RESUMO
The risks and benefits of bedaquiline (BDQ) for treatment of drug-resistant tuberculosis (DR-TB) have not been firmly established. We aimed to assess the safety and efficacy of BDQ-containing regimens for the treatment of DR-TB as evidenced in available randomized controlled trials (RCTs). In this systematic review and meta-analysis, five databases (i.e., ClinicalTrials.gov, Cochrane CENTRAL, PubMed, ScienceDirect, and SinoMed) were searched. RCTs among DR-TB patients that had a control arm were eligible. The safety endpoints were all-cause mortality and serious adverse effects (SAEs). Efficacy outcomes were sputum culture conversion rate at 8-12 weeks and 24-26 weeks, treatment success, and time to culture conversion. A total of 476 records were screened; 18 met the eligibility criteria. The pooled analysis included 2520 participants (55.8% received BDQ-containing regimens, n = 1408). Pooled safety outcomes showed no significant reduction in all-cause mortality (relative risk [RR] [95%confidence interval (CI)] = 0.94 [0.41-2.20]) or SAEs (RR [95%CI] = 0.91 [0.67-1.23]) in the BDQ-regimen group. Pooled efficacy outcomes showed significantly superior culture conversion rates at 8-12 weeks (RR [95%CI] = 1.35 [1.10-1.65]) and 24-26 weeks (RR [95%CI] = 1.25 [1.15-1.36]), more treatment success (RR [95%CI] = 1.30 [1.17-1.44]), and a 17-day reduction in the time to culture conversion (standardized mean difference [SMD] [95%CI] = -17.46 [-34.82 to -0.11]) in the BDQ-regimen group (reference: non-BDQ regimen). Overall, BDQ regimens showed significant treatment effect against DR-TB but did not reduce mortality or SAEs.
Assuntos
Antituberculosos , Diarilquinolinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Diarilquinolinas/uso terapêutico , Diarilquinolinas/efeitos adversos , Antituberculosos/uso terapêutico , Antituberculosos/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Resultado do TratamentoRESUMO
Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.
Assuntos
Diarilquinolinas , Eletrocardiografia , Estudos de Viabilidade , Hanseníase , Rifampina , Humanos , Diarilquinolinas/administração & dosagem , Diarilquinolinas/efeitos adversos , Masculino , Adulto , Feminino , Hanseníase/tratamento farmacológico , Hanseníase/diagnóstico , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Pessoa de Meia-Idade , Hansenostáticos/efeitos adversos , Hansenostáticos/administração & dosagem , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Adulto Jovem , Quimioterapia Combinada/métodosAssuntos
Antituberculosos , Diarilquinolinas , Toxidermias , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Diarilquinolinas/efeitos adversos , Diarilquinolinas/uso terapêutico , Antituberculosos/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Toxidermias/etiologia , Toxidermias/patologia , Masculino , Adulto , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamenteRESUMO
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.
Assuntos
Antituberculosos , Eletrocardiografia , Síndrome do QT Longo , Moxifloxacina , Rifampina , Humanos , Rifampina/uso terapêutico , Rifampina/efeitos adversos , Masculino , Adulto , Feminino , Moxifloxacina/uso terapêutico , Moxifloxacina/efeitos adversos , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Pessoa de Meia-Idade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , África do Sul , Clofazimina/uso terapêutico , Clofazimina/efeitos adversos , Diarilquinolinas/uso terapêutico , Diarilquinolinas/efeitos adversos , República de BelarusRESUMO
INTRODUCTION: The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. METHODS: This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China. The trial design mainly mirrors that of the "Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB" (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority. DISCUSSION: PROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16. TRIAL REGISTRATION: ClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Adulto , Humanos , Antituberculosos , Ensaios Clínicos Fase IV como Assunto , Diarilquinolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
Multi and extensively drug-resistant tuberculosis is a grave cause of global public health concern due to its high mortality and limited treatment options. We conducted this systemic review and meta-analysis to evaluate the efficacy and safety of bedaquiline and delamanid, which have been added to the WHO-recommended regimen for treating drug-resistant tuberculosis. Electronic databases were searched from their inception until December 1st, 2021, for eligible studies assessing the efficacy and safety of bedaquiline and delamanid for treating drug-resistant tuberculosis. Binary outcomes were pooled using a DerSimonian-Laird random-effects model and arcsine transformation and reported on a log scale with a 95% confidence interval (CIs). Twenty-one studies were shortlisted in which bedaquiline, delamanid, and a combination of both were administered in 2477, 937, and 169 patients. Pooled culture conversion at 6 months was 0.801 (p < 0.001), 0.849 (p = 0.059) for bedaquiline and delamanid, respectively, and 0.823 (p = 0.017), concomitantly. In the bedaquiline cohort, the pooled proportion of all-cause mortality at 6 months was reported as 0.074 (p < 0.001), 0.031 (p = 0.372) in the delamanid cohort, and 0.172 in the combined cohort. The incidence of adverse events in the bedaquiline cohort ranged from 11.1% to 95.2%, from 13.2% to 86.2% in the delamanid cohort, and 92.5% in a study in the combined cohort. The incidence of QTC prolongation reported in each cohort is as follows: bedaquiline 0.163 (p < 0.001), delamanid 0.344 (p = 0.272) and combined 0.340 (p < 0.001). Our review establishes the efficacy of delamanid, bedaquiline, and their combined use in treating drug-resistant tuberculosis with reasonable rates of culture conversion, low mortality rates, and safety of co-administration, as seen with their effect on the QTc interval.
Assuntos
Antituberculosos , Diarilquinolinas , Nitroimidazóis , Oxazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/efeitos adversos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/efeitos adversos , Oxazóis/uso terapêutico , Oxazóis/efeitos adversos , Diarilquinolinas/uso terapêutico , Diarilquinolinas/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Adulto , Resultado do TratamentoRESUMO
AIMS: Bedaquiline, pretomanid and linezolid (BPaL) combination treatment against Mycobacterium tuberculosis is promising, yet safety and adherence concerns exist that motivate exploration of alternative dosing regimens. We developed a mechanistic modelling framework to compare the efficacy of the current and alternative BPaL treatment strategies. METHODS: Pharmacodynamic models for each drug in the BPaL combination treatment were developed using in vitro time-kill data. These models were combined with pharmacokinetic models, incorporating body weight, lesion volume, site-of-action distribution, bacterial susceptibility and pharmacodynamic interactions to assemble the framework. The model was qualified by comparing the simulations against the observed clinical data. Simulations were performed evaluating bedaquiline and linezolid approved (bedaquiline 400 mg once daily [QD] for 14 days followed by 200 mg three times a week, linezolid 1200 mg QD) and alternative dosing regimens (bedaquiline 200 mg QD, linezolid 600 mg QD). RESULTS: The framework adequately described the observed antibacterial activity data in patients following monotherapy for each drug and approved BPaL dosing. The simulations suggested a minor difference in median time to colony forming unit (CFU)-clearance state with the bedaquiline alternative compared to the approved dosing and the linezolid alternative compared to the approved dosing. Median time to non-replicating-clearance state was predicted to be 15 days from the CFU-clearance state. CONCLUSIONS: The model-based simulations suggested that comparable efficacy can be achieved using alternative bedaquiline and linezolid dosing, which may improve safety and adherence in drug-resistant tuberculosis patients. The framework can be utilized to evaluate treatment optimization approaches, including dosing regimen and duration of treatment predictions to eradicate both replicating- and non-replicating bacteria from lung and lesions.
Assuntos
Antituberculosos , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Diarilquinolinas/efeitos adversosRESUMO
OBJECTIVE: The study aimed to observe the efficacy and safety of an all-oral bedaquiline (BDQ)-containing regimen for pediatric multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) through a multicenter, retrospective study in China. METHODS: In the study, pediatric patients receiving all-oral BDQ-containing regimen (BDQ group) with clinical matched control group were included, the control group received an injection-containing regimen. The treatment outcomes and the incidence of adverse events (AEs) were compared and analyzed. RESULTS: 79 pediatric patients were enrolled, including 37 cases in BDQ group and 42 cases in the control group, the median age was 12 {8-16} and 11 {9-15} in both groups respectively. Favorable treatment outcome and cure rate in BDQ group were significantly higher than those in control group (100%vs 83.3%, p 0.03; 94.6%vs 63.3%, p 0.00). Median time of sputum culture conversion in BDQ group was significantly shorter than that in the control group (4 weeks vs 8 weeks, p 0.00). The incidence of AEs in the BDQ group was significantly less than that in the control group (48.6% vs 71.4%, p 0.03). No AEs leading to treatment discontinuation of BDQ occurred. CONCLUSIONS: The all-oral BDQ-containing regimens may be effective and safe in the Chinese pediatric population.
Assuntos
Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Criança , Rifampina/efeitos adversos , Estudos Retrospectivos , Estudos de Coortes , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Diarilquinolinas/efeitos adversosRESUMO
BACKGROUND: Implementation of newer anti-tuberculosis (TB) drugs may prolong the QT interval, increasing the risk of arrythmias and sudden cardiac death. The potential for cardiac adverse events has prompted recommendations for frequent cardiac monitoring during treatment. However, unknowns remain, including the association between drug concentrations and QT interval. METHODS: An observational prospective cohort study design was used. Patients undergoing treatment for drug-resistant TB in Georgia were assessed. Serial blood samples were collected at 4-6 weeks for pharmacokinetics. Electrocardiograms were recommended to be performed monthly. A generalized estimating equation spline model was used to investigate (1) the effect difference between bedaquiline and delamanid, (2) the cumulative effect of number of anti-TB drugs, and (3) the relationship between serum drug concentrations on QTc interval. RESULTS: Among 94 patients receiving either bedaquiline (n = 64) or delamanid (n = 30)-based treatment, most were male (82%), and the mean age was 39 years. The mean maximum QTc increase during the first six months was 37.5 ms (IQR: 17.8-56.8). Bedaquiline- and delamanid-based regimens displayed similar increased mean QTc change from baseline during drug administration (P = 0.12). Increasing number of anti-TB drugs was associated with an increased QTc (P = 0.01), but participants trended back towards baseline after drug discontinuation (P = 0.25). A significant association between AUC, Cmin, Cmax, and increased QTc interval was found for bedaquiline (months 1-6) and levofloxacin (months 1-12). CONCLUSION: Bedaquiline- and delamanid-based regimens and increasing number of QT prolonging agents led to modest increases in the QTc interval with minimal clinical effect.
Assuntos
Síndrome do QT Longo , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Masculino , Adulto , Feminino , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Estudos Prospectivos , Diarilquinolinas/efeitos adversos , Nitroimidazóis/efeitos adversos , Nitroimidazóis/farmacocinética , Oxazóis/efeitos adversos , Oxazóis/farmacocinética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Síndrome do QT Longo/induzido quimicamenteRESUMO
Antimicrobial resistance in Mycobacterium tuberculosis is a serious threat to global tuberculosis(TB) control. WHO listed bedaquiline as one of the first-choice drugs for the treatment of MDR/RR-TB in 2018. Bedaquiline is marketed for adult patients with MDR-TB and XDR-TB. However, there are few studies of bedaquiline in adolescents, pregnant women, the elderly, and other special populations with drug-resistant TB. This paper aimed to review the effectiveness and safety of bedaquiline in the treatment of special populations of drug-resistant TB for the clinical use.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Adolescente , Adulto , Idoso , Feminino , Humanos , Gravidez , Antituberculosos/efeitos adversos , Diarilquinolinas/efeitos adversos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.
Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Estados Unidos , Rifampina/efeitos adversos , Linezolida/efeitos adversos , Antituberculosos/efeitos adversos , Tuberculose/tratamento farmacológico , Diarilquinolinas/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoAssuntos
Síndrome do QT Longo , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Diarilquinolinas/efeitos adversos , Antituberculosos/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Síndrome do QT Longo/induzido quimicamente , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).
Assuntos
Antituberculosos , Diarilquinolinas , Linezolida , Rifampina , Tuberculose Pulmonar , Humanos , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Etambutol/efeitos adversos , Etambutol/uso terapêutico , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Pirazinamida/efeitos adversos , Pirazinamida/uso terapêutico , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/complicações , Diarilquinolinas/efeitos adversos , Diarilquinolinas/uso terapêuticoRESUMO
BACKGROUND: Multidrug-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. METHODS: A 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. RESULTS: The 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. CONCLUSIONS: The 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.
Assuntos
Diarilquinolinas , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Diarilquinolinas/efeitos adversos , Antituberculosos/efeitos adversos , Estudos Prospectivos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Resultado do Tratamento , República da CoreiaRESUMO
The introduction of two novel drugs, bedaquiline and delamanid, has given hope for better and shorter treatments of drug-resistant tuberculosis. A systematic review was conducted to evaluate the efficacy and safety of concomitant bedaquiline and delamanid administration. Pooled estimates of World Health Organization-defined favorable treatment outcome and significant QTc-interval prolongation (QTc ≥500 ms or ≥60 ms increase from baseline) were calculated using a random-effects model. Thirteen studies including a total of 1031 individuals with multidrug-resistant/rifampicin-resistant tuberculosis who received bedaquiline and delamanid were included. The pooled estimate of favorable treatment outcome was 73.1% (95% confidence interval [CI]: 64.3-81.8%). Sputum culture conversion at 6 months ranged from 61% to 95%. Overall, the pooled proportion of QTc-prolongation was 7.8% (95% CI: 4.1-11.6%) and few cardiac events were reported (0.8%; n = 6/798). Rates of sputum culture conversion and favorable treatment outcome were high in patients treated concomitantly with bedaquiline and delamanid, and the treatment seemed tolerable with low rates of clinically significant cardiac toxicity.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Antituberculosos/efeitos adversos , Diarilquinolinas/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Nitroimidazóis/efeitos adversos , Oxazóis/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: World Health Organization recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR). METHODS: Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid [LZD], clofazimine, and/or pyrazinamide) for patients with RR-TB without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021. RESULTS: A total of 108 patients were enrolled in this study. Overall, 63 of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, six (6%) were lost-to-follow-up, one (1%) died, and four (4%) had treatment failure, including three with permanent regimen change owing to adverse events (AE) and one with culture reversion. Of 108, 32 (30%) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening, or death). The median time to AE was 3 months (IQR: 2-5). A total of 26 AEs led to regimen adaptation: either dose reduction (N = 1), drug temporary interruption (N = 19), or drug permanent discontinuation (N = 6, 4 attributed to LZD). CONCLUSION: The high treatment success of 5-drug mSTR might replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using LZD throughout.
Assuntos
Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/efeitos adversos , Rifampina/efeitos adversos , Vietnã , Estudos Prospectivos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Diarilquinolinas/efeitos adversos , Linezolida/uso terapêuticoRESUMO
Corrected QT duration (QTc) interval prolongation is the most frequent adverse event associated with bedaquiline (BDQ) use. It may affect the safety of antituberculosis therapy, which leads to the consequent demands of needing to monitor during therapy. Our objective was to establish and validate a prediction model for estimating the risk of QTc prolongation after initiation of BDQ-containing regimens to multidrug-resistant tuberculosis (MDR-TB) patients. We constructed an individualized nomogram model based on baseline demographic and clinical characteristics of each patient within a Chinese cohort during BDQ treatment. The generalizability of this model was further validated through use of externally acquired data obtained from Beijing Chest Hospital from 2019 to 2020. Overall, 1,215 and 165 patients were included in training and external validation cohorts, respectively, whereby during anti-TB drug treatment, QTc prolongation was observed in 273 (22.5%) and 29 (17.6%) patients within these respective cohorts, for whom QTc values were >500 ms in 86 (31.5%) and 10 (34.7%) patients, respectively. Next, a total of four Cox proportional hazards models were created and assessed; then, nomograms derived from the models were plotted based on independent predictors of clofazimine, baseline QTc interval, creatinine, extensive drug-resistance (XDR), moxifloxacin, levofloxacin, and sex. Nomogram analysis revealed concordance index values of 0.723 (95% confidence interval [CI], 0.695 to 0.750) for the training cohort and 0.710 (95% CI, 0.627 to 0.821) for the external validation cohort, thus indicating relatively fair agreement between predicted and observed probabilities of QTc prolongation occurrence based on data obtained during 8-week, 16-week, and 24-week anti-TB treatment of both cohorts. Taken together, results obtained using these models demonstrated that coadministration of clofazimine and abnormal baseline QTc interval significantly contributed to QTc prolongation development during MDR-TB patient treatment with a BDQ-containing anti-TB treatment regimen.
Assuntos
Síndrome do QT Longo , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/efeitos adversos , Clofazimina/uso terapêutico , Creatinina , Diarilquinolinas/efeitos adversos , Humanos , Levofloxacino/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico , Moxifloxacina/efeitos adversos , Nomogramas , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).
Assuntos
Antituberculosos , Linezolida , Nitroimidazóis , Tuberculose Resistente a Múltiplos Medicamentos , Aminoglicosídeos/uso terapêutico , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Diarilquinolinas/efeitos adversos , Fluoroquinolonas , Humanos , Linezolida/efeitos adversos , Linezolida/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Rifampina/uso terapêutico , Medição de Risco , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.
Assuntos
Diarilquinolinas , Nitroimidazóis , Diarilquinolinas/efeitos adversos , Eletrocardiografia , Frequência Cardíaca , Humanos , Nitroimidazóis/efeitos adversos , OxazóisRESUMO
BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µgâ â â h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in childrenâ ≥â 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.