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Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data.
PLoS Med 2020; 17(1):e1003008PM

Abstract

BACKGROUND

The 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 FINDINGS

Aggregated 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 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2-6.4) and Belarus (5.3%, 95% CI 0.1-26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%-80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%-16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%-8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries.

CONCLUSIONS

In this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen.

Authors+Show Affiliations

Global TB Programme, World Health Organization, Geneva, Switzerland.Global TB Programme, World Health Organization, Geneva, Switzerland.Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.Global TB Programme, World Health Organization, Geneva, Switzerland.Global TB Programme, World Health Organization, Geneva, Switzerland.Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.Department of Genetics, University of Cambridge, Cambridge, United Kingdom.Global TB Programme, World Health Organization, Geneva, Switzerland.Global TB Programme, World Health Organization, Geneva, Switzerland.Centre for Tuberculosis, National Institute for Communicable Diseases, Johannesburg, South Africa.National TB Reference Laboratory, National Tuberculosis Control Programme, Islamabad, Pakistan.National TB Reference Laboratory, Research Institute for Tropical Medicine, Muntinlupa City, Philippines.Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.Main Medical Department, Ministry of Justice, Baku, Azerbaijan.National TB Reference Laboratory, Dhaka, Bangladesh.Global TB Programme, World Health Organization, Geneva, Switzerland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31961877

Citation

Dean, Anna S., et al. "Prevalence and Genetic Profiles of Isoniazid Resistance in Tuberculosis Patients: a Multicountry Analysis of Cross-sectional Data." PLoS Medicine, vol. 17, no. 1, 2020, pp. e1003008.
Dean AS, Zignol M, Cabibbe AM, et al. Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data. PLoS Med. 2020;17(1):e1003008.
Dean, A. S., Zignol, M., Cabibbe, A. M., Falzon, D., Glaziou, P., Cirillo, D. M., ... Floyd, K. (2020). Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data. PLoS Medicine, 17(1), pp. e1003008. doi:10.1371/journal.pmed.1003008.
Dean AS, et al. Prevalence and Genetic Profiles of Isoniazid Resistance in Tuberculosis Patients: a Multicountry Analysis of Cross-sectional Data. PLoS Med. 2020;17(1):e1003008. PubMed PMID: 31961877.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data. AU - Dean,Anna S, AU - Zignol,Matteo, AU - Cabibbe,Andrea Maurizio, AU - Falzon,Dennis, AU - Glaziou,Philippe, AU - Cirillo,Daniela Maria, AU - Köser,Claudio U, AU - Gonzalez-Angulo,Lice Y, AU - Tosas-Auget,Olga, AU - Ismail,Nazir, AU - Tahseen,Sabira, AU - Ama,Maria Cecilia G, AU - Skrahina,Alena, AU - Alikhanova,Natavan, AU - Kamal,S M Mostofa, AU - Floyd,Katherine, Y1 - 2020/01/21/ PY - 2019/06/28/received PY - 2019/12/05/accepted PY - 2020/1/22/entrez PY - 2020/1/22/pubmed PY - 2020/1/22/medline SP - e1003008 EP - e1003008 JF - PLoS medicine JO - PLoS Med. VL - 17 IS - 1 N2 - BACKGROUND: The 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 FINDINGS: Aggregated 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 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2-6.4) and Belarus (5.3%, 95% CI 0.1-26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%-80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%-16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%-8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries. CONCLUSIONS: In this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/31961877/Prevalence_and_genetic_profiles_of_isoniazid_resistance_in_tuberculosis_patients:_A_multicountry_analysis_of_cross-sectional_data L2 - http://dx.plos.org/10.1371/journal.pmed.1003008 DB - PRIME DP - Unbound Medicine ER -