Federica Fregonese1, Shama D Ahuja2, Onno W Akkerman3, Denise Arakaki-Sanchez4, Irene Ayakaka5, Parvaneh Baghaei6, Didi Bang7, Mayara Bastos8, Andrea Benedetti9, Maryline Bonnet10, Adithya Cattamanchi11, Peter Cegielski12, Jung-Yien Chien13, Helen Cox14, Martin Dedicoat15, Connie Erkens16, Patricio Escalante17, Dennis Falzon18, Anthony J Garcia-Prats19, Medea Gegia18, Stephen H Gillespie20, Judith R Glynn21, Stefan Goldberg22, David Griffith23, Karen R Jacobson24, James C Johnston25, Edward C Jones-López24, Awal Khan22, Won-Jung Koh26, Afranio Kritski27, Zhi Yi Lan9, Jae Ho Lee28, Pei Zhi Li1, Ethel L Maciel29, Rafael Mello Galliez30, Corinne S C Merle31, Melinda Munang15, Gopalan Narendran32, Viet Nhung Nguyen33, Andrew Nunn34, Akihiro Ohkado35, Jong Sun Park28, Patrick P J Phillips36, Chinnaiyan Ponnuraja37, Randall Reves38, Kamila Romanowski39, Kwonjune Seung40, H Simon Schaaf19, Alena Skrahina41, Dick van Soolingen42, Payam Tabarsi6, Anete Trajman43, Lisa Trieu2, Velayutham V Banurekha32, Piret Viiklepp44, Jann-Yuan Wang13, Takashi Yoshiyama45, Dick Menzies46. 1. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, Canada. 2. Bureau of Tuberculosis Control, New York City Department of Health and Mental Hygiene, Queens, NY, USA. 3. University Medical Centre Groningen, Department of Pulmonary Diseases and Tuberculosis, University of Groningen, Groningen, Netherlands. 4. National Tuberculosis Control Program, Brasilia, Brazil. 5. Uganda Tuberculosis Research Consortium, Kampala, Uganda. 6. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Statens Serum Institut, Copenhagen, Denmark. 8. Epidemiology Department, Social Medicine Institute, University of Rio de Janeiro, Brazil. 9. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, Canada; Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada. 10. Institut de Recherche pour le Développement UM233, INSERM U1175, Université de Montpellier, Montpellier, France; Epicentre MSF, Paris, France. 11. Division of Pulmonary and Critical Care Medicine and Curry International Tuberculosis Center, University of California San Francisco, San Francisco, CA, USA. 12. Division of Global HIV and TB, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA. 13. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. 14. Division of Medical Microbiology and Institute of Infectious Diseases and Molecular Medicine University of Cape Town, Cape Town, South Africa. 15. Heart of England NHS Foundation Trust, Birmingham, UK. 16. KNCV Tuberculosis Foundation, Team The Netherlands and Elimination, The Hague, Netherlands. 17. Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Mayo Clinic Center for Tuberculosis, Mayo Clinic, Rochester, USA. 18. Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland. 19. Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 20. School of Medicine, University of St Andrews North Haugh, St Andrews, UK. 21. Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK. 22. Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA. 23. The University of Texas Health Science Center, Tyler, TX, USA. 24. Section of Infectious Diseases, Department of Medicine Boston University School of Medicine and Boston Medical Center, Boston, MA, USA. 25. Department of Medicine, University of British Columbia, Vancouver, BC, Canada; British Columbia Centre for Disease Control, Vancouver, BC, Canada. 26. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 27. Academic Tuberculosis Program, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 28. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, South Korea. 29. Laboratory of Epidemiology, Federal University of Espirito Santo, Espírito Santo, Brazil. 30. State Institute of Infectology São Sebastião, Center for Research and Tuberculosis, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 31. Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK. 32. Department of Clinical Research, The National Institute for Research in Tuberculosis, Chennai, India. 33. National Lung Hospital, Ba Dinh, Hanoi, Vietnam; Hanoi Medical University, Hanoi, Vietnam. 34. Medical Research Council UK Clinical Trials Unit, University College London, London, UK. 35. Department of Epidemiology and Clinical Research, the Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan; Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. 36. Division of Pulmonary & Critical Medicine, University of California San Francisco, San Francisco, CA, USA. 37. The National Institute for Research in Tuberculosis, Chetpet, India. 38. Denver Public Health Department, Denver, CO, USA. 39. British Columbia Centre for Disease Control, Vancouver, BC, Canada. 40. Partners in Health, Boston, MA, USA. 41. Republican Scientific and Practical Centre of Pulmonology and Tuberculosis, Ministry of Health, Minsk, Belarus. 42. National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven, Netherlands. 43. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, Canada; Epidemiology Department, Social Medicine Institute, University of Rio de Janeiro, Brazil. 44. Estonian Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia. 45. Research Institute of Tuberculosis, Tokyo, Japan. 46. Montreal Chest Institute, McGill University Health Center Research Institute, McGill University, Montreal, Canada. Electronic address: dick.menzies@mcgill.ca.
Abstract
BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING: World Health Organization and Canadian Institutes of Health Research.
BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING: World Health Organization and Canadian Institutes of Health Research.
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