Kathryn Schnippel1, Norbert Ndjeka2, Gary Maartens3, Graeme Meintjes4, Iqbal Master5, Nazir Ismail6, Jennifer Hughes7, Hannetjie Ferreira8, Xavier Padanilam9, Rodolfo Romero10, Julian Te Riele11, Francesca Conradie12. 1. Health Economics Unit, School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. 2. National TB Programme, South African National Department of Health, Pretoria, South Africa. Electronic address: norbert.ndjeka@health.gov.za. 3. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 4. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. 5. King Dinizulu Hospital Complex, Kwazulu Natal Department of Health, Durban, South Africa. 6. Centre for Tuberculosis, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa; Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa. 7. Médecins sans Frontières, Khayelitsha, Cape Town, South Africa. 8. Klerksdorp Tshepong Hospital Complex, North West Department of Health, Klerksdorp, South Africa. 9. Sizwe Tropical Disease Hospital, Gauteng Department of Health, Johannesburg, South Africa. 10. District Clinical Specialist Team, Northern Cape Department of Health, Namakwa, South Africa. 11. Brooklyn Chest Hospital, Cape Town, South Africa. 12. Right to Care, Johannesburg, South Africa; University of Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa.
Abstract
BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline. METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. FINDINGS: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens. INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. FUNDING: None.
BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline. METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. FINDINGS: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens. INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. FUNDING: None.
Authors: Francesca Conradie; Andreas H Diacon; Nosipho Ngubane; Pauline Howell; Daniel Everitt; Angela M Crook; Carl M Mendel; Erica Egizi; Joanna Moreira; Juliano Timm; Timothy D McHugh; Genevieve H Wills; Anna Bateson; Robert Hunt; Christo Van Niekerk; Mengchun Li; Morounfolu Olugbosi; Melvin Spigelman Journal: N Engl J Med Date: 2020-03-05 Impact factor: 91.245
Authors: Max R O'Donnell; Nesri Padayatchi; Amrita Daftary; Catherine Orrell; Kelly E Dooley; K Rivet Amico; Gerald Friedland Journal: Lancet HIV Date: 2019-03 Impact factor: 12.767
Authors: S D Masuku; R Berhanu; C Van Rensburg; N Ndjeka; S Rosen; L Long; D Evans; B E Nichols Journal: Int J Tuberc Lung Dis Date: 2020-04-01 Impact factor: 2.373
Authors: Payam Nahid; Sundari R Mase; Giovanni Battista Migliori; Giovanni Sotgiu; Graham H Bothamley; Jan L Brozek; Adithya Cattamanchi; J Peter Cegielski; Lisa Chen; Charles L Daley; Tracy L Dalton; Raquel Duarte; Federica Fregonese; C Robert Horsburgh; Faiz Ahmad Khan; Fayez Kheir; Zhiyi Lan; Alfred Lardizabal; Michael Lauzardo; Joan M Mangan; Suzanne M Marks; Lindsay McKenna; Dick Menzies; Carole D Mitnick; Diana M Nilsen; Farah Parvez; Charles A Peloquin; Ann Raftery; H Simon Schaaf; Neha S Shah; Jeffrey R Starke; John W Wilson; Jonathan M Wortham; Terence Chorba; Barbara Seaworth Journal: Am J Respir Crit Care Med Date: 2019-11-15 Impact factor: 21.405