Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method

Carole D Mitnick¹, Richard A White², Chunling Lu³, Carly A Rodriguez⁴, Jaime Bayona⁵, Mercedes C Becerra⁶, Marcos Burgos⁷, Rosella Centis⁸, Theodore Cohen⁹, Helen Cox¹⁰, Lia D'Ambrosio¹¹, Manfred Danilovitz¹², Dennis Falzon¹³, Irina Y Gelmanova¹⁴, Maria T Gler¹⁵, Jennifer A Grinsdale¹⁶, Timothy H Holtz¹⁷, Salmaan Keshavjee⁶, Vaira Leimane¹⁸, Dick Menzies¹⁹, Giovanni Battista Migliori⁸, Meredith B Milstein²⁰, Sergey P Mishustin²¹, Marcello Pagano²², Maria I Quelapio²³, Karen Shean²⁴, Sonya S Shin²⁵, Arielle W Tolman⁴, Martha L van der Walt²⁶, Armand Van Deun²⁷, Piret Viiklepp²⁸; Collaborative Group for Analysis of Bacteriology Data in MDR-TB Treatment

Affiliations

¹ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA carole_mitnick@hms.harvard.edu.
² Dept of Infectious Disease Epidemiology, Norwegian Institute of Public Health, Oslo, Norway Dept of Health Statistics, Norwegian Institute of Public Health, Oslo, Norway.
³ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA.
⁴ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Socios en Salud Sucursal, Lima, Peru.
⁶ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA.
⁷ Dept of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁸ WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy.
⁹ Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
¹⁰ Médecins Sans Frontières, Cape Town, South Africa.
¹¹ WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy Public Health Consulting Group, Lugano, Switzerland.
¹² Tartu University Hospital, Lung Clinic, Tartu, Estonia.
¹³ Global TB Programme, World Health Organization, Geneva, Switzerland.
¹⁴ Partners in Health Russia, Moscow, Russia.
¹⁵ Makati Medical Center, Manila, Philippines.
¹⁶ Tuberculosis Control, San Francisco Department of Public Health, San Francisco, CA, USA.
¹⁷ US Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁸ State Agency for Tuberculosis and Lung Diseases (TPSVA), Riga, Latvia.
¹⁹ Montreal Chest Institute, McGill University, Montreal, QC, Canada.
²⁰ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA.
²¹ Tomsk TB and Pulmonary Medical Center, Tomsk Oblast, Russia.
²² Dept of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
²³ Tropical Disease Foundation, Philippine Institute of Tuberculosis, Makati City, Philippines.
²⁴ Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Dept of Medicine, University of Cape Town, Cape Town, South Africa.
²⁵ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA Socios en Salud Sucursal, Lima, Peru.
²⁶ South African Medical Research Council, Tuberculosis Research Platform, Pretoria, South Africa.
²⁷ Institute of Tropical Medicine, Antwerp, Belgium.
²⁸ National Institute for Heath Development, Tallinn, Estonia.

PMID: 27587552
PMCID: PMC5045442
DOI: 10.1183/13993003.00462-2016

Meta-Analysis

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method

Carole D Mitnick et al. Eur Respir J. 2016 Oct.

. 2016 Oct;48(4):1160-1170.

doi: 10.1183/13993003.00462-2016. Epub 2016 Sep 1.

Authors

Affiliations

¹ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA carole_mitnick@hms.harvard.edu.
² Dept of Infectious Disease Epidemiology, Norwegian Institute of Public Health, Oslo, Norway Dept of Health Statistics, Norwegian Institute of Public Health, Oslo, Norway.
³ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA.
⁴ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
⁵ Socios en Salud Sucursal, Lima, Peru.
⁶ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA.
⁷ Dept of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁸ WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy.
⁹ Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
¹⁰ Médecins Sans Frontières, Cape Town, South Africa.
¹¹ WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy Public Health Consulting Group, Lugano, Switzerland.
¹² Tartu University Hospital, Lung Clinic, Tartu, Estonia.
¹³ Global TB Programme, World Health Organization, Geneva, Switzerland.
¹⁴ Partners in Health Russia, Moscow, Russia.
¹⁵ Makati Medical Center, Manila, Philippines.
¹⁶ Tuberculosis Control, San Francisco Department of Public Health, San Francisco, CA, USA.
¹⁷ US Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁸ State Agency for Tuberculosis and Lung Diseases (TPSVA), Riga, Latvia.
¹⁹ Montreal Chest Institute, McGill University, Montreal, QC, Canada.
²⁰ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA.
²¹ Tomsk TB and Pulmonary Medical Center, Tomsk Oblast, Russia.
²² Dept of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
²³ Tropical Disease Foundation, Philippine Institute of Tuberculosis, Makati City, Philippines.
²⁴ Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Dept of Medicine, University of Cape Town, Cape Town, South Africa.
²⁵ Dept of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA Partners in Health, Boston, MA, USA Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA Socios en Salud Sucursal, Lima, Peru.
²⁶ South African Medical Research Council, Tuberculosis Research Platform, Pretoria, South Africa.
²⁷ Institute of Tropical Medicine, Antwerp, Belgium.
²⁸ National Institute for Heath Development, Tallinn, Estonia.

PMID: 27587552
PMCID: PMC5045442
DOI: 10.1183/13993003.00462-2016

Abstract

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

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Conflict of interest statement

can be found alongside this article at erj.ersjournals.com

Figures

**FIGURE 1**
Search strategy and results. MDR-TB: multidrug-resistant tuberculosis; CDC: US Centers for Disease Control and Prevention; XDR-TB: extensively drug-resistant tuberculosis.

**FIGURE 2**
Intra-observation agreement of smear and culture during the first 24 months of treatment, stratified by treatment outcome.

**FIGURE 3**
The timing of failure detection in the last 12 months of treatment within and across the monitoring strategies. Data are presented as hazard ratio (95% CI). IQR: interquartile range.

**FIGURE 4**
Stratified analysis of failure detection in the last 12 months of treatment, comparing monthly smear to monthly culture. Panel a) presents individual (by study) and pooled hazard ratios (95% confidence intervals). Panel b) presents hazard ratios (95% confidence intervals) stratified by risk factors. BMI: body mass index. HR: isoniazid–rifampicin.

See this image and copyright information in PMC

References

1. World Health Organization. Global Tuberculosis Report 2014. Geneva, World Health Organization, 2014. WHO/HTM/TB/2014.08.
1. Keshavjee S, Farmer PE. Picking up the pace – scale-up of MDR tuberculosis treatment programs. N Engl J Med 2010; 363: 1781–1784. - PubMed
1. World Health Organization. Guidelines for the Programmatic Management of Drug-resistant Tuberculosis: Emergency Update 2008. Geneva, World Health Organization, 2008.
1. Wang M, Guan X, Chi Y, et al. . Chinese herbal medicine as adjuvant treatment to chemotherapy for multidrug-resistant tuberculosis (MDR-TB): a systematic review of randomised clinical trials. Tuberculosis 2015; 95: 364–372. - PubMed
1. Gammino VM, Taylor AB, Rich ML, et al. . Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects. Int J Tuberc Lung Dis 2011; 15: 1315–1322. - PubMed

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Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method

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Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method

Authors

Affiliations

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Conflict of interest statement

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