Jonathon R Campbell1, Anete Trajman2, Victoria J Cook3, James C Johnston4, Menonli Adjobimey5, Rovina Ruslami6, Lisa Eisenbeis7, Federica Fregonese8, Chantal Valiquette8, Andrea Benedetti1, Dick Menzies9. 1. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill International TB Centre, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada; Department of Epidemiology and Biostatistics, McGill University, Montréal, QC, Canada. 2. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill International TB Centre, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada; Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 3. Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Provincial TB Services, British Columbia Centre for Disease Control, Vancouver, BC, Canada. 4. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill International TB Centre, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada; Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Provincial TB Services, British Columbia Centre for Disease Control, Vancouver, BC, Canada. 5. National Hospitalier Universitaire de Pneumo-Phtisiologie, Cotonou, Benin. 6. Department of Biomedical Sciences, Division of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. 7. University of Alberta, Edmonton, AB, Canada. 8. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill International TB Centre, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada. 9. Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill International TB Centre, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada; Department of Epidemiology and Biostatistics, McGill University, Montréal, QC, Canada. Electronic address: dick.menzies@mcgill.ca.
Abstract
BACKGROUND: An important problem limiting treatment of latent tuberculosis infection is the occurrence of adverse events with isoniazid. We combined populations from phase 2 and phase 3 open-label, randomised controlled trials, to establish risk factors for adverse events during latent tuberculosis infection treatment. METHODS: We did a post-hoc safety analysis based on data from two open-label, randomised controlled trials done in health-care facilities in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea. Participants were consenting adults (aged ≥18 years) with a positive latent tuberculosis infection diagnostic test, indication for treatment, and without contraindications torifampicin or isoniazid. Patients were centrally randomly assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5 mg/kg isoniazid. The primary outcome evaluated was adverse events (including grade 1-2 rash and all events of grade 3-5) resulting in permanent discontinuation of study medication and judged possibly or probably related to study drug by a masked, independent, three-member adjudication panel (trial registration: NCT00170209; NCT00931736). FINDINGS:Participants were recruited from April 27, 2004, up until Jan 31, 2007 (phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety populations for each group comprised 3205 individuals receivingisoniazid and 3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280 who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to -0·5). Age was associated with adverse events in adults receiving isoniazid. Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0 (1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of 1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group. INTERPRETATION: In patients without a contraindication, rifampicin is likely to be the safest latent tuberculosis infection treatment option. With more widespread use of rifampicin, rare, but serious adverse events might be seen. However, within these randomised trials, rifampicin was safer than isoniazid and adverse events were not associated with older age. Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety. FUNDING: Canadian Institutes of Health Research.
RCT Entities:
BACKGROUND: An important problem limiting treatment of latent tuberculosis infection is the occurrence of adverse events with isoniazid. We combined populations from phase 2 and phase 3 open-label, randomised controlled trials, to establish risk factors for adverse events during latent tuberculosis infection treatment. METHODS: We did a post-hoc safety analysis based on data from two open-label, randomised controlled trials done in health-care facilities in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea. Participants were consenting adults (aged ≥18 years) with a positive latent tuberculosis infection diagnostic test, indication for treatment, and without contraindications to rifampicin or isoniazid. Patients were centrally randomly assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5 mg/kg isoniazid. The primary outcome evaluated was adverse events (including grade 1-2 rash and all events of grade 3-5) resulting in permanent discontinuation of study medication and judged possibly or probably related to study drug by a masked, independent, three-member adjudication panel (trial registration: NCT00170209; NCT00931736). FINDINGS:Participants were recruited from April 27, 2004, up until Jan 31, 2007 (phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety populations for each group comprised 3205 individuals receiving isoniazid and 3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280 who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to -0·5). Age was associated with adverse events in adults receiving isoniazid. Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0 (1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of 1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group. INTERPRETATION: In patients without a contraindication, rifampicin is likely to be the safest latent tuberculosis infection treatment option. With more widespread use of rifampicin, rare, but serious adverse events might be seen. However, within these randomised trials, rifampicin was safer than isoniazid and adverse events were not associated with older age. Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety. FUNDING: Canadian Institutes of Health Research.
Authors: Lufina Tsirizani-Galileya; Elasma Milanzi; Randy Mungwira; Titus Divala; Jane Mallewa; Donnie Mategula; Nginache Nampota; Victor Mwapasa; Andrea Buchwald; Matthew B Laurens; Miriam K Laufer; Joep J Van Oosterhout Journal: Medicine (Baltimore) Date: 2022-09-30 Impact factor: 1.817