Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data

Abstract

BackgroundThe surveillance of drug resistance among tuberculosis (TB) patients is central to combatting the global TB epidemic and preventing the spread of antimicrobial resistance. Isoniazid and rifampicin are two of the most powerful first-line anti-TB medicines, and resistance to either of them increases the risk of treatment failure, relapse, or acquisition of resistance to other drugs. The global prevalence of rifampicin resistance is well documented, occurring in 3.4% (95% CI 2.5%-4.4%) of new TB patients and 18% (95% CI 7.6%-31%) of previously treated TB patients in 2018, whereas the prevalence of isoniazid resistance at global and regional levels is less understood. In 2018, the World Health Organization (WHO) recommended a modified 6-month treatment regimen for people with isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), which includes rifampicin, pyrazinamide, ethambutol, and levofloxacin. We estimated the global prevalence of Hr-TB among TB patients and investigated associated phenotypic and genotypic drug resistance patterns. Methods and findingsAggregated drug resistance data reported to WHO from either routine continuous surveillance or nationally representative periodic surveys of TB patients for the period 2003-2017 were reviewed. Isoniazid data were available from 156 countries or territories for 211,753 patients. Among these, the global prevalence of Hr-TB was 7.4% (95% CI 6.5%-8.4%) among new TB patients and 11.4% (95% CI 9.4%-13.4%) among previously treated TB patients. Additional data on pyrazinamide and levofloxacin resistance were available from 6 PLOS Medicine | https://doi.

Isoniazid resistance profile and associated levofloxacin and pyrazinamide resistance in rifampicin resistant and sensitive isolates/from pulmonary and extrapulmonary tuberculosis patients in Pakistan: A laboratory based surveillance study 2015-19

“…We studied 4542 INH resistant isolates for molecular markers and mutations causing INH resistance were identified in 85.5% with frequency of katG, inhA and combined katG and inhA mutations in 72.7%, 9.9% and 2.8% respectively. Our findings are consistent with the published data [11,12,30] but with a lower proportion of combined katG and inhA mutations in our population [12,31]. INH resistance profiles when studied, stratified by RMP results, significant differences were reported between RrHr-TB (n = 4078) and RsHr-TB(n = 464) with regard to proportion of INH conferring mutation detected (87.1% vs 71.6%) and frequency of the mutations in inhA (7.6 vs 30.2%), katG (76.3 vs 41.2%) and combined inhA and katG (3.1% vs 0.2%).…”

“…A high treatment success rates of at least 85% for new TB cases is regularly reported by all countries [7]. The estimated global prevalence of INH resistance among RMP sensitive new and previously treated TB (RsHr-TB) is 7.4% (95%CI: 6.5%-8.4%) and 11.4% (95%CI:9.4%-13.4%) respectively [12]. People infected with a TB strain that is resistant to INH, are reported to have a higher rate of unfavorable treatment outcomes with standard first line treatment [13].…”

“…Subsequently, DRS isolates were also tested for FQ and PZA resistance among RMP resistant and sensitive population as part of a multicounty surveillance project and FQ resistance was reported respectively in 21�8% (95%CI;13�1-30�5)and 11�1%(95%CI:7�8-14�3) and PZA resistance in 39.5% (30.1-48.9) and 0.5%(0.1-0.8) [14,15]. However there is limited published data on molecular markers for INH resistance [12]. We analyzed routine laboratory data to study diagnostic and clinical implications of the prevalent phenotypic and genotypic profile of INH resistance and LFX and PZA resistance associated with INH resistance in RMP resistant (RrHr) and sensitive (RsHr) isolates from pulmonary and extrapulmonary TB (EPTB) patients.…”

Clarity with INHindsight: High-Dose Isoniazid for Drug-Resistant Tuberculosis with inhA Mutations

“…Isoniazid has been a cornerstone of tuberculosis treatment and prevention since clinical introduction in the early 1950s and remains a key drug in the standard, first-line regimen. Its utility is threatened by expansion of drug-resistant tuberculosis; isoniazid monoresistance, estimated at 10% globally (although in some regions of the world as many as 27% of Mycobacterium tuberculosis strains have isoniazid resistance [1]), is associated with substantially worse treatment outcomes even with rifamycincontaining regimens (2). Multidrug resistance (MDR; resistance to at least isoniazid plus rifampin) requires longer and less-effective therapy, threatening the prospects of the global goal to end tuberculosis in the next decade (3).…”

“…This results in rapid killing of replicating bacilli at drug concentrations achieved with standard isoniazid dosing at 4 to 6 mg/kg, even for individuals with "fast acetylator" genotypes (5). Mutations in the inhA active site or promoter region, causing reduced target affinity or overexpression, respectively, lead to moderate minimum inhibitory concentration (MIC) elevations (0.25-2 mg/ml) (6) and are responsible for approximately 7% of isoniazid resistance globally (1). Because isoniazid displays dose-dependent EBA (7), higher doses may result in exposures that overcome inhA-mediated resistance and translate into efficacy.…”