Bedaquiline In Patients Research Articles

Bedaquiline in the postoperative period of complex therapy of tuberculosis

Introduction. The experience of domestic phthisiatry, which has been using bedaquiline for more than 10 years, testifies to the efficacy and safety of the drug for the treatment of drug-resistant forms of tuberculosis. At the present stage, the evaluation of the effect and safety of bedaquiline in the postoperative stage of chemotherapy, including patients with HIV/tuberculosis co-infection, becomes the most relevant.Aim. To evaluate the results of bedaquiline application in the postoperative stage of complex tuberculosis therapy.Materials and methods. Results of a retrospective study of medical records of 57 patients. The inclusion criterion was the surgery performed for tuberculosis and the presence of bedaquiline in the postoperative chemotherapy regimen. Frequency of tuberculosis progression 1 month after surgery was evaluated as an efficacy criterion. The frequency of QTc interval prolongation with clinical manifestations, frequency and nature of hepatotoxic reactions were evaluated as the drug safety criterion.Results. In the absolute majority of patients – 54 (94.7%) postoperative period, during which bedaquiline was used, proceeded without complications. Cases of tuberculosis progression were observed only in patients with severe concomitant diseases. Undesirable side effects on bedaquiline were observed in 9 (15.8%) patients, the absolute majority of patients resumed taking the drug in full after drug correction. The average duration of bedaquiline prescription was 282 ± 5 doses.Conclusions. The use of bedaquiline in the postoperative period increases the effectiveness of complex therapy and prevents progression of tuberculosis and according to our data should be regarded as safe. Administration of bedaquiline in patients with HIV/tuberculosis co-infection also contributes to the positive result of the therapy. Repeated courses of bedaquiline after surgical intervention, including in patients with HIV/tuberculosis co-infection, prevent progression of tuberculosis in the postoperative period. The tolerability of the bedaquiline-containing regimen in this category of patients, including long courses of more than 24 weeks, was assessed as quite satisfactory.

Comprehensive clinical evaluation of bedaquiline in the treatment of multidrug-resistant tuberculosis

Objective: To assess the clinical value of bedaquiline in five dimensions: effectiveness, safety, economics, appropriateness, and social benefits, to provide a reference for medical and health insurance-related decisions. Methods: A total of 792 patients with multidrug-resistant tuberculosis who were hospitalized at Wuhan Pulmonary Hospital, Ganzhou Fifth People's Hospital and Jiangxi Chest Hospital between January 2018 and December 2020 were included in the study. Based on a retrospective survey of case data, and each evaluation dimension of bedaquiline was statistically analyzed by causal analysis or chi-square test, using linezolid as the reference drug. Results: In terms of effectiveness, bedaquiline significantly increased treatment success by 23.9% (95%CI:4.8%-43.0%) and shortened treatment duration by 64 days(95%CI:18-109 days). In terms of safety, the incidence of adverse reactions to bedaquiline and the discontinuation rate of adverse reactions (5.11%,4.55%) were significantly lower than those for linezolid (22.49%,15.24%), with statistically significant differences (χ2=27.50,P<0.001;χ2=14.09,P<0.001). In terms of economics, patients treated with bedaquiline had a significantly higher anti-TB drug course cost of RMB 48 209.4 Yuan(95%CI: 28 336.0-68 082.8 Yuan). In terms of appropriateness, the proportion of bedaquiline in patients' initial treatment regimens was lower than that of linezolid (16.7% vs. 86.5%) in the 2020 observation sample, with a statistically significant difference (χ2=238.96,P<0.001). In terms of social benefits, the infection control rate was significantly increased by 27.8% (95%CI:8.2%-47.5%) in patients using bedaquiline. Conclusions: Bedaquiline performed well in terms of efficacy, safety, and social benefits. However, it was less economical and the actual use rate of bedaquiline in clinical practice was lower than that of its counterpart drug, linezolid. Price reductions might be needed to increase the clinical use and performance of bedaquiline in the future.

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Early efficacy of individual regimens containing bedaquiline in patients with drug resistant tuberculosis

Objective: To evaluate early efficacy of sputum conversion within 6 months of individual regimens containing bedaquiline in patients with drug resistant tuberculosis. Methods: We conducted a retrospective study among patients with drug resistant tuberculosis who were receiving individual regimens containing bedaquiline. The primary outcome was sputum conversion of both smear and culture within 6 months of treatment. We used medical records of drug resistant tuberculosis patients from January 2020 to December 2021. The study was conducted at Dr. Soetomo Hospital, Indonesia from August to October 2022. Results: In this study, 44 eligible drug resistant tuberculosis patients were initiated on regimens containing bedaquiline. There were 52.3% males and the median age was 45.5 years. The rates of previous treatment (70.5%) and lung cavity (36.4%) were high. The most common companion drugs included clofazimine, cycloserine, levofloxacin, and linezolid. Sputum smear and culture conversion was seen in 79.4% and 82.1% at the 2nd month, respectively. More than 97% patients had smear and culture conversion at the end of 6 months. Conclusions: Among drug resistant tuberculosis patients, individual regimens containing bedaquiline were associated with high rates of smear and culture conversion at the end of 6 months. Early efficacy of regimens containing bedaquiline can be used to predict cure rate at the end of treatment.

Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients.

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06mg (0.008-0.25mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400mg once daily for 14 days followed by 200mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

A prospective patient registry to monitor safety, effectiveness, and utilisation of bedaquiline in patients with multidrug-resistant tuberculosis in South Korea

BackgroundMultidrug-resistant tuberculosis (MDR-TB) represents a major public health concern, with an ongoing need for new effective treatments. Bedaquiline is an oral diarylquinoline that has shown encouraging treatment success and culture conversion rates in MDR-TB.MethodsA South Korean patient registry was set up across 19 centres between 2016 and 2018 for the prospective collection of data from patients with MDR-TB who received either a bedaquiline-containing or a non-bedaquiline-containing regimen. Treatment was at the physician’s discretion (bedaquiline use requiring approval by special committee) and was based on patient characteristics, disease status, and local treatment guidelines.ResultsThe safety population included 172 patients (88 bedaquiline and 84 non-bedaquiline). The mean (standard deviation, SD) duration of follow-up was 24.3 (9.5) months. Mean (SD) durations of treatment were 5.4 (1.8) months in bedaquiline-treated patients and 15.7 (6.7) months in the non-bedaquiline group. Treatment success (cured and treatment completed according to WHO 2013 treatment outcome definitions) was achieved by 56.3% of bedaquiline-treated and 45.2% of non-bedaquiline-treated patients. Sputum culture conversion rates were 90.4% and 83.7% with and without bedaquiline, respectively. Diarrhoea and nausea were the most frequently reported treatment-emergent adverse events (TEAEs) in the bedaquiline group (27.3% [24/88] and 22.7% [20/88], respectively). The most frequent bedaquiline-related TEAEs were prolonged QT interval (10.2%; 9/88), and diarrhoea and nausea (9.1% each; 8/88). QT interval prolongation was reported in 19.3% (17/88) of bedaquiline-treated and 2.4% (2/84) of non-bedaquiline-treated patients, but bedaquiline was not discontinued for any patient for this reason. There were 13 (14.7%) and three (3.6%) deaths in the bedaquiline-treated and non-bedaquiline groups, respectively. Review of fatal cases revealed no unexpected safety findings, and no deaths were bedaquiline-related. The most common cause of death was worsening cancer (three patients). Patients in the bedaquiline group tended to have poorer baseline risk profiles than non-bedaquiline patients and were more likely to have relapsed or already failed second-line treatment. Interpretation of mortality data was complicated by high rates of loss to follow-up in both groups.ConclusionsThe South Korean registry findings support previous risk/benefit observations and the continued use of bedaquiline as part of combination therapy in patients with MDR-TB.

Tolerability and Efficacy of Chemotherapy Containing Bedaquiline in Patients with Multiple Drug Resistant Pulmonary Tuberculosis

The objective: to evaluate safety and efficacy of bedaquiline in the treatment of patients with multiple drug resistant tuberculosis (MDR-TB).Subjects and Methods. Clinical data of 523 patients above 18 years old registered for MDR TB treatment as per regimen 4 were retrospectively analyzed. HIV-negative patients were selected and divided into two groups by the use of bedaquiline in the chemotherapy regimen.Results. In MDR TB treatment regimen containing bedaquiline, adverse reactions were observed in 95.7% of cases, the majority of them (65.2%) were of mild or moderate degree of severity. In 30.4% of such cases, bedaquiline was temporarily discontinued (mostly due to hepatotoxic reactions). No cardiotoxicity was observed as a response to bedaquiline, the median corrected QT interval made 413 ms, the maximum value was 438 ms. Adding bedaquiline to the regimen resulted in faster (in the first 3 months of treatment) and more frequent (in 94.7%) sputum conversion by culture (in the regimens with no bedaquiline, it was achieved in 63.8% of cases, p = 0.019). Treatment with regimens containing bedaquiline was effective in 82.61% of patients, while regimens with no bedaquiline were effective in 65.2% of cases, p = 0.085.

Bedaquiline in the treatment of extensively drugresistant tuberculosis

Introduction. Extensive drug resistance (XDR) M. Tuberculosis (MBT) is considered the main factor that reduces the effectiveness of the treatment of TB patients around the world, including Russia. A significant role in improving the effectiveness of chemotherapy (CT) in people with resistant TB belongs to the introduction of new anti-TB drugs, the first of which was bedaquiline (LP-002281).Objective. To assess the profile of an XDR-TB patient receiving bedaquiline and the efficacy of chemotherapy regimens including bedaquiline in patients with XDR pulmonary tuberculosis.Materials and methods. The study is retrospective, non-comparative, descriptive. The data of 88 patients who received bedaquiline in the XDR-TB treatment regimen in anti-tuberculosis institutions of the Saratov region in 2017–2018.Results. Patients with chronic TB prevailed – 50/88 [56.8%, 95% CI 46.3–67.4], every fourth patient had a history of surgery. The cessation of bacterial excretion, confirmed by bacterioscopy, was achieved in 51/67 [76.1%, 95% CI 65.7–86.5] patients; by cultural method – in 47/67 [70,1%, 95% CI 59.0–81.3]. Negative sputum smear in a significant proportion of patients 43/51 [84.3%, 95% CI 52.4–75.9] was observed after 12 weeks of therapy, negative cultures in 36/47 [76.6%, 95% CI 41.6–65.9] – after 16 weeks.Discussion. Compared to individual patient analyzes – 43% success rate in the treatment of XDR-TB, in our cohort of XDR-TB patients treated with bedaquiline, the success rate was 53.4%, which is consistent with data from a large study describing the safety in 2017, tolerability and efficacy of bedaquiline and could be higher in the absence of “discontinuations from treatment”.Conclusion. The regimens of treatment of patients with XDR-tuberculosis with the inclusion of bedaquiline are effective in terms of the termination of bacterial excretion, confirmed by bacterioscopy and culture in patients with a complex course of a specific process with previous ineffective therapy.

Population pharmacokinetics of bedaquiline in patients with drug-resistant TB.

OBJECTIVE: To develop a population pharmacokinetic (PK) model for bedaquiline (BDQ) to describe the concentration-time data from patients with multidrug-resistant TB (MDR-TB) in China.METHOD: A total of 306 PK observations from 69 patients were used in a non-linear, mixed-effects modelling (NONMEM) approach. BDQ PK can be adequately described by a three-compartment model with a transit absorption model. The impact of baseline covariates, including age, sex, height, weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST), apolipoprotein (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), creatinine (CR), potassium (K+), calcium (Ca++) and magnesium (Mg++) on the oral clearance (CL/F) of BDQ were investigated.RESULTS: In final population PK model, no significant covariates were found in the population PK model for BDQ. The population PK parameter estimate values for oral clearance (CL/F); CL/F between central compartment and peripheral compartment (Q1/F, Q2/F); peripheral volume of distribution (Vp1/F, VP2/F) were respectively 1.50 L/h (95% CI 1.07-1.93), 2.54 L/h (95% CI 1.67-3.41), 1,250 L (95% CI 616.9-1883.1), 2.00 L/h (95% CI 1.10-2.90) and 4,960 L (95% CI 1647.6-8272.4). Inter-individual variability on CL/F was 65.0%.CONCLUSION: This is the first study to establish a population PK model for BDQ in Chinese patients with MDR-TB. The final model adequately described the data and had good simulation characteristics. Despite some limitations, the final population PK model was stable with good accuracy of parameter estimation.

The potential perils of a drug protection framework in tuberculosis

When bedaquiline was approved by stringent regulatory agencies for the treatment of drug-resistant tuberculosis in 2012, it was as the first novel agent for the treatment of tuberculosis to be developed in almost 50 years. 1 Zumla A Gillespie S Hoelscher M et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances and future prospects. Lancet Infect Dis. 2014; 14: 327-340 Summary Full Text Full Text PDF PubMed Scopus (257) Google Scholar Given the gruelling therapeutic regimens being used for drug-resistant tuberculosis at the time—with success rates hovering at a dismal 50% globally—it would seem this novel medication would be embraced as a breakthrough and rapidly rolled out. 2 WHOGlobal TB Report 2012. https://www.who.int/tb/publications/global_report/gtbr12_main.pdfDate: 2012 Date accessed: August 14, 2021 Google Scholar However, data on bedaquiline use painted a different picture, with fewer than 20% of those in need of the medication actually receiving it by 2016. 3 Cox V Brigden G Crespo RH et al. Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2018; 22: 407-412 Crossref PubMed Scopus (32) Google Scholar Although multiple reasons were given for this low uptake of bedaquiline—including costs, safety concerns, and limited practical experience with its use—one often cited reason for denying people access to bedaquiline was fear of generating resistance to the medication. 4 Furin J Brigden G Lessem E et al. Global progress and challenges in the implementation of new medications for the treatment of multidrug-resistant tuberculosis. Emerg Infect Dis. 2016; 22e151430 Crossref PubMed Scopus (39) Google Scholar “We have to protect the drug” was a common mantra among those working in the field. In fact, so invested was the tuberculosis community in this framework of drug protection that early WHO recommendations on the use of bedaquiline specified it should only be given to people who had limited treatment options, either because of resistance or intolerance to other second-line medications 5 WHOThe use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim guidance. World Health Organization, Geneva2013 Google Scholar —a population vastly different from those included in the clinical trials that led to the purported evidence-based recommendations regarding how bedaquiline should be used. Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal studyBedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. Full-Text PDF

Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study

Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. National Institute for Communicable Diseases of South Africa.

Results of treatment with bedaquiline containing regimens of MDR/XDR tuberculosis patients including those with concurrent HIV infection (the experience of Leningrad Region)

The effectiveness of tuberculosis control is associated with efficacy of treatment of TB patients and above all patients with multiple and extensive drug resistance (MDR/XDR MTB). Patients with TB/HIV co-infection providethe significant impact on the situation.The objective of the studyis to assess outcomes of chemotherapy regimens containing bedaquiline in patients with MDR/XDR TB including those with concurrent HIV infection.Subjects and methods. The efficacy and safety of the regimes containing bedaquiline were assessed in the intensive phase of chemotherapy in 80 patients with MDR/XDR TB: Group1 consisted of 46 patients with negative HIV status (ICD10 code A15-A19); Group 2 – 34 HIV positive patients at the advanced stage with manifestations of a mycobacterial infection (ICD10 code B20.0).Results. Treatment outcomes in the groups were as follows: the effective treatment was statistically significantly more frequent in Group 1 versus Group 2 (80.4 and 52.9%, respectively, p = 0.0088). Treatment failure was registered in 3 patients from each group; treatment defaults were statistically significantly more frequent in Group 2 compared to Group 1: in 8/34 versus 2/46 (p = 0.011). 3 patients were transferred out in both Group 1 and Group 2 (3/46 and 3/34, p = 0.69). During treatment, only 1 patient from Group 2 developed an adverse event, most likely associated with the in-take of bedaquiline, a heart rhythm disorder (ventricular arrhythmia) and prolongation of QTcF &gt; 450 ms.

Adverse effects of bedaquiline in patients with extensively drug-resistant tuberculosis.

BackgroundThe World Health Organisation (WHO) guidelines recommend that, because of the resistance patterns of extensively drug-resistant (XDR) tuberculosis (TB) and its unique mechanism of action, bedaquiline be included in the regimen. Although the results of clinical trials have shown bedaquiline to be beneficial, it also carries the risk of adverse effects, some potentially life-threatening. The aim of the study was to determine the incidence of adverse effects caused by bedaquiline in patients diagnosed with XDR-TB. The subsequent management of these adverse effects was also analysed.MethodsThe medical records of patients aged 18 years or older living with XDR-TB who were prescribed bedaquiline in combination with a background regimen at a public-sector drug-resistant TB hospital in the Eastern Cape were reviewed.ResultsThirty records were reviewed in September 2016. Female patients constituted 66.67% (n = 20) of the sample. Nearly half (46.67%; n = 14) of the patients were living with human immunodeficiency virus, and six (42.86%) of them were female. Adverse effects were recorded for 26 patients (86.67%) including corrected QT prolongation (40%; n = 12), skin rash (33.33%; n = 10) and hyperlactataemia (33.33%; n = 10) as the most common. There were no treatment discontinuations or deaths. The management of adverse effects varied from omitting doses of bedaquiline to pharmacological intervention.ConclusionAll patients completed bedaquiline treatment, indicating that the adverse effects did not require discontinuation of the drug. However, when pharmacological intervention is required for the management of adverse effects, care should be taken to ensure that there is minimal interaction with other TB drugs and a low risk of further adverse effects.

Daily Dosing for Bedaquiline in Patients with Tuberculosis.

The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD. Using pharmacokinetic simulations, we explored alternative QD bedaquiline regimens and determined that 200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the approved regimen. This simpler regimen is under clinical evaluation.

A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis.

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline-delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline-delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.A bedaquiline-delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.

ЭФФЕКТИВНОСТЬ И БЕЗОПАСНОСТЬ ОСНОВАННЫХ НА ИСПОЛЬЗОВАНИИ БЕДАКВИЛИНА РЕЖИМОВ ХИМИОТЕРАПИИ У БОЛЬНЫХ ТУБЕРКУЛЕЗОМ ОРГАНОВ ДЫХАНИЯ: НЕПОСРЕДСТВЕННЫЕ И ОКОНЧАТЕЛЬНЫЕ РЕЗУЛЬТАТЫ

The objective of the study: to determine the efficacy and safety of chemotherapy regimens with bedaquiline in patients with respiratory tuberculosis in the context of everyday clinical practice with minimal non-inclusion criteria. Subjects and methods. In a prospective, open-label, non-randomized, single-center trial which included 315 patients, the efficacy and safety of chemotherapy regimens were evaluated, when prescribing a regimen the priority was given to bedaquiline, linezolid, levofloxacin/moxifloxacin, and cycloserine/terizidone. Patients were followed up for at least 24 months, 52.4% suffered from extensive drug resistance of M. tuberculosis (MTB), the majority of patients (50.8%) had a failure of the previous course of treatment, and serious co-morbidities were found in 89.5% of patients. Results. In 104 patients, the duration of treatment with bedaquiline was limited to standard 24 weeks, in 42 patients, it lasted for 36 weeks, in 56 patients – 48 weeks, and 94 patients received bedaquiline for more than 48 weeks. The increased duration of treatment with bedaquiline for more than 24 weeks provided a significant increase of treatment efficacy (regardless of drug resistance profile) from 66.2% (95% CI 54.4-77.9%) to 84.3% (95% CI 80.0-89.7%). The used regimens were well tolerated: serious adverse events (AE) were observed only in 27.6% of patients, and bedaquiline contribution to their development was not significant (bedaquiline had to be discontinued due to AE in 2.2% of cases). The range of AE practically did not differ from that when using only traditional anti-tuberculosis drugs.

Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis.

Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain. Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen. We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012-2014) and after (2015-2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider's perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%. For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted. Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease

Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease. We describe a case series of off-label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. The 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). The patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline. Common side effects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG findings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months. After 6 months of therapy, 60% of patients (six of 10) had a microbiologic response, with 50% (five of 10) having one or more negative cultures. This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but the findings require confirmation with larger studies.