Effectiveness and safety of delamanid-containing regimens in patients with drug-resistant tuberculosis and cardiovascular comorbidities

Aim. To study the effectiveness of treatment with delamanid-containing regimens in patients with multidrug-resistant and extensively drug-resistant tuberculosis and comorbid cardiovascular diseases, to assess the frequency, structure, and severity of adverse events in the cardiovascular system in this group of patients.
Materials and methods. The study included 125 adult patients with multidrug and extensive drug resistance who started treatment with delamanid-containing regimens from July 2016 to February 2018 at the Republican Research and Practical Center for Pulmonology and Tuberculosis and six regional anti-TB institutions. The main group included patients with multiple and extensive drug resistance and comorbid cardiovascular diseases (N = 46). The control group included patients with multiple and extensive drug resistance without comorbid cardiovascular diseases (N = 79). The formulation and coding of the diagnosis (the underlying disease and comorbid diseases (conditions)) corresponded to the International Classification of Diseases (ICD) of the 10th revision. Adverse events were classified according to the international dictionary MedDRA (Medical Dictionary for Regulatory Activities). The severity of adverse events classification complied with CTCAE (Common Terminology Criteria for Adverse Events). The severity of adverse events was determined in accordance with the definitions of ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), and the treatment outcomes were identified in accordance with clinical guidelines and WHO recommendations. The study materials were the data from the medical records of the patients in the E-Register “Tuberculosis”. Sputum culture conversion was defined as two consecutive negative test results. Treatment outcomes were classified as successful and unsuccessful. For the analysis of adverse events, each event was considered as a unit of analysis both in the aggregate of all adverse events in the cardiovascular system and in groups of patients. Testing of statistical hypotheses was carried out at a critical level of significance p = 0.05, i.e. the difference was considered statistically significant if p < 0.05.
Results. The effectiveness of treatment with delamanid-containing regimens in the group of patients with comorbid cardiovascular diseases was 88.0%, sputum conversion after 6 months of treatment (abacillation by culture) was observed in 93.0% of patients in this group, when compared no statistical difference was present in the effectiveness of treatment (p = 0.785) of the patients of the main group and those of the comparison group. In the analysis of long-term results, only one patient with cardiovascular comorbidity (3.0%) had a relapse of tuberculosis more than one year after successful treatment. 78.0% of patients of the main study group (with comorbid cardiovascular diseases) and 70.0% of the comparison group manifested cardiovascular adverse events during treatment. The most common adverse event in both groups was prolongation of the QTcF interval, which was recorded in 37.0% of patients with comorbid cardiovascular diseases and in 42.0% of patients without cardiovascular diseases (p = 0.597). Timely correction and careful monitoring of adverse events made it possible to avoid the development of life-threatening conditions in both groups of patients. In this regard, no withdrawal of anti-tuberculosis drugs was registered due to cardiovascular adverse events, including those due to the prolongation of the QTcF interval. The highest frequency of cardiovascular adverse events was detected during the first month of treatment of patients, then, in the course of treatment, it decreased, which may indirectly indicate the absence of a cumulative cardiotoxic effect of delamanid-containing treatment regimens.
Conclusions. Treatment with delamanid-containing regimens in adult patients with multidrug-resistant tuberculosis and comorbid cardiovascular disease was effective and had an overall favorable cardiovascular safety profile comparable to the comparison group. Despite a large number of cardiovascular adverse events, they were manageable at the program level (prevailing at the initial stages of treatment, having light, mild or moderate severity, having been relieved), which made it possible to complete anti-tuberculosis treatment with delamanid-containing regimens.

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