Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea

Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea Abstract Objectives Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB. Methods We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea. Results A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5–81) using solid medium and 57 days (range = 8–96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms. Conclusions The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB. Introduction The current treatment for MDR-TB is long, complicated and toxic. As a result, poor treatment outcomes are inevitable; successful treatment was achieved in only 52% and high frequency of loss to follow-up (15%) and death (17%) was observed in a 2013 MDR-TB cohort.1 In addition, the treatment success rate in patients with XDR-TB was only 26%. The lack of effective drugs is the main challenge for current MDR-TB control. New drugs, bedaquiline and delamanid, have been recently introduced and promise to improve the treatment outcomes of MDR-TB. Delamanid significantly improved the 2 month culture conversion in a Phase IIb randomized controlled trial (Trial 204)2 and treatment outcomes (treatment success and mortality) in an extended observational study (Trial 208/116).3 A mortality benefit was also observed in XDR-TB.4 Based on this evidence, delamanid was granted a conditional regulatory approval by the EMA and the WHO published interim policy guidance on delamanid use in 2014.5 Because delamanid has just been recently introduced, few published data exist on delamanid use outside clinical trials. While clinical trials could provide more objective evidence, data about real-world experience are also important to fill the knowledge gap between clinical trials and actual clinical practice. Recently, two studies regarding early outcomes for patients with MDR/XDR-TB treated with delamanid were published and showed encouraging results.6,7 However, these two studies were conducted under a compassionate use programme rather than a routine programmatic setting. In South Korea, delamanid was introduced in routine clinical practice in November 2015. The objective of this study is to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen in a routine, programmatic setting for MDR‐TB treatment. Materials and methods Study sites and subjects In South Korea, a total of 39245 patients with TB, 852 with MDR-TB and 59 with XDR-TB were newly notified in 2016.8 Delamanid was approved by the regulatory authority in October 2014 and has been marketed from November 2015 in South Korea. Delamanid is approved for the treatment of pulmonary MDR-TB in adults as part of an appropriate background regimen when an effective treatment regimen cannot be administered because of resistance or intolerability to existing anti-TB drugs. If properly used for the above indication, national medical insurance provides reimbursement for the total cost for 24 weeks of delamanid treatment. During the early periods, the attending physicians individually decided on the administration of delamanid, according to the WHO guidelines.5,9 From the official notification in September 2016, the national expert committee has reviewed all delamanid and bedaquiline uses. When physicians intend on prescribing delamanid or bedaquiline to their patients, it is mandatory for them to submit an application form to the committee prior to administering these drugs. The committee grants approval of use, as well as comments on background regimens. We retrospectively screened patients with MDR/XDR-TB who received delamanid for at least 1 month from 1 November 2015 to 31 January 2017 at six university affiliated hospitals and one national TB hospital in South Korea. To evaluate the interim outcomes as well as the safety and tolerability of a delamanid-containing regimen, we included patients with MDR/XDR-TB who completed delamanid treatment by 31 January 2017, i.e. patients who completed 24 weeks of delamanid treatment or stopped delamanid treatment prematurely. Study design and data collection This is a retrospective multicentre observational cohort study. Patient selection and treatment regimen design were conducted independently in each hospital in accordance with the WHO guidelines.5,9 The anti-TB agents were administered under directly observed therapy during hospitalization and subsequently self-administered after discharge. Delamanid was administered at a dose of 100 mg twice daily for 24 weeks. Data were retrospectively extracted from the medical records. The objective of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen. We determined the proportion of negative culture conversion of sputum at 8 and 24 weeks of delamanid treatment, time to sputum smear and culture conversion, and frequency of serious adverse events, discontinuation of delamanid and QT prolongation. Efficacy evaluation was performed in patients who had positive culture sputum at the time of initiation of delamanid treatment. The culture was performed using both liquid medium (BACTEC MGIT 960 system; BD Diagnostic Systems, Sparks, MD, USA) and solid medium (Ogawa medium). However, only one of these media was used in some patients. Sputum examinations were repeated every 1 or 2 weeks until culture conversion and at least monthly thereafter. Drug susceptibility testing (DST) was conducted for 15 anti-TB drugs using an absolute concentration method in the Korean Institute of Tuberculosis, Osong, South Korea. DST for delamanid was not conducted. The tested drugs and their critical concentrations for resistance were as follows: 0.2 mg/L isoniazid; 40 mg/L rifampicin; 2.0 mg/L ethambutol; 20 mg/L rifabutin; 10 mg/L streptomycin; 40 mg/L amikacin; 40 mg/L kanamycin; 40 mg/L capreomycin; 2.0 mg/L ofloxacin; 2.0 mg/L levofloxacin; 2.0 mg/L moxifloxacin; 40 mg/L prothionamide; 30 mg/L cycloserine; and 1.0 mg/L para-aminosalicylic acid. Pyrazinamide susceptibility was determined by a pyrazinamidase test. Safety evaluation was performed in all included patients. Adverse drug reaction (ADR) was graded based on the Common Terminology Criteria for Adverse Events.10 The grade of ADR and its relation to delamanid were evaluated by the attending physician in each hospital. ECG data were collected at baseline and subsequently at 1, 2, 4, 8, 12, 16, 20 and 24 weeks of delamanid treatment. The protocol of this study was approved and the requirement for obtaining an informed consent was waived by the Institutional Review Board of all participating hospitals. Definitions MDR-TB was defined as TB that was resistant to both isoniazid and rifampicin. XDR-TB was defined as MDR-TB further resistant to any fluoroquinolone and at least one of the three second-line injectable drugs (SLIDs; kanamycin, amikacin or capreomycin). Pre-XDR-TB was defined as MDR-TB further resistant to either a fluoroquinolone or any SLID, but not both. Uncomplicated MDR-TB was defined as MDR-TB without additional resistance to fluoroquinolones and SLIDs. Baseline data were defined as the data collected at the time of initiation of delamanid treatment. Sputum smear and culture conversion were defined as two consecutive negative results, collected at least 30 days apart, in a patient with a positive specimen at baseline. The time of sputum smear or culture conversion was defined as the day of sputum collection for the first of two consecutive negative results. A serious adverse event was defined as any ADR that results in any of the following outcomes: death, life-threatening event, hospitalization, disability or permanent damage, required intervention to prevent permanent impairment or damage, and other serious important medical events. QT interval was corrected for heart rate using Fridericia's Correction Formula (QTcF).11 A prolongation of the QT interval was defined as an increase in QTcF of ≥60 ms from the baseline or QTcF of >500 ms at any timepoint.12 Statistical analysis Continuous variables are presented as medians with ranges or means with standard deviations, and categorical variables are presented as frequencies and percentages. One-way analysis of variance was used to assess intergroup differences in continuous variables. Pearson’s χ2 test or Fisher’s exact test was used to compare categorical variables. The Kaplan–Meier curve was used to determine the time to sputum smear and culture conversion. P < 0.05 was considered significant. The statistical analyses were performed using SPSS Statistics, version 17.0 (SPSS Inc., Chicago, IL, USA). Results Patient characteristics A total of 62 patients received delamanid for at least 1 month in the study sites during the study period; 30 of them were excluded because they were still taking delamanid on 31 January 2017. None of them prematurely and permanently discontinued delamanid. A total of 32 patients were included and all completed 24 weeks of delamanid treatment. The median age was 44.5 years (range = 22–82) and 22 (68.8%) were male (Table 1). All patients were HIV negative. Of the 32 patients, 12 (37.5%) had at least one comorbidity. Table 1. Baseline demographics and clinical characteristics of 32 patients with MDR-TB Characteristic  n (%) or median (range)  Male  22 (68.8)  Age (years)  44.5 (22–82)  Weight (kg)  55.0 (40.1–86.5)  BMI (kg/m2)  20.2 (13.5–33.8)  Ever a smoker  11 (34.4)  Alcohol abuse  1 (3.1)  Comorbiditya  12 (37.5)  Previous TB treatment   new  12 (37.5)   first-line drug only  3 (9.4)   second-line drug  17 (53.1)  Radiological finding   severity    minimal  10 (31.2)    moderate advanced  6 (18.8)    far advanced  16 (50.0)   extent, bilateral  19 (59.4)   cavity  20 (62.5)  Smear positive  14 (43.8)  Culture positive  19 (59.4)  Number of resistant drugs  9 (2–13)  Drug-resistance pattern   uncomplicated MDRb  6 (18.8)   pre-XDR with SLID resistance  4 (12.5)   pre-XDR with fluoroquinolone resistance  16 (50.0)   XDR  6 (18.8)  Characteristic  n (%) or median (range)  Male  22 (68.8)  Age (years)  44.5 (22–82)  Weight (kg)  55.0 (40.1–86.5)  BMI (kg/m2)  20.2 (13.5–33.8)  Ever a smoker  11 (34.4)  Alcohol abuse  1 (3.1)  Comorbiditya  12 (37.5)  Previous TB treatment   new  12 (37.5)   first-line drug only  3 (9.4)   second-line drug  17 (53.1)  Radiological finding   severity    minimal  10 (31.2)    moderate advanced  6 (18.8)    far advanced  16 (50.0)   extent, bilateral  19 (59.4)   cavity  20 (62.5)  Smear positive  14 (43.8)  Culture positive  19 (59.4)  Number of resistant drugs  9 (2–13)  Drug-resistance pattern   uncomplicated MDRb  6 (18.8)   pre-XDR with SLID resistance  4 (12.5)   pre-XDR with fluoroquinolone resistance  16 (50.0)   XDR  6 (18.8)  a Twelve patients had comorbidities as follows: diabetes mellitus was the most common (n = 4, 12.5%), followed by cardiovascular disease (n = 3, 9.4%), chronic respiratory disease (n = 3, 9.4%), chronic kidney disease (n = 2, 6.3%), gout (n = 2, 6.3%), psychiatric disease (n = 2, 6.3%) and chronic liver disease (n = 1, 3.1%). b MDR-TB without additional resistance to fluoroquinolones and SLIDs. All patients had pulmonary TB, of which two had concomitant extrapulmonary TB (meningitis and pleurisy, respectively). When patients were categorized based on their previous treatment histories, 12 (37.5%) were new patients, 3 (9.4%) had been treated previously with the first-line drugs only and 17 (53.1%) had been treated previously with second-line drugs. A median of 9 (range = 2–13) of the 15 tested drugs showed resistance on baseline DST. Drug susceptibilities and companion drugs are shown in Table 2. When patients were categorized based on drug-resistance pattern, 6 (18.8%) had uncomplicated MDR-TB, 4 (12.5%) had pre-XDR-TB with SLID resistance, 16 (50.0%) had pre-XDR-TB with fluoroquinolone resistance and 6 (18.8%) had XDR-TB. Table 2. Drug susceptibilities and companion drugs among 32 patients with MDR-TB Drug  Resistant drug  Companion drug  Isoniazid  32 (100)  0  Rifampicin  32 (100)  0  Rifabutin  22 (68.8)  0  Ethambutol  25 (78.1)  6 (18.8)  Pyrazinamide  14 (43.8)  20 (62.5)  Streptomycin  13 (40.6)  2 (6.3)  Kanamycin  9 (28.1)  7 (21.9)  Amikacin  6 (18.8)  13 (40.6)  Capreomycin  9 (28.1)  0  Ofloxacin  20 (62.5)  0  Levofloxacin  21 (65.6)  5 (15.6)  Moxifloxacin  16 (50.0)  12 (37.5)  Prothionamide  15 (46.9)  17 (53.1)  Cycloserine  8 (25.0)  23 (71.9)  Para-aminosalicylic acid  9 (28.1)  8 (25.0)  Linezolid  ND  23 (71.9)  Clofazimine  ND  8 (25.0)  Amoxicillin/clavulanate  ND  9 (28.1)  Meropenem  ND  2 (6.3)  Clarithromycin  ND  2 (6.3)  Drug  Resistant drug  Companion drug  Isoniazid  32 (100)  0  Rifampicin  32 (100)  0  Rifabutin  22 (68.8)  0  Ethambutol  25 (78.1)  6 (18.8)  Pyrazinamide  14 (43.8)  20 (62.5)  Streptomycin  13 (40.6)  2 (6.3)  Kanamycin  9 (28.1)  7 (21.9)  Amikacin  6 (18.8)  13 (40.6)  Capreomycin  9 (28.1)  0  Ofloxacin  20 (62.5)  0  Levofloxacin  21 (65.6)  5 (15.6)  Moxifloxacin  16 (50.0)  12 (37.5)  Prothionamide  15 (46.9)  17 (53.1)  Cycloserine  8 (25.0)  23 (71.9)  Para-aminosalicylic acid  9 (28.1)  8 (25.0)  Linezolid  ND  23 (71.9)  Clofazimine  ND  8 (25.0)  Amoxicillin/clavulanate  ND  9 (28.1)  Meropenem  ND  2 (6.3)  Clarithromycin  ND  2 (6.3)  ND, not done. Data are presented as n (%). Treatment Of the 32 patients, 23 (71.9%) received delamanid within 30 days from the initiation of MDR-TB treatment, while 9 (28.1%) received it as an add-on to their existing regimen at a median of 251 days (range = 67–404) from the initiation of MDR/XDR-TB treatment. The treatment regimen included a median of five companion drugs (range = 4–9), of which a median of three drugs (range = 1–5) were susceptible on DST and a median of two drugs (range = 0–5) were susceptible and had never been previously used. A median of one drug (range = 0–4) in group 5 was administered to 23 (71.9%) patients. The companion drugs administered to 32 patients are shown in Table 2. Injectable drugs were administered to 22 (68.8%) patients, fluoroquinolones to 17 (53.1%), linezolid to 23 (71.9%) and clofazimine to 8 (25.0%). One patient received a lobectomy after 8 weeks of delamanid treatment. Twenty (62.5%) patients were hospitalized for a median of 51.5 days (range = 3–445) from delamanid initiation. Microbiological outcome Efficacy evaluation was performed in 19 patients (59.4%) who had positive culture sputum at baseline. Culture results of both liquid and solid media were available in 13 patients, only solid medium in five patients and only liquid medium in one patient. The proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. Only one patient failed to achieve culture conversion during 24 weeks of delamanid treatment. This patient had previously failed to respond to treatment with second-line drugs and was infected with an MDR-TB strain that was additionally resistant to fluoroquinolones and prothionamide. All of the 13 patients who had negative cultures at baseline maintained a culture-negative status at 24 weeks of delamanid treatment. The median time to culture conversion was 33 days (range = 5–81) using solid medium and 57 days (range = 8–96) using liquid medium. The median time to smear conversion was 50 days (range = 7–141) in 14 patients who had smear-positive sputums at baseline. Safety and tolerability Safety and tolerability were assessed in all the 32 patients included in the study. During the 24 weeks of treatment with a delamanid-containing regimen, 75 ADRs were reported in 25 (78.1%) patients. Of these, 48 ADRs in 18 patients were considered possibly (81.3%), probably (12.5%) and definitely (6.3%) related to delamanid (Table 3). The most frequent ADRs were nausea, vomiting and dyspepsia. The majority of ADRs were considered as grade 1 (50.0%) or grade 2 (43.8%). Grade 3 ADR was QT prolongation, which occurred in three patients. Serious adverse event or death was not observed. All the 32 patients completed the 24 weeks of delamanid treatment. Four patients transiently discontinued delamanid (two experienced QTcF interval of >500 ms probably due to delamanid, one experienced elevated ALT probably due to pyrazinamide and one experienced tremor probably due to linezolid). Table 3. ADRs related to delamanid among 32 patients with MDR-TB ADR  n (%)  Any eventa  48 (100)  Related to delamanid   possibly/probably/definitely  39 (81.3)/6 (12.5)/3 (6.3)  Grade   1/2  24 (50.0)/21 (43.8)   3/4  3 (6.3)/0 (0)  Serious adverse event  0 (0)  Adverse event occurring in at least two patients   nausea and vomiting  9 (18.8)   dyspepsia  8 (16.7)   peripheral neuropathy  4 (8.3)   pruritus  4 (8.3)   QT interval prolongation  3 (6.3)   headache  2 (4.2)   dizziness  2 (4.2)   gastritis  2 (4.2)  Leading to temporary discontinuation of delamanid  2 (4.2)  ADR  n (%)  Any eventa  48 (100)  Related to delamanid   possibly/probably/definitely  39 (81.3)/6 (12.5)/3 (6.3)  Grade   1/2  24 (50.0)/21 (43.8)   3/4  3 (6.3)/0 (0)  Serious adverse event  0 (0)  Adverse event occurring in at least two patients   nausea and vomiting  9 (18.8)   dyspepsia  8 (16.7)   peripheral neuropathy  4 (8.3)   pruritus  4 (8.3)   QT interval prolongation  3 (6.3)   headache  2 (4.2)   dizziness  2 (4.2)   gastritis  2 (4.2)  Leading to temporary discontinuation of delamanid  2 (4.2)  a ADRs related to delamanid occurred in 18 patients. Of the 32 patients, the baseline QTcF interval was a mean of 419.7 ms and the maximal QTcF increase was a mean of 27.7 ms during delamanid treatment. The maximal QTcF increase was significantly higher in patients who received clofazimine than those who did not receive clofazimine (Table 4). Three patients experienced QTcF interval of >500 ms at 4 weeks (n = 1) and 12 weeks (n = 2) from delamanid initiation and two of them received clofazimine as a companion drug. Two of the three patients transiently discontinued and subsequently reintroduced delamanid at 7 and 10 days after discontinuation of delamanid, respectively. All the three patients completed 24 weeks of delamanid treatment without significant adverse events or further QT prolongation after reintroduction. A clinically significant arrhythmia or event was not observed in any of the included patients. Table 4. Comparison of QTcF interval change according to the companion drug   Moxifloxacina (n = 12)  Clofaziminea (n = 8)  Neither moxifloxacin nor clofazimine (n = 13)  Total (n = 32)  Pb  Baseline QTcF, mean (SD)  416.0 ± 19.7  428.1 ± 27.3  417.9 ± 16.0  419.7 ± 20.7  0.409  Maximal QTcF increase, mean (SD)  19.0 ± 7.7  47.6 ± 27.8  23.5 ± 19.9  27.7 ± 21.7  0.006  QTcF >500 ms, nc  0  2  1  3  0.159    Moxifloxacina (n = 12)  Clofaziminea (n = 8)  Neither moxifloxacin nor clofazimine (n = 13)  Total (n = 32)  Pb  Baseline QTcF, mean (SD)  416.0 ± 19.7  428.1 ± 27.3  417.9 ± 16.0  419.7 ± 20.7  0.409  Maximal QTcF increase, mean (SD)  19.0 ± 7.7  47.6 ± 27.8  23.5 ± 19.9  27.7 ± 21.7  0.006  QTcF >500 ms, nc  0  2  1  3  0.159  a One patient received both moxifloxacin and clofazimine simultaneously. b Comparison among three groups according to the companion drug. c Number of patients who experienced QTcF interval >500 ms during delamanid treatment. Discussion To the best of our knowledge, this is the first report in a routine, programmatic setting for MDR‐TB treatment regarding interim outcomes for patients with MDR/XDR-TB who were treated with delamanid-containing regimens for 24 weeks. This study showed that delamanid-containing regimens achieved 95% culture conversion at 6 months as well as acceptable safety and tolerability. As the new drugs have been introduced in real clinical practice, several questions about their rational use were raised such as: (i) How much can the new drugs improve the treatment outcome in difficult-to-treat patients treated with existing drugs? (ii) What is the optimized background regimen combined with the new drugs? (iii) Are these new drugs safe and tolerable in various combinations with the existing drugs? The result of our study may provide some answers to these questions. Compared with the results of the previous clinical trials (Trial 204 and Trial 208/116),2,3 the proportion of culture conversion at 2 months was comparable (72% versus 54% in solid medium; 50% versus 45% in liquid medium) and the proportion of culture conversion at 6 months was probably higher. The results of this study could not be directly compared with those of the previous clinical trials because of the heterogeneity in the study population. In our study, the proportion of patients who had been previously treated with second-line drugs was higher than that of Trial 204 (53.1% versus 37.8%).2 In addition, our patients had a TB strain with a higher level of additional drug resistance. Of the 19 patients with a positive culture sputum at baseline, only 1 (5.3%) had uncomplicated MDR-TB, 2 (10.5%) had pre-XDR-TB with SLID resistance, 12 (63.2%) had pre-XDR with fluoroquinolone resistance and 4 (21.1%) had XDR-TB. In contrast, the proportion of XDR-TB in Trial 204 was 5.4%.2 Despite the high level of additional drug resistance in our study, a delamanid-containing regimen could achieve 95% culture conversion at 6 months. Our 6 month culture conversion rate is probably higher than that of the previous cohort studies using the conventional second-line drugs. In a meta-analysis of individual patient data for MDR-TB treated with the conventional second-line drugs, treatment success was 64%, 56%, 48% and 40% in MDR-TB, pre-XDR-TB with SLID resistance, pre-XDR-TB with fluoroquinolone resistance and XDR-TB, respectively.13 In South Korea, the largest retrospective multicentre study (n = 1407 patients with MDR-TB) published in 2008 indicated a treatment success rate of 46.2% in MDR-TB and 29.3% in XDR-TB patients.14 In 2016, a prospective multicentre study (n = 151 patients with MDR-TB) reported an 82.1% treatment success rate in patients with fluoroquinolone-susceptible MDR-TB.15 The high culture conversion rate of our study is comparable to that of the cohort studies on the compassionate use of delamanid6,7 and bedaquiline.16,17 Similar to our study, the majority of subjects in these studies were pre-XDR- and XDR-TB patients, and had received linezolid as a companion drug. Such real-world experiences, including our study, reflect the current role of new drugs and the general approach of choosing a companion drug in the treatment of highly resistant MDR-TB. Two new drugs are currently recommended when an effective and reasonably well-tolerated MDR-TB regimen cannot be composed. In these patients with difficult-to-treat MDR-TB, linezolid has been used as a core drug in real clinical practice. Linezolid has demonstrated its efficacy in several meta-analyses18,19 and two randomized controlled trials.20,21 Based on this evidence, linezolid was recently included in the core second-line drugs by the WHO.22 In our study, 16 (84.2%) of the 19 patients with positive culture sputum at baseline received linezolid. Linezolid probably contributed to the high culture conversion rate in our study. This study could not demonstrate the efficacy of delamanid alone in MDR-TB treatment. However, our result suggests that the rational use of delamanid combined with repurposed or existing drugs could achieve a high culture conversion rate even in pre-XDR-TB and XDR-TB patients. Although the current role of new drugs is primarily focused on strengthening the conventional regimen for patients with difficult-to-treat MDR-TB, the potential for shortening the treatment duration is expected to become a crucial target in the near future. Several clinical trials for shorter treatment regimens using the new drugs are ongoing.23 This study showed that delamanid was safe and tolerable when combined with various existing anti-TB drugs. One of the major concerns using delamanid is QT prolongation. In our study, transient QTcF prolongation was observed in 9.4% (3 of 32) of patients, which is very similar to participants who received 100 mg of delamanid in Trial 204 (9.9%) and 208 (9.1%).24 Although QTcF prolongation in delamanid-treated patients reached its peak by week 8 and did not further increase in the clinical trials,24 two of the three patients developed QTcF prolongation at 12 weeks of delamanid treatment in our study. In contrast to the previous clinical trials, we included 4 (12.5%) patients >65 years old and 12 (37.5%) patients who received moxifloxacin, which had been excluded or prohibited in the previous clinical trials. None of them developed QTcF of >500 ms. In contrast, two of the three patients who experienced QTcF interval of >500 ms received clofazimine as a companion drug, which was consistent with findings in a recent report.6 Delamanid could be reintroduced safely in all patients within 10 days of discontinuation. This study has several limitations. First, it has an inherent limitation because it is a retrospective observational study conducted in seven hospitals. As patient management was not performed under a single protocol, some data were missing, particularly for 5 of the 19 patients who lacked culture results using liquid medium. Second, the number of included patients was small. Third, our result was an interim outcome of a 24 week treatment rather than a final outcome. The culture conversion rate at 6 months is not a perfect surrogate for predicting successful final outcomes, but it has higher sensitivity than the culture conversion rate at 2 months in patients treated with a conventional MDR-TB regimen.25 Further studies including more patients with long-term follow-up in different settings are warranted. In conclusion, the use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB. Funding This study was conducted as part of our routine work. Transparency declarations None to declare. References 1 WHO. Global Tuberculosis Report 2016 . Geneva: WHO, 2016. http://www.who.int/tb/publications/global_report/en/. 2 Gler MT, Skripconoka V, Sanchez-Garavito E et al.   Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med  2012; 366: 2151– 60. Google Scholar CrossRef Search ADS PubMed  3 Skripconoka V, Danilovits M, Pehme L et al.   Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J  2013; 41: 1393– 400. Google Scholar CrossRef Search ADS PubMed  4 Gupta R, Geiter LJ, Wells CD et al.   Delamanid for extensively drug-resistant tuberculosis. N Engl J Med  2015; 373: 291– 2. Google Scholar CrossRef Search ADS PubMed  5 WHO. The Use of Delamanid in the Treatment of Multidrug-Resistant Tuberculosis, Interim Policy Guidance . Geneva: WHO, 2014. http://www.who.int/tb/publications/delamanid-in-mdr-tb-treatment/en/. 6 Hafkin J, Hittel N, Martin A et al.   Early outcomes in MDR-TB and XDR-TB patients treated with delamanid under compassionate use. Eur Respir J  2017; 50: 1700311. Google Scholar CrossRef Search ADS PubMed  7 Hewison C, Ferlazzo G, Avaliani Z et al.   Six-month response to delamanid treatment in MDR TB patients. Emerg Infect Dis  2017; doi:10.3201/eid2310.170468. 8 Korea Centers for Disease Control & Prevention. Annual Report on the Notified Tuberculosis Patients in Korea 2016 . Cheongwon: Korea Centers for Disease Control & Prevention, 2017. http://tbzero.cdc.go.kr/tbzero/board/boardView.do. 9 WHO. Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis . Geneva: WHO, 2014. http://www.who.int/tb/publications/pmdt_companionhandbook/en/. 10 National Cancer Institute, NIH, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5×7.pdf. 11 Fridericia LS. The duration of systole in an electrocardiogram in normal humans and in patients with heart disease. 1920. Ann Noninvasive Electrocardiol  2003; 8: 343– 51. Google Scholar CrossRef Search ADS PubMed  12 Mason JW. Antimicrobials and QT prolongation. J Antimicrob Chemother  2017; 72: 1272– 4. Google Scholar CrossRef Search ADS PubMed  13 Falzon D, Gandhi N, Migliori GB et al.   Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J  2013; 42: 156– 68. Google Scholar CrossRef Search ADS PubMed  14 Kim DH, Kim HJ, Park SK et al.   Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med  2008; 178: 1075– 82. Google Scholar CrossRef Search ADS PubMed  15 Kang YA, Shim TS, Koh WJ et al.   Choice between levofloxacin and moxifloxacin and multidrug-resistant tuberculosis treatment outcomes. Ann Am Thorac Soc  2016; 13: 364– 70. Google Scholar CrossRef Search ADS PubMed  16 Guglielmetti L, Le DD, Jachym M et al.   Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Infect Dis  2015; 60: 188– 94. Google Scholar CrossRef Search ADS PubMed  17 Udwadia ZF, Ganatra S, Mullerpattan JB. Compassionate use of bedaquiline in highly drug-resistant tuberculosis patients in Mumbai, India. Eur Respir J  2017; 49: 1601699. Google Scholar CrossRef Search ADS PubMed  18 Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis  2012; 16: 447– 4. Google Scholar CrossRef Search ADS PubMed  19 Sotgiu G, Centis R, D’Ambrosio L et al.   Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J  2012; 40: 1430– 42. Google Scholar CrossRef Search ADS PubMed  20 Lee M, Lee J, Carroll MW et al.   Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med  2012; 367: 1508– 18. Google Scholar CrossRef Search ADS PubMed  21 Tang S, Yao L, Hao X et al.   Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China. Eur Respir J  2015; 45: 161– 70. Google Scholar CrossRef Search ADS PubMed  22 WHO. WHO Treatment Guidelines for Drug-Resistant Tuberculosis, 2016 Update.  Geneva: WHO, 2016. http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/. 23 Dheda K, Gumbo T, Maartens G et al.   The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med  2017; 5: 291– 360. Google Scholar CrossRef Search ADS   24 Gupta R, Geiter L, Hafkin J et al.   Delamanid and QT prolongation in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis  2015; 19: 1261– 2. Google Scholar CrossRef Search ADS PubMed  25 Kurbatova EV, Cegielski JP, Lienhardt C et al.   Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies. Lancet Respir Med  2015; 3: 201– 9. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea

Loading next page...
 
/lp/ou_press/interim-outcomes-of-delamanid-for-the-treatment-of-mdr-and-xdr-tb-in-b5I2UltR8c
Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dkx373
Publisher site
See Article on Publisher Site

Abstract

Abstract Objectives Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB. Methods We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea. Results A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5–81) using solid medium and 57 days (range = 8–96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms. Conclusions The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB. Introduction The current treatment for MDR-TB is long, complicated and toxic. As a result, poor treatment outcomes are inevitable; successful treatment was achieved in only 52% and high frequency of loss to follow-up (15%) and death (17%) was observed in a 2013 MDR-TB cohort.1 In addition, the treatment success rate in patients with XDR-TB was only 26%. The lack of effective drugs is the main challenge for current MDR-TB control. New drugs, bedaquiline and delamanid, have been recently introduced and promise to improve the treatment outcomes of MDR-TB. Delamanid significantly improved the 2 month culture conversion in a Phase IIb randomized controlled trial (Trial 204)2 and treatment outcomes (treatment success and mortality) in an extended observational study (Trial 208/116).3 A mortality benefit was also observed in XDR-TB.4 Based on this evidence, delamanid was granted a conditional regulatory approval by the EMA and the WHO published interim policy guidance on delamanid use in 2014.5 Because delamanid has just been recently introduced, few published data exist on delamanid use outside clinical trials. While clinical trials could provide more objective evidence, data about real-world experience are also important to fill the knowledge gap between clinical trials and actual clinical practice. Recently, two studies regarding early outcomes for patients with MDR/XDR-TB treated with delamanid were published and showed encouraging results.6,7 However, these two studies were conducted under a compassionate use programme rather than a routine programmatic setting. In South Korea, delamanid was introduced in routine clinical practice in November 2015. The objective of this study is to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen in a routine, programmatic setting for MDR‐TB treatment. Materials and methods Study sites and subjects In South Korea, a total of 39245 patients with TB, 852 with MDR-TB and 59 with XDR-TB were newly notified in 2016.8 Delamanid was approved by the regulatory authority in October 2014 and has been marketed from November 2015 in South Korea. Delamanid is approved for the treatment of pulmonary MDR-TB in adults as part of an appropriate background regimen when an effective treatment regimen cannot be administered because of resistance or intolerability to existing anti-TB drugs. If properly used for the above indication, national medical insurance provides reimbursement for the total cost for 24 weeks of delamanid treatment. During the early periods, the attending physicians individually decided on the administration of delamanid, according to the WHO guidelines.5,9 From the official notification in September 2016, the national expert committee has reviewed all delamanid and bedaquiline uses. When physicians intend on prescribing delamanid or bedaquiline to their patients, it is mandatory for them to submit an application form to the committee prior to administering these drugs. The committee grants approval of use, as well as comments on background regimens. We retrospectively screened patients with MDR/XDR-TB who received delamanid for at least 1 month from 1 November 2015 to 31 January 2017 at six university affiliated hospitals and one national TB hospital in South Korea. To evaluate the interim outcomes as well as the safety and tolerability of a delamanid-containing regimen, we included patients with MDR/XDR-TB who completed delamanid treatment by 31 January 2017, i.e. patients who completed 24 weeks of delamanid treatment or stopped delamanid treatment prematurely. Study design and data collection This is a retrospective multicentre observational cohort study. Patient selection and treatment regimen design were conducted independently in each hospital in accordance with the WHO guidelines.5,9 The anti-TB agents were administered under directly observed therapy during hospitalization and subsequently self-administered after discharge. Delamanid was administered at a dose of 100 mg twice daily for 24 weeks. Data were retrospectively extracted from the medical records. The objective of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen. We determined the proportion of negative culture conversion of sputum at 8 and 24 weeks of delamanid treatment, time to sputum smear and culture conversion, and frequency of serious adverse events, discontinuation of delamanid and QT prolongation. Efficacy evaluation was performed in patients who had positive culture sputum at the time of initiation of delamanid treatment. The culture was performed using both liquid medium (BACTEC MGIT 960 system; BD Diagnostic Systems, Sparks, MD, USA) and solid medium (Ogawa medium). However, only one of these media was used in some patients. Sputum examinations were repeated every 1 or 2 weeks until culture conversion and at least monthly thereafter. Drug susceptibility testing (DST) was conducted for 15 anti-TB drugs using an absolute concentration method in the Korean Institute of Tuberculosis, Osong, South Korea. DST for delamanid was not conducted. The tested drugs and their critical concentrations for resistance were as follows: 0.2 mg/L isoniazid; 40 mg/L rifampicin; 2.0 mg/L ethambutol; 20 mg/L rifabutin; 10 mg/L streptomycin; 40 mg/L amikacin; 40 mg/L kanamycin; 40 mg/L capreomycin; 2.0 mg/L ofloxacin; 2.0 mg/L levofloxacin; 2.0 mg/L moxifloxacin; 40 mg/L prothionamide; 30 mg/L cycloserine; and 1.0 mg/L para-aminosalicylic acid. Pyrazinamide susceptibility was determined by a pyrazinamidase test. Safety evaluation was performed in all included patients. Adverse drug reaction (ADR) was graded based on the Common Terminology Criteria for Adverse Events.10 The grade of ADR and its relation to delamanid were evaluated by the attending physician in each hospital. ECG data were collected at baseline and subsequently at 1, 2, 4, 8, 12, 16, 20 and 24 weeks of delamanid treatment. The protocol of this study was approved and the requirement for obtaining an informed consent was waived by the Institutional Review Board of all participating hospitals. Definitions MDR-TB was defined as TB that was resistant to both isoniazid and rifampicin. XDR-TB was defined as MDR-TB further resistant to any fluoroquinolone and at least one of the three second-line injectable drugs (SLIDs; kanamycin, amikacin or capreomycin). Pre-XDR-TB was defined as MDR-TB further resistant to either a fluoroquinolone or any SLID, but not both. Uncomplicated MDR-TB was defined as MDR-TB without additional resistance to fluoroquinolones and SLIDs. Baseline data were defined as the data collected at the time of initiation of delamanid treatment. Sputum smear and culture conversion were defined as two consecutive negative results, collected at least 30 days apart, in a patient with a positive specimen at baseline. The time of sputum smear or culture conversion was defined as the day of sputum collection for the first of two consecutive negative results. A serious adverse event was defined as any ADR that results in any of the following outcomes: death, life-threatening event, hospitalization, disability or permanent damage, required intervention to prevent permanent impairment or damage, and other serious important medical events. QT interval was corrected for heart rate using Fridericia's Correction Formula (QTcF).11 A prolongation of the QT interval was defined as an increase in QTcF of ≥60 ms from the baseline or QTcF of >500 ms at any timepoint.12 Statistical analysis Continuous variables are presented as medians with ranges or means with standard deviations, and categorical variables are presented as frequencies and percentages. One-way analysis of variance was used to assess intergroup differences in continuous variables. Pearson’s χ2 test or Fisher’s exact test was used to compare categorical variables. The Kaplan–Meier curve was used to determine the time to sputum smear and culture conversion. P < 0.05 was considered significant. The statistical analyses were performed using SPSS Statistics, version 17.0 (SPSS Inc., Chicago, IL, USA). Results Patient characteristics A total of 62 patients received delamanid for at least 1 month in the study sites during the study period; 30 of them were excluded because they were still taking delamanid on 31 January 2017. None of them prematurely and permanently discontinued delamanid. A total of 32 patients were included and all completed 24 weeks of delamanid treatment. The median age was 44.5 years (range = 22–82) and 22 (68.8%) were male (Table 1). All patients were HIV negative. Of the 32 patients, 12 (37.5%) had at least one comorbidity. Table 1. Baseline demographics and clinical characteristics of 32 patients with MDR-TB Characteristic  n (%) or median (range)  Male  22 (68.8)  Age (years)  44.5 (22–82)  Weight (kg)  55.0 (40.1–86.5)  BMI (kg/m2)  20.2 (13.5–33.8)  Ever a smoker  11 (34.4)  Alcohol abuse  1 (3.1)  Comorbiditya  12 (37.5)  Previous TB treatment   new  12 (37.5)   first-line drug only  3 (9.4)   second-line drug  17 (53.1)  Radiological finding   severity    minimal  10 (31.2)    moderate advanced  6 (18.8)    far advanced  16 (50.0)   extent, bilateral  19 (59.4)   cavity  20 (62.5)  Smear positive  14 (43.8)  Culture positive  19 (59.4)  Number of resistant drugs  9 (2–13)  Drug-resistance pattern   uncomplicated MDRb  6 (18.8)   pre-XDR with SLID resistance  4 (12.5)   pre-XDR with fluoroquinolone resistance  16 (50.0)   XDR  6 (18.8)  Characteristic  n (%) or median (range)  Male  22 (68.8)  Age (years)  44.5 (22–82)  Weight (kg)  55.0 (40.1–86.5)  BMI (kg/m2)  20.2 (13.5–33.8)  Ever a smoker  11 (34.4)  Alcohol abuse  1 (3.1)  Comorbiditya  12 (37.5)  Previous TB treatment   new  12 (37.5)   first-line drug only  3 (9.4)   second-line drug  17 (53.1)  Radiological finding   severity    minimal  10 (31.2)    moderate advanced  6 (18.8)    far advanced  16 (50.0)   extent, bilateral  19 (59.4)   cavity  20 (62.5)  Smear positive  14 (43.8)  Culture positive  19 (59.4)  Number of resistant drugs  9 (2–13)  Drug-resistance pattern   uncomplicated MDRb  6 (18.8)   pre-XDR with SLID resistance  4 (12.5)   pre-XDR with fluoroquinolone resistance  16 (50.0)   XDR  6 (18.8)  a Twelve patients had comorbidities as follows: diabetes mellitus was the most common (n = 4, 12.5%), followed by cardiovascular disease (n = 3, 9.4%), chronic respiratory disease (n = 3, 9.4%), chronic kidney disease (n = 2, 6.3%), gout (n = 2, 6.3%), psychiatric disease (n = 2, 6.3%) and chronic liver disease (n = 1, 3.1%). b MDR-TB without additional resistance to fluoroquinolones and SLIDs. All patients had pulmonary TB, of which two had concomitant extrapulmonary TB (meningitis and pleurisy, respectively). When patients were categorized based on their previous treatment histories, 12 (37.5%) were new patients, 3 (9.4%) had been treated previously with the first-line drugs only and 17 (53.1%) had been treated previously with second-line drugs. A median of 9 (range = 2–13) of the 15 tested drugs showed resistance on baseline DST. Drug susceptibilities and companion drugs are shown in Table 2. When patients were categorized based on drug-resistance pattern, 6 (18.8%) had uncomplicated MDR-TB, 4 (12.5%) had pre-XDR-TB with SLID resistance, 16 (50.0%) had pre-XDR-TB with fluoroquinolone resistance and 6 (18.8%) had XDR-TB. Table 2. Drug susceptibilities and companion drugs among 32 patients with MDR-TB Drug  Resistant drug  Companion drug  Isoniazid  32 (100)  0  Rifampicin  32 (100)  0  Rifabutin  22 (68.8)  0  Ethambutol  25 (78.1)  6 (18.8)  Pyrazinamide  14 (43.8)  20 (62.5)  Streptomycin  13 (40.6)  2 (6.3)  Kanamycin  9 (28.1)  7 (21.9)  Amikacin  6 (18.8)  13 (40.6)  Capreomycin  9 (28.1)  0  Ofloxacin  20 (62.5)  0  Levofloxacin  21 (65.6)  5 (15.6)  Moxifloxacin  16 (50.0)  12 (37.5)  Prothionamide  15 (46.9)  17 (53.1)  Cycloserine  8 (25.0)  23 (71.9)  Para-aminosalicylic acid  9 (28.1)  8 (25.0)  Linezolid  ND  23 (71.9)  Clofazimine  ND  8 (25.0)  Amoxicillin/clavulanate  ND  9 (28.1)  Meropenem  ND  2 (6.3)  Clarithromycin  ND  2 (6.3)  Drug  Resistant drug  Companion drug  Isoniazid  32 (100)  0  Rifampicin  32 (100)  0  Rifabutin  22 (68.8)  0  Ethambutol  25 (78.1)  6 (18.8)  Pyrazinamide  14 (43.8)  20 (62.5)  Streptomycin  13 (40.6)  2 (6.3)  Kanamycin  9 (28.1)  7 (21.9)  Amikacin  6 (18.8)  13 (40.6)  Capreomycin  9 (28.1)  0  Ofloxacin  20 (62.5)  0  Levofloxacin  21 (65.6)  5 (15.6)  Moxifloxacin  16 (50.0)  12 (37.5)  Prothionamide  15 (46.9)  17 (53.1)  Cycloserine  8 (25.0)  23 (71.9)  Para-aminosalicylic acid  9 (28.1)  8 (25.0)  Linezolid  ND  23 (71.9)  Clofazimine  ND  8 (25.0)  Amoxicillin/clavulanate  ND  9 (28.1)  Meropenem  ND  2 (6.3)  Clarithromycin  ND  2 (6.3)  ND, not done. Data are presented as n (%). Treatment Of the 32 patients, 23 (71.9%) received delamanid within 30 days from the initiation of MDR-TB treatment, while 9 (28.1%) received it as an add-on to their existing regimen at a median of 251 days (range = 67–404) from the initiation of MDR/XDR-TB treatment. The treatment regimen included a median of five companion drugs (range = 4–9), of which a median of three drugs (range = 1–5) were susceptible on DST and a median of two drugs (range = 0–5) were susceptible and had never been previously used. A median of one drug (range = 0–4) in group 5 was administered to 23 (71.9%) patients. The companion drugs administered to 32 patients are shown in Table 2. Injectable drugs were administered to 22 (68.8%) patients, fluoroquinolones to 17 (53.1%), linezolid to 23 (71.9%) and clofazimine to 8 (25.0%). One patient received a lobectomy after 8 weeks of delamanid treatment. Twenty (62.5%) patients were hospitalized for a median of 51.5 days (range = 3–445) from delamanid initiation. Microbiological outcome Efficacy evaluation was performed in 19 patients (59.4%) who had positive culture sputum at baseline. Culture results of both liquid and solid media were available in 13 patients, only solid medium in five patients and only liquid medium in one patient. The proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. Only one patient failed to achieve culture conversion during 24 weeks of delamanid treatment. This patient had previously failed to respond to treatment with second-line drugs and was infected with an MDR-TB strain that was additionally resistant to fluoroquinolones and prothionamide. All of the 13 patients who had negative cultures at baseline maintained a culture-negative status at 24 weeks of delamanid treatment. The median time to culture conversion was 33 days (range = 5–81) using solid medium and 57 days (range = 8–96) using liquid medium. The median time to smear conversion was 50 days (range = 7–141) in 14 patients who had smear-positive sputums at baseline. Safety and tolerability Safety and tolerability were assessed in all the 32 patients included in the study. During the 24 weeks of treatment with a delamanid-containing regimen, 75 ADRs were reported in 25 (78.1%) patients. Of these, 48 ADRs in 18 patients were considered possibly (81.3%), probably (12.5%) and definitely (6.3%) related to delamanid (Table 3). The most frequent ADRs were nausea, vomiting and dyspepsia. The majority of ADRs were considered as grade 1 (50.0%) or grade 2 (43.8%). Grade 3 ADR was QT prolongation, which occurred in three patients. Serious adverse event or death was not observed. All the 32 patients completed the 24 weeks of delamanid treatment. Four patients transiently discontinued delamanid (two experienced QTcF interval of >500 ms probably due to delamanid, one experienced elevated ALT probably due to pyrazinamide and one experienced tremor probably due to linezolid). Table 3. ADRs related to delamanid among 32 patients with MDR-TB ADR  n (%)  Any eventa  48 (100)  Related to delamanid   possibly/probably/definitely  39 (81.3)/6 (12.5)/3 (6.3)  Grade   1/2  24 (50.0)/21 (43.8)   3/4  3 (6.3)/0 (0)  Serious adverse event  0 (0)  Adverse event occurring in at least two patients   nausea and vomiting  9 (18.8)   dyspepsia  8 (16.7)   peripheral neuropathy  4 (8.3)   pruritus  4 (8.3)   QT interval prolongation  3 (6.3)   headache  2 (4.2)   dizziness  2 (4.2)   gastritis  2 (4.2)  Leading to temporary discontinuation of delamanid  2 (4.2)  ADR  n (%)  Any eventa  48 (100)  Related to delamanid   possibly/probably/definitely  39 (81.3)/6 (12.5)/3 (6.3)  Grade   1/2  24 (50.0)/21 (43.8)   3/4  3 (6.3)/0 (0)  Serious adverse event  0 (0)  Adverse event occurring in at least two patients   nausea and vomiting  9 (18.8)   dyspepsia  8 (16.7)   peripheral neuropathy  4 (8.3)   pruritus  4 (8.3)   QT interval prolongation  3 (6.3)   headache  2 (4.2)   dizziness  2 (4.2)   gastritis  2 (4.2)  Leading to temporary discontinuation of delamanid  2 (4.2)  a ADRs related to delamanid occurred in 18 patients. Of the 32 patients, the baseline QTcF interval was a mean of 419.7 ms and the maximal QTcF increase was a mean of 27.7 ms during delamanid treatment. The maximal QTcF increase was significantly higher in patients who received clofazimine than those who did not receive clofazimine (Table 4). Three patients experienced QTcF interval of >500 ms at 4 weeks (n = 1) and 12 weeks (n = 2) from delamanid initiation and two of them received clofazimine as a companion drug. Two of the three patients transiently discontinued and subsequently reintroduced delamanid at 7 and 10 days after discontinuation of delamanid, respectively. All the three patients completed 24 weeks of delamanid treatment without significant adverse events or further QT prolongation after reintroduction. A clinically significant arrhythmia or event was not observed in any of the included patients. Table 4. Comparison of QTcF interval change according to the companion drug   Moxifloxacina (n = 12)  Clofaziminea (n = 8)  Neither moxifloxacin nor clofazimine (n = 13)  Total (n = 32)  Pb  Baseline QTcF, mean (SD)  416.0 ± 19.7  428.1 ± 27.3  417.9 ± 16.0  419.7 ± 20.7  0.409  Maximal QTcF increase, mean (SD)  19.0 ± 7.7  47.6 ± 27.8  23.5 ± 19.9  27.7 ± 21.7  0.006  QTcF >500 ms, nc  0  2  1  3  0.159    Moxifloxacina (n = 12)  Clofaziminea (n = 8)  Neither moxifloxacin nor clofazimine (n = 13)  Total (n = 32)  Pb  Baseline QTcF, mean (SD)  416.0 ± 19.7  428.1 ± 27.3  417.9 ± 16.0  419.7 ± 20.7  0.409  Maximal QTcF increase, mean (SD)  19.0 ± 7.7  47.6 ± 27.8  23.5 ± 19.9  27.7 ± 21.7  0.006  QTcF >500 ms, nc  0  2  1  3  0.159  a One patient received both moxifloxacin and clofazimine simultaneously. b Comparison among three groups according to the companion drug. c Number of patients who experienced QTcF interval >500 ms during delamanid treatment. Discussion To the best of our knowledge, this is the first report in a routine, programmatic setting for MDR‐TB treatment regarding interim outcomes for patients with MDR/XDR-TB who were treated with delamanid-containing regimens for 24 weeks. This study showed that delamanid-containing regimens achieved 95% culture conversion at 6 months as well as acceptable safety and tolerability. As the new drugs have been introduced in real clinical practice, several questions about their rational use were raised such as: (i) How much can the new drugs improve the treatment outcome in difficult-to-treat patients treated with existing drugs? (ii) What is the optimized background regimen combined with the new drugs? (iii) Are these new drugs safe and tolerable in various combinations with the existing drugs? The result of our study may provide some answers to these questions. Compared with the results of the previous clinical trials (Trial 204 and Trial 208/116),2,3 the proportion of culture conversion at 2 months was comparable (72% versus 54% in solid medium; 50% versus 45% in liquid medium) and the proportion of culture conversion at 6 months was probably higher. The results of this study could not be directly compared with those of the previous clinical trials because of the heterogeneity in the study population. In our study, the proportion of patients who had been previously treated with second-line drugs was higher than that of Trial 204 (53.1% versus 37.8%).2 In addition, our patients had a TB strain with a higher level of additional drug resistance. Of the 19 patients with a positive culture sputum at baseline, only 1 (5.3%) had uncomplicated MDR-TB, 2 (10.5%) had pre-XDR-TB with SLID resistance, 12 (63.2%) had pre-XDR with fluoroquinolone resistance and 4 (21.1%) had XDR-TB. In contrast, the proportion of XDR-TB in Trial 204 was 5.4%.2 Despite the high level of additional drug resistance in our study, a delamanid-containing regimen could achieve 95% culture conversion at 6 months. Our 6 month culture conversion rate is probably higher than that of the previous cohort studies using the conventional second-line drugs. In a meta-analysis of individual patient data for MDR-TB treated with the conventional second-line drugs, treatment success was 64%, 56%, 48% and 40% in MDR-TB, pre-XDR-TB with SLID resistance, pre-XDR-TB with fluoroquinolone resistance and XDR-TB, respectively.13 In South Korea, the largest retrospective multicentre study (n = 1407 patients with MDR-TB) published in 2008 indicated a treatment success rate of 46.2% in MDR-TB and 29.3% in XDR-TB patients.14 In 2016, a prospective multicentre study (n = 151 patients with MDR-TB) reported an 82.1% treatment success rate in patients with fluoroquinolone-susceptible MDR-TB.15 The high culture conversion rate of our study is comparable to that of the cohort studies on the compassionate use of delamanid6,7 and bedaquiline.16,17 Similar to our study, the majority of subjects in these studies were pre-XDR- and XDR-TB patients, and had received linezolid as a companion drug. Such real-world experiences, including our study, reflect the current role of new drugs and the general approach of choosing a companion drug in the treatment of highly resistant MDR-TB. Two new drugs are currently recommended when an effective and reasonably well-tolerated MDR-TB regimen cannot be composed. In these patients with difficult-to-treat MDR-TB, linezolid has been used as a core drug in real clinical practice. Linezolid has demonstrated its efficacy in several meta-analyses18,19 and two randomized controlled trials.20,21 Based on this evidence, linezolid was recently included in the core second-line drugs by the WHO.22 In our study, 16 (84.2%) of the 19 patients with positive culture sputum at baseline received linezolid. Linezolid probably contributed to the high culture conversion rate in our study. This study could not demonstrate the efficacy of delamanid alone in MDR-TB treatment. However, our result suggests that the rational use of delamanid combined with repurposed or existing drugs could achieve a high culture conversion rate even in pre-XDR-TB and XDR-TB patients. Although the current role of new drugs is primarily focused on strengthening the conventional regimen for patients with difficult-to-treat MDR-TB, the potential for shortening the treatment duration is expected to become a crucial target in the near future. Several clinical trials for shorter treatment regimens using the new drugs are ongoing.23 This study showed that delamanid was safe and tolerable when combined with various existing anti-TB drugs. One of the major concerns using delamanid is QT prolongation. In our study, transient QTcF prolongation was observed in 9.4% (3 of 32) of patients, which is very similar to participants who received 100 mg of delamanid in Trial 204 (9.9%) and 208 (9.1%).24 Although QTcF prolongation in delamanid-treated patients reached its peak by week 8 and did not further increase in the clinical trials,24 two of the three patients developed QTcF prolongation at 12 weeks of delamanid treatment in our study. In contrast to the previous clinical trials, we included 4 (12.5%) patients >65 years old and 12 (37.5%) patients who received moxifloxacin, which had been excluded or prohibited in the previous clinical trials. None of them developed QTcF of >500 ms. In contrast, two of the three patients who experienced QTcF interval of >500 ms received clofazimine as a companion drug, which was consistent with findings in a recent report.6 Delamanid could be reintroduced safely in all patients within 10 days of discontinuation. This study has several limitations. First, it has an inherent limitation because it is a retrospective observational study conducted in seven hospitals. As patient management was not performed under a single protocol, some data were missing, particularly for 5 of the 19 patients who lacked culture results using liquid medium. Second, the number of included patients was small. Third, our result was an interim outcome of a 24 week treatment rather than a final outcome. The culture conversion rate at 6 months is not a perfect surrogate for predicting successful final outcomes, but it has higher sensitivity than the culture conversion rate at 2 months in patients treated with a conventional MDR-TB regimen.25 Further studies including more patients with long-term follow-up in different settings are warranted. In conclusion, the use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB. Funding This study was conducted as part of our routine work. Transparency declarations None to declare. References 1 WHO. Global Tuberculosis Report 2016 . Geneva: WHO, 2016. http://www.who.int/tb/publications/global_report/en/. 2 Gler MT, Skripconoka V, Sanchez-Garavito E et al.   Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med  2012; 366: 2151– 60. Google Scholar CrossRef Search ADS PubMed  3 Skripconoka V, Danilovits M, Pehme L et al.   Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J  2013; 41: 1393– 400. Google Scholar CrossRef Search ADS PubMed  4 Gupta R, Geiter LJ, Wells CD et al.   Delamanid for extensively drug-resistant tuberculosis. N Engl J Med  2015; 373: 291– 2. Google Scholar CrossRef Search ADS PubMed  5 WHO. The Use of Delamanid in the Treatment of Multidrug-Resistant Tuberculosis, Interim Policy Guidance . Geneva: WHO, 2014. http://www.who.int/tb/publications/delamanid-in-mdr-tb-treatment/en/. 6 Hafkin J, Hittel N, Martin A et al.   Early outcomes in MDR-TB and XDR-TB patients treated with delamanid under compassionate use. Eur Respir J  2017; 50: 1700311. Google Scholar CrossRef Search ADS PubMed  7 Hewison C, Ferlazzo G, Avaliani Z et al.   Six-month response to delamanid treatment in MDR TB patients. Emerg Infect Dis  2017; doi:10.3201/eid2310.170468. 8 Korea Centers for Disease Control & Prevention. Annual Report on the Notified Tuberculosis Patients in Korea 2016 . Cheongwon: Korea Centers for Disease Control & Prevention, 2017. http://tbzero.cdc.go.kr/tbzero/board/boardView.do. 9 WHO. Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis . Geneva: WHO, 2014. http://www.who.int/tb/publications/pmdt_companionhandbook/en/. 10 National Cancer Institute, NIH, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5×7.pdf. 11 Fridericia LS. The duration of systole in an electrocardiogram in normal humans and in patients with heart disease. 1920. Ann Noninvasive Electrocardiol  2003; 8: 343– 51. Google Scholar CrossRef Search ADS PubMed  12 Mason JW. Antimicrobials and QT prolongation. J Antimicrob Chemother  2017; 72: 1272– 4. Google Scholar CrossRef Search ADS PubMed  13 Falzon D, Gandhi N, Migliori GB et al.   Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J  2013; 42: 156– 68. Google Scholar CrossRef Search ADS PubMed  14 Kim DH, Kim HJ, Park SK et al.   Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med  2008; 178: 1075– 82. Google Scholar CrossRef Search ADS PubMed  15 Kang YA, Shim TS, Koh WJ et al.   Choice between levofloxacin and moxifloxacin and multidrug-resistant tuberculosis treatment outcomes. Ann Am Thorac Soc  2016; 13: 364– 70. Google Scholar CrossRef Search ADS PubMed  16 Guglielmetti L, Le DD, Jachym M et al.   Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Infect Dis  2015; 60: 188– 94. Google Scholar CrossRef Search ADS PubMed  17 Udwadia ZF, Ganatra S, Mullerpattan JB. Compassionate use of bedaquiline in highly drug-resistant tuberculosis patients in Mumbai, India. Eur Respir J  2017; 49: 1601699. Google Scholar CrossRef Search ADS PubMed  18 Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis  2012; 16: 447– 4. Google Scholar CrossRef Search ADS PubMed  19 Sotgiu G, Centis R, D’Ambrosio L et al.   Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J  2012; 40: 1430– 42. Google Scholar CrossRef Search ADS PubMed  20 Lee M, Lee J, Carroll MW et al.   Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med  2012; 367: 1508– 18. Google Scholar CrossRef Search ADS PubMed  21 Tang S, Yao L, Hao X et al.   Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China. Eur Respir J  2015; 45: 161– 70. Google Scholar CrossRef Search ADS PubMed  22 WHO. WHO Treatment Guidelines for Drug-Resistant Tuberculosis, 2016 Update.  Geneva: WHO, 2016. http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/. 23 Dheda K, Gumbo T, Maartens G et al.   The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med  2017; 5: 291– 360. Google Scholar CrossRef Search ADS   24 Gupta R, Geiter L, Hafkin J et al.   Delamanid and QT prolongation in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis  2015; 19: 1261– 2. Google Scholar CrossRef Search ADS PubMed  25 Kurbatova EV, Cegielski JP, Lienhardt C et al.   Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies. Lancet Respir Med  2015; 3: 201– 9. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off