Treatment outcomes and survival based on drug resistance patterns in multidrug-resistant

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1 Treatment outcomes and survival based on drug resistance patterns in multidrug-resistant tuberculosis Doh Hyung Kim, Hee Jin Kim, Seung-Kyu Park, Suck-Jun Kong, Young Sam Kim, Tae-Hyung Kim, Eun Kyung Kim, Ki Man Lee, Sung-Soon Lee, Jae Seuk Park, Won-Jung Koh, Chang- Hoon Lee, Tae Sun Shim Online Data Supplement 1

2 Online supplement Methods In South Korea, patients with multidrug-resistant tuberculosis (MDR-TB) were usually treated using individualized regimens based on drug-susceptibility test (DST) results and their histories of previous anti-tb drug use during the study period. The anti-tb regimen included at least four effective drugs, when available, and doses were administered daily according to existing MDR- TB management guidelines (E1). In patients for whom four effective drugs were not available, anti-tb drugs of unknown (amikacin, moxifloxacin, and rifabutin) or unclear anti-tb efficacy (clofazimine and amoxicillin/clavulanate) were included. The injectable anti-tb drug was used for at least 6 months unless significant adverse events were encountered. Treatment was continued for at least 18 months in total and for 12 months after culture conversion (defined as at least two consecutive negative culture results obtained at least 1 month apart), except for patients who defaulted or died, and for those for whom treatment was discontinued owing to a favorable clinical response (short-term treatment completion) (E2). Most patients received drugs on an outpatient basis, and directly observed therapy (DOT) was provided only to patients hospitalized in national TB institutions. Results Treatment modalities When previous and current regimens at commencement of treatment were analyzed in the extensively drug-resistant (XDR) TB and pre-xdr-tb groups, more prior anti-tb drugs (4.1 ± 3.2) had been prescribed to patients with disease classed as XDR (XDR-TB re ) by the revised 2

3 definition, and those with ofloxacin-resistant pre-xdr-tb (pre-xdr-tb o ) (3.9 ± 3.2) than to patients with the other forms of MDR-TB (non-xdr and non-pre-xdr MDR-TB) (3.0 ± 2.3) (P < 0.05 for each comparison), and most potentially effective drugs were used at initiation of current treatment in patients with the other form of MDR-TB (3.8 ± 1.5), followed by those with second-line drug-resistant pre-xdr-tb (pre-xdr-tb s ) (2.9 ± 1.6), pre-xdr-tb o (2.4 ± 1.5), and XDR-TB re (1.5 ± 1.4) (P < 0.05 for each comparison). Surgical resection was more frequently performed in patients with pre-xdr-tb o than in those with the other form of MDR- TB (10.1% vs 3.1%, P < 0.001) (Table 1E). Treatment outcomes based on the six WHO-recommended outcome categories Treatment outcomes were also analyzed according to the six WHO-recommended outcome categories, and results were almost the same as the data obtained based on the seven outcome categories (the six WHO outcomes plus short-term treatment completion ) used in the present study. When outcomes were compared between groups classified by the revised or original XDR-TB definitions, treatment success rates were 17.3% in XDR-TB re patients, 27.5% in those with XDR- TB or, 34.5% in XDR-TB (or-re) patients (defined as those with XDR-TB or but not XDR-TB re ), and 38.1% in non-xdr MDR-TB patients; only XDR-TB re patients showed a significantly lower success rate than those with non-xdr MDR-TB (P < 0.001) (Table 2E). When outcomes were compared according to OFX- and SLID-resistance, treatment success rates were 17.3% in XDR-TB re patients, 27.0% in those with pre-xdr-tb o, 40.2% in pre-xdr- TB s patients, and 39.3% in those with the other form of MDR-TB (non-xdr and non-pre-xdr MDR-TB). The success rates of XDR-TB re and pre-xdr-tb o patients were significantly lower 3

4 than the rate of those with the other form of MDR-TB (P < 0.05 for each comparison), and the success rate of XDR-TB re treatment was also significantly lower than seen with pre-xdr-tb s patients (P = 0.006) (Table 3E). When outcomes were compared based on SM susceptibility in the pre-xdr-tb groups, treatment success rates were 30.4% in SM-resistant pre-xdr-tb o patients, 25.2% in those with SM-susceptible pre-xdr-tb o, 19.7% in patients with SM-resistant pre-xdr-tb s, and 45.0% in those with SM-susceptible pre-xdr-tb s. SM-susceptible pre-xdr-tb s patients showed the highest success rate among the pre-xdr-tb subgroups, but the success rate differed only between patients with SM-susceptible pre-xdr-tb o and those with SM-susceptible pre-xdr- TB s (P = 0.031) (Table 4E). Discussion The present study analyzed treatment outcomes based on seven outcome categories, including the six recommended by the WHO and short-term treatment completion. In the absence of the short-term treatment completion category, such patients would have to be classified into a default outcome because they did not meet the criteria for cure or treatment completion. However, patients completing short-term treatment should be distinguished from defaulting patients because the definition of short-term treatment completion was reserved for those whose treatment was completed by attending physicians who recorded favorable clinical and microbiological responses. MDR-TB is occasionally successfully treated by short-course, firstline drug treatment only (E3). In addition, relapse rates did not differ among cured patients (8.2%), those who completed treatment (7.5%), and those who completed short-term treatment (12.6%) (P > 0.05 for each comparison), as reported previously (E1). Analysis of outcomes based 4

5 only on the six WHO-recommended categories yielded results almost identical to those based on the seven categories of the present study. Among additional drug-resistance patterns, SM susceptibility was associated with favorable long-term survival in pre-xdr-tb patients. Kaplan-Meier survival analysis showed that SMsusceptible pre-xdr-tb s patients experienced the best survival among the four pre-xdr-tb groups. A possible explanation is the availability of both FQN and an injectable drug (SM) for SM-susceptible pre-xdr-tb s patients; by contrast, in the other three pre-xdr-tb groups, only one of either a FQN or an injectable drug could be prescribed. These data also indicate that simultaneous use of both a FQN and an injectable drug was important to achieve successful treatment outcomes in MDR-TB patients. However, by multivariate analyses, SM-susceptible pre-xdr-tb was associated with a greater long-term survival than was SM-resistant pre-xdr- TB, irrespective of resistance to OFX or SLID. 5

6 Table 1E Definition of abbreviations: MDR = multidrug-resistant, TB = tuberculosis, XDR = extensively drug-resistant, XDR-TB re = revised definition of XDR-TB, pre-xdr-tb o = ofloxacin-resistant non-xdr MDR-TB, pre-xdr-tb s = second-line injectable drug-resistant non-xdr MDR-TB Values are numbers (with percentages) or means ± SDs and interquartile range. * Definitions of treatment modalities: 1) TB drugs used before: drugs used for more than 1 month during previous treatment, 2) drugs with unknown activity: anti-tb drugs with unknown drug susceptibility test results (amikacin, moxifloxacin and rifabutin) or unclear anti-tb efficacy (clofazimine and amoxicillin/clavulanate), 3) potentially effective drugs: either previously unused and active drugs or previously unused and activity-unknown drugs. Statistical analyses were performed using chi-square tests with Bonferroni correction and oneway ANOVA tests. P < 0.05, XDR-TB re vs pre-xdr-tb o, XDR-TB re vs pre-xdr-tb s, XDR-TB re vs other MDR-TB, ll pre-xdr-tb o vs pre-xdr-tb s, ** pre-xdr-tb o vs other MDR-TB, pre-xdr- TB s vs other MDR-TB. Table 2E. Definition of abbreviations: MDR = multidrug-resistant, TB = tuberculosis, XDR = extensively drug-resistant, XDR-TB re = revised definition of XDR-TB, XDR-TB or = original definition of XDR-TB, XDR-TB (or-re) = XDR-TB or excluding XDR-TB re Values are numbers (with percentages). Statistical analyses were performed using chi-square tests. Bonferroni-corrected P < 0.05, * XDR-TB re vs. non-xdr MDR-TB, XDR-TB or vs. non-xdr 6

7 MDR-TB, XDR-TB (or-re) vs. non-xdr MDR-TB. Table 3E. For definition of abbreviations, see Table 1E. Values are numbers (with percentages). Statistical analyses were performed using chi-square tests. Bonferroni-corrected P < 0.05, * XDR-TB re vs pre-xdr-tb s, XDR-TB re vs other MDR-TB, pre-xdr-tb o vs other MDR-TB. Table 4E. Definition of abbreviations: SM = streptomycin, TB = tuberculosis, XDR = extensively drugresistant, pre-xdr-tb o = ofloxacin-resistant non-xdr MDR-TB, pre-xdr-tb s = second-line injectable drug-resistant non-xdr MDR-TB. Values are numbers (with percentages). Statistical analyses were performed using chi-square tests. Bonferroni-corrected P < 0.05, * SM-resistant pre-xdr-tb o vs. SM-susceptible pre-xdr-tb s, SM-susceptible pre-xdr-tb o vs. SM-susceptible pre-xdr-tb s. Table 5E. Definition of abbreviations: AFB = acid-fast bacilli, BMI = body mass index, CI = confidence interval, Hb = hemoglobin, HR = hazard ratio, SM = streptomycin, TB = tuberculosis, XDR = extensively drug-resistant, XDR-TB re = revised definition of XDR-TB, pre-xdr-tb o = ofloxacin-resistant non-xdr MDR-TB, pre-xdr-tb s = second-line injectable drug-resistant non-xdr MDR-TB. 7

8 Values are numbers (with percentages) or mean ± SD and range. * Hazard ratio for all-cause mortality. 8

9 Table 1E. Initial treatment modalities. XDR-TB re Pre-XDR-TB o Pre-XDR-TB s Other MDR-TB Total Treatment modalities * (n=75) (n=159) (n=117) (n=1,056) (n=1,407) 4.1 ± ± ± ± ± 2.5 No. of TB drugs used before, ** (4-4) (0-5) (0-4) (0-4) (0-4) No. of TB drugs at current treatment initiation 4.8 ± ± ± ± ± 0.8 Total No. of anti-tb drugs prescribed ** (4-5) (4-5) (4-5) (4-5) (4-5) 1.7 ± ± ± ± ± 1.7 No. of active drugs,,, **, (1-3) (2-4) (2-4) (2-5) (2-5) 0.2 ± ± ± ± ± 1.5 No. of drugs with unknown activity, **, (0-0) (0-0) (0-0) (0-1) (0-1) 1.5 ± ± ± ± ± 1.6 No. of potentially effective drugs,,, ll, **, (0-3) (1-4) (2-4) (3-5) (3-5) Surgical resection ** 3 (4.0) 16 (10.1) 8 (6.8) 33 (3.1) 60 (4.3) 9

10 Table 2E. Outcomes according to the six WHO-recommended outcome categories in XDR-TB patients. Treatment outcomes XDR-TB re XDR-TB or XDR-TB (or-re) Non-XDR MDR-TB (n=75) (n=149) (n=84) (n=1,248) P value Cure *, 9 (12.0) 31 (20.8) 22 (26.2) 394 (31.6) < Treatment completion 4 (5.3) 10 (6.7) 7 (8.3) 82 (6.6) Failure *,, 12 (16.0) 24 (16.1) 12 (14.3) 41 (3.3) < Transfer out 9 (12.0) 15 (10.1) 8 (9.5) 91 (7.3) Default, 21 (28.0) 40 (26.8) 22 (26.2) 529 (42.4) < Death *, 20 (26.7) 29 (19.5) 13 (15.5) 111 (8.9) < Treatment success * 13 (17.3) 41 (27.5) 29 (34.5) 476 (38.1) <

11 Table 3E. Outcomes according to the six WHO-recommended outcome categories in XDR-TB re and pre-xdr-tb patients. Treatment outcomes XDR-TB re Pre-XDR-TB o Pre-XDR-TB s Other MDR-TB Total (n=75) (n=159) (n=117) (n=1,056) (n=1,407) P value Cure *,, 9 (12.0) 34 (21.4) 34 (29.1) 348 (33.0) 425 (30.2) < Treatment completion 4 (5.3) 9 (5.7) 13 (11.1) 67 (6.3) 93 (6.6) Failure, 12 (16.0) 22 (13.8) 7 (6.0) 24 (2.3) 65 (4.6) < Transfer out 9 (12.0) 12 (7.5) 11 (9.4) 76 (7.2) 108 (7.7) Default, 21 (28.0) 50 (31.4) 39 (33.3) 462 (43.8) 572 (40.7) Death *,, 20 (26.7) 32 (20.1) 13 (11.1) 79 (7.5) 144 (10.2) < Treatment success *,, 13 (17.3) 43 (27.0) 47 (40.2) 415 (39.3) 518 (36.8) <

12 Table 4E. Outcomes according to the six WHO-recommended outcome categories with respect to SM susceptibility in pre-xdr-tb patients. Pre-XDR-TB o Pre-XDR-TB s Treatment outcomes SM-resistant SM-susceptible SM-resistant SM-susceptible (n=56) (n=103) (n=37) (n=80) P value Cure 12 (21.4) 22 (21.4) 8 (21.6) 26 (32.5) Treatment completion 5 (8.9) 4 (3.9) 3 (8.1) 10 (12.5) Failure * 13 (23.2) 9 (8.7) 3 (8.1) 4 (5.0) Transfer out 4 (7.1) 8 (7.8) 5 (13.5) 6 (7.5) Default 12 (21.4) 38 (36.9) 14 (37.8) 25 (31.2) Death 10 (17.9) 22 (21.4) 4 (10.8) 9 (11.2) Treatment success 17 (30.4) 26 (25.2) 11 (29.7) 36 (45.0)

13 Table 5E. Impact of SM susceptibility on long-term survival in patients with XDR and pre-xdr-tb. Variables No. of deaths Univariate analysis Multivariate analysis (n=393) HR * (95% CI) P value HR * (95% CI) P value Age > 40 years 276 (70.2) Male sex 313 (79.6) BMI < 18.5 kg/m 2 91 (23.2) < ( ) ( ) ( ) ( ) < ( ) ( ) < < Previous TB treatment with second-line drugs 96/373 (25.7) < ( ) ( ) previous TB treatments 142/367 (38.7) 1.81 ( ) < Far advanced disease 204/360 (56.7) < ( ) ( ) <

14 Hb < 10.0g/dL 41/314 (13.1) < ( ) ( ) Positive AFB smear at treatment initiation 287 (73.0) 1.31 ( ) Mean no. of TB drugs used before 3.75 ± ± SD (0-4) ( ) Mean no. of potentially effective 3.00 ± TB drugs ± SD (2-4) ( ) < < Surgical treatment 7 (1.8) Drug resistant patterns 0.37 ( ) XDR-TB re 43/75 (57.3) SM-resistant pre-xdr-tb o 24/56 (42.9) < ( ) ( ) ( ) ( ) <

15 SM-susceptible pre-xdr-tb o 45/103 (43.7) 2.15 ( ) < SM-resistant pre-xdr-tb s 16/37 (43.2) ( ) ( ) SM-susceptible pre-xdr-tb s 21/80 (26.3) 1.12 ( ) Other MDR-TB 244/1,056 (23.1) 1 15

16 References E1. Crofton J, Chaulet P. Guidelines for the management of drug-resistant tuberculosis. WHO/TB/ Geneva, Switzerland: WHO; E2. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, H Kim EK, Lee KM, Lee SS, Park JS, Koh WJ, Lee CH, Kim JY, Shim TS. Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med 2008;178: E3. Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, Baez J, Kochi A, Dye C, Raviglione MC. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000;283:

Supplementary Appendix

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