Low-fitness rpoB mutations in rifampicin-resistant Mycobacterium tuberculosis: Host immunity, compensatory evolution,...

The rpoB S450L mutation is the most prevalent high-fitness rifampicin resistance-conferring mutation in Mycobacterium tuberculosis. However, numerous alternative rpoB mutations associated with varying fitness costs have been reported, particularly in specific clinical settings. This systematic review critically evaluates the relationship between low-fitness rpoB mutations, host immune status, HIV co-infection, compensatory evolution, and diagnostic discordance.

A systematic literature search was conducted across multiple scientific databases. Studies reporting genetic, phenotypic, structural, or clinical data on rifampicin-resistant M. tuberculosis carrying alternative or borderline rpoB mutations were included. Data were qualitatively synthesized to examine associations among host immune status, bacterial fitness, compensatory evolution, and diagnostic performance.

Twenty-one studies met the inclusion criteria. Available clinical evidence indicated a higher prevalence of low-fitness non-S450L rpoB mutations, particularly at codons 430, 435, 441, and 445, among patients with advanced HIV infection. The available evidence suggests that HIV-associated immunosuppression may reduce host-driven purifying selection, facilitating the persistence of low-fitness resistant variants. Genomic and structural studies identified compensatory mutations in rpoA, rpoB, and rpoC that may partially restore bacterial fitness while maintaining rifampicin resistance. Several borderline rpoB mutations also produced discordant results between molecular assays and phenotypic drug susceptibility testing.

HIV-associated immunosuppression may influence the evolutionary trajectory of rifampicin-resistant M. tuberculosis by facilitating the persistence of low-fitness rpoB mutations. Integrating molecular diagnostics, genomic surveillance, and host immune profiling may improve the detection and clinical management of rifampicin-resistant tuberculosis, particularly in regions with a high burden of TB-HIV co-infection.