Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Günther G, Lange C, Alexandru S, et al. Treatment outcomes in multidrug-resistant tuberculosis. N Engl J Med 2016;375: DOI: /NEJMc (PDF updated September 22, 2016.)

2 Online Appendix Günther G. et al.: Treatment Outcomes in Multidrug Resistant Tuberculosis Table of contents: Methods page 2 Results page 3 Acknowledgement page 5 References page 5 Appendix figure 1 page 6 Appendix table 1 page 7 Appendix table 2 page 7 Appendix table 3 page 8

3 Online Appendix: Günther et al.: Treatment Outcomes in Multidrug Resistant Tuberculosis Methods Ethical consideration Ethical approval was first provided by the ethics committee of the University of Lübeck (Ref.nr.: ) (Germany) and thereafter at all local ethics committees of the participating centers. Setting The study was performed at 23 sites in 16 European countries collaborating in the TBNET 1 as part of the EU FP7 funded large collaborative project TB PANNET. According to the WHO/European Centre for Disease Prevention and Control (ECDC) estimates for the study period, there were two countries with a high (>100/100,000 population), four with an intermediate (20 100/100,000) and ten with a low (<20/100,000) incidence of TB 2. All study sites are referral centers for patients with MDR TB, and represent the respective national approaches to MDR treatment. TBNET is an officially recognized Clinical Research Collaboration (CRC) of the European Respiratory Society (ERS) for the study of MDR TB. A description of the baseline characteristics of the cohort has been described recently elsewhere 3,4. Design The study was a prospective cohort study where patients were enrolled at the start of their treatment for drug resistant tuberculosis, and followed up until a treatment outcome was declared by the treating physician. Patients who were successfully treated (WHO defined cure or WHOdefined treatment completion) were further followed for 12 months after completion of treatment. Study population Eligible patients were those starting treatment for drug resistant tuberculosis at the participating centers and providing informed consent. Patients were categorized according their resistance profile at enrolment. Those infected with rifampicin and isoniazid resistant strains of M. tuberculosis without additional bacillary resistance were classified as MDR TB proper. Pre XDR TB was defined by MDR TB plus additional bacillary resistance to at least one fluoroquinolone or one SLID. XDR TB was defined by MDR TB plus bacillary resistance to at least one drug from both groups 5. The resistance pattern defining classification was based on the nearest positive culture to the start of an appropriate second line treatment regimen within the period of 90 days before to 30 days after treatment initiation of such treatment. Patients were consecutively enrolled between January 2010 and December A limited number of patients (n=41; 5.4%) with on going treatment in January 2010 were retrospectively included. To avoid over representation of patients from high burden countries of MDR TB, enrolment was stopped at sites in Belarus, Latvia, Moldova and Romania after an a priori defined number of patients from these countries had been included. The resulting relative contributions of patients in the study sample reflected the incidence of notified MDR TB patients in Europe. Data collection Collection of routine clinical and laboratory data was performed according to site and country specific practices. The study protocol did not require data collection outside routine patient management. Data were entered directly online in an Open Clinica electronic case record form 2

4 ( At sites in Belarus, Estonia, Republic of Moldova, and Romania, data were initially recorded on a paper case record form, and later transferred to the online database by designated data entry clerks due to the absence of reliable internet connections. Investigators were trained on site in data recording before enrolment started. Continuous data management training was ensured through annual investigator meetings, regular site audit visits and newsletters. Laboratory testing Microscopy, culture and drug resistance testing (DST) for first and second line anti tuberculosis drugs was performed in local laboratories. All laboratories participate in an external quality control protocol for culture and DST by the Supranational Reference Laboratory Network of the WHO. Statistical analyses Culture conversion was defined as a negative culture after a positive culture, while reversion was defined as a positive culture after a negative culture. All actual culture dates were grouped into specific time points (with related time window) to ensure fair comparisons between treatment groups. If more than one culture classified for a time point, the culture with the date nearest to the midpoint of the time window was selected in which a positive culture always had priority over a negative culture. Time to culture conversion and reversion was assessed through survival analysis and reported as the Kaplan Meier estimate at two and six months after start of treatment. The association between conversion/reversion and treatment group was assessed through Cox proportional Hazard analysis in which the assumption of proportionality was assessed by visual inspection and statistical testing, and deemed being met. Statistical significance was assumed at the 5% level. Factors associated with treatment success were assessed by logistic regression. Variables were included in a multivariable analysis if the p value for the univariable association with the outcome was < 0.2. Nested models were tested by log likelihood test, which was deemed significant at the 10% level. In the multivariable model, the variables treatment group, sex, and, age (dichotomised at 45 years) were pre fixed, and the dichotomised at yes/no variables of unemployment, (past) homelessness, (past) intravenous drug use, hepatitis B infection, hepatitis C infection, self reported diabetes, self reported HIV status, previous TB episode, and (past) imprisonment. Treatment outcomes (WHO defined and simplified) were assessed as frequencies and reported as proportions. Twenty five (3.3%) cases with only extra pulmonary TB were excluded from the analyses of culture conversion and reversion, but included in the treatment outcome analysis. Results The cohort has been described in detail elsewhere. 3,4 It consists of 380 patients with MDR TB, of which 258 patients had MDR TB proper, 89 pre XDR TB, and 33 XDR TB. Culture conversion and reversion Of all enrolled patients, only 64.1% in low, 72.1% in intermediate and 60.2% in high incidence countries had a further culture performed after starting treatment according to the resistance diagnosis. The Kaplan Meier estimates for culture conversion at month two were 39.7%, 35.3%, and 34.8%, for patients with MDR TB proper, pre XDR TB, and XDR TB, respectively. For six months culture conversion, these estimates were 81.7%, 72.8%, and 58.9%, respectively (Figure a). The Hazard Ratio for culture conversion in pre XDR TB and XDR TB patients compared to patients with MDR TB 3

5 proper was 0.86 (95% Confidence Interval [CI]: ; p=0.347) and 0.60 (95%CI: ; p=0.051), respectively. The Hazard ratio for culture reversion was 1.82 (95% CI: ; p=0.087) for pre XDR TB patients and 2.42 (95% CI: ; p=0.076) for patients with XDR TB, compared to patients with MDR TB proper (Figure b). Treatment outcomes Using the simplified definitions, relapse free cure was achieved in 61.2% of the patients with MDR TB proper, 51.7% of patients with pre XDR TB, and 39.4% of patients with XDR TB. (figure c, Appendix table 1). Using the formal WHO definitions, cure was achieved in 30.6% and the patients with MDR TB proper, 27% of patients with pre XDR TB, and 24.2% of patients with XDR TB. An additional 33.3%, 31.4%, and 42.2%, respectively had a reported outcome of treatment completion (figure d, Appendix table 1). Only 12.6% of patients enrolled in low incidence countries had three or more cultures recorded during the continuation phase vs. 58.1% and 52.3% in intermediate and high incidence countries (Appendix figure 1). According to the WHO treatment outcome definition only this proportion of patients qualify for an assessment of cure. WHO defined cure was therefore recorded for only 9.7% of patients in low incidence countries vs. 34.9% and 37.2% of patients in intermediate and high incidence countries. Recurrence Data on the TB status one year after end of treatment was available for 306 (80.5%) of the 380 patients included in the cohort. Of those 11 (2.9%) reported a recurrence of TB, which did not differ markedly between the patient groups (7 (2.7%) MDR TB proper, 3 (3.4%) pre XDR TB, 1 (3.0%) XDR TB). Of patients with a negative culture status at six months, 35 (11%) reverted in the continuation phase, while 9 (3%) had a post treatment relapse. Factors associated with relapse free cure Appendix table 2 reports the factors associated with relapse free cure. In the multivariable analysis, patients with pre XDR TB and XDR TB had a lower odds of relapse free cure, compared to patients with MDR TB proper, while previous TB treatment, HIV positivity, and current or past intravenous drug use were independently of treatment group associated with relapse free cure. Treatment The most commonly used fluoroquinolone and SLID for the treatment of MDR TB in Europe are ofloxacin (65.3%) and capreomycin (70.0%) (Appendix table 3). Fluoroquinolones were frequently used in patients with XDR TB (moxifloxacin 60.6%, ofloxacin 36.4%, levofloxacin 33.3%). Also SLID were used frequently and for a considerable duration in patients with XDR TB. Irrespective of treatment group, pyrazinamide was used in almost 90% of the patients, while ethambutol was used by just over half the patients. Ethionamide/prothionamide and cycloserine were used in over 80% of all patients irrespective of the level of drug resistance, while PAS was more frequently used with increasing levels of drug resistance. Clofazimine was used in 10.4% of patients with pre XDR TB and 12.4% with XDR TB for a median duration of 481 and 361 days. Linezolid was used in 22.5% of cases with pre XDR TB and 42.4% with XDR TB for a median duration of 341 and 358 days. 4

6 Acknowledgement: Our friend and colleague Diego Zallocco, project manager of the TB PANNET consortium, would have enjoyed reading the fruits of this work. Thank you for your smile and support, we miss you. References: 1. Giehl C, Lange C, Duarte R, et al. TBNET Collaborative research on tuberculosis in Europe. European journal of microbiology & immunology 2012;2: World Health Organization/European Centre for Disease Prevention and Control. Tuberculosis Surveillance and monitoring in Europe Copenhagen, Denmark 3. Gunther G, van Leth F, Alexandru S, et al. Multidrug resistant tuberculosis in Europe, Emerg Infect Dis 2015;21: Gunther G, van Leth F, Altet N, et al. Beyond multidrug resistant tuberculosis in Europe: a TBNET study. Int J Tuberc Lung Dis 2015;19: World Health Organization. Companion handbook to the WHO guidelines of programmatic management of drug resistant tuberculosis Geneva, Switzerland 6. World Health Organization. Definitions and reporting framework for tuberculosis revision Geneva, Switzerland 5

7 Appendix figure 1 * Patients with MDR TB N = 380 MDR TB proper: N = 258 pre XDR TB: N = 89 XDR TB: N = 33 Low incidence N = 103 Intermediate incidence N = 86 High incidence N = 191 Intensive phase Died: N = 1 (1.0%) LFU: N = 15 (14.6%) Intensive phase Died: N = 0 LFU: N = 3 (3.5%) Intensive phase Died: N = 2 (1.0%) LFU: N = 17 (8.9%) Reached continuation phase N = 87 (84.5%) Reached continuation phase N = 83 (96.5%) Reached continuation phase N = 172 (90.1%) Died N = 1 (1.0%) Assessed cure * N = 68 (66.0 %) Died N = 2 (2.4%) Assessed cure * N = 62 (72.1 %) Died N = 16 (9.3%) Assessed cure * N = 117 (61.3 %) >= 3 cultures available N = 13 (12.6%) Available cultures # 6 (5 10) >= 3 cultures available N = 50 (58.1%) Available cultures # 14 (11 17) >= 3 cultures available N = 100 (52.4%) Available cultures # 14 (11 18) *patients with a positive culture after the start of second line therapy; # median (interquartile range) Appendix figure 1: Flow chart to derive at WHO treatment outcome classification for the definition of cure at an European cohort of patients with MDR TB. 6

8 Appendix table 1: Treatment outcome, by treatment group and definition used Simplified definition WHO definition MDR proper Pre XDR XDR MDR proper Pre XDR XDR TB N = 258 N = 89 N = 33 N = 258 N = 89 N = 33 n (%) n (%) n (%) n (%) n (%) n (%) Cure 158 (61.2) 46 (51.7) 13 (39.4) 79 (30.6) 24 (27.0) 8 (24.2) Treatment completed n/a 86 (33.3) 28 (31.4) 14 (42.2) Fail 45 (17.4) 23 (25.8) 13 (39.4) 29 (11.2) 12 (13.5) 4 (12.1) Death 13 (5.0) 8 (9.0) 1 (3.0) 13 (5.0) 8 (9.0) 1 (3.0) Lost to follow up 3 (1.2) (19.8) 17 (19.1) 6 (18.20 Undeclared 39 (15.1) 12 (13.5) 6 (18.2) n/a n/a: not applicable Appendix table 2: Factors associated with relapse free cure Bi variable model * Multivariable model # OR 95% CI p value OR 95% CI p value MDR proper 1 1 Pre XDR XDR Male Age < 45 yrs Unemployed Homeless IDU < HIV infected < Hep B infected Hep C infected Diabetes Previous TB Incarceration * treatment group fixed in the model; # treatment group, sex, and age fixed in the model 7

9 Appendix table 3: Drugs used and duration of use, by treatment group MDR proper Pre XDR XDR Total N = 258 N = 89 N = 33 N = 380 Use (%) Duration (days) Use (%) Duration (days) Use (%) Duration (days) Use (%) Duration (days) Med IQR Med IQR Med IQR Med IQR Group 1 ethambutol pyrazinamide Group 2 amikacin capreomycin kanamycin streptomycin Group 3 ciprofloxacin levofloxacin moxifloxacin ofloxacin Group 4 aminosalicylic acid cycloserin/terizidone ethionamide/prothionamide Group 5 amoxicillin/clavulanic acid clarithromycin clofazimine linezolid Med: median; IQR: interquartile range 8