Aliasgar Esmail1,2, Suzette Oelofse1,2, Carl Lombard3,4, Rubeshan Perumal1,2, Linda Mbuthini1, Akhter Goolam Mahomed5, Ebrahim Variava6,7,8, John Black9, Patrick Oluboyo10, Nelile Gwentshu11, Eric Ngam11, Tertius Ackerman12, Linde Marais12, Lynelle Mottay1,2, Stuart Meier1,2, Anil Pooran1,2, Michele Tomasicchio1,2, Julian Te Riele13, Brigitta Derendinger14, Norbert Ndjeka15, Gary Maartens16, Robin Warren14, Neil Martinson17,18, Keertan Dheda1,2,19. 1. Division of Pulmonology, Department of Medicine, Centre for Lung Infection and Immunity, University of Cape Town Lung Institute, Cape Town, South Africa. 2. Centre for the Study of Antimicrobial Resistance, South African Medical Research Council, and. 3. Biostatistics Unit, South African Medical Research Council, Cape Town, South Africa. 4. Division of Epidemiology and Biostatistics, Department of Global Health, University of Stellenbosch, Cape Town, South Africa. 5. Department of Intensive Care, Medunsa Campus, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa. 6. Department of Internal Medicine, and. 7. Department of Health, North West Province, Mahikeng, South Africa. 8. Perinatal HIV Research Unit, Soweto, South Africa. 9. Department of Internal Medicine, Livingstone Tertiary Hospital, Walter Sisulu University, Gqeberha, South Africa. 10. Department of Medicine, Head of Pulmonology, Nelson Mandela Academic Hospital, Walter Sisulu University, Mthatha, South Africa. 11. Don Makenzie Hospital, Durban, South Africa. 12. Harry Comay Hospital, George, South Africa. 13. Brooklyn Chest Hospital, Cape Town, South Africa. 14. Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa. 15. Drug Resistant Tuberculosis Directorate, National Department of Health, Pretoria, South Africa. 16. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 17. Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa. 18. Johns Hopkins University Center for Tuberculosis Research, Baltimore, Maryland; and. 19. Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Abstract
Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).
Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).