The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study.
BACKGROUND
Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance.


METHODS
In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers.


RESULTS
Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control.


CONCLUSIONS
Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.
Department of Global Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. a.h.vanthoog@aighd.org.|Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands. a.h.vanthoog@aighd.org.
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AH
Van't Hoog
KIT Biomedical Research, Royal Tropical Institute, Amsterdam, The Netherlands. i.bergval@kit.nl.
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Bergval
National Tuberculosis Reference Laboratory, National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia. marikushane@yahoo.com.
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Tukvadze
KIT Biomedical Research, Royal Tropical Institute, Amsterdam, The Netherlands. s.sengstake@kit.nl.
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Sengstake
National Tuberculosis Reference Laboratory, National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia. asporusiko@yahoo.com.
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Aspindzelashvili
KIT Biomedical Research, Royal Tropical Institute, Amsterdam, The Netherlands. r.anthony@kit.nl.
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Anthony
Department of Global Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. f.cobelens@aighd.org.|Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands. f.cobelens@aighd.org.|KNCV Tuberculosis Foundation, The Hague, The Netherlands. f.cobelens@aighd.org.
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Cobelens
D000995:Antitubercular Agents / Q000627:therapeutic use; D003365:Costs and Cost Analysis; D003428:Cross Infection / Q000188:drug therapy / Q000517:prevention & control; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D042241:Early Diagnosis; D005846:Georgia (Republic); D057166:High-Throughput Screening Assays / Q000191:economics / Q000379:methods*; D006801:Humans; D017053:Infection Control; D008875:Middle Aged; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000302:isolation & purification; D013183:Sputum / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000188:drug therapy / Q000191:economics / Q000235:genetics*
D000995:Antitubercular Agents