 cases, the overall mean age was 35.45 ± 16.11 years, 90 (52.9%) were males, 156 (91.8%) had mutations within the RRDR, and 14 (8.2%) had mutations outside the RRDR. Age, sex, or body mass index demonstrated no association with non-RRDR mutations (all p > 0.05). Isoniazid resistance was higher in RRDR cases (84.0% vs. 57.1%; p = 0.025). Amikacin resistance was only observed in non-RRDR cases (0.0% vs. 7.1%; p = 0.024). Out of 133 MDR-TB cases, 125 (94.0%) had missing probes A to E, including 109 (82.0%) with missing probe E. However, 8 (6.0%) MDR-TB cases had no missing probes.

Conclusions

Mutations in the RRDR remained the primary drivers of MDR-TB. However, mutations outside the RRDR suggested a potential association with amikacin resistance, necessitating expanded molecular surveillance and larger studies for validation.