Insignificant difference in culture conversion between bedaquiline-containing and bedaquiline-free all-oral short regimens for multidrug-resistant tuberculosis

  • Author Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Liang Fu
    Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Author Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Taoping Weng
    Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Affiliations
    Departments of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
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  • Author Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Feng Sun
    Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
    Affiliations
    Departments of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
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  • Peize Zhang
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Hui Li
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Yang Li
    Affiliations
    Departments of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
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  • Qianting Yang
    Affiliations
    Guangdong Key Lab for Diagnosis &Treatment of Emerging Infectious Disease, Shenzhen Third People's Hospital, National clinical research center for infectious disease, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Yi Cai
    Affiliations
    Department of Pathogen Biology, Guangdong Key Laboratory of Regional Immunity and Diseases, Shenzhen University School of Medicine, Shenzhen, 518060, China
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  • Xilin Zhang
    Affiliations
    The Fourth People's Hospital of Foshan, Foshan, 528000, China
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  • Hancheng Liang
    Affiliations
    Tuberculosis Diseases Department Two, The Sixth People's Hospital of Dongguan, Dongguan, 523000, China
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  • Xinchun Chen
    Affiliations
    Department of Pathogen Biology, Guangdong Key Laboratory of Regional Immunity and Diseases, Shenzhen University School of Medicine, Shenzhen, 518060, China
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  • Zhaoqin Wang
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Lei Liu
    Correspondence
    Correspondence to.
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Wenhong Zhang
    Correspondence
    Correspondence to.
    Affiliations
    Departments of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
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  • Guofang Deng
    Correspondence
    Correspondence to.
    Affiliations
    Pulmonary Diseases Department Two, National Clinical Research Center for Infectious Disease (Shenzhen), Guangdong Provincial Clinical Research Center for Infectious Diseases (Tuberculosis), Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China
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  • Author Footnotes
    † L.F., T.W. and F.S. contributed equally to this work.
Open AccessPublished:August 25, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.055

      Highlights

      • The first trial to explore all-oral short regimens for MDR-TB in China.
      • Two optimized regimens, designed according to local conditions.
      • Similar high culture conversion in the early stage in both regimens.
      • High treatment success rate for patients who completed the treatment.
      • Good adherence in the pandemic of COVID-19.

      Abstract

      Background

      Multidrug-resistant tuberculosis (MDR-TB) patients have been suffering long, ineffective, and toxic treatment until short-course injectable-free regimens emerged. However, the new WHO-recommended regimens might be less feasible in the real-world setting. Here, we evaluated two optimized all-oral short-course regimens in China.

      Methods

      From April 2019 to August 2020, we conducted a prospective nonrandomized controlled trial and consecutively included 103 MDR-TB patients diagnosed with pulmonary MDR-TB in Shenzhen, China. A 4-5 drug regimen of 9-12 months was tailored to the strain's resistance patterns, patients' affordability, and tolerance to drugs. This was an interim analysis, focusing on the early treatment period.

      Results

      53.4% (55/103) of patients were prescribed linezolid, fluoroquinolone (FQ), clofazimine, cycloserine, and pyrazinamide, followed by a regimen in which clofazimine was replaced by bedaquiline (35/103, 34.0%). The culture conversion rate was 83.1% and 94.4% at two and four months, respectively, with no significant difference between bedaquiline-free and bedaquiline-containing cases and between FQ-susceptible and FQ-resistant cases. Among 41 patients who completed treatment, 40 (97.6%) patients had a favorable outcome and no relapse was observed. Peripheral neuropathy and arthralgia/myalgia were the most frequent AEs (56.3%, 58/103). 18 AEs caused permanent discontinuation of drugs, mostly due to pyrazinamide and linezolid.

      Conclusion

      Optimized all-oral short-course regimens showed satisfactory efficacy and safety in early treatment stage. Further research is needed to confirm these results.

      Keywords

      Introduction

      Tuberculosis (TB) gained the whole world's attention again due to drug resistance (
      WHO
      Global tuberculosis report 2020.
      ). The treatment success rate of RR/MDR-TB patients only reached 57% globally (
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ). The long-term therapy, unbearable adverse events (AEs), and catastrophic cost reduced the compliance and resulted in a worse outcome (
      • Hirasen K
      • Berhanu R
      • Evans D
      • Rosen S
      • Sanne I
      • Long L.
      High rates of death and loss to follow-up by 12 months of rifampicin resistant TB treatment in South Africa.
      ). We have witnessed two notable advancements recently. Firstly, the Bangladesh regimen successfully shortened the course to nine months, which was validated in the STREAM trial later (
      • Nunn A J
      • Phillips P
      • Meredith S K
      • Chiang C Y
      • Conradie F
      • Dalai D
      • et al.
      A trial of a shorter regimen for rifampin-resistant tuberculosis.
      ). Secondly, clinicians were gradually aware of the unfavorable safety profile of injectable agents, which were associated with worse outcomes. WHO reprioritized anti-TB drugs in 2019 and recommended replacing injectables with bedaquiline in a shorter regimen in 2020. The bedaquiline-containing shorter regimen and the BPaL (bedaquiline, pretomanid, linezolid) regimen are now the only two validated short regimens (
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ). However, enthusiasm over these regimens has been curtailed following concerns of strict indications. In the real world, the regimen needed to be tailored to the resistance pattern, patients' tolerability and affordability. Meanwhile, the good results with linezolid should be strengthened with previous reports of its central role in new MDR-TB regimens. Optimized and optional shorter all-oral regimens are urgently needed. We present here the analysis of two all-oral shorter regimens of 9-12 months for RR/MDR-TB in China.

      Methods

       Study Design

      With the approval of the Ethics Committee of the Shenzhen Third People's Hospital, we conducted a prospective nonrandomized controlled trial (registration number: ChiCTR2000032298). Patients afforded all medicines themselves. Written informed consent was obtained from the participants or legal guardian of each child.

       Regimen design

      Patients were actively involved, and four consecutive steps were conducted when designing the regimens (Figure 2). (1) To choose bedaquiline or not, depending on the patients' affordability and will. (2) To choose clofazimine or not, after carefully considering the skin hyperpigmentation impact on the patient's daily life. (3) If FQ-resistant, substitute FQ with ethambutol or protionamide in bedaquiline-free regimen, or with clofazimine in bedaquiline-containing regimen; the substituting drug should be susceptible. (4) To obtain the susceptibility of pyrazinamide, with a similar substituting process mentioned in (3). Four to five effective drugs were needed to compose the regimen. Treatment duration was nine months and could be prolonged to 12 months when necessary. Drug dosages are listed in the supplemental appendix.

       Bacteriological study

      Direct smear was performed using light-emitting diode fluorescence microscopy for acid fast bacilli (AFB). A sputum specimen was digested by using the N-acetyl-L-cysteine (NALC)-NaOH method for 15 minutes, and then neutralized with sterile phosphate buffer (PBS, pH = 6.8). After centrifugation at 3,000 × g for 15 minutes, the pellet was resuspended in 2 mL PBS buffer. A 0.5 mL proportion of the decontaminated specimens was cultured on Mycobacterial Growth Indicator Tubes (MGIT, Becton Dickinson, USA). Positive cultures were confirmed as mycobacteria with Ziehl-Neelsen staining. Further species identification was performed using a commercial MPB64 monoclonal antibody assay (Genesis, Hangzhou, China). Positive liquid isolates were then transferred to the Roche solid culture inoculation for conventional DST, which was performed using the absolute concentration method until December 2019 and then the minimum inhibitory concentration (MIC) method (Sensititre® MYCOTB; Thermo Scientific, USA) thereafter at the laboratory of Shenzhen Third People's Hospital (
      • Abdelrahman S M
      • Erfan D
      • Abdellatif W
      • Kholeif H.
      Evaluation of Sensititre® MYCOTB Panel for the Susceptibility Testing of Mycobacterium tuberculosis to First and Second Lines Anti-Tuberculosis Drugs.
      ).

       Participants

      From 30th April 2019 to 31st August 2020, pulmonary RR/MDR-TB patients confirmed by GeneXpert MTB/RIF (Cepheid), aged between 15 to 80, were eligible. Until this report, the patients had been in the trial for at least four months, and this interim analysis will focus on the culture conversion in the early treatment period, though some patients who already completed their treatment will also be analyzed for their treatment outcomes. Detailed inclusion and exclusion criteria are shown in the Supplementary data.

       Outcome Assessments

      The outcome assessments included (1) the proportion of conversion of sputum cultures at two and four months; (2) risk factors associated with delayed culture conversion at two months; (3) the proportion of the favorable outcome for those who completed their treatment. Patients were considered to have a favorable outcome if sputum cultures had been converted and stayed negative till the last follow-up with no previous unfavorable outcome. The unfavorable outcome was defined by one of the following: (1) more than one drug in the initial regimen was replaced due to AEs, (2) death from any cause, (3) a positive culture from one of the two most recent specimens, (4) no culture was acquired, or no sputum sample was provided. Safety assessments were evaluated based on (1) reported treatment-emergent AEs (TEAEs), (2) clinical laboratory tests, (3) electrocardiograms, and (4) physical examinations. TEAEs were assessed based on the dose reduction or interruption of the agents.

       Sample Size Calculation

      This study was designed as a nonrandomized controlled trial to evaluate two all-oral short-course regimens, assuming that the treatment success rate of the bedaquiline-free regimen is non-inferior to that of the bedaquiline-containing regimen. Assuming that 85% of the participants in the bedaquiline-containing group and 80% in the bedaquiline-free group would obtain favorable outcomes and assuming that up to 20% of the participants will be lost to follow up, we estimated that 198 participants would need to be enrolled for the trial to have 80% power to show the noninferiority of the bedaquiline-free regimen to the bedaquiline-containing regimen, at two-sided level of significance of 0.05. Until this report, more than half of the sample size (52%, 103/198) had been reached.

       Statistical Analysis

      Statistical analysis was performed by SPSS, version 26.0 (IBM, NY, USA). Categorical variables were reported with descriptive statistics (counts, percentages, and proportions) and continuous variables with a mean (standard deviations, SD) and medians (interquartile range, IQR). Continuous variables were compared using the Student's t-test. Chi-square test and Fisher's exact test were used to compare categorical variables. A Cox proportional hazards model with robust estimation of Confidence Interval (CI) was used to assess the association between time to culture conversion and explanatory variables. Variables associated with the delayed culture conversion at two months in univariate analysis (p<0.05) combined with clinical value were introduced into a multivariate model following a stepwise forward strategy. The test of the proportional hazards assumption was used to assess the model validity. A p<0.05 was considered significant. Data visualization was plotted based on flow figure and Kaplan–Meier curves. Missing values were classified as a separate category in the analysis.

      Results

       Participants

      A total of 134 participants were enrolled, and 31 were lost to follow up (LTFU), including 23 isolated during the COVID-19 epidemic (Figure 1). Finally, 103 participants were analyzed. The median age was 35 years old (range, 15 to 78 years); 28 (27.2%) patients were female; 59 (57.3%) were previously treated, of whom 36 (34.9%) received anti-TB therapy more than once. Fifty-one had cavities on chest radiographs, with 22 (21.4%) representing bilateral cavities. Among all patients, 34 (33.0%) were confirmed as pure MDR-TB, 32 (31.1%) FQ-resistant MDR-TB (Pre-XDR-TB, according to the new WHO definitions (
      WHO
      Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis.
      )), and 15 (14.6%) RR-TB. By November 2020, 41 patients completed the treatment (Table 1).
      Figure 2
      Figure 2Flow chart of regimen adjustments when drug resistant or intolerant
      Table 1Baseline Characteristics of study population
      Overall (N=103)Bedaquiline-free (N=68)Bedaquiline-containing (N=35)
      Age
       Average (range)38.2 (15-78)39.21 (19-67)36.2 (15-78)
       Median (IQR)35 (26.5-49.5)36 (29.0-50.25)32 (25-48)
      Gender, Female28 (27.18%)18 (26.47%)10 (28.57%)
      BMI
       Average (range)20.08 (14.37-27.76)19.92 (14.37-27.28)20.39 (15.74-27.76)
       Median (IQR)19.61 (17.73-22.04)19.20 (17.67-21.87)20.14 (18.16-22.81)
      Symptoms
       Cough68 (66.02%)47 (69.12%)21 (60.00%)
       Expectoration58 (56.31%)40 (58.82%)18 (51.43%)
       Hemoptysis12 (11.65%)9 (13.24%)3 (8.57%)
       Chest pain19 (18.45%)17 (25.00%)2 (5.71%)
       Asthma32 (31.07%)22 (32.35%)10 (28.57%)
       Fever17 (16.50%)10 (14.71%)7 (20.00%)
       Night sweating23 (22.33%)12 (17.65%)11 (31.43%)
      Smoker39 (37.86%)27 (39.71%)12 (34.29%)
      Occupation
       Office worker23 (22.33%)11 (16.18%)12 (34.29%)
       Manual worker29 (29.16%)19 (27.94%)10 (28.57%)
       Farmer6 (5.83%)6 (8.82%)0 (0%)
       Unemployed27 (26.21%)23 (33.82%)4 (11.43%)
       Retired9 (8.74%)6 (8.82%)3 (8.57%)
       Student7 (6.80%)2 (2.94%)5 (14.29%)
       Others2 (1.94%)1 (1.47%)1 (2.86%)
      Medical insured55 (53.40%)25 (36.76%)30 (85.71%)
      Hospitalized patients91 (88.35%)60 (88.24%)31 (88.57%)
      Previous treatment history90 (87.38%)59 (86.76%)31 (88.57%)
       Less than twice67 (65.05%)43 (63.24%)24 (68.57%)
       Twice or more23 (22.33%)16 (23.53%)7 (20.00%)
       Non-MDR treatment84 (81.55%)57 (83.82%)27 (77.14%)
       MDR treatment19 (18.45%)11 (16.18%)8 (22.86%)
      Previous treatment of FQ31 (30.10%)20 (29.41%)11(31.43%)
      Previous treatment of SLID15 (14.56%)10 (14.71%)5 (14.29%)
      Diabetes mellitus19 (18.45%)14 (20.59%)5 (14.29%)
       HbA1c < 8%12 (11.6%)8 (22.86%)4 (5.88%)
       HbA1c ≥ 8%7 (6.80%)6 (17.14%)1 (1.47%)
      Liver function at baseline
       AST, ALT < 40U79 (76.70%)51 (75.00%)28 (80.00%)
       AST, ALT ≥ 40U24 (23.30%)17 (25.00%)7 (20.00%)
      Chest radiograph
       Bilateral involvement76 (73.79%)54 (79.41%)22 (62.86%)
       Presence of cavity51 (49.51%)36 (52.94%)15 (42.86%)
       Bilateral cavities22 (21.36%)15 (22.06%)7 (20.00%)
       Extensive TB77 (74.76%)55 (80.88%)22 (62.86%)
      Phenotypic DST
       RR-TB15 (14.56%)10 (14.71%)5 (14.29%)
       MDR-TB34 (33.01%)28 (41.18%)6 (17.14%)
       FQ resistance32 (31.07%)20 (29.41%)12 (34.29%)
       SLID resistance1 (0.97%)1 (1.47%)0 (0.0%)
       XDR-TB4 (3.88%)1 (1.47%)3 (8.57%)
       Not assessable17 (16.50%)8 (11.76%)9 (25.71%)
      Abbreviations: IQR, interquartile range; BMI, body mass index; FQ, fluoroquinolone; SLID, second-line injectable drug; TB, tuberculosis; DST, drug susceptibility testing; RR, rifampicin resistant; MDR, multidrug resistant; XDR, extensively drug-resistant.
      Table 2.
      Table 2Culture conversion at two and four months of regimens
      Sputum CultureEnrolled patientsPatients completed treatment (N=41)
      Total (N=103)Without bedaquline (N=68)With bedaquline (N=35)PFQ-resistant (N=39)FQ-susceptible (N=64)P
      On the second month
      Conversion to negative (Culture Conversion%)54(83.08%)35(79.55%)19(90.48%)0.27222(78.57%)32(86.49%)0.39925(92.59%)
      Remain positive1192652
      Not assessable1385764
      Initial negative before treatment2516942110
      On the fourth month
      Conversion to negative (Culture Conversion%)67(94.37%)44(93.62%)23(95.83%)0.70228(90.32%)39(97.5%)0.19330(100%)
      Remain positive431310
      Not assessable752431
      Initial negative before treatment2516942110
      66.0% (68/103) of patients received a regimen without bedaquiline, followed by a regimen with bedaquiline (34.0%, 35/103) (Supplemental Material). Of 41 patients who completed treatment, only one (2.44%, 1/41) used bedaquiline.

       Efficacy Analysis

      At the end of the second and fourth months of the treatment, culture conversion was found in 83.1% (54/65) and 94.4% (67/71) patients, respectively. Culture conversion rates were comparable between FQ-susceptible and FQ-resistant patients (at two months, 78.6% vs. 86.5%, P=0.509; at four months, 90.3% vs. 97.%, P=0.311), and between bedaquiline-free and bedaquiline-containing patients (at two months, 79.5% vs. 90.5%, P=0.480; at four months, 93.6% vs. 95.8%, P=1.000).
      A total of 41 patients had completed treatment until this report, of whom 40 (97.6%) patients had a favorable outcome, and only one had an unfavorable outcome with two drugs replaced due to intolerant AEs (Table 4).
      Multivariable hazards model was used to find predictors of the delayed culture conversion at two months, like the previous treatment times, history of previous use of FQ or SLID, cavities detected in chest computed tomography (CT), and bedaquiline contained in the regimen (Supplemental Material). Only previous usage of SLID was found to be associated with delayed culture conversion at two months (P 0.037, OR 0.12, 95% CI 0.02-0.88).
      35, 17, and one patient were successfully followed up for three months, six months, and nine months after the end of treatment, respectively, and no recurrence was observed.

       Safety and Tolerance

      There were 517 AEs in total (grade 1 to 4), 42 AEs causing dose adjustment or interruption of anti-tuberculosis agents (mostly grade 1 to 2), and 18 AEs causing permanent discontinuation of anti-tuberculosis agents (mostly grade 3 to 4) (Table 3, Supplemental Material). In total, 90.3% (93/103) patients reported at least one AE in total, while 97.6% in those completed treatments (Table 3). Peripheral neuropathy and arthralgia/myalgia were the most frequent AEs, observed in 56.3% (58/103) of patients, respectively. 17.48% (18/103) were detected with corrected QT interval (QTc) prolongation. Treatment adjustment or interruption due to AEs occurred in the frequency of 42 cases, including liver injury (19.5%, 8/103), anemia (17.1%, 7/103), and arthralgia/myalgia (14.63%, 6/103). 18 AEs causing permanent discontinuation of drugs in 17 patients, with pyrazinamide (five liver injury, four arthralgia/myalgia) and linezolid (two peripheral neuritis, one optic neuritis, one anemia) being the top two responsible drugs, while QTc prolongation was uncommon, and happened in only one case with a bedaquiline-free regimen.
      Table 3Adverse events occurred or worsened during treatment in total
      Adverse EventsEnrolled patientsAdverse EventsPatients completed treatment (N=41)
      Total (N=103)Without bedaquiline (N=68)With bedaquiline (N=35)P
      Peripheral neuritis58 (56.31%)45(66.18%)13(37.14%)0.005Peripheral neuritis31(75.61%)
      Arthralgia or myalgia58 (56.31%)41(60.29%)17(48.57%)0.256Arthralgia or myalgia27 (65.85%)
      Hyperuricemia50 (48.54%)27(39.71%)23(65.71%)0.012Hypopsia24 (58.54%)
      Hypopsia or optic neuritis48 (46.60%)37(54.41%)11(31.43%)0.027Gastrointestinal symptoms24 (58.54%)
      Gastrointestinal symptoms48 (46.60%)33(48.53%)15(42.86%)0.585Weakness23 (56.10%)
      Weakness45 (43.69%)33(48.53%)12(34.29%)0.167Dizziness or headache23 (56.10%)
      Dizziness or headache44 (42.72%)33(48.53%)11(31.43%)0.097Rash21 (51.22%)
      Rash31 (30.10%)28(41.18%)3(8.57%)0.001Hyperuricemia16 (39.02%)
      Anxiety27 (26.21%)16(23.53%)11(31.43%)0.388Anxiety10 (24.39%)
      Palpitation27 (26.21%)13(19.12%)14(40.00%)0.022Depression7 (17.07%)
      Depression19 (18.45%)12(17.65%)7(20.00%)0.771Palpitation6 (14.63%)
      QTc prolongation18 (17.48%)10(14.71%)8(22.86%)0.302Skin hyperpigmentation5 (12.20%)
      Anemia10 (9.71%)6(8.82%)4(11.43%)0.672Leukopenia4 (9.76%)
      Insomnia10 (9.71%)4(5.88%)6(17.14%)0.068Anemia3 (7.32%)
      Liver injury9 (8.74%)6(8.82%)3(8.57%)0.966Insomnia3 (7.32%)
      Leukopenia5 (4.85%)5(7.35%)00.100Thrombocytopenia2 (4.88%)
      Skin hyperpigmentation5 (4.85%)5(7.35%)00.100QTc prolongation intervention2 (4.88%)
      Thrombocytopenia2 (1.94%)1(1.47%)1(2.86%)0.629liver injury1 (2.44%)
      Allergy2 (1.94%)2(2.94%)00.306Allergy1 (2.44%)
      Gout1 (0.97%)1(1.47%)00.471Gout0
      In total, the bedaquiline-free group had more AEs of peripheral neuritis (66.2% vs. 37.1%, P=0.005), optic neuritis (54.41% vs. 31.43%, P=0.027), and rash (41.18% vs. 8.57%, P=0.001), while the bedaquiline-containing group had more hyperuricemia (65.71% vs. 39.71%, P=0.012) and palpitation (40.00% vs. 19.12%, P=0.022) (Table 3). Regarding dose adjustment or interruption of drugs, between the two groups, there was no significant difference in the top three AEs (liver injury, 7.3% vs. 8.6%, P=0.827; anemia, 7.3% vs. 5.7%, P=0.754; arthralgia/myalgia, 4.4% vs. 8.6%, P=0.393) (Table 4). Regarding permanent discontinuation of drugs, the bedaquiline-free group had more AEs than the bedaquiline-containing group (14 vs. 4).
      Table 4Adverse events occurred or worsened during treatment with dose adjustment and interruption of anti-tuberculosis agents
      Adverse EventsEnrolled patientsAdverse EventsTherapy completed patients (N=41)
      Total (N=103)Without bedaquiline (N=68)With bedaquiline (N=35)P
      Liver injury8 (19.51%)5(7.35%)3(8.57%)0.827Depression3 (7.32%)
      Anemia7 (17.07%)5(7.35%)2(5.71%)0.754Anemia3 (7.32%)
      Arthralgia or myalgia6 (14.63%)3(4.41%)3(8.57%)0.393Arthralgia or myalgia2 (4.88%)
      Depression4 (9.76%)4(5.88%)00.143Leukopenia2 (4.88%)
      Dizziness or headache3 (7.32%)3(4.41%)00.207Peripheral neuritis1 (2.44%)
      Gastrointestinal symptoms2 (4.88%)2(2.94%)00.306Hypopsia1 (2.44%)
      Leukopenia2 (4.88%)2(2.94%)00.306Skin hyperpigmentation1 (2.44%)
      Peripheral neuritis1 (2.44%)1(1.47%)00.471Thrombocytopenia1 (2.44%)
      Hyperuricemia1 (2.44%)1(1.47%)00.471Liver injury1 (2.44%)
      Hypopsia1 (2.44%)1(1.47%)00.471Allergy0
      Anxiety1 (2.44%)1(1.47%)00.471Anxiety0
      QTc prolongation1 (2.44%)1(1.47%)00.161Dizziness or headache0
      Insomnia1 (2.44%)1(1.47%)00.471Gastrointestinal symptoms0
      Skin hyperpigmentation1 (2.44%)1(1.47%)00.471Gout0
      Thrombocytopenia1 (2.44%)01(2.86%)0.161Hyperuricemia0
      Allergy1 (2.44%)1(1.47%)00.471Insomnia0
      Gout1 (0.97%)1(1.47%)00.471Palpitation0
      Palpitation000QTc prolongation intervention0
      Rash000Rash0
      Weakness000Weakness0

      Discussion

      The effort described in this report is the first of its kind to address the barrier to implementing the new WHO guidelines and optimizing the regimens in the real-world clinic under China's national conditions, considering the local drug resistance, drug price, reimbursement policy, and patients' wishes. To our knowledge, there were no other interim or final analyses of short all-oral regimens for RR/MDR-TB reported in China, except this one.
      In this non-randomized controlled trial, we demonstrated all-oral short-course regimens of 4-5 drugs and 9-12 months, which gained a culture conversion rate of 83.1% and 94.4% at the second and fourth months of treatment, respectively, and 97.6% of patients who finished their treatment had a favorable outcome. These satisfactory results were derived from a series of optimized strategies (
      • Cox V
      • McKenna L
      • Acquah R
      • Reuter A
      • Wasserman S
      • Vambe D
      • et al.
      Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.
      ). (1) A significant feature of this study is the design of a real-world experimental study, which significantly increases the feasibility of future promotion of it, not limited to clinical trial scenarios. (2) We made all efforts to ensure access to DST, using the DST to guide regimen adjustment. (3) We enhanced educational counseling and psychological support by social application Wechat. (4) Material support for patients was rare in this study, but Shenzhen's medicine insurance policy helped, which is superior to other parts of China.
      The regimens were composed of linezolid, later-generation fluoroquinolone, bedaquiline, cycloserine, clofazimine, pyrazinamide, ethambutol/protionamide, in the order of priority. Poor accessibility and high price of bedaquiline hindered its application and promotion since it entered the Chinese market on 1st January 2020. Linezolid is not included in 2020 WHO's new bedaquiline-containing short regimen because of the lack of adequate direct data (
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ), but it worked as a key drug in our regimens. Although FQs weigh a lot in MDR-TB regimens, we did not exclude patients with FQs resistance, and we substituted FQs with suitable drugs in that case. Levofloxacin at a dose of 500-750 mg was used in our study, which is also routine in China's clinical practice (
      • Davies F L
      • Niward K
      • Kuhlin J
      • Zheng X
      • Zheng R
      • Ke R
      • et al.
      Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China.
      ), instead of 750-1000 mg as recommended by WHO (
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ). For clofazimine, the main side effect is skin hyperpigmentation, which is prominent and quite a challenge in Asian populations (
      • Murashov M D
      • LaLone V
      • Rzeczycki P M
      • Keswani R K
      • Yoon G S
      • Sud S
      • et al.
      The physicochemical basis of clofazimine-induced skin pigmentation.
      ,
      • Sachdeva K S
      • Parmar M
      • Patel Y
      • Gupta R
      • Rathod S
      • Chauhan S
      • et al.
      Evolutionary journey of programmatic services and treatment outcomes among drug resistant tuberculosis (DR-TB) patients under National TB Elimination Programme in India (2005-2020).
      ). When bedaquiline was available, and no other drug resistance existed, we avoided clofazimine in the bedaquiline-free regimen to improve patient compliance. Pyrazinamide has an important sterilizing role in shortening treatment by diffusing into caseous lesions rather than airway surfaces (
      • Zhang Y
      • Mitchison D.
      The curious characteristics of pyrazinamide: a review.
      ,
      • Prideaux B
      • Via L E
      • Zimmerman M D
      • Eum S
      • Sarathy J
      • O'Brien P
      • et al.
      The association between sterilizing activity and drug distribution into tuberculosis lesions.
      ,
      • Strydom N
      • Gupta S V
      • Fox W S
      • Via L E
      • Bang H
      • Lee M
      • et al.
      Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.
      ,
      • Sun F
      • Li Y
      • Chen Y
      • Guan W
      • Jiang X
      • Wang X
      • et al.
      Introducing molecular testing of pyrazinamide susceptibility improves multidrug-resistant tuberculosis treatment outcomes: a prospective cohort study.
      ), so it was our preferred choice among all group C drugs (
      • Kuhlin J
      • Davies F L
      • Mansjö M
      • Jonsson N M
      • Wijkander M
      • Wagrell C
      • et al.
      Genotypic resistance of pyrazinamide but not MIC is associated with longer time to sputum culture conversion in patients with multidrug-resistant tuberculosis.
      ).
      The most important interim indicator of the efficacy of anti-TB treatment for MDR-TB is the culture conversion at two months and six months (
      • Holtz T H
      • Sternberg M
      • Kammerer S
      • Laserson K F
      • Riekstina V
      • Zarovska E
      • et al.
      Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.
      ,
      • Bastard M
      • Sanchez-Padilla E
      • Hayrapetyan A
      • Kimenye K
      • Khurkhumal S
      • Dlamini T
      • et al.
      What is the best culture conversion prognostic marker for patients treated for multidrug-resistant tuberculosis?.
      ). Culture conversion at two months was 52% (16/31) in South Africa (
      • Mohr E
      • Hughes J
      • Reuter A
      • Trivino D L
      • Ferlazzo G
      • Daniels J
      • et al.
      Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.
      ), 57.4% (81/141) in South Korea (
      • Kang H
      • Jo K W
      • Jeon D
      • Yim J J
      • Shim T.S.
      nterim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea.
      ), 77% (129/167) in Latvia (
      • Holtz T H
      • Sternberg M
      • Kammerer S
      • Laserson K F
      • Riekstina V
      • Zarovska E
      • et al.
      Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.
      ). Culture conversion at six months was 81% (25/31) in South Africa (
      • Mohr E
      • Hughes J
      • Reuter A
      • Trivino D L
      • Ferlazzo G
      • Daniels J
      • et al.
      Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.
      ), 89.4% (126/141) in South Korea (
      • Kang H
      • Jo K W
      • Jeon D
      • Yim J J
      • Shim T.S.
      nterim treatment outcomes in multidrug-resistant tuberculosis using bedaquiline and/or delamanid in South Korea.
      ), 97% (28/29) in France (
      • Guglielmetti L
      • Le Dû D
      • Jachym M
      • Henry B
      • Martin D
      • Caumes E
      • et al.
      Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort.
      ). In the endTB Observational Study with regimens containing bedaquiline (63%), delamanid (27%), or both (10%), 85% (939/1109) experienced culture conversion within six months (
      • Franke M F
      • Khan P
      • Hewison C
      • Khan U
      • Huerga H
      • Seung K J
      • et al.
      Culture conversion in patients treated with bedaquiline and/or delamanid. A prospective multicountry study.
      ). Our results (83.1% and 94.4% at two and four months) were similar to or better than those studies above. We should be aware that the 2-month culture status modestly predicts end-of-treatment outcomes and that the supporting evidence largely came from drug-susceptible tuberculosis. In RR/MDR-TB, evidence was contradictory. Some reports supported its use while others suggested that the 6-month culture status is a better predictor (
      • Kurbatova E V
      • Cegielski J P
      • Lienhardt C
      • Akksilp R
      • Bayona J
      • Becerra M 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.
      ,
      • Meyvisch P
      • Kambili C
      • Andries K
      • Lounis N
      • Theeuwes M
      • Dannemann B
      • et al.
      Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial.
      ). There was scarce information for the all-oral short regimens.
      FQs were associated with significantly greater treatment success for MDR-TB (
      • Ahmad N
      • Ahuja S D
      • Akkerman O W
      • Alffenaar J C
      • Anderson L F
      • Baghaei P
      • et al.
      Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.
      ). In our study, if FQ-resistant, Bdq-Lzd-Cfz-Cs-Pza or Lzd-Cfz-Cs-Pza-Pto for 12 months were applied. Here, the culture conversion rate was comparable between FQ-resistant and FQ-susceptible cases at two months (78.6% vs. 86.5%, P=0.509) and at four months (90.3% vs. 97.5%, P=0.311), supporting the efficacy to some extent.
      Bedaquiline and clofazimine is the unique drug in these two regimens, respectively. Generally speaking, bedaquiline is widely praised (
      • Ahmad N
      • Ahuja S D
      • Akkerman O W
      • Alffenaar J C
      • Anderson L F
      • Baghaei P
      • et al.
      Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.
      ,
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ), but the two regimens showed similar efficacy on culture conversion at two months (79.5% vs. 90.5%, P=0.480) and four months (93.6% vs. 95.8%, P=1.000), and these two groups had no significant difference in age, gender, BMI, symptoms, previous treatment history, diabetes mellitus, FQ and SLID DST, and lung lesion on chest radiograph (Supplemental Material). It was effective to introduce 9-month Lzd-Mfx-Cfz-Cs-Pza, which is much cheaper than the bedaquiline-containing regimen (roughly 26 vs. 63 US dollars a day in the 9-month regimen). Actually, we have been conducting another randomized controlled study, named TB-TRUST (NCT03867136), to assess the efficacy and feasibility of this bedaquiline-free regimen (
      • Weng T
      • Sun F
      • Li Y
      • Chen J
      • Chen X
      • Li R
      • et al.
      Refining MDR-TB treatment regimens for ultra short therapy (TB-TRUST): study protocol for a randomized controlled trial.
      ).
      Being culture positive at two months was related to recurrence (
      • Moosazadeh M
      • Bahrampour A
      • Nasehi M
      • Khanjani N.
      The incidence of recurrence of tuberculosis and its related factors in smear-positive pulmonary tuberculosis patients in Iran: A retrospective cohort study.
      ,
      • Mirsaeidi M
      • Sadikot R T
      Patients at high risk of tuberculosis recurrence.
      ) and unsuccessful treatment outcomes (
      • Atif M
      • Bashir A
      • Ahmad N
      • Fatima R K
      • Saba S
      • Scahill S.
      Predictors of unsuccessful interim treatment outcomes of multidrug resistant tuberculosis patients.
      ). In our study, the history of previously using SLID was a predictor of delayed time to culture conversion at two months in the multivariable analysis (Figure 3), which was coincident with series of previous studies (
      • Qazi F
      • Khan U
      • Khowaja S
      • Javaid M
      • Ahmed A
      • Salahuddin N
      • et al.
      Predictors of delayed culture conversion in patients treated for multidrug-resistant tuberculosis in Pakistan.
      ).
      Fig. 3
      Figure 3Time to Culture-Negative Status among Patients Who were Positive at Baseline
      a) Time to culture-negative status among enrolled patients who were positive at baseline
      b) Time to culture-negative status between patients with FQ-resistance and without FQ-resistance who were positive at baseline
      c) Time to culture-negative status among enrolled patients who were positive at baseline among RR/MDR-TB, pre-XDR-TB with FLQ-resistance and XDR-TB
      d) Time to culture-negative status among enrolled patients who were positive at baseline between the regimen with bedaquiline and the one without bedaquiline
      Fig. 3
      Figure 3Time to Culture-Negative Status among Patients Who were Positive at Baseline
      a) Time to culture-negative status among enrolled patients who were positive at baseline
      b) Time to culture-negative status between patients with FQ-resistance and without FQ-resistance who were positive at baseline
      c) Time to culture-negative status among enrolled patients who were positive at baseline among RR/MDR-TB, pre-XDR-TB with FLQ-resistance and XDR-TB
      d) Time to culture-negative status among enrolled patients who were positive at baseline between the regimen with bedaquiline and the one without bedaquiline
      The AEs were generally tolerable in our regimens, since some effective interventions were given to deal with it (
      • Mitnick C D
      • Rodriguez C A
      • Hatton M L
      • Brigden G
      • Cobelens F
      • Grobusch M P
      • et al.
      Programmatic management of drug-resistant tuberculosis: An updated research agenda.
      ,

      EndTB Consortium. endTB clinical and programmatic guide for patient management with new tb drugs. Version 4.0.2018.

      ,
      • Lange C
      • Dheda K
      • Chesov D
      • Mandalakas A M
      • Udwadia Z
      • Horsburgh C.J.
      Management of drug-resistant tuberculosis.
      ). (1) For linezolid, two AEs in two patients (2/103, 1.94%) caused permanent discontinuation, which were similar to the data of linezolid in the WHO active TB drug safety monitoring and management project (total AEs, 12.9%, 69/536; SAEs, 2.8%, 15/536) (
      • Borisov S
      • Danila E
      • Maryandyshev A
      • Dalcolmo M
      • Miliauskas S
      • Kuksa L
      • et al.
      Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.
      ). The most frequent AEs were anemia (7/103, 17.07%) and arthralgia/myalgia (6/103, 14.63%). (2) In the bedaquiline-containing regimens, we inclusively prolonged the bedaquiline duration to 9-12 months in all cases, and its safety profile seemed good. There were eight instances of QTc prolongation (>450 ms, <500 ms) in 35 patients (22.86%, 8/35), and no QTc prolongation >500 ms occurred. Between bedaquiline-containing regimen and bedaquiline-free regimen, QTc prolongation was similar (14.71% vs. 22.86%, P=0.302).
      One of the limitations of this study is that there was no randomized control group to draw a high-evidence conclusion (
      • Booth C M
      • Karim S
      • Mackillop W.J.
      Real-world data: towards achieving the achievable in cancer care.
      ); however, we undertook this study design for several reasons. Firstly, WHO's shorter regimens experienced frequent updates and were unstable in recent years (
      WHO
      WHO treatment guidelines for drug-resistant tuberculosis. 2016 update.
      ,
      WHO
      WHO treatment guidelines for multidrug and rifampicin-resistant tuberculosis 2018 update Pre-final text.
      ,
      WHO
      WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment.
      ), making it not a good choice for being a control arm. Secondly, this non-randomization design aimed to enhance universal applicability to real-world clinical practice (
      • Franklin J M
      • Pawar A
      • Martin D
      • Glynn R J
      • Levenson M
      • Temple R
      • et al.
      Nonrandomized real-world evidence to support regulatory decision making: Process for a randomized trial replication project.
      ). Another limitation of this study was that we could not provide free drugs, and the social-economic status of the patients may be a confounding factor impacting their treatment outcomes, which was not significant as the treatment outcomes were favorable in both regimens. Additionally, part of the sputum samples were not collected due to LTFU, which was quite a challenge during and after the COVID-19 pandemic in China (
      • McQuaid C F
      • McCreesh N
      • Read J M
      • Sumner T
      • Houben R
      • White R G
      • et al.
      The potential impact of COVID-19-related disruption on tuberculosis burden.
      ), indicating that we need to maintain and strengthen TB-related health services at challenging times. Also, the sample size of our study was relatively small, suggesting that the conclusion needed to be validated in a larger population.

      Conclusions

      Two optimized all-oral short regimens for MDR-TB had high culture conversion in all patients and a high treatment success rate in patients who completed the treatment. There was an insignificant difference in culture conversion between bedaquiline-free and bedaquiline-containing regimens, providing options for patients with different needs. The AEs were endurable and manageable. As the first report of its kind in China, these findings may benefit the uptake and programmatic use of all-oral short regimens in this country and the world. In the future, more well-designed high-evidence studies are needed to confirm our findings, and medical insurance reimbursement policies should be improved to deal with the MDR-TB epidemic.

      Acknowledgments

      We thank all the physicians and assistants that participated in this study and enrolled patients. We thank the statistician (Junyan Zhang) for assistance in data management and analysis. The authors declare no conflict of interest.

      Conflict of interest

      All authors have nothing to disclose.

      Funding Source

      This work was supported by the National Key Research and Development Plan (No. 2020YFA0907200, 2019YFC0840602), the Guangdong Foundation for Basic and Applied Basic Research (No. 2019B1515120041), the Guangdong Science and Technology Plan (No. 2020B1111170014), the Shenzhen Scientific and Technological Foundation (No. KCXFZ202002011007083), Summit Plan for Foshan High-level Hospital Construction (No. FSSYKF-2020001) and Clinical Research Plan of SHDC (No. SHDC2020CR1011B).

      Ethical Approval statement

      The Ethical Committee of the Shenzhen Third People's Hospital approved this study. After providing a clear explanation of their rights and duties to all subjects, written informed consent was obtained from all study participants or a guardian in the case of minors before screening and assignment. The study was conducted according to the principles of the World Medical Association Declaration of Helsinki, Good Clinical Practice Guidelines, and local laws and regulations.

      Appendix. Supplementary materials

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