Active drug-safety monitoring and management in the treatment of rifampicin-resistant tuberculosis: a nationwide multicenter prospective study

Background Active tuberculosis drug-safety monitoring and management (aDSM) is recommended in the treatment of rifampicin-resistant tuberculosis. We established comprehensive aDSM and conducted a nationwide multicenter prospective study in Taiwan. Methods We designed a treatment initiation form to capture characteristics of patients at baseline, a treatment review form to monitor symptoms, blood tests, QT intervals, and audiometry during treatment, and an adverse event report form for reporting severe adverse events (grade 3 or more), serious adverse events and adverse events resulting in discontinuation of anti-tuberculosis drugs. Severity of adverse events were categorized by using Common Terminology Criteria for Adverse Events v4.03, and causality was assessed by using the World Health Organization - Uppsala Monitoring Centre system. Results Of 333 patients with rifampicin-resistant tuberculosis enrolled from May 2017 to February 2020, 329 (98.8 %) had adverse events and 196 (58.9 %) had severe adverse events during treatment. The top three severe adverse events were metabolism disorders (104, 31.2 %), hearing impairment (102, 30.6 %), and hepatotoxicity (64, 19.2 %). Of 403 severe adverse events reported, 284 (70.5 %) were classified as drug-related. The top five drugs associated with severe adverse events were bedaquiline (27.6 %), clofazimine (26.7 %), kanamycin (25.1 %), pyrazinamide (22.4 %) and linezolid (22.2 %). Forty-four (13.2 %) patients were hospitalized and 15 (4.5 %) had prolonged hospitalization due to adverse events. One death was considered drug-related. Conclusion Severe adverse events in the treatment of rifampicin-resistant tuberculosis were more frequent than previously reported and needed to be closely monitored and timely managed by systematic and comprehensive aDSM.