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Background: Drug resistance and HIV co-infection are challenges for the global control of tuberculosis. Methods: We collected Mycobacterium tuberculosis isolates from adult patients in Cote d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing (DST) was done locally and at the Swiss tuberculosis reference laboratory. We examined mortality during treatment according to DST results and treatment adequacy in logistic regression models adjusting for sex, age, sputum microscopy and HIV status. Findings: 634 tuberculosis patients were included; median age was 33.2 years, 239 (37.7%) were female, 272 (42.9%) HIV-positive and 69 (10.9%) patients died. Based on the reference laboratory DST, 394 (62.2%) strains were pan-susceptible, 45 (7.1%) mono-resistant, 163 (25.7%) multidrug-resistant (MDR-TB), and 30 (4.7%) had pre-extensive or extensive drug resistance (pre-XDR/XDR-TB). Results of reference and local laboratories were discordant in 121 (19.1%) cases, corresponding to a sensitivity of 84.3% and a specificity of 90.8%. In patients with drug-resistant tuberculosis, discordant results were associated with increased mortality (risk ratio 1.81; 95% CI 1.07-3.07). In logistic regression, compared to adequately treated patients with pan-susceptible strains, the adjusted odds ratio for death was 4.23 (95% CI 2.16-8.29) for adequately treated patients with drug-resistant strains and 21.54 (95% CI 3.36-138.1) for inadequately treated patients with drug-resistant strains. HIV status was not associated with mortality. Interpretation: Using a reference laboratory standard, inaccurate DST leading to inappropriate treatment of drug-resistant tuberculosis, but not HIV infection, contributed to mortality. Funding Statement: This research was supported by the Swiss National Science Foundation (grant numbers 153442, 310030_166687 and 174281), the National Institutes of Allergy and Infectious Diseases (NIAID) under award numbers U01 AI096299, U01 AI069919, U01 AI069924, U01 AI069911, U01 AI069907, U01 AI096186, and U01 AI069923, and Swiss National Center for Mycobacteria, University of Zurich, Switzerland. Declaration of Interests: AA has received honoraria fees from Jensen-Cilag, Gilead and Bristol-Myers Squibb. All other authors have no conflicts of interest to declare. Ethics Approval Statement:Local institutional review boards or ethics committees approved the study at all participating sites. Informed consent was obtained where requested per local regulations. The study was also approved by the Cantonal Ethics Committee in Bern, Switzerland. |
