Effectiveness and safety of delamanid- or bedaquiline-containing regimens among children and adolescents with multidrug resistant or extensively drug resistant tuberculosis: A nationwide study from Belarus, 2015-19.

There is limited evidence describing the safety and effectiveness of bedaquiline and delamanid containing regimens in children and adolescents with Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) globally. In this nationwide descriptive cohort study from Belarus, we examined adverse drug events, time to culture conversion, treatment outcomes including post-treatment recurrence among children and adolescents (<18 years of age) treated with bedaquiline and/or delamanid containing regimens from 2015 to 2019. Of the 40 participants included (55% females; age range 10-17 years), 20 (50%) had XDR-TB and 15 (38%) had resistance to either fluoroquinolone or second-line injectable. Half of the patients received delamanid and another half received bedaquiline with one patient receiving both drugs. AEs were reported in all the patients. A total of 224 AEs were reported, most of which (76%) were mild in nature. Only 10 (5%) AEs were graded severe and one AE was graded life-threatening. A total of 7 AEs (3%) were classified as 'serious' and only one patient required permanent discontinuation of the suspected drug (linezolid). Most of the AEs (94%) were resolved before the end of treatment. All patients culture-positive at baseline (n=34) became culture-negative within three months of treatment. Median time to culture conversion was 1.1 months (interquartile range: 0.9-1.6). Two patients were still receiving treatment at the time of analysis. The remaining 38 patients successfully completed treatment. Among those eligible and assessed at 6 (n=32) and 12 months (n=27) post-treatment, no recurrences were detected. In conclusion, treatment of children and adolescents with MDR-TB and XDR-TB using bedaquiline and/or delamanid containing regimens was effective and had favourable safety profile. Achieving such excellent outcomes under programmatic settings is encouraging for other national tuberculosis programmes, which are in the process of introducing or scaling-up the use of these new drugs in their countries.

Effectiveness and cardiovascular safety of delamanid-containing regimens in adults with multidrug-resistant or extensively drug-resistant tuberculosis: A nationwide cohort study from Belarus, 2016-18.

To address the sub-optimal treatment outcomes among patients with multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the National TB Programme in Belarus started using new drugs such as bedaquiline and delamanid in 2015-16. In this study, we assessed cardiovascular safety and effectiveness (culture conversion, treatment outcomes and post-treatment recurrence) of delamanid-containing regimens among adults (>18 years) with MDR-TB or XDR-TB from June 2016 to February 2018. This was a nationwide cohort study involving analysis of routinely collected programme data from the national and six regional TB hospitals. Cardiovascular adverse events (AEs) were classified as serious or not, based on international guidelines. We conducted Cox proportional hazards regression and calculated adjusted hazards ratio(aHR) and 95% confidence intervals(CI) to evaluate factors associated with AEs and unsuccessful treatment outcomes (death, failure and lost-to-follow-up). Of 125 patients enrolled (35, 28% females; mean age 43 years), 85(68%) had XDR-TB. All the patients received delamanid and 20 patients received both delamanid and bedaquiline. Cardiovascular AEs (177 episodes in total), were observed in the majority (73%) of patients but were mild and managed easily. The most common cardiovascular AEs were QTcF prolongation (64/177, 36%) and other electrocardiography (ECG) abnormalities (40/177, 23%). There were two instances of serious AEs leading to death, both of which were not related to delamanid. In multivariable analysis, male sex (aHR 0.72; 95% CI 0.51-0.99), and baseline ECG abnormalities (aHR 1.68; 95% CI 1.19-2.36) were associated with cardiovascular AEs. Median time to culture conversion was 1.1 months (interquartile range: 1.0-2.1). Culture conversion was observed in 115 (92%) patients at six months of treatment and 110 (88%) completed the treatment successfully. Loss to follow-up, failure and death were observed in 6%, 4% and 2% patients respectively. Among those assessed at 12 months post-treatment (n=33), recurrence was seen in one patient. The only factor associated with unsuccessful treatment outcomes in multivariable analysis was baseline Hepatitis C co-infection (aHR 3.61; 95% CI 1.09-11.95). In conclusion, treatment using delamanid-containing regimens was effective and had a favourable safety profile. We hope our findings inform the development of national clinical guidelines and scale-up of new drugs in other countries.