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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Bacterial factors that predict relapse after tuberculosis therapy
New England Journal of Medicine, Volume 379, No. 9, Year 2018
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Description
BACKGROUND Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort). RESULTS In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P = 0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. CONCLUSIONS In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases). Copyright © 2018 Massachusetts Medical Society.
Authors & Co-Authors
Kim, Soyeon
United States, Piscataway
Rutgers School of Public Health
Ma, Shuyi
United States, Seattle
Seattle Biomedical Research Institute
Chakravorty, Soumitesh
United States, Newark
Rutgers new Jersey Medical School
Sizemore, Erin E.
United States, Atlanta
Centers for Disease Control and Prevention
Diem, Lois A.
United States, Atlanta
Centers for Disease Control and Prevention
Sherman, David R.
United States, Seattle
Seattle Biomedical Research Institute
Okwera, Alphonse
United States, Cleveland
Case Western Reserve University
Dietze, Reynaldo
Brazil, Vitoria
Universidade Federal do Espírito Santo
Boom, W. Henry
United States, Cleveland
University Hospitals Case Medical Center
Johnson, John L.
United States, Cleveland
University Hospitals Case Medical Center
Kenzie, William R.Mac
United States, Atlanta
Centers for Disease Control and Prevention
Alland, David
United States, Newark
Rutgers new Jersey Medical School
Statistics
Citations: 86
Authors: 12
Affiliations: 7
Identifiers
Doi:
10.1056/NEJMoa1715849
ISSN:
00284793
Research Areas
Health System And Policy
Study Design
Cohort Study