title: Epidemiology of isoniazid resistance mutations and their effect on tuberculosis treatment outcomes.
abstract: Isoniazid resistance is highly prevalent in Vietnam. We investigated the molecular and epidemiological characteristics and the association with first-line treatment outcomes of the main isoniazid resistance mutations in Mycobacterium tuberculosis in codon 315 of the katG and in the promoter region of the inhA gene. Mycobacterium tuberculosis strains with phenotypic resistance to isoniazid from consecutively diagnosed smear-positive tuberculosis patients in rural Vietnam were subjected to Genotype MTBDRplus testing to identify katG and inhA mutations. Treatment failure and relapse were determined by sputum culture. In total, 227 of 251 isoniazid-resistant strains (90.4%) had detectable mutations: 75.3% in katG codon 315 (katG315) and 28.2% in the inhA promoter region. katG315 mutations were significantly associated with pretreatment resistance to streptomycin, rifampin, and ethambutol but not with the Beijing genotype and predicted both unfavorable treatment outcome (treatment failure or death) and relapse; inhA promoter region mutations were only associated with resistance to streptomycin and relapse. In tuberculosis patients, M. tuberculosis katG315 mutations but not inhA mutations are associated with unfavorable treatment outcome. inhA mutations do, however, increase the risk of relapse, at least with treatment regimens that contain only isoniazid and ethambutol in the continuation phase.
authors.affiliation: Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam.
authors.forename: Mai N T
authors.initials: MN
authors.lastname: Huyen
authors.forename: Frank G J
authors.initials: FG
authors.lastname: Cobelens
authors.forename: Tran N
authors.initials: TN
authors.lastname: Buu
authors.forename: Nguyen T N
authors.initials: NT
authors.lastname: Lan
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Dung
authors.forename: Kristin
authors.initials: K
authors.lastname: Kremer
authors.forename: Edine W
authors.initials: EW
authors.lastname: Tiemersma
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D003062:Codon; D024901:Drug Resistance, Multiple, Bacterial; D004977:Ethambutol / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012008:Recurrence; D012293:Rifampin / Q000494:pharmacology; D013307:Streptomycin / Q000494:pharmacology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000453:epidemiology*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D014744:Vietnam; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003062:Codon; D004977:Ethambutol; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D007538:Isoniazid; D012293:Rifampin; D013307:Streptomycin