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.

Safety and Effectiveness of Highly Active Antiretroviral Therapy in Treatment-Naïve HIV Patients: Preliminary Findings of a Cohort Event Monitoring Study in Belarus.

BACKGROUND AND OBJECTIVE: Antiretroviral drugs have well-documented evidence-based favorable benefit-risk ratios. Although various studies have investigated and characterized the safety profile of antiretroviral medicines, there are a limited number of studies evaluating the safety of first-line antiretroviral therapy (ART) in patients with a specific co-morbidity. A cohort event monitoring (CEM) study of the safety and effectiveness of antiretroviral medicines in a target population that has a significant level of co-morbidities (chronic infectious diseases, peripheral blood cytopenias) was implemented. The aim was to evaluate the safety profile of the highly active ART (HAART) in the target population and subpopulations with risk factors, to optimize the monitoring and decision-making procedure for subgroups of patients with specific types of co-morbidity, and to implement a more vigilant approach to therapy management in risk groups of patients. METHODS: Prospective observational CEM was implemented among HAART-naïve HIV-positive patients at four clinical sites from December 2012. Eligible patients were those starting first-line HAART. Close medical supervision of all enrolled patients, with regular clinical and laboratory monitoring, was provided by healthcare professionals within 1 year after commencement of therapy. Standardized forms were used for data collection on initial and subsequent visits. All objective or subjective deviations in condition (events) were assessed for a causal relationship with ART, and for severity, seriousness, reversibility, preventability, and pre-existing risk factors in the case of adverse drug reactions (ADRs). RESULTS: A total of 518 HAART-naïve HIV-positive patients were enrolled in the CEM study. Of these patients, 65% (337) experienced one or several ADRs related to one or more components of HAART. Most of the ADRs reported were non-serious, expected, common (very common), transient (correctable), or reversible. The most common were hematotoxic, hepatotoxic, and neurotoxic adverse reactions. In several cases, some types of toxicities, associated with zidovudine, efavirenz, and nevirapine, had a high level of severity, necessitating hospitalization and drug regimen or single-agent substitution. Severe cases of hematological, hepatobiliary, and psychiatric toxicities were associated with pre-existing risk factors. CONCLUSION: CEM is an effective tool for safety and effectiveness monitoring and could be successfully implemented for intensive study of important safety issues and for overcoming knowledge gaps regarding safety. In order to achieve a favorable benefit-risk ratio for HAART in the specific sections of the population with pre-existing risk factors for development of ART toxicities, more vigilant consideration and careful assessment before therapy is commenced and further regular monitoring of key laboratory parameters is required.