- Email: [email protected]
Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009–2013
Accepted Manuscript Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009-2013 Le Zhang, Qiong Meng, Songhua Chen, Minwu Zhang, Bin Chen, Beibei Wu, Guangsen Yan, Xiaomeng Wang, Zhongwei Jia PII:
S1198-743X(17)30363-4
DOI:
10.1016/j.cmi.2017.07.008
Reference:
CMI 1005
To appear in:
Clinical Microbiology and Infection
Received Date: 26 February 2017 Revised Date:
2 July 2017
Accepted Date: 7 July 2017
Please cite this article as: Zhang L, Meng Q, Chen S, Zhang M, Chen B, Wu B, Yan G, Wang X, Jia Z, Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009-2013, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page
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Title: Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China,
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2009-2013
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Running title: Treatment outcomes of MDR-TB
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Authors: Le Zhang1,3, Qiong Meng2, Songhua Chen2*, Minwu Zhang2, Bin Chen2, Beibei Wu2,
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Guangsen Yan4, Xiaomeng Wang2*, Zhongwei Jia3*
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Affiliations:
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1. Department of epidemiology and biostatistics, School of Public Health, Peking University,
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Beijing, P. R. China
2. Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang 310006, P. R. China
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3. National Institute of Drug Dependence, Peking University, Beijing, P. R. China
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4. School of Computer Science, University of Nottingham, Computer Science Bldg Jubilee
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Campus, Nottingham, NG8 1BB, United Kingdom Le Zhang and Qiong Meng are co-first authors.
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First Correspondence:
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Songhua Chen, Zhejiang Provincial Centre for Disease Control and Prevention. No. 630 Xincheng Road, Binjiang District, Hangzhou, Zhejiang 310051, China. Tel: 86-13906535138;
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Fax: 057187115183; E-mail: [email protected].
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Co-correspondence:
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Zhongwei Jia, National Institute of Drug Dependence, Peking University, 38 Xueyuan Road, Beijing 100191, P.R. China. Tel: 86-010-82802457; Email: [email protected].
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Xiaomeng Wang, Zhejiang Provincial Centre for Disease Control and Prevention. No. 630
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Xincheng Road, Binjiang District, Hangzhou, Zhejiang 310051, China. Tel: 86-13906525336;
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Fax: 057187115183; E-mail: [email protected].
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Keywords: tuberculosis; drug resistant tuberculosis; MDR-TB; treatment outcomes;
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standardized treatment.
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Running title: MDR-TB Treatment Outcomes
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Objectives. To examine treatment outcomes and factors associated with poor outcome of
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MDR-TB in China.
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Methods. Prospective observational cohort study including consecutive patients with MDR-TB
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between 2009-2013 in six regions of Zhejiang province. Patients were prescribed treatments by
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infectious disease specialists and treatment outcomes were recorded. Sociodemographic
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characteristics were obtained through a structured questionnaire. The primary endpoint was
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poor treatment outcomes, defined as treatment failure based on microbiological persistence,
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default (lost to follow-up) or death at 24 months. We assessed risk factors for poor treatment
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outcomes using a Cox proportional hazards model.
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Results. 820 MDR-TB patients were observed and 537 with known treatment outcomes were
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included in our study. Overall, the treatment success rate was 40.2 per 100 years (374/537
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participants, 69.6%), while treatment failure, death and default rates were 10.0 per 100 years
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(101 participants, 18.8%), 3.4 per 100 years (36 participants, 6.7%) and 2.7 per 100 years (26
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participants, 4.8%), respectively. Independent predictors of poor treatment outcomes included:
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age>60 years (HR 2.3, 95% CI 1.2-4.2), patients registered as relapse (HR 2.2 95% CI 1.1-4.4),
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patients registered as treatment after failure (HR 2.4 95% CI 1.2-4.9), use of standardized
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MDR-TB regimens (HR 0.6 95% CI 0.4-1.0), cavitary disease (HR 4.9 95% CI 2.8-8.6) and
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adverse events (HR 2.5 95% CI 1.2-5.5).
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Conclusions. Under well-designed treatment and management scheme, high treatment success
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rates were achieved in a high MDR-TB burden country. Antimicrobial susceptibility testing for
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all second-line drugs should be conducted to further assist the treatment of MDR-TB.
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Main Text – 2624 words
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INTRODUCTION
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The emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) continue to pose a great threat to the elimination of TB, with
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estimates of 3.9% of new and 21% of previously treated TB cases being MDR-TB and 0.25
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million people dying from MDR-TB worldwide [1]. MDR-TB develops with poor
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management, or as a result of previous exposure to anti-TB drugs [2, 3].
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To achieve the global target of ending the TB epidemic by 2030, providing high-quality
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disease management to improve treatment outcome is one of the key strategies [4]. To date, the
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treatment success rate of MDR-TB patients was described as only 52% globally [5]. However,
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this was mainly based on a small cohort and also confounded by hospital admission bias.
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Different MDR-TB treatment regimens were prescribed to patients according to their medical
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conditions and registration group, since there is little evidence for management based on
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randomized controlled trials. Apart from treatment regimen, there are many other factors
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affecting treatment outcomes including gender, hospitalization, previous treatment [6],
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residence, acid-fast bacilli (AFB) result at baseline [7], HIV status [8] and more. Factors
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associated with MDR-TB treatment outcomes vary largely from settings to settings.
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China is among the 30 high MDR-TB burden countries worldwide. A national TB resistance survey has presented that 5.7% and 25.6% of new and previously treated cases were
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MDR-TB [9], 1.55 and 1.28 times higher than the global average, respectively. However,
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China has few reports regarding treatment outcomes of MDR-TB, and all studies were
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conducted in hospitals [10, 11]. To investigate treatment outcomes and factors associated with
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poor outcomes in China, we conducted this population-based study and intended to further
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support TB control and management.
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METHODS
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Study population and procedures
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Prospective observational cohort study from 7/2009 - 7/2013 in six regions of Zhejiang
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Province: Hangzhou, Huzhou, Jiaxing, Lishui, Quzhou, and Shaoxing, initiated by the Zhejiang
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Disease Control and Prevention Center (CDC) and Global Fund MDR-TB Project. Zhejiang
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has set up routine drug resistance monitoring since 1999, and details can be found in our 3
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previous studies [12]. All MDR-TB patients involved in the study met the inclusion criteria: (1) MDR-TB was
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confirmed by antimicrobial susceptibility testing (AST) from a regional reference laboratory;
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(2) patients were sputum smear-positive for AFB and culture-positive for M. tuberculosis; (3)
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receiving treatment. Due to the delay in receiving AST results, before patients switched to the
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definitive MDR-TB treatment, all newly-diagnosed TB patients received the national standard
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“new patient regimen” - two months of isoniazid, rifampicin, pyrazinamide and ethambutol
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followed by four months of isoniazid and rifampicin (2HRZE/4HR) and retreatment patients
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received the “retreatment regimen” - two months of isoniazid, rifampicin, pyrazinamide and
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ethambutol followed by four months of isoniazid and rifampicin (2HRZES/6HRE). We
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classified patients’ definitive MDR-TB treatments into five types of standard regimens (SRs),
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each including 4-5 drugs that the patients were sensitive to according to the AST results. Four
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SRs were given for 24 months and one for 36 months (Table S1), and the doses of all anti-TB
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drugs are described in Table S2. If treated differently, patients were classified as individualized
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regimen (IR). IR was based on AST and TB treatment history. Treatments were prescribed by
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infectious disease specialists.
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Patients were followed daily until the end of follow-up or the outcome event had been reached and drugs were given under direct observation. We examined sputum smear, sputum culture, liver function, body weight, and blood routine examination periodically to prevent
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adverse event (ADE). Additionally, 70 Renminbi (the currency of China) nutritional subsidies
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and 70 Renminbi traffic subsidies were given to impoverished patients every month. Those in
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poor mental health status received 2 free psychological consultations, and health education was
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also provided.
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Information on socio-demographic characteristics (age, sex, occupation and household),
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MDR-TB-related characteristics (registration group, previous treatment history, hospitalization,
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treatment regimen and baseline resistance pattern) and indicators of severity (hemoptysis,
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cavity, and ADE) was collected through questionnaires and medical records by trained health
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workers. Treatment outcomes, sputum culture and smear conversion, and chest X-rays were
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monitored periodically.
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Approval of the study was obtained from ethics committees at Zhejiang CDC. Written 4
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informed consents were obtained from all participants.
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Definitions
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MDR-TB and XDR-TB were defined as in WHO guidelines [7]. Pre-XDR-TB was defined as TB with resistance to both isoniazid and rifampicin, and either a fluoroquinolone (ofloxacin)
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or a second-line injectable drug (kanamycin).
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Treatment outcomes were categorized according to the Global Fund MDR-TB Project. Cure was defined as a patient who completed treatment, and at least 5 final consecutive
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cultures of his/her sputum during the final 12 months of treatment were negative; or if 1 culture
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was positive, then at least 3 of its following consecutive cultures should have been negative.
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Treatment completed was defined as patients who had completed their treatments without
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evidence of failure but with inadequate bacteriological records to be defined as cure. Treatment
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failure was defined when there were ≥ 2 positive sputum cultures of the five final cultures, or 1
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positive culture of the final three cultures during the final 12 months of treatment. Died was
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defined as patients who died due to any cause during treatment. Lost to follow-up (default) was
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defined as patients whose treatment were interrupted for ≥ 2 consecutive months against
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clinicians’ advice.
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Treatment success was defined as cured or treatment completed, whereas poor treatment outcome was defined as treatment failure, default or death.
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Laboratory Cultures and Antimicrobial Susceptibility Testing
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Sputum smear microscopy was performed directly at the tuberculosis bacterium laboratory of each region, where direct AFB smear microscopy and AFB culture on Lowenstein-Jensen
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solid medium were applied. The identification of M. Tuberculosis and AST was performed at a
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provincial reference laboratory. Susceptibility testing of 4 first-line drugs (isoniazid, rifampin,
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streptomycin, ethambutol) and 2 second-line drugs (ofloxacin, kanamycin) was performed for
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sputum culture-positive stains by the proportion method [13], and results were compared with
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standardized strains. Drug concentrations for rifampin, isoniazid, ethambutol, streptomycin,
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ofloxacin, and kanamycin were 40.0, 0.2, 2.0, 4.0, 2.0, and 30.0 µg/ml, respectively.
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Statistical analysis
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Socio-demographic, MDR-TB related characteristics and indicators of severity were described as percentages stratified by regions. To investigate risk factors for poor outcomes, we 5
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for setting-associated confounding). We also developed a sensitivity analysis excluding patients
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whose treatment were unrecorded to examine our findings. Hazard ratios and 95% confidence
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intervals were calculated to demonstrate the risks for poor outcomes. We also used Kaplan–
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Meier method with log-rank test to compare survival curves of time to poor outcomes by
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baseline resistance patterns. Statistical analysis was conducted using R 3.3.0, and P < 0.05
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indicated statistical significance.
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RESULTS
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Study Cohort and characteristics of participants
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From July 1, 2009 to July 13, 2013, 820 patients were diagnosed as sputum smear-positive MDR-TB in six regions of Zhejiang province. 204 MDR-TB were not treated due to refusal to
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receive treatment, death or default before treatment, no effective treatment regimen, moving
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out and having underlying medical conditions (not suitable for chemotherapy or could not
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receive treatment at the present time, Figure 1). Among 616 patients receiving treatment, 79
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patients had incomplete outcome records. Overall, 537 patients were involved in our analysis.
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Basic characteristics stratified by regions are shown in Table 1.
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Of all 537 individuals, 382 were male, with mean age of 47 years (SD 16.0), while females were younger on average (41years, SD 15.1). The delay in starting appropriate MDR-TB
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treatment after TB diagnosis was a median of 88 days (IQR 17-163). AST for second-line
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drugs were conducted for 159 patients. The majority of MDR-TB patients were resistant only
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to first-line drugs (71.1%, 113/159). Pre-XDR-TB was seen in 27 MDR-TB patients (17.0%),
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of which 26 were resistant to fluoroquinolones, and 1 was resistant to second-line injectable
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drugs. XDR-TB was seen in 19 patients (11.9%, Figure 2).
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Treatment outcomes
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MDR-TB patients were followed for a mean of 20 months after treatment initiation.
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During 917.3 person-years of follow-up, treatment success rate was 40.2/100 person-years
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(369/917.3 person-years), while the treatment failure, death and default rate were 10.0/100
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person-years (92/917.3 person-years), 3.4/100 person-years (31/917.3 person-years) and
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2.7/100 person-years (25/917.3 person-years), respectively (Table 2). The number of
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participants with success, failure, death, and default outcomes out of 537 participants were 374 6
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patients had the highest treatment success rate (82.3%, 65/79). The success rate of relapse
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patients (65.3%, 128/196) was lower than patients registered as treatment after failure (71%,
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169/238) and patients registered as treatment after default (71.4%, 5/7).
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Risk factors for poor treatment outcome
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In our multivariable cox model (Table 3), patients older than 60 were associated with a
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greater likelihood of poor outcomes compared with patients under 30 (HR 2.3, 95% CI 1.2-4.2).
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Compared with newly-diagnosed patients, those registered as relapse and treatment after failure
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were both at increased risk of poor outcomes (HR 2.2 95% CI 1.1-4.4; HR 2.4 95% CI 1.2-4.9),
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while the risk for patients registered as treatment after default was not significant. Standardized
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treatment regimens were associated with a lower risk of poor outcomes (HR 0.6 95% CI
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0.4-1.0), though the result was not significant in our sensitivity analysis restricted to patients
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whose treatment regimen was available (N=415, Table S4). Having a cavity on chest
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radiograph was a strong predictor for poor outcomes (HR 4.9 95% CI 2.8-8.6). Experiencing
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adverse events increased the risk of poor outcomes 2.5 times (HR 2.5 95% CI 1.2-5.5).
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Survival curves stratified by resistance pattern
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Survival days to poor outcomes between different resistance pattern are shown in Figure 3. Pre-XDR-TB and XDR-TB patients reached poor outcomes more rapidly than
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MDR-TB-First-Line patients. Poor outcomes increased with levels of resistance patterns
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(MDR-TB-First-Line, Pre-XDR-TB, XDR-TB), and the log-rank test for trend of survival
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functions was significant (P = 0.0018).
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DISCUSSION
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In our prospective study, the treatment success rate of MDR-TB reached 69.6% (374/537).
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We identified significant risk factors for poor treatment outcomes: age group, patient
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registration group, cavity on baseline chest X-ray, treatment regimen, and occurrence of
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adverse events. The treatment success rate in our cohort was much higher than the national
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average (55%), the global average (52%), as well as the WHO western pacific average (57%)
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[1]. Pre-planned standardized regimens based on local susceptibility patterns, individualized
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regimens based on personal AST results, as well as adequate supplementary measures may
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have played important roles. These measures included incentives for both DOT-performing 7
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clinicians and patients, nutritional supplementation and emotional support. Offering free
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diagnosis and drugs may have ensured the adherence.
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Our supplementary measures might have produced a positive effect on compliance, with default rates of only 4.8%, much lower than the global average (15%). Worldwide, most
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cohorts have reported >10% default rates: 17% in Estonia [7], 26% in Latvia [14], 20.9% in
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South Africa [15], and 10.0% in Peru [16]. In China the default rate was significantly lower:
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12.5% in Shenzhen [17], 6% in Guangzhou [18], and 4% in a meta-analysis [19].
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However, this success rate was far below the global target of 75% [20]. The rate was lower than Korea, Kenya, Myanmar, Nigeria, and Somalia, who were also among the 30 high
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MDR-TB burden countries reporting treatment success of >75% [1]. The high success rates in
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these countries were probably due to application of new drugs [21] and broader access to
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second-line drug-susceptibility testing. WHO treatment guidelines for drug-resistant TB
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recommend prescribing at least five effective TB drugs [22]. However, due to financial
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constraint, China has not ensured universal access to second-line drug-susceptibility testing, so
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there remain many MDR-TB patients treated with inadequate number of effective drugs.
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Improving diagnostic capacity can result in better MDR-TB treatment and can reduce
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MDR-TB transmission and further drug resistance in China.
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We found that patients older than 60 were at risk for poor outcomes, which is consistent
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with previous studies [23-25]. This result may be attributable to the ADE of anti-TB drugs and
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economic status of older people. ADE caused by anti-TB drugs was reported to be age-related
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[26, 27], and some second-line drugs are not free in China.
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Not surprisingly, our study demonstrated that retreated patients were at higher risks of poor
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outcomes than newly-diagnosed patients, which is consistent with published studies [28-30].
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We divided retreated patients into four groups, which have not been normally analyzed in other
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studies. We found it was patients registered as treatment after failure among retreated patients
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that contributed to the higher risk of poor outcome. This implies that we should provide better
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treatment and management to retreated patients registered as treatment after failure.
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Standardized treatment regimens were a protective factor for poor outcomes. However,
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this result is subjected to selection bias though we adjusted for indicators of severity and also
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this factor was not significant in our sensitivity analysis. Well-designed SR is highly 8
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cost-effective and may achieve high treatment success rates, especially in low- and
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middle-income settings. Nonetheless, it is important to underline that the clinical effectiveness
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of a drug cannot be predicted by AST with 100% certainty [31]. Treating MDR-TB patients
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with SR would reduce expenses and human resources in China. Cavity was significantly associated with poor outcomes. Bilateral cavitation was found
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linked to poor outcomes in some studies [32]. Adverse event was also a strong predictor for
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poor outcomes, which may lead to poor compliance and inadequate treatment.
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In our study, Pre-XDR-TB patients were not associated with poor outcomes, which is
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inconsistent with published studies. This was due to a high proportion of unknown second-line
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drug-susceptibility testing results. In fact, AST for 2nd-line drugs were conducted for all
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patients in 2 regions (Huzhou and Quzhou) but not conducted in Jiaxing and Lishui. In
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Hangzhou and Shaoxing, the testing was conducted for 13% and 52.2% of patients,
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respectively. The implementation of second-line drug-susceptibility testing was based on the
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results of individual’s smear sputum and local capacity of laboratory testing. Our analysis of
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159 patients with AST results showed that the risk of poor outcome increased with baseline
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resistance pattern (MDR-FL, Pre-XDR, XDR). Pre-XDR-TB patients should receive careful
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management and treatment, in case their condition progresses.
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The current study has several limitations. First, many MDR-TB patients were not enrolled
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on treatment due to physical conditions, and there were also a few patients with unknown
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treatment outcomes due to missing data and incorrect documentation. This may overestimate
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treatment success rates. Second, our study was an observational study, and although we
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adjusted carefully for indicators of disease severity, residual confounding may still be possible.
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For example, in our MDR-TB program, HIV status was only available for 7% (59/820) patients
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and they were all HIV negative. The mean incidence of HIV in Zhejiang Province is
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1.27/100,000 population over the study period. This uncontrolled confounding may have
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biased our results. Third, second-line drug-susceptibility testing was only performed for 159
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patients, which may lead to bias in the measurement of association between drug resistant
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pattern and poor outcomes. Fourth, the treatment outcomes were defined mainly on
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microbiological response, there might be some differences of clinical responses among patients
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in the same treatment outcome group. Fifth, we did not test the susceptibilities of all
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second-line drugs used in our treatment, only ofloxacin of fluoroquinolones and kanamycin of
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injectable drugs. We may underestimate the proportion of Pre-XDR-TB and XDR-TB patients. In spite of these limitations, to our knowledge, our study is the first population-based study
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to investigate treatment outcomes and factors associated with poor treatment outcome of
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MDR-TB patients in China. Our study indicated that aging, cavitary disease, occurrence of
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adverse events, standardized regimen, retreatment and relapsed disease are independent risk
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factors for poor outcomes. Rapid diagnostics and universal access to antimicrobial
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susceptibility testing should be emphasized in current MDR-TB control policy. In addition,
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antimicrobial susceptibility testing for all second-line drugs should be ensured to further assist
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the treatment and control of MDR-TB.
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Notes
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Financial support. This study was supported by National Natural Science Foundation in China
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(No. U1611264 and 61571001)
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Potential conflict of interest. All Authors declared no potential conflicts.
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[1] World Health Organization, Global tuberculosis report 2015, World Health Organization, 2015. [2] M.D. Iseman Treatment of Multidrug-Resistant Tuberculosis, New England Journal of Medicine 329(11) (1993) 784-791. [3] A. Faustini, A.J. Hall, C.A. Perucci, Risk factors for multidrug resistant tuberculosis in Europe: a systematic review, Thorax 61(2) (2006) 158-163. [4] World Health Organization, Gear up to end TB: introducing the end TB strategy, Geneva, Switzerland: World Health Organization, 2015. [5] Y.S. Kwon, Y.H. Kim, G.Y. Suh, M.P. Chung, H. Kim, O.J. Kwon, Y.S. Choi, K. Kim, J. Kim, Y.M. Shim, Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis, Clinical Infectious Diseases 47(4) (2008) 496-502. [6] K.E. Dooley, O. Lahlou, J. Knudsen, M.D. Elmessaoudi, I. Cherkaoui, R. El Aouad, Risk factors for tuberculosis treatment failure, default, or relapse and outcomes of retreatment in Morocco, BMC Public Health 11(1) (2011) 1. [7] K. Kliiman, A. Altraja, Predictors of poor treatment outcome in multi-and extensively drug-resistant pulmonary TB, European Respiratory Journal 33(5) (2009) 1085-1094. [8] E.V. Kurbatova, A. Taylor, V.M. Gammino, J. Bayona, M. Becerra, M. Danilovitz, D. Falzon, I. Gelmanova, S. Keshavjee, V. Leimane, C.D. Mitnick, M.I. Quelapio, V. Riekstina, P. Viiklepp, M. Zignol, J.P. Cegielski, Predictors of poor outcomes among patients treated for multidrug-resistant tuberculosis at DOTS-plus projects, Tuberculosis (Edinburgh, Scotland) 92(5) (2012) 397-403. [9] Y. Zhao, S. Xu, L. Wang, D.P. Chin, S. Wang, G. Jiang, H. Xia, Y. Zhou, Q. Li, X. Ou, National survey of drug-resistant tuberculosis in China, New England Journal of Medicine 366(23) (2012) 2161-2170. [10] S. Tang, S. Tan, L. Yao, F. Li, L. Li, X. Guo, Y. Liu, X. Hao, Y. Li, X. Ding, Z. Zhang, L. Tong, J. Huang, Risk Factors for Poor Treatment Outcomes in Patients with MDR-TB and XDR-TB in China: Retrospective Multi-Center Investigation, PLOS ONE 8(12) (2013) e82943. [11] C.H. Liu, L. Li, Z. Chen, Q. Wang, Y.L. Hu, B. Zhu, P.C. Woo, Characteristics and treatment outcomes of patients with MDR and XDR tuberculosis in a TB referral hospital in Beijing: a 13-year experience, PloS one 6(4) (2011) e19399. [12] X. Wang, Drug-Resistant Tuberculosis in Zhejiang Province, China, 1999–2008, Emerging Infectious Disease, 18(3) (2012) 496. [13] World Health Organization, Policy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs, 2008. [14] V. Leimane, V. Riekstina, T.H. Holtz, E. Zarovska, V. Skripconoka, L.E. Thorpe, K.F. Laserson, C.D. Wells, Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study, The Lancet 365(9456) (2005) 318-326. [15] J.E. Farley, M. Ram, W. Pan, S. Waldman, G.H. Cassell, R.E. Chaisson, K. Weyer, J. Lancaster, M. Van der Walt, Outcomes of multi-drug resistant tuberculosis (MDR-TB) among a cohort of South African patients with high HIV prevalence, PloS one 6(7) (2011) e20436. [16] M.F. Franke, S.C. Appleton, J. Bayona, F. Arteaga, E. Palacios, K. Llaro, S.S. Shin, M.C. Becerra, M.B. Murray, C.D. Mitnick, Risk factors and mortality associated with default from
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multidrug-resistant tuberculosis treatment, Clinical infectious diseases 46(12) (2008) 1844-1851. [17] L. Deliang, Treatment outcomes in a MDR-TB cohort, Shenzhen, China, China Tropical Medicine 16(7) (2016) 649-665. [18] D. yuhua, Risk factors for treatment outcomes of 116 MDR-TB patients in Guangzhou, China, Chinese journal of antituberculosis 34(1) (2012) 19-22. [19] Z. Ying, Meta analysis of treatment outcomes of multi-drug resistant tuberculosis patients in China, Journal of Tropical Medicine 16(3) (2016) 325-328. [20] World Health Organization, The global plan to stop TB 2011-2015: transforming the fight towards elimination of tuberculosis, 2010. [21] B.H. Jeong, H.Y. Park, H.K. Kim, J.G. Kim, N.Y. Lee, The Korean Academy of Tuberculosis and Respiratory Diseases: Slide Session; OS-027: Mycobacterial Diseases; Outcomes of Multidrug-Resistant Tuberculosis: Impacts of Fluoroquinolone Resistance and Linezolid Treatment, Korean Journal of Internal Medicine 2014(1) (2014) 416-416. [22] World Health Organization, WHO treatment guidelines for drug-resistant tuberculosis 2016 update. WHO/HTM/TB/2016.04, 2016. [23] M.K. Lalor, J. Greig, S. Allamuratova, S. Althomsons, Z. Tigay, A. Khaemraev, K. Braker, O. Telnov, P. du Cros, Risk factors associated with default from multi- and extensively drug-resistant tuberculosis treatment, Uzbekistan: a retrospective cohort analysis, PloS one 8(11) (2013) e78364. [24] N. Ahmad, A. Javaid, A. Basit, A.K. Afridi, M.A. Khan, I. Ahmad, S.A. Sulaiman, A.H. Khan, Management and treatment outcomes of MDR-TB: results from a setting with high rates of drug resistance, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 19(9) (2015) 1109-14, i-ii. [25] P.C. Chan, S.H. Huang, M.C. Yu, S.W. Lee, Y.W. Huang, S.T. Chien, J.J. Lee, Effectiveness of a government-organized and hospital-initiated treatment for multidrug-resistant tuberculosis patients--a retrospective cohort study, PloS one 8(2) (2013) e57719. [26] D. Yee, C. Valiquette, M. Pelletier, I. Parisien, I. Rocher, D. Menzies, Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis, American journal of respiratory and critical care medicine 167(11) (2003) 1472-1477. [27] T. Schaberg, K. Rebhan, H. Lode, Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis, European Respiratory Journal 9(10) (1996) 2026-2030. [28] C.D. Mitnick, M.F. Franke, M.L. Rich, F.A. Alcantara Viru, S.C. Appleton, S.S. Atwood, J.N. Bayona, C.A. Bonilla, K. Chalco, H.S. Fraser, J.J. Furin, D. Guerra, R.M. Hurtado, K. Joseph, K. Llaro, L. Mestanza, J.S. Mukherjee, M. Munoz, E. Palacios, E. Sanchez, K.J. Seung, S.S. Shin, A. Sloutsky, A.W. Tolman, M.C. Becerra, Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality, PloS one 8(3) (2013) e58664. [29] O. Oliveira, R. Gaio, M. Villar, R. Duarte, Predictors of treatment outcome in multidrug-resistant tuberculosis in Portugal, The European respiratory journal 42(6) (2013) 1747-9. [30] V. Leimane, V. Riekstina, T.H. Holtz, E. Zarovska, V. Skripconoka, L.E. Thorpe, K.F.
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Laserson, C.D. Wells, Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study, Lancet (London, England) 365(9456) (2005) 318-26. [31] S. Kim, M. Espinal, C. Abe, G. Bai, F. Boulahbal, L. Fattorin, C. Gilpin, S. Hoffner, K. Kam, N. Martin-Casabona, Is second-line anti-tuberculosis drug susceptibility testing reliable?, The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 8(9) (2004) 1157-1158. [32] M. Rodriguez, I. Monedero, J.A. Caminero, M. Encarnacion, Y. Dominguez, I. Acosta, E. Munoz, E. Camilo, S. Martinez-Selmo, S. de los Santos, M. del Granado, M. Casals, J. Cayla, B. Marcelino, Successful management of multidrug-resistant tuberculosis under programme conditions in the Dominican Republic, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 17(4) (2013) 520-5.
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ACCEPTED MANUSCRIPT Table 1. Characteristics of MDR-TB cases, stratified by counties, Zhejiang Province, China, 2009–2013
Huzhou 41
Region Jiaxing Lishui 8 46 1 (12.5) 7 (87.5) 0 (0.0)
155 (28.9) 92 (28.5) 13 (31.7) 382 (71.1) 231 (71.5) 28 (68.3)
2 (25.0) 6 (75.0)
287 (53.4) 140 (43.3) 17 (41.5) 250 (46.6) 183 (56.7) 24 (58.5)
Shaoxing 80
5 (10.9) 19 (41.3) 22 (47.8)
5 (12.8) 21 (53.8) 13 (33.3)
14 (17.5) 45 (56.2) 21 (26.2)
10 (21.7) 36 (78.3)
15 (38.5) 24 (61.5)
23 (28.7) 57 (71.2)
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124 (23.1) 94 (29.1) 5 (12.2) 300 (55.9) 180 (55.7) 28 (68.3) 113 (21.0) 49 (15.2) 8 (19.5)
Quzhou 39
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Hangzhou 323
4 (50.0) 4 (50.0)
34 (73.9) 12 (26.1)
24 (61.5) 15 (38.5)
68 (85.0) 12 (15.0)
8 (100.0) 0 (0.0)
8 (17.4) 38 (82.6)
1 (2.6) 38 (97.4)
9 (11.2) 71 (88.8)
79 (14.7) 34 (10.5) 4 (9.8) 196 (36.5) 97 (30.0) 7 (17.1) 238 (44.3) 173 (53.6) 29 (70.7) 7 (1.3) 5 (1.5) 1 (2.4) 17 (3.2) 14 (4.3) 0 (0.0)
2 (25.0) 3 (37.5) 3 (37.5) 0 (0.0) 0 (0.0)
11 (23.9) 18 (39.1) 13 (28.3) 1 (2.2) 3 (6.5)
6 (15.4) 23 (59.0) 10 (25.6) 0 (0.0) 0 (0.0)
22 (27.5) 48 (60.0) 10 (12.5) 0 (0.0) 0 (0.0)
22 (4.1) 6 (1.9) 1 (2.4) 351 (65.3) 210 (65.0) 16 (39.0) 164 (30.5) 107 (33.1) 24 (58.5)
0 (0.0) 7 (87.5) 1 (12.5)
11 (23.9) 28 (60.9) 7 (15.2)
2 (5.1) 32 (82.1) 5 (12.8)
2 (2.5) 58 (72.5) 20 (25.0)
8 (100.0) 0 (0.0)
0 (0.0) 46 (100.0)
28 (71.8) 11 (28.2)
5 (6.2) 75 (93.8)
6 (75.0) 2 (25.0) 0 (0.0)
0 (0.0) 46 (100.0) 0 (0.0)
9 (23.1) 28 (71.8) 2 (5.1)
50 (62.5) 15 (18.8) 15 (18.8)
0 (0.0) 0 (0.0) 0 (0.0) 8 (100.0)
0 (0.0) 0 (0.0) 1 (2.2) 45 (97.8)
20 (51.3) 18 (46.2) 1 (2.6) 0 (0.0)
42 (52.5) 0 (0.0) 0 (0.0) 38 (47.5)
6 (75.0) 2 (25.0)
42 (91.3) 4 (8.7)
31 (79.5) 8 (20.5)
74 (92.5) 6 (7.5)
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268 (49.9) 226 (70.0) 16 (39.0) 269 (50.1) 97 (30.0) 25 (61.0)
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Total Age groups <=30 yr 30-60 yr >60 yr Gender Female Male Occupation Farmer Other Household registration* Floating Local Patient Registration group Newly-diagnosed patients Relapse patients Treatment after failure patients Treatment after default patients Other previously treated patients Previous treatment history None First-line drugs only Second-line drugs Hospitalization Yes No
Overall 537
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91 (16.9) 30 (9.3) 20 (48.8) 446 (83.1) 293 (90.7) 21 (51.2)
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Treatment regimen Individualized 94 (17.5) 25 (7.7) 4 (9.8) Standardized 340 (63.3) 213 (65.9) 36 (87.8) Unknown 103 (19.2) 85 (26.3) 1 (2.4) # MDR-TB baseline resistance pattern MDR-FL 117 (21.8) 19 (5.9) 36 (87.8) Pre-XDR 29 (5.4) 6 (1.9) 5 (12.2) XDR 19 (3.5) 17 (5.3) 0 (0.0) Unknown 372 (69.3) 281 (87.0) 0 (0.0) Hemoptysis at diagnosis No 283 (52.7) 96 (29.7) 34 (82.9) Yes 254 (47.3) 227 (70.3) 7 (17.1) Cavity on chest
ACCEPTED MANUSCRIPT 186 (34.6) 71 (22.0) 20 (48.8) 235 (43.8) 161 (49.8) 19 (46.3) 116 (21.6) 91 (28.2) 2 (4.9)
4 (50.0) 4 (50.0) 0 (0.0)
44 (95.7) 2 (4.3) 0 (0.0)
21 (53.8) 18 (46.2) 0 (0.0)
26 (32.5) 31 (38.8) 23 (28.7)
62 (11.5) 0 (0.0) 22 (53.7) 230 (42.8) 104 (32.2) 15 (36.6) 245 (45.6) 219 (67.8) 4 (9.8)
2 (25.0) 6 (75.0) 0 (0.0)
3 (6.5) 42 (91.3) 1 (2.2)
11 (28.2) 28 (71.8) 0 (0.0)
24 (30.0) 35 (43.8) 21 (26.2)
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No Yes Unknown Adverse events No Yes Unknown
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* People who keep their ‘hukou’ (a record in a government system of household registration determining where citizens are allowed to live in China) in their hometown but reside in other areas for various reasons. # MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
ACCEPTED MANUSCRIPT Table 2. Treatment outcome of MDR-TB in Zhejiang Province, China, 2009–2013.
Total*
Total No event (Success) Failure Death Default
537 374 (69.6%) 101 (18.8%) 36 (6.7%) 26 (4.8%)
No. of patients included in the time to event analysis* 517 369 (71%) 92 (18%) 31 (6%) 25 (5%)
Rate# (95% CI) 917.3 person-years 40.2 (35.5 - 45.7) 10.0 (8.2 - 12.3) 3.4 (2.4 - 4.8) 2.7 (1.8 - 4)
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*Data is shown as Number (Percentage); #Rates are presented as per 100 person-years.
ACCEPTED MANUSCRIPT Table 3. Multivariable analysis of factors associated with poor treatment outcomes in patients with MDR-TB, Zhejiang Province, China, 1999-2013
uHR
aHR(95%CI)
243.65 513.63 159.98
8.62 (5.62 - 13.22) 15.58 (12.51 - 19.39) 29.38 (22.07 - 39.10)
Reference 1.7 (1.1, 2.8) 3.1 (1.8, 5.2)
Reference 1.3 (0.8, 2.2) 2.3 (1.2, 4.2)
264.44 652.83
16.26 (12.06 - 21.93) 16.08 (13.28 - 19.47)
Reference 0.9 (0.7, 1.3)
Reference 0.8 (0.6, 1.2)
478.05 439.22
19.24 (15.69 - 23.61) 12.75 (9.81 - 16.57)
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Rate (95% CI) /100 person-years
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Reference 0.9 (0.6, 1.4)
474.24 443.02
13.28 (10.38 - 17.01) 19.19 (15.51 - 23.73)
Reference 1.4 (1.0, 1.9)
Reference 1.2 (0.8, 1.9)
149.27 326.38 405.74 11.52 24.36
8.04 (4.57 - 14.16) 18.38 (14.27 - 23.68) 16.51 (13 - 20.98) 17.36 (4.34 - 69.43) 28.74 (13.7 - 60.28)
Reference 2.4 (1.3, 4.5) 2.4 (1.3, 4.6) 3.0 (0.7, 13.4) 4.1 (1.6, 10.4)
Reference 2.2 (1.1, 4.4) 2.4 (1.2, 4.9) 3.3 (0.7, 15.6) 3.5 (1.2, 9.8)
599.94 283.25 34.07
15.33 (12.5 - 18.81) 17.65 (13.38 - 23.29) 17.61 (7.91 - 39.2)
Reference 1.2 (0.8, 1.6) 1.0 (0.4, 2.4)
Reference 1.2 (0.8, 1.8) 1.7 (0.7, 4.2)
155.11 762.15
16.76 (11.41 - 24.62) 16.01 (13.4 - 19.12)
Reference 1.0 (0.6, 1.5)
Reference 1.2 (0.7, 2.1)
152.14 557.44 207.69
21.03 (14.87 - 29.74) 17.94 (14.75 - 21.82) 7.70 (4.72 - 12.57)
Reference 1.0 (0.7, 1.5) 0.4 (0.2, 0.7)
Reference 0.6 (0.4, 1.0) 0.2 (0.1, 0.5)
194.8 44 29.61 648.87
17.97 (12.9 - 25.02) 22.73 (12.23 - 42.24) 43.91 (25.5 - 75.62) 13.87 (11.28 - 17.05)
Reference 1.3 (0.6, 2.6) 2.7 (1.4, 5.2) 0.8 (0.5, 1.2)
Reference 0.7 (0.3, 1.7) 1.0 (0.4, 2.3) 0.6 (0.3, 1.1)
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Soci-demographic characteristics Age groups <=30 yr 21/124 30-60 yr 80/300 >60 yr 47/113 Gender Female 43/155 Male 105/382 Occupation Farmer 92/287 Other 56/250 Household registration* Floating 63/268 Local 85/269 MDR-TB characteristics Patient Registration group Newly-diagnosed patients 12/79 Relapse patients 60/196 Treatment after failure patients 67238 Treatment after default patients 2/7 Other previously treated patients 7/17 Previous treatment history First-line drugs only 92/351 Second-line drugs 50/164 None 6/22 Hospitalization Yes 26/91 No 122/446 Treatment Regimen Individualized 32/94 Standardized 100/340 Unknown 16/103 # MDR-TB baseline resistance pattern MDR-FL 35/117 Pre-XDR 10/29 XDR 13/19 Unknown 90/372 Indicators of severity Hemoptysis at diagnosis
Person -years
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Events/ Patients†
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485.93 431.34
14.2 (11.22 - 17.98) 18.32 (14.69 - 22.83)
Reference 1.5 (1.1, 2.1)
Reference 1.2 (0.7, 2.3)
30/186 96/235 22/116
319.37 377 220.9
9.39 (6.57 - 13.43) 25.46 (20.85 - 31.1) 9.96 (6.56 - 15.13)
Reference 2.8 (1.8, 4.2) 1.0 (0.6, 1.7)
Reference 4.9 (2.8, 8.6) 5.0 (1.7, 14.8)
10/62 65/230 73/245
113.91 372.56 430.8
8.78 (4.72 - 16.32) 17.45 (13.68 - 22.25) 16.95 (13.47 - 21.31)
Reference 2.0 (1.0, 3.8) 2.0 (1.0, 3.7)
Reference 2.5 (1.2, 5.5) 5.6 (2.3, 13.5)
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No Yes Cavity on chest No Yes Unknown Adverse events No Yes Unknown
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Abbreviations: uHR, unadjusted hazard ratio; aHR, adjusted hazard ratio. † Events/Patients, No. of patients with poor treatment outcomes / No. of patients evaluated. * People who keep their ‘hukou’ (a record in a government system of household registration determining where citizens are allowed to live in China) in their hometown but reside in other areas for various reasons. # MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
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Figure 1. Inclusion of MDR-TB patients in the analysis.
Abbreviation: MDR-TB, multidrug resistance tuberculosis.
ACCEPTED MANUSCRIPT Figure 2. Drug resistance among 159 MDR-TB patients whose second-line drug-susceptibility testing results were available.
44 8 39 22 1 5 3 9 9 2 1 6 10 159
Pre-XDR-TB 27 (17.0%)
XDR-TB 19 (11.9%)
H/R H/R/E H/R/S H/R/E/S H/R/S/Km H/R/Ofx H/R/E/Ofx H/R/S/Ofx H/R/E/S/Ofx H/R/Km/Ofx H/R/E/Km/Ofx H/R/S/Km/Ofx H/R/E/S/Km/Ofx
Total
27.7 5.0 24.5
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MDR-TB-FL 113 (71.1%)
Percent of resistance pattern (%)
13.8
0.6 3.1 1.9 5.7 5.7 1.3 0.6 3.8
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Resistance pattern
6.3
Abbreviations: R, rifampicin; H, isoniazid; E, ethambutol; S, streptomycin; Ofx, ofloxacin; Km, kanamycin.
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MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
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Figure 3. Time to poor treatment outcome of MDR-TB by drug resistance pattern*.
* Poor treatment outcome, defined as treatment failure, death or death.
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MDR-FL, TB with resistance to INH and RFP, but not any second-line drugs. Pre-XDR-TB, TB with resistance to INH, RFP, and either OFX or KM. XDR, TB with resistance to INH, RFP, and both OFX and KM
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Log-rank test p value for trend of survivor functions=0.0018.
S1198-743X(17)30363-4
DOI:
10.1016/j.cmi.2017.07.008
Reference:
CMI 1005
To appear in:
Clinical Microbiology and Infection
Received Date: 26 February 2017 Revised Date:
2 July 2017
Accepted Date: 7 July 2017
Please cite this article as: Zhang L, Meng Q, Chen S, Zhang M, Chen B, Wu B, Yan G, Wang X, Jia Z, Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009-2013, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title Page
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Title: Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China,
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2009-2013
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Running title: Treatment outcomes of MDR-TB
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Authors: Le Zhang1,3, Qiong Meng2, Songhua Chen2*, Minwu Zhang2, Bin Chen2, Beibei Wu2,
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Guangsen Yan4, Xiaomeng Wang2*, Zhongwei Jia3*
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Affiliations:
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1. Department of epidemiology and biostatistics, School of Public Health, Peking University,
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Beijing, P. R. China
2. Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang 310006, P. R. China
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3. National Institute of Drug Dependence, Peking University, Beijing, P. R. China
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4. School of Computer Science, University of Nottingham, Computer Science Bldg Jubilee
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Campus, Nottingham, NG8 1BB, United Kingdom Le Zhang and Qiong Meng are co-first authors.
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First Correspondence:
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Songhua Chen, Zhejiang Provincial Centre for Disease Control and Prevention. No. 630 Xincheng Road, Binjiang District, Hangzhou, Zhejiang 310051, China. Tel: 86-13906535138;
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Fax: 057187115183; E-mail: [email protected].
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Co-correspondence:
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Zhongwei Jia, National Institute of Drug Dependence, Peking University, 38 Xueyuan Road, Beijing 100191, P.R. China. Tel: 86-010-82802457; Email: [email protected].
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Xiaomeng Wang, Zhejiang Provincial Centre for Disease Control and Prevention. No. 630
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Xincheng Road, Binjiang District, Hangzhou, Zhejiang 310051, China. Tel: 86-13906525336;
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Fax: 057187115183; E-mail: [email protected].
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Keywords: tuberculosis; drug resistant tuberculosis; MDR-TB; treatment outcomes;
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standardized treatment.
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Running title: MDR-TB Treatment Outcomes
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ACCEPTED MANUSCRIPT Abstract – 248 words
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Objectives. To examine treatment outcomes and factors associated with poor outcome of
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MDR-TB in China.
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Methods. Prospective observational cohort study including consecutive patients with MDR-TB
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between 2009-2013 in six regions of Zhejiang province. Patients were prescribed treatments by
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infectious disease specialists and treatment outcomes were recorded. Sociodemographic
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characteristics were obtained through a structured questionnaire. The primary endpoint was
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poor treatment outcomes, defined as treatment failure based on microbiological persistence,
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default (lost to follow-up) or death at 24 months. We assessed risk factors for poor treatment
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outcomes using a Cox proportional hazards model.
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Results. 820 MDR-TB patients were observed and 537 with known treatment outcomes were
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included in our study. Overall, the treatment success rate was 40.2 per 100 years (374/537
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participants, 69.6%), while treatment failure, death and default rates were 10.0 per 100 years
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(101 participants, 18.8%), 3.4 per 100 years (36 participants, 6.7%) and 2.7 per 100 years (26
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participants, 4.8%), respectively. Independent predictors of poor treatment outcomes included:
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age>60 years (HR 2.3, 95% CI 1.2-4.2), patients registered as relapse (HR 2.2 95% CI 1.1-4.4),
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patients registered as treatment after failure (HR 2.4 95% CI 1.2-4.9), use of standardized
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MDR-TB regimens (HR 0.6 95% CI 0.4-1.0), cavitary disease (HR 4.9 95% CI 2.8-8.6) and
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adverse events (HR 2.5 95% CI 1.2-5.5).
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Conclusions. Under well-designed treatment and management scheme, high treatment success
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rates were achieved in a high MDR-TB burden country. Antimicrobial susceptibility testing for
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all second-line drugs should be conducted to further assist the treatment of MDR-TB.
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Main Text – 2624 words
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INTRODUCTION
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The emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) continue to pose a great threat to the elimination of TB, with
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estimates of 3.9% of new and 21% of previously treated TB cases being MDR-TB and 0.25
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million people dying from MDR-TB worldwide [1]. MDR-TB develops with poor
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management, or as a result of previous exposure to anti-TB drugs [2, 3].
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To achieve the global target of ending the TB epidemic by 2030, providing high-quality
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disease management to improve treatment outcome is one of the key strategies [4]. To date, the
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treatment success rate of MDR-TB patients was described as only 52% globally [5]. However,
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this was mainly based on a small cohort and also confounded by hospital admission bias.
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Different MDR-TB treatment regimens were prescribed to patients according to their medical
64
conditions and registration group, since there is little evidence for management based on
65
randomized controlled trials. Apart from treatment regimen, there are many other factors
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affecting treatment outcomes including gender, hospitalization, previous treatment [6],
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residence, acid-fast bacilli (AFB) result at baseline [7], HIV status [8] and more. Factors
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associated with MDR-TB treatment outcomes vary largely from settings to settings.
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China is among the 30 high MDR-TB burden countries worldwide. A national TB resistance survey has presented that 5.7% and 25.6% of new and previously treated cases were
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MDR-TB [9], 1.55 and 1.28 times higher than the global average, respectively. However,
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China has few reports regarding treatment outcomes of MDR-TB, and all studies were
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conducted in hospitals [10, 11]. To investigate treatment outcomes and factors associated with
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poor outcomes in China, we conducted this population-based study and intended to further
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support TB control and management.
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METHODS
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Study population and procedures
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Prospective observational cohort study from 7/2009 - 7/2013 in six regions of Zhejiang
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Province: Hangzhou, Huzhou, Jiaxing, Lishui, Quzhou, and Shaoxing, initiated by the Zhejiang
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Disease Control and Prevention Center (CDC) and Global Fund MDR-TB Project. Zhejiang
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has set up routine drug resistance monitoring since 1999, and details can be found in our 3
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previous studies [12]. All MDR-TB patients involved in the study met the inclusion criteria: (1) MDR-TB was
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confirmed by antimicrobial susceptibility testing (AST) from a regional reference laboratory;
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(2) patients were sputum smear-positive for AFB and culture-positive for M. tuberculosis; (3)
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receiving treatment. Due to the delay in receiving AST results, before patients switched to the
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definitive MDR-TB treatment, all newly-diagnosed TB patients received the national standard
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“new patient regimen” - two months of isoniazid, rifampicin, pyrazinamide and ethambutol
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followed by four months of isoniazid and rifampicin (2HRZE/4HR) and retreatment patients
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received the “retreatment regimen” - two months of isoniazid, rifampicin, pyrazinamide and
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ethambutol followed by four months of isoniazid and rifampicin (2HRZES/6HRE). We
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classified patients’ definitive MDR-TB treatments into five types of standard regimens (SRs),
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each including 4-5 drugs that the patients were sensitive to according to the AST results. Four
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SRs were given for 24 months and one for 36 months (Table S1), and the doses of all anti-TB
95
drugs are described in Table S2. If treated differently, patients were classified as individualized
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regimen (IR). IR was based on AST and TB treatment history. Treatments were prescribed by
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infectious disease specialists.
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Patients were followed daily until the end of follow-up or the outcome event had been reached and drugs were given under direct observation. We examined sputum smear, sputum culture, liver function, body weight, and blood routine examination periodically to prevent
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adverse event (ADE). Additionally, 70 Renminbi (the currency of China) nutritional subsidies
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and 70 Renminbi traffic subsidies were given to impoverished patients every month. Those in
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poor mental health status received 2 free psychological consultations, and health education was
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also provided.
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Information on socio-demographic characteristics (age, sex, occupation and household),
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MDR-TB-related characteristics (registration group, previous treatment history, hospitalization,
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treatment regimen and baseline resistance pattern) and indicators of severity (hemoptysis,
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cavity, and ADE) was collected through questionnaires and medical records by trained health
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workers. Treatment outcomes, sputum culture and smear conversion, and chest X-rays were
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monitored periodically.
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Approval of the study was obtained from ethics committees at Zhejiang CDC. Written 4
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informed consents were obtained from all participants.
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Definitions
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MDR-TB and XDR-TB were defined as in WHO guidelines [7]. Pre-XDR-TB was defined as TB with resistance to both isoniazid and rifampicin, and either a fluoroquinolone (ofloxacin)
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or a second-line injectable drug (kanamycin).
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Treatment outcomes were categorized according to the Global Fund MDR-TB Project. Cure was defined as a patient who completed treatment, and at least 5 final consecutive
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cultures of his/her sputum during the final 12 months of treatment were negative; or if 1 culture
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was positive, then at least 3 of its following consecutive cultures should have been negative.
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Treatment completed was defined as patients who had completed their treatments without
122
evidence of failure but with inadequate bacteriological records to be defined as cure. Treatment
123
failure was defined when there were ≥ 2 positive sputum cultures of the five final cultures, or 1
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positive culture of the final three cultures during the final 12 months of treatment. Died was
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defined as patients who died due to any cause during treatment. Lost to follow-up (default) was
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defined as patients whose treatment were interrupted for ≥ 2 consecutive months against
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clinicians’ advice.
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Treatment success was defined as cured or treatment completed, whereas poor treatment outcome was defined as treatment failure, default or death.
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Laboratory Cultures and Antimicrobial Susceptibility Testing
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Sputum smear microscopy was performed directly at the tuberculosis bacterium laboratory of each region, where direct AFB smear microscopy and AFB culture on Lowenstein-Jensen
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solid medium were applied. The identification of M. Tuberculosis and AST was performed at a
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provincial reference laboratory. Susceptibility testing of 4 first-line drugs (isoniazid, rifampin,
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streptomycin, ethambutol) and 2 second-line drugs (ofloxacin, kanamycin) was performed for
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sputum culture-positive stains by the proportion method [13], and results were compared with
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standardized strains. Drug concentrations for rifampin, isoniazid, ethambutol, streptomycin,
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ofloxacin, and kanamycin were 40.0, 0.2, 2.0, 4.0, 2.0, and 30.0 µg/ml, respectively.
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Statistical analysis
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Socio-demographic, MDR-TB related characteristics and indicators of severity were described as percentages stratified by regions. To investigate risk factors for poor outcomes, we 5
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for setting-associated confounding). We also developed a sensitivity analysis excluding patients
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whose treatment were unrecorded to examine our findings. Hazard ratios and 95% confidence
145
intervals were calculated to demonstrate the risks for poor outcomes. We also used Kaplan–
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Meier method with log-rank test to compare survival curves of time to poor outcomes by
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baseline resistance patterns. Statistical analysis was conducted using R 3.3.0, and P < 0.05
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indicated statistical significance.
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RESULTS
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Study Cohort and characteristics of participants
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From July 1, 2009 to July 13, 2013, 820 patients were diagnosed as sputum smear-positive MDR-TB in six regions of Zhejiang province. 204 MDR-TB were not treated due to refusal to
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receive treatment, death or default before treatment, no effective treatment regimen, moving
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out and having underlying medical conditions (not suitable for chemotherapy or could not
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receive treatment at the present time, Figure 1). Among 616 patients receiving treatment, 79
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patients had incomplete outcome records. Overall, 537 patients were involved in our analysis.
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Basic characteristics stratified by regions are shown in Table 1.
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Of all 537 individuals, 382 were male, with mean age of 47 years (SD 16.0), while females were younger on average (41years, SD 15.1). The delay in starting appropriate MDR-TB
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treatment after TB diagnosis was a median of 88 days (IQR 17-163). AST for second-line
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drugs were conducted for 159 patients. The majority of MDR-TB patients were resistant only
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to first-line drugs (71.1%, 113/159). Pre-XDR-TB was seen in 27 MDR-TB patients (17.0%),
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of which 26 were resistant to fluoroquinolones, and 1 was resistant to second-line injectable
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drugs. XDR-TB was seen in 19 patients (11.9%, Figure 2).
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Treatment outcomes
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MDR-TB patients were followed for a mean of 20 months after treatment initiation.
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During 917.3 person-years of follow-up, treatment success rate was 40.2/100 person-years
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(369/917.3 person-years), while the treatment failure, death and default rate were 10.0/100
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person-years (92/917.3 person-years), 3.4/100 person-years (31/917.3 person-years) and
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2.7/100 person-years (25/917.3 person-years), respectively (Table 2). The number of
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participants with success, failure, death, and default outcomes out of 537 participants were 374 6
ACCEPTED MANUSCRIPT (69.6%), 101 (18.8%), 36 (6.7%) and 26 (4.8%), respectively (Table S3). Newly-diagnosed
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patients had the highest treatment success rate (82.3%, 65/79). The success rate of relapse
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patients (65.3%, 128/196) was lower than patients registered as treatment after failure (71%,
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169/238) and patients registered as treatment after default (71.4%, 5/7).
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Risk factors for poor treatment outcome
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In our multivariable cox model (Table 3), patients older than 60 were associated with a
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greater likelihood of poor outcomes compared with patients under 30 (HR 2.3, 95% CI 1.2-4.2).
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Compared with newly-diagnosed patients, those registered as relapse and treatment after failure
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were both at increased risk of poor outcomes (HR 2.2 95% CI 1.1-4.4; HR 2.4 95% CI 1.2-4.9),
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while the risk for patients registered as treatment after default was not significant. Standardized
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treatment regimens were associated with a lower risk of poor outcomes (HR 0.6 95% CI
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0.4-1.0), though the result was not significant in our sensitivity analysis restricted to patients
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whose treatment regimen was available (N=415, Table S4). Having a cavity on chest
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radiograph was a strong predictor for poor outcomes (HR 4.9 95% CI 2.8-8.6). Experiencing
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adverse events increased the risk of poor outcomes 2.5 times (HR 2.5 95% CI 1.2-5.5).
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Survival curves stratified by resistance pattern
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Survival days to poor outcomes between different resistance pattern are shown in Figure 3. Pre-XDR-TB and XDR-TB patients reached poor outcomes more rapidly than
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MDR-TB-First-Line patients. Poor outcomes increased with levels of resistance patterns
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(MDR-TB-First-Line, Pre-XDR-TB, XDR-TB), and the log-rank test for trend of survival
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functions was significant (P = 0.0018).
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DISCUSSION
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In our prospective study, the treatment success rate of MDR-TB reached 69.6% (374/537).
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We identified significant risk factors for poor treatment outcomes: age group, patient
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registration group, cavity on baseline chest X-ray, treatment regimen, and occurrence of
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adverse events. The treatment success rate in our cohort was much higher than the national
198
average (55%), the global average (52%), as well as the WHO western pacific average (57%)
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[1]. Pre-planned standardized regimens based on local susceptibility patterns, individualized
200
regimens based on personal AST results, as well as adequate supplementary measures may
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have played important roles. These measures included incentives for both DOT-performing 7
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clinicians and patients, nutritional supplementation and emotional support. Offering free
203
diagnosis and drugs may have ensured the adherence.
204
Our supplementary measures might have produced a positive effect on compliance, with default rates of only 4.8%, much lower than the global average (15%). Worldwide, most
206
cohorts have reported >10% default rates: 17% in Estonia [7], 26% in Latvia [14], 20.9% in
207
South Africa [15], and 10.0% in Peru [16]. In China the default rate was significantly lower:
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12.5% in Shenzhen [17], 6% in Guangzhou [18], and 4% in a meta-analysis [19].
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However, this success rate was far below the global target of 75% [20]. The rate was lower than Korea, Kenya, Myanmar, Nigeria, and Somalia, who were also among the 30 high
211
MDR-TB burden countries reporting treatment success of >75% [1]. The high success rates in
212
these countries were probably due to application of new drugs [21] and broader access to
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second-line drug-susceptibility testing. WHO treatment guidelines for drug-resistant TB
214
recommend prescribing at least five effective TB drugs [22]. However, due to financial
215
constraint, China has not ensured universal access to second-line drug-susceptibility testing, so
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there remain many MDR-TB patients treated with inadequate number of effective drugs.
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Improving diagnostic capacity can result in better MDR-TB treatment and can reduce
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MDR-TB transmission and further drug resistance in China.
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We found that patients older than 60 were at risk for poor outcomes, which is consistent
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with previous studies [23-25]. This result may be attributable to the ADE of anti-TB drugs and
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economic status of older people. ADE caused by anti-TB drugs was reported to be age-related
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[26, 27], and some second-line drugs are not free in China.
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Not surprisingly, our study demonstrated that retreated patients were at higher risks of poor
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outcomes than newly-diagnosed patients, which is consistent with published studies [28-30].
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We divided retreated patients into four groups, which have not been normally analyzed in other
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studies. We found it was patients registered as treatment after failure among retreated patients
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that contributed to the higher risk of poor outcome. This implies that we should provide better
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treatment and management to retreated patients registered as treatment after failure.
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Standardized treatment regimens were a protective factor for poor outcomes. However,
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this result is subjected to selection bias though we adjusted for indicators of severity and also
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this factor was not significant in our sensitivity analysis. Well-designed SR is highly 8
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cost-effective and may achieve high treatment success rates, especially in low- and
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middle-income settings. Nonetheless, it is important to underline that the clinical effectiveness
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of a drug cannot be predicted by AST with 100% certainty [31]. Treating MDR-TB patients
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with SR would reduce expenses and human resources in China. Cavity was significantly associated with poor outcomes. Bilateral cavitation was found
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linked to poor outcomes in some studies [32]. Adverse event was also a strong predictor for
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poor outcomes, which may lead to poor compliance and inadequate treatment.
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In our study, Pre-XDR-TB patients were not associated with poor outcomes, which is
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inconsistent with published studies. This was due to a high proportion of unknown second-line
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drug-susceptibility testing results. In fact, AST for 2nd-line drugs were conducted for all
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patients in 2 regions (Huzhou and Quzhou) but not conducted in Jiaxing and Lishui. In
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Hangzhou and Shaoxing, the testing was conducted for 13% and 52.2% of patients,
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respectively. The implementation of second-line drug-susceptibility testing was based on the
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results of individual’s smear sputum and local capacity of laboratory testing. Our analysis of
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159 patients with AST results showed that the risk of poor outcome increased with baseline
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resistance pattern (MDR-FL, Pre-XDR, XDR). Pre-XDR-TB patients should receive careful
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management and treatment, in case their condition progresses.
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The current study has several limitations. First, many MDR-TB patients were not enrolled
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on treatment due to physical conditions, and there were also a few patients with unknown
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treatment outcomes due to missing data and incorrect documentation. This may overestimate
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treatment success rates. Second, our study was an observational study, and although we
253
adjusted carefully for indicators of disease severity, residual confounding may still be possible.
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For example, in our MDR-TB program, HIV status was only available for 7% (59/820) patients
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and they were all HIV negative. The mean incidence of HIV in Zhejiang Province is
256
1.27/100,000 population over the study period. This uncontrolled confounding may have
257
biased our results. Third, second-line drug-susceptibility testing was only performed for 159
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patients, which may lead to bias in the measurement of association between drug resistant
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pattern and poor outcomes. Fourth, the treatment outcomes were defined mainly on
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microbiological response, there might be some differences of clinical responses among patients
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in the same treatment outcome group. Fifth, we did not test the susceptibilities of all
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second-line drugs used in our treatment, only ofloxacin of fluoroquinolones and kanamycin of
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injectable drugs. We may underestimate the proportion of Pre-XDR-TB and XDR-TB patients. In spite of these limitations, to our knowledge, our study is the first population-based study
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to investigate treatment outcomes and factors associated with poor treatment outcome of
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MDR-TB patients in China. Our study indicated that aging, cavitary disease, occurrence of
267
adverse events, standardized regimen, retreatment and relapsed disease are independent risk
268
factors for poor outcomes. Rapid diagnostics and universal access to antimicrobial
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susceptibility testing should be emphasized in current MDR-TB control policy. In addition,
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antimicrobial susceptibility testing for all second-line drugs should be ensured to further assist
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the treatment and control of MDR-TB.
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Notes
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Financial support. This study was supported by National Natural Science Foundation in China
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(No. U1611264 and 61571001)
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Potential conflict of interest. All Authors declared no potential conflicts.
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[1] World Health Organization, Global tuberculosis report 2015, World Health Organization, 2015. [2] M.D. Iseman Treatment of Multidrug-Resistant Tuberculosis, New England Journal of Medicine 329(11) (1993) 784-791. [3] A. Faustini, A.J. Hall, C.A. Perucci, Risk factors for multidrug resistant tuberculosis in Europe: a systematic review, Thorax 61(2) (2006) 158-163. [4] World Health Organization, Gear up to end TB: introducing the end TB strategy, Geneva, Switzerland: World Health Organization, 2015. [5] Y.S. Kwon, Y.H. Kim, G.Y. Suh, M.P. Chung, H. Kim, O.J. Kwon, Y.S. Choi, K. Kim, J. Kim, Y.M. Shim, Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis, Clinical Infectious Diseases 47(4) (2008) 496-502. [6] K.E. Dooley, O. Lahlou, J. Knudsen, M.D. Elmessaoudi, I. Cherkaoui, R. El Aouad, Risk factors for tuberculosis treatment failure, default, or relapse and outcomes of retreatment in Morocco, BMC Public Health 11(1) (2011) 1. [7] K. Kliiman, A. Altraja, Predictors of poor treatment outcome in multi-and extensively drug-resistant pulmonary TB, European Respiratory Journal 33(5) (2009) 1085-1094. [8] E.V. Kurbatova, A. Taylor, V.M. Gammino, J. Bayona, M. Becerra, M. Danilovitz, D. Falzon, I. Gelmanova, S. Keshavjee, V. Leimane, C.D. Mitnick, M.I. Quelapio, V. Riekstina, P. Viiklepp, M. Zignol, J.P. Cegielski, Predictors of poor outcomes among patients treated for multidrug-resistant tuberculosis at DOTS-plus projects, Tuberculosis (Edinburgh, Scotland) 92(5) (2012) 397-403. [9] Y. Zhao, S. Xu, L. Wang, D.P. Chin, S. Wang, G. Jiang, H. Xia, Y. Zhou, Q. Li, X. Ou, National survey of drug-resistant tuberculosis in China, New England Journal of Medicine 366(23) (2012) 2161-2170. [10] S. Tang, S. Tan, L. Yao, F. Li, L. Li, X. Guo, Y. Liu, X. Hao, Y. Li, X. Ding, Z. Zhang, L. Tong, J. Huang, Risk Factors for Poor Treatment Outcomes in Patients with MDR-TB and XDR-TB in China: Retrospective Multi-Center Investigation, PLOS ONE 8(12) (2013) e82943. [11] C.H. Liu, L. Li, Z. Chen, Q. Wang, Y.L. Hu, B. Zhu, P.C. Woo, Characteristics and treatment outcomes of patients with MDR and XDR tuberculosis in a TB referral hospital in Beijing: a 13-year experience, PloS one 6(4) (2011) e19399. [12] X. Wang, Drug-Resistant Tuberculosis in Zhejiang Province, China, 1999–2008, Emerging Infectious Disease, 18(3) (2012) 496. [13] World Health Organization, Policy guidance on drug-susceptibility testing (DST) of second-line antituberculosis drugs, 2008. [14] V. Leimane, V. Riekstina, T.H. Holtz, E. Zarovska, V. Skripconoka, L.E. Thorpe, K.F. Laserson, C.D. Wells, Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study, The Lancet 365(9456) (2005) 318-326. [15] J.E. Farley, M. Ram, W. Pan, S. Waldman, G.H. Cassell, R.E. Chaisson, K. Weyer, J. Lancaster, M. Van der Walt, Outcomes of multi-drug resistant tuberculosis (MDR-TB) among a cohort of South African patients with high HIV prevalence, PloS one 6(7) (2011) e20436. [16] M.F. Franke, S.C. Appleton, J. Bayona, F. Arteaga, E. Palacios, K. Llaro, S.S. Shin, M.C. Becerra, M.B. Murray, C.D. Mitnick, Risk factors and mortality associated with default from
AC C
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multidrug-resistant tuberculosis treatment, Clinical infectious diseases 46(12) (2008) 1844-1851. [17] L. Deliang, Treatment outcomes in a MDR-TB cohort, Shenzhen, China, China Tropical Medicine 16(7) (2016) 649-665. [18] D. yuhua, Risk factors for treatment outcomes of 116 MDR-TB patients in Guangzhou, China, Chinese journal of antituberculosis 34(1) (2012) 19-22. [19] Z. Ying, Meta analysis of treatment outcomes of multi-drug resistant tuberculosis patients in China, Journal of Tropical Medicine 16(3) (2016) 325-328. [20] World Health Organization, The global plan to stop TB 2011-2015: transforming the fight towards elimination of tuberculosis, 2010. [21] B.H. Jeong, H.Y. Park, H.K. Kim, J.G. Kim, N.Y. Lee, The Korean Academy of Tuberculosis and Respiratory Diseases: Slide Session; OS-027: Mycobacterial Diseases; Outcomes of Multidrug-Resistant Tuberculosis: Impacts of Fluoroquinolone Resistance and Linezolid Treatment, Korean Journal of Internal Medicine 2014(1) (2014) 416-416. [22] World Health Organization, WHO treatment guidelines for drug-resistant tuberculosis 2016 update. WHO/HTM/TB/2016.04, 2016. [23] M.K. Lalor, J. Greig, S. Allamuratova, S. Althomsons, Z. Tigay, A. Khaemraev, K. Braker, O. Telnov, P. du Cros, Risk factors associated with default from multi- and extensively drug-resistant tuberculosis treatment, Uzbekistan: a retrospective cohort analysis, PloS one 8(11) (2013) e78364. [24] N. Ahmad, A. Javaid, A. Basit, A.K. Afridi, M.A. Khan, I. Ahmad, S.A. Sulaiman, A.H. Khan, Management and treatment outcomes of MDR-TB: results from a setting with high rates of drug resistance, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 19(9) (2015) 1109-14, i-ii. [25] P.C. Chan, S.H. Huang, M.C. Yu, S.W. Lee, Y.W. Huang, S.T. Chien, J.J. Lee, Effectiveness of a government-organized and hospital-initiated treatment for multidrug-resistant tuberculosis patients--a retrospective cohort study, PloS one 8(2) (2013) e57719. [26] D. Yee, C. Valiquette, M. Pelletier, I. Parisien, I. Rocher, D. Menzies, Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis, American journal of respiratory and critical care medicine 167(11) (2003) 1472-1477. [27] T. Schaberg, K. Rebhan, H. Lode, Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis, European Respiratory Journal 9(10) (1996) 2026-2030. [28] C.D. Mitnick, M.F. Franke, M.L. Rich, F.A. Alcantara Viru, S.C. Appleton, S.S. Atwood, J.N. Bayona, C.A. Bonilla, K. Chalco, H.S. Fraser, J.J. Furin, D. Guerra, R.M. Hurtado, K. Joseph, K. Llaro, L. Mestanza, J.S. Mukherjee, M. Munoz, E. Palacios, E. Sanchez, K.J. Seung, S.S. Shin, A. Sloutsky, A.W. Tolman, M.C. Becerra, Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality, PloS one 8(3) (2013) e58664. [29] O. Oliveira, R. Gaio, M. Villar, R. Duarte, Predictors of treatment outcome in multidrug-resistant tuberculosis in Portugal, The European respiratory journal 42(6) (2013) 1747-9. [30] V. Leimane, V. Riekstina, T.H. Holtz, E. Zarovska, V. Skripconoka, L.E. Thorpe, K.F.
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Laserson, C.D. Wells, Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study, Lancet (London, England) 365(9456) (2005) 318-26. [31] S. Kim, M. Espinal, C. Abe, G. Bai, F. Boulahbal, L. Fattorin, C. Gilpin, S. Hoffner, K. Kam, N. Martin-Casabona, Is second-line anti-tuberculosis drug susceptibility testing reliable?, The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 8(9) (2004) 1157-1158. [32] M. Rodriguez, I. Monedero, J.A. Caminero, M. Encarnacion, Y. Dominguez, I. Acosta, E. Munoz, E. Camilo, S. Martinez-Selmo, S. de los Santos, M. del Granado, M. Casals, J. Cayla, B. Marcelino, Successful management of multidrug-resistant tuberculosis under programme conditions in the Dominican Republic, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 17(4) (2013) 520-5.
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ACCEPTED MANUSCRIPT Table 1. Characteristics of MDR-TB cases, stratified by counties, Zhejiang Province, China, 2009–2013
Huzhou 41
Region Jiaxing Lishui 8 46 1 (12.5) 7 (87.5) 0 (0.0)
155 (28.9) 92 (28.5) 13 (31.7) 382 (71.1) 231 (71.5) 28 (68.3)
2 (25.0) 6 (75.0)
287 (53.4) 140 (43.3) 17 (41.5) 250 (46.6) 183 (56.7) 24 (58.5)
Shaoxing 80
5 (10.9) 19 (41.3) 22 (47.8)
5 (12.8) 21 (53.8) 13 (33.3)
14 (17.5) 45 (56.2) 21 (26.2)
10 (21.7) 36 (78.3)
15 (38.5) 24 (61.5)
23 (28.7) 57 (71.2)
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124 (23.1) 94 (29.1) 5 (12.2) 300 (55.9) 180 (55.7) 28 (68.3) 113 (21.0) 49 (15.2) 8 (19.5)
Quzhou 39
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Hangzhou 323
4 (50.0) 4 (50.0)
34 (73.9) 12 (26.1)
24 (61.5) 15 (38.5)
68 (85.0) 12 (15.0)
8 (100.0) 0 (0.0)
8 (17.4) 38 (82.6)
1 (2.6) 38 (97.4)
9 (11.2) 71 (88.8)
79 (14.7) 34 (10.5) 4 (9.8) 196 (36.5) 97 (30.0) 7 (17.1) 238 (44.3) 173 (53.6) 29 (70.7) 7 (1.3) 5 (1.5) 1 (2.4) 17 (3.2) 14 (4.3) 0 (0.0)
2 (25.0) 3 (37.5) 3 (37.5) 0 (0.0) 0 (0.0)
11 (23.9) 18 (39.1) 13 (28.3) 1 (2.2) 3 (6.5)
6 (15.4) 23 (59.0) 10 (25.6) 0 (0.0) 0 (0.0)
22 (27.5) 48 (60.0) 10 (12.5) 0 (0.0) 0 (0.0)
22 (4.1) 6 (1.9) 1 (2.4) 351 (65.3) 210 (65.0) 16 (39.0) 164 (30.5) 107 (33.1) 24 (58.5)
0 (0.0) 7 (87.5) 1 (12.5)
11 (23.9) 28 (60.9) 7 (15.2)
2 (5.1) 32 (82.1) 5 (12.8)
2 (2.5) 58 (72.5) 20 (25.0)
8 (100.0) 0 (0.0)
0 (0.0) 46 (100.0)
28 (71.8) 11 (28.2)
5 (6.2) 75 (93.8)
6 (75.0) 2 (25.0) 0 (0.0)
0 (0.0) 46 (100.0) 0 (0.0)
9 (23.1) 28 (71.8) 2 (5.1)
50 (62.5) 15 (18.8) 15 (18.8)
0 (0.0) 0 (0.0) 0 (0.0) 8 (100.0)
0 (0.0) 0 (0.0) 1 (2.2) 45 (97.8)
20 (51.3) 18 (46.2) 1 (2.6) 0 (0.0)
42 (52.5) 0 (0.0) 0 (0.0) 38 (47.5)
6 (75.0) 2 (25.0)
42 (91.3) 4 (8.7)
31 (79.5) 8 (20.5)
74 (92.5) 6 (7.5)
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268 (49.9) 226 (70.0) 16 (39.0) 269 (50.1) 97 (30.0) 25 (61.0)
EP
Total Age groups <=30 yr 30-60 yr >60 yr Gender Female Male Occupation Farmer Other Household registration* Floating Local Patient Registration group Newly-diagnosed patients Relapse patients Treatment after failure patients Treatment after default patients Other previously treated patients Previous treatment history None First-line drugs only Second-line drugs Hospitalization Yes No
Overall 537
TE D
Characteristics
91 (16.9) 30 (9.3) 20 (48.8) 446 (83.1) 293 (90.7) 21 (51.2)
AC C
Treatment regimen Individualized 94 (17.5) 25 (7.7) 4 (9.8) Standardized 340 (63.3) 213 (65.9) 36 (87.8) Unknown 103 (19.2) 85 (26.3) 1 (2.4) # MDR-TB baseline resistance pattern MDR-FL 117 (21.8) 19 (5.9) 36 (87.8) Pre-XDR 29 (5.4) 6 (1.9) 5 (12.2) XDR 19 (3.5) 17 (5.3) 0 (0.0) Unknown 372 (69.3) 281 (87.0) 0 (0.0) Hemoptysis at diagnosis No 283 (52.7) 96 (29.7) 34 (82.9) Yes 254 (47.3) 227 (70.3) 7 (17.1) Cavity on chest
ACCEPTED MANUSCRIPT 186 (34.6) 71 (22.0) 20 (48.8) 235 (43.8) 161 (49.8) 19 (46.3) 116 (21.6) 91 (28.2) 2 (4.9)
4 (50.0) 4 (50.0) 0 (0.0)
44 (95.7) 2 (4.3) 0 (0.0)
21 (53.8) 18 (46.2) 0 (0.0)
26 (32.5) 31 (38.8) 23 (28.7)
62 (11.5) 0 (0.0) 22 (53.7) 230 (42.8) 104 (32.2) 15 (36.6) 245 (45.6) 219 (67.8) 4 (9.8)
2 (25.0) 6 (75.0) 0 (0.0)
3 (6.5) 42 (91.3) 1 (2.2)
11 (28.2) 28 (71.8) 0 (0.0)
24 (30.0) 35 (43.8) 21 (26.2)
RI PT
No Yes Unknown Adverse events No Yes Unknown
AC C
EP
TE D
M AN U
SC
* People who keep their ‘hukou’ (a record in a government system of household registration determining where citizens are allowed to live in China) in their hometown but reside in other areas for various reasons. # MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
ACCEPTED MANUSCRIPT Table 2. Treatment outcome of MDR-TB in Zhejiang Province, China, 2009–2013.
Total*
Total No event (Success) Failure Death Default
537 374 (69.6%) 101 (18.8%) 36 (6.7%) 26 (4.8%)
No. of patients included in the time to event analysis* 517 369 (71%) 92 (18%) 31 (6%) 25 (5%)
Rate# (95% CI) 917.3 person-years 40.2 (35.5 - 45.7) 10.0 (8.2 - 12.3) 3.4 (2.4 - 4.8) 2.7 (1.8 - 4)
RI PT
Treatment Outcome
AC C
EP
TE D
M AN U
SC
*Data is shown as Number (Percentage); #Rates are presented as per 100 person-years.
ACCEPTED MANUSCRIPT Table 3. Multivariable analysis of factors associated with poor treatment outcomes in patients with MDR-TB, Zhejiang Province, China, 1999-2013
uHR
aHR(95%CI)
243.65 513.63 159.98
8.62 (5.62 - 13.22) 15.58 (12.51 - 19.39) 29.38 (22.07 - 39.10)
Reference 1.7 (1.1, 2.8) 3.1 (1.8, 5.2)
Reference 1.3 (0.8, 2.2) 2.3 (1.2, 4.2)
264.44 652.83
16.26 (12.06 - 21.93) 16.08 (13.28 - 19.47)
Reference 0.9 (0.7, 1.3)
Reference 0.8 (0.6, 1.2)
478.05 439.22
19.24 (15.69 - 23.61) 12.75 (9.81 - 16.57)
RI PT
Rate (95% CI) /100 person-years
EP
AC C
Reference 0.7 (0.5, 1.0)
Reference 0.9 (0.6, 1.4)
474.24 443.02
13.28 (10.38 - 17.01) 19.19 (15.51 - 23.73)
Reference 1.4 (1.0, 1.9)
Reference 1.2 (0.8, 1.9)
149.27 326.38 405.74 11.52 24.36
8.04 (4.57 - 14.16) 18.38 (14.27 - 23.68) 16.51 (13 - 20.98) 17.36 (4.34 - 69.43) 28.74 (13.7 - 60.28)
Reference 2.4 (1.3, 4.5) 2.4 (1.3, 4.6) 3.0 (0.7, 13.4) 4.1 (1.6, 10.4)
Reference 2.2 (1.1, 4.4) 2.4 (1.2, 4.9) 3.3 (0.7, 15.6) 3.5 (1.2, 9.8)
599.94 283.25 34.07
15.33 (12.5 - 18.81) 17.65 (13.38 - 23.29) 17.61 (7.91 - 39.2)
Reference 1.2 (0.8, 1.6) 1.0 (0.4, 2.4)
Reference 1.2 (0.8, 1.8) 1.7 (0.7, 4.2)
155.11 762.15
16.76 (11.41 - 24.62) 16.01 (13.4 - 19.12)
Reference 1.0 (0.6, 1.5)
Reference 1.2 (0.7, 2.1)
152.14 557.44 207.69
21.03 (14.87 - 29.74) 17.94 (14.75 - 21.82) 7.70 (4.72 - 12.57)
Reference 1.0 (0.7, 1.5) 0.4 (0.2, 0.7)
Reference 0.6 (0.4, 1.0) 0.2 (0.1, 0.5)
194.8 44 29.61 648.87
17.97 (12.9 - 25.02) 22.73 (12.23 - 42.24) 43.91 (25.5 - 75.62) 13.87 (11.28 - 17.05)
Reference 1.3 (0.6, 2.6) 2.7 (1.4, 5.2) 0.8 (0.5, 1.2)
Reference 0.7 (0.3, 1.7) 1.0 (0.4, 2.3) 0.6 (0.3, 1.1)
TE D
Soci-demographic characteristics Age groups <=30 yr 21/124 30-60 yr 80/300 >60 yr 47/113 Gender Female 43/155 Male 105/382 Occupation Farmer 92/287 Other 56/250 Household registration* Floating 63/268 Local 85/269 MDR-TB characteristics Patient Registration group Newly-diagnosed patients 12/79 Relapse patients 60/196 Treatment after failure patients 67238 Treatment after default patients 2/7 Other previously treated patients 7/17 Previous treatment history First-line drugs only 92/351 Second-line drugs 50/164 None 6/22 Hospitalization Yes 26/91 No 122/446 Treatment Regimen Individualized 32/94 Standardized 100/340 Unknown 16/103 # MDR-TB baseline resistance pattern MDR-FL 35/117 Pre-XDR 10/29 XDR 13/19 Unknown 90/372 Indicators of severity Hemoptysis at diagnosis
Person -years
SC
Events/ Patients†
M AN U
Predictors
ACCEPTED MANUSCRIPT 69/283 79/254
485.93 431.34
14.2 (11.22 - 17.98) 18.32 (14.69 - 22.83)
Reference 1.5 (1.1, 2.1)
Reference 1.2 (0.7, 2.3)
30/186 96/235 22/116
319.37 377 220.9
9.39 (6.57 - 13.43) 25.46 (20.85 - 31.1) 9.96 (6.56 - 15.13)
Reference 2.8 (1.8, 4.2) 1.0 (0.6, 1.7)
Reference 4.9 (2.8, 8.6) 5.0 (1.7, 14.8)
10/62 65/230 73/245
113.91 372.56 430.8
8.78 (4.72 - 16.32) 17.45 (13.68 - 22.25) 16.95 (13.47 - 21.31)
Reference 2.0 (1.0, 3.8) 2.0 (1.0, 3.7)
Reference 2.5 (1.2, 5.5) 5.6 (2.3, 13.5)
RI PT
No Yes Cavity on chest No Yes Unknown Adverse events No Yes Unknown
AC C
EP
TE D
M AN U
SC
Abbreviations: uHR, unadjusted hazard ratio; aHR, adjusted hazard ratio. † Events/Patients, No. of patients with poor treatment outcomes / No. of patients evaluated. * People who keep their ‘hukou’ (a record in a government system of household registration determining where citizens are allowed to live in China) in their hometown but reside in other areas for various reasons. # MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 1. Inclusion of MDR-TB patients in the analysis.
Abbreviation: MDR-TB, multidrug resistance tuberculosis.
ACCEPTED MANUSCRIPT Figure 2. Drug resistance among 159 MDR-TB patients whose second-line drug-susceptibility testing results were available.
44 8 39 22 1 5 3 9 9 2 1 6 10 159
Pre-XDR-TB 27 (17.0%)
XDR-TB 19 (11.9%)
H/R H/R/E H/R/S H/R/E/S H/R/S/Km H/R/Ofx H/R/E/Ofx H/R/S/Ofx H/R/E/S/Ofx H/R/Km/Ofx H/R/E/Km/Ofx H/R/S/Km/Ofx H/R/E/S/Km/Ofx
Total
27.7 5.0 24.5
RI PT
MDR-TB-FL 113 (71.1%)
Percent of resistance pattern (%)
13.8
0.6 3.1 1.9 5.7 5.7 1.3 0.6 3.8
SC
NO.
M AN U
Resistance pattern
6.3
Abbreviations: R, rifampicin; H, isoniazid; E, ethambutol; S, streptomycin; Ofx, ofloxacin; Km, kanamycin.
AC C
EP
TE D
MDR-FL, TB with resistance to isoniazid and rifampin, but not any second-line drugs. Pre-XDR-TB, TB with resistance to isoniazid, rifampin, and either ofloxacin or kanamycin. XDR, TB with resistance to isoniazid, rifampin, and both ofloxacin and kanamycin.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Figure 3. Time to poor treatment outcome of MDR-TB by drug resistance pattern*.
* Poor treatment outcome, defined as treatment failure, death or death.
TE D
MDR-FL, TB with resistance to INH and RFP, but not any second-line drugs. Pre-XDR-TB, TB with resistance to INH, RFP, and either OFX or KM. XDR, TB with resistance to INH, RFP, and both OFX and KM
AC C
EP
Log-rank test p value for trend of survivor functions=0.0018.