treatment outcomes and survival based on drug resistant pattern in multidrug resistant tuberculosis

7/27/2019 Treatment Outcomes and Survival Based on Drug Resistant Pattern in Multidrug Resistant Tuberculosis

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Treatment Outcomes and Survival Based on DrugResistance Patterns in Multidrug-resistant Tuberculosis

Doh Hyung Kim1, Hee Jin Kim2, Seung-Kyu Park3, Suck-Jun Kong4, Young Sam Kim5, Tae-Hyung Kim6,Eun Kyung Kim7, Ki Man Lee8, Sung-Soon Lee9, Jae Seuk Park1, Won-Jung Koh10, Chang-Hoon Lee11,and Tae Sun Shim12

1Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Dankook University College of Medicine, Dankook University Hospital,

Cheonan, South Korea; 2Department of Epidemiology, The Korean Institute of Tuberculosis, Seoul, South Korea; 3Clinical Research Center, National MasanHospital, Masan, South Korea; 4Department of Thoracic Surgery, Mokpo National Hospital, Mokpo, South Korea; 5Department of Internal Medicine, YonseiUniversity College of Medicine, Severance Hospital, Seoul, South Korea; 6Department of Internal Medicine, Hanyang University College of Medicine, Seoul,South Korea; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Pochon CHA University,Seongnam, South Korea; 8Department of Internal Medicine, Chungbuk National University College of Medicine, Chungbuk National University Hospital,Cheongju, South Korea; 9Department of Internal Medicine, Inje University School of Medicine, Ilsan Paik Hospital, Goyang, South Korea; 10Division ofPulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, SouthKorea; 11Division of HIV and TB control, Department of Disease Prevention, Korea Centers for Disease Control and Prevention, Seoul, South Korea;12Division of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

Rationale: Few large-scale studies have investigated multidrug-

resistant tuberculosis (MDR-TB) treatment outcomes relative to

drug-resistance patterns.Objectives: To assess the impact of additional drug resistances on

treatment outcomes and long-term survival in a large HIV-negative

MDR-TB cohort.

Methods: Treatment outcomes and long-term survival of patientswith MDR-TB newly diagnosed or retreated in 2000 to 2002 were

retrospectively analyzed basedon drug-resistancepatternsafter 58

years of follow-up.

Measurements and Main Results: Of 1,407 patients with MDR-TB, 75

(5.3%) had extensively drug-resistant TB (XDR-TBre) by the revised

definition; 159 (11.3%) had ofloxacin-resistant preXDR-TB (preXDR-

TBo); and 117 (8.3%) had second-line injectable drug (SLID)resistantpreXDR-TB (preXDR-TBs). Patients with XDR-TBreshowed the lowest

treatment success rate(29.3%)and thepoorestlong-term survival, and

XDR-TBre was more strongly associated with long-term mortality than

XDR-TB as originally defined (hazards ratio [HR], 3.15; 95% confidence

interval [CI], 2.064.83; P, 0.001 vs. HR, 2.15; 95% CI, 1.493.09; P,0.001). Patients with either form of preXDR-TB showed poorer

cumulative survival than those with ofloxacin-susceptible/SLID-suscep-

tible MDR-TB (P, 0.05 for each comparison). Although streptomycin

susceptibility did not affect the treatment outcomes of patients with

preXDR-TB, streptomycin-resistant preXDR-TB was more strongly

associated with long-term mortality than ofloxacin-susceptible/SLID-susceptible MDR-TB (HR, 2.17; 95% CI, 1.223.84; P, 0.008 for pre

XDR-TBo; andHR, 2.69; 95% CI, 1.405.16; P5 0.003 for preXDR-TBs).

Conclusions: The revised XDR-TB definition is appropriate for defining

patients with MDR-TB with the poorest outcomes. Both preXDR-TBoand preXDR-TBs were independently associated with poor long-term

survival in patients with MDR-TB. SM susceptibility was linked to better

survival in patients with preXDR-TB.

Keywords: tuberculosis; multidrug-resistant; survival rate; treatmentoutcome; drug susceptibility

Drug-resistant tuberculosis (TB), especially multidrug-resistant (MDR) TB, defined as TB resistant to both isoniazidand rifampicin, remains a serious threat to public health andTB control programs worldwide (1). In addition, the emer-

gence of extensively drug-resistant (XDR) TB, a subset ofMDR-TB, has complicated treatment and control of thisdisease. XDR-TB was originally defined as MDR-TB resistantto at least three of six main classes of second-line drugs(aminoglycosides, polypeptides, fluoroquinolones [FQNs], thi-oamides, cycloserine, and p-aminosalicylic acid) (2), but themost recent definition of the World Health Organization(WHO), defined in 2006 (3), considers MDR-TB to be presentif resistance is demonstrated to any FQN and to at least onesecond-line injectable drug (SLID), including amikacin, cap-reomycin, and kanamycin. Treatment outcomes with respectto additional drug-resistance patterns in patients with MDR-TB have varied among reports. Several recent studies showedthat resistance to additional first-line drugs, other than iso-

niazid and rifampicin (4), FQNs (5, 6), kanamycin (7),

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Treatment outcomes and long-term survival with respect tothe original and revised definitions of extensively drug-resistant (XDR-TB) have not been compared in previousstudies, and the impact of preXDR-TB (multidrug-resistanttuberculosis [MDR-TB] resistant to either any fluoroqui-nolones or at least one second-line injectable drug, but notto both) on MDR-TB treatment outcomes has also notreceived attention.

What This Study Adds to the Field

Our results confirmed that the revised XDR-TB definitionwas adequate to define a subset of MDR-TB patients with

the poorest treatment outcome and the worst long-termsurvival. Moreover, the presence of preXDR-TB was anindependent prognostic factor of poor outcomes and survivalin patients with MDR-TB. Streptomycin susceptibility wasan important predictor of favorable long-term survival inpatients with preXDR-TB.

(Received in original form November 3, 2009; accepted in final form March 9, 2010)

Supported by the International Tuberculosis Research Center (ITRC-2006010

and 2008002).

Correspondence and requests for reprints should be addressed to Tae Sun Shim, M.D.,

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,

University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong,

Songpa-gu, Seoul, 138-736, South Korea. E-mail: [email protected]

This article has an online supplement, which is accessible from this issues table of

contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 182. pp 113119, 2010

Originally Published in Press as DOI: 10.1164/rccm.200911-1656OC on March 11, 2010

Internet address: www.atsjournals.org


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capreomycin (8), and streptomycin (SM) (9), was indepen-dently associated with unfavorable treatment outcomes. Al-though the presence of XDR-TB has become the most seriousnegative prognostic factor in MDR-TB treatment (1015),treatment outcomes with respect to the original and reviseddefinitions of XDR-TB have not been compared, and theimpact of the division of patients with preXDR-TB (definedas those with MDR-TB resistant to either any FQN or at leastone SLID, but not to both) into two subsets on MDR-TB

treatment outcomes has also not received attention. AlthoughSM is included in the class of aminoglycoside drugs, along withkanamycin and amikacin, SM susceptibility is not included inthe definition of XDR-TB. Thus, the impact of SM suscepti-bility on treatment outcomes should be evaluated separatelyfrom the definition of XDR-TB. To investigate the impact ofthese drug-resistance patterns on treatment outcomes andsurvival in patients with MDR-TB, we analyzed outcomes ina large cohort of patients with MDR-TB, most of who werenot coinfected with HIV, with respect to drug-resistancepatterns. Preliminary results were presented at the 107thConference of the Korean Academy of Tuberculosis andRespiratory Diseases held in 2008 in Seoul, South Korea (16).

METHODS

Study Participants and Data Collection

A total of 1,407 Korean patients with MDR-TB were enrolled fromJanuary 2000 to December 2002; their details have been describedpreviously (10). Medical records were retrospectively reviewed fordemography, TB treatment history, comorbidities, acid-fast bacilli(AFB) cultures and drug susceptibility test (DST) results, chest ra-diographs, treatment modalities, and outcomes. All patients werefollowed-up for 58 years after commencement of treatment, andinformation on vital status as of December 2007 was obtained from thedeath registry of the Korea National Statistical Office; however, thisregistry does not provide information on cause of death. This study wasapproved by the Institutional Review Board of the Asan MedicalCenter, Seoul, South Korea, and other institutions.

AFB Cultures and DST

AFB were examined by Ziehl-Neelsen staining, and were culturedon egg-based Ogawa medium. DSTs for isoniazid, rifampicin,ethambutol, pyrazinamide, SM, kanamycin, cycloserine, p-amino-salicylic acid, prothionamide, and ofloxacin (OFX) were performedat all participating laboratories. Enviomycin-capreomycin suscepti-bility was determined at the Korean Institute of Tuberculosis, theSupranational TB Reference Laboratory, Seoul, South Korea, andone private laboratory. The proportion method and the pyrazinami-dase test were used for DST at the Korean Institute of Tuberculosis.Of the FQNs and second-line aminoglycosides, only OFX andkanamycin susceptibility tests, respectively, were routinely per-formed during the study period. Thus, DSTs of amikacin and otherFQNs were not evaluated.

Classification of Patients

Four groups were defined as follows: (1) XDR-TBre (revised defini-tion), MDR-TB with bacillary resistance to OFX and at least one ofthe SLIDs (kanamycin, capreomycin, or enviomycin); (2) XDR-TBor(original definition), MDR-TB with bacillary resistance to at least threeof the six main classes of second-line drugs (2); (3) XDR-TB(or-re),XDR-TBor excluding XDR-TBre; and (4) preXDR-TB, MDR-TBresistant to either OFX (preXDR-TBo) or at least one SLID (preXDR-TBs), but not to both drugs.

Definitions of Treatment Outcomes

The seven categories of outcome definitions included the six WHO-recommended categories (cure, treatment completion, transfer out,

default, death, and failure) (17) and short-term treatment completion

(10). Adequate treatment duration was defined as 18 months, in-cluding 12 months after culture conversion. Short-term treatmentcompletion was defined as follows: (1) inadequate treatment dura-tion, but more than 6 months; (2) three consecutive negative culturesbefore treatment completion; and (3) treatment completion assessedby a physician based on favorable response. Treatment success wasdefined as the sum of cure, treatment completion, and short-termtreatment completion. All outcomes were the initial treatment out-comes during the study period, and were analyzed based on AFBculture results.

Statistical Analysis

Chi-square and one-way analysis of variance tests were used inunivariate analyses. Bonferroni correction was used if multiple com-parisons were performed, and all Pvalues evaluated in chi-square testswere Bonferroni-corrected. Cumulative survival was estimated by theKaplan-Meier method and compared by the log-rank test. Cox re-gression was used to define the predictors of long-term survival bymultivariate analysis using the backward elimination procedure. SPSSsoftware, version 13.0 (SPSS Inc., Chicago, IL), was used for allanalyses, with P, 0.05 indicating significance.

RESULTS

Demographics

Of 1,407 patients with MDR-TB, 75 (5.3%) were diagnosedwith XDR-TBre; 159 (11.3%) with preXDR-TBo; 117 (8.3%)with preXDR-TBs; and 1,056 (75.1%) with the other form ofMDR-TB (susceptible to both OFX and SLID). The mean ageof the study patients was 42.9 years (range, 1389 years); themale to female ratio was 2.8:1; and the mean body mass indexwas 19.2 kg/m2 (range, 1232 kg/m2). HIV-ELISA tests wereconducted on 66 (4.7%) patients, with only one found to beseropositive. Patient demographic characteristics are shown inTable 1.

A previous history of treatment with second-line TBdrugs was more common in patients with XDR-TBre (35.6%)and preXDR-TBo (32%) than in those with preXDR-TBs(17.5%) or the other form of MDR-TB (8.8%) (P, 0.05 foreach comparison), and a history of at least two previous TBtreatments was more common in patients with XDR-TBre(47.7%), preXDR-TBo (38.4%), and preXDR-TBs (27%)than in those with the other form of MDR-TB (24.9%) (P,0.05 for each comparison). The proportion of patients with far-advanced disease on simple chest radiograph examination washigher in patients with XDR-TBre and preXDR-TBo than inthe other patients with MDR-TB (50.7%, 45.5%, and 29%,respectively; P, 0.05 for each comparison).

Treatment Outcomes and Survival Based on the Definitions

of XDR-TB

The overall treatment success rate of the 1,407 study partic-ipants was 45.3% (cure 30.2%, treatment completion 6.6%,and short-term treatment completion 8.5%). Treatment suc-cess rates for patients with XDR-TBre (n 5 75), XDR-TBor(n 5 149, including 65 patients with XDR-TBre), and XDR-TB(or-re) (n 5 84) were 29.3, 38.9, and 44%, respectively, andthese rates did not significantly differ among groups (P. 0.05for each comparison). However, the success rate of the groupwith XDR-TBre was significantly higher than that of those withnon-XDR MDR-TB (n 5 1,248; success rate 46.3%) (P 50.025) (Table 2).

Mean survival times were 61.7, 68, and 72.2 months inpatients with XDR-TBre, XDR-TBor, and XDR-TB(or-re), re-spectively, and were thus lower than that (89.2 months) in

patients with non-XDR MDR-TB (P, 0.001 for each compar-

114 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 182 2010


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ison) (Figure 1). Among the three groups with XDR-TB,presence of XDR-TBre was the strongest predictor of poorlong-term survival in multivariate analyses. Compared with thepresence of non-XDR MDR-TB, the hazard ratio (HR) was

3.15 (95% confidence interval [CI], 2.064.83; P , 0.001) inpatients with XDR-TBre; 2.15 (95% CI, 1.493.09; P, 0.001) inthose with XDR-TBor; and 1.38 (95% CI, 0.802.39; P5 0.252)in patients with XDR-TB(or-re), respectively (Table 3).

TABLE 1. CLINICAL CHARACTERISTICS OF 1,407 PATIENTS WITH MDR-TB

XDR-TBre PreXDR-TBo PreXDR-TBs Other MDR-TB Total

Characteristics (n 5 75) (n 5 159) (n 5 117) (n 5 1,056) (n 5 1,407)

Mean age, y 6 SD (range)* 47.8 6 15.5

(1680)

44.8 6 14.4

(1779)

41.7 6 16

(1380)

42.4 6 14.7

(1389)

42.9 6 14.9

(1389)

Male sex 53 (70.7) 112 (70.4) 75 (64.1) 799 (75.7) 1,039 (73.8)

Mean BMI 6 SD (range) 18.5 6 2.7

(13.223.7)

19.1 6 3.3

(12.727)

18.7 6 3

(13.925.2)

19.4 6 3.3

(1232)

19.2 6 3.2

(1232)

Previous history of TB treatment

(n 5 1,359)

(n 5 73) (n 5 150) (n 5 114) (n 5 1,022) (n 5 1,359)

No history of previous TB treatment 14 (19.2) 40 (26.7) 29 (25.4) 302 (29.5) 385 (28.3)

History of TB treatment with

first-line drugs onlyx33 (45.2) 62 (41.3) 65 (57) 631 (61.7) 791 (58.2)

History of TB treatment with second-line drugs*xk 26 (35.6) 48 (32) 20 (17.5) 89 (8.7) 183 (13.5)

No. of previous TB treatment:

>2 times (n 5 1,335)*x31/65 (47.7) 58/151 (38.4) 30/111 (27) 251/1,008 (24.9) 370/1,335 (27.7)

Underlying diseases

Diabetes mellitus 14 (18.7) 27 (17) 17 (14.5) 181 (17.1) 239 (17)

Chronic liver disease 1 (1.3) 5 (3.1) 4 (3.4) 16 (1.5) 26 (1.8)

Malignancy 1 (1.3) 1 (0.6) 1 (0.9) 10 (0.9) 13 (0.9)

Others{ 4 (5.4) 6 (3.8) 4 (3.4) 26 (2.5) 40 (2.8)

HIV seropositive (n 5 66) 0/6 (0) 1/14 (7.1) 0/8 (0) 0/38 (0) 1/66 (1.5)

Extrapulmonary TB 1 (1.3) 6 (3.8) 5 (4.3) 41 (3.9) 53 (3.8)

Positive AFB smear at treatment

initiation

52 (69.3) 107 (67.3) 82 (70.1) 717 (67.9) 958 (68.1)

Radiologic severity (n 5 1,251)** (n 5 67) (n 5 143) (n 5 107) (n 5 934) (n 5 1,251)Minimal 2 (3) 10 (7) 6 (5.6) 77 (8.2) 95 (7.6)

Moderately advanced 31 (46.3) 68 (47.6) 59 (55.1) 586 (62.7) 744 (59.5)

Far advancedx 34 (50.7) 65 (45.5) 42 (39.3) 271 (29) 412 (32.9)

Cavitary disease 37 (49.3) 68 (42.8) 48 (41) 446 (42.2) 599 (42.6)

Bilateral disease (n 5 1,190) 51/67 (76.1) 103/130 (79.2) 71/104 (68.3) 655/889 (73.7) 880/1,190 (73.9)

Definition of abbreviations: AFB 5 acid-fast bacilli; BMI 5 body mass index; HIV5 human immunodeficiency virus; MDR 5 multidrug-resistant; TB 5 tuberculosis;

XDR5 extensively drug-resistant; XDR-TBre5 revised definition of XDR-TB; preXDR-TBo 5 ofloxacin-resistant non-XDR MDR-TB; preXDR-TBs 5 second-line injectable

drug-resistant non-XDR MDR-TB.

Values are n ( %), means 6 SD, and (ranges), as shown.

Statistical analyses were performed using chi-square test with Bonferroni correction and one-way analysis of variance test.

P, 0.05.

* XDR-TBre vs. preXDR-TBs. XDR-TBre vs. other MDR-TB. preXDR-TBs vs. other MDR-TB.x

preXDR-TBo vs. other MDR-TB.k preXDR-TBo vs. preXDR-TBs.{ Others included chronic lung disease (n 5 9), chronic renal disease (n 5 4), hypothyroidism or hyperthyroidism (n 5 5), connective tissue disease (n 5 3),

psychiatric disease (n 5 5), malnutrition and postgastrectomy state (n 5 14).

** Radiographic severity was adopted from the recommendation of the National Tuberculosis Association of America.

TABLE 2. TREATMENT OUTCOME BY XDR-TB DEFINITION

XDR-TBre XDR-TBor XDR-TB(or-re) Non-XDR MDR-TB

P ValueTreatment outcomes (n 5 75) (n 5 149) (n 5 84) (n 5 1,248)

Cure* 9 (12) 31 (20.8) 22 (26.2) 394 (31.6) ,0.001Treatment completion 4 (5.3) 10 (6.7) 7 (8.3) 82 (6.6) 0.895

Short-term treatment completion 9 (12) 17 (11.4) 8 (9.5) 102 (8.2) 0.408

Failure* 12 (16) 24 (16.1) 12 (14.3) 41 (3.3) ,0.001

Transfer out 9 (12) 15 (10.1) 8 (9.5) 91 (7.3) 0.304

Default* 12 (16) 23 (15.4) 14 (16.7) 427 (34.2) ,0.001

Death* 20 (26.7) 29 (19.5) 13 (15.5) 111 (8.9) ,0.001

Treatment success* 22 (29.3) 58 (38.9) 37 (44) 578 (46.3) 0.015

Definition of abbreviations: MDR5multidrug-resistant; TB5 tuberculosis; XDR5 extensively drug-resistant; XDR-TBre5 revised

definition of XDR-TB; XDR-TBor5 original definition of XDR-TB; XDR-TB(or-re) 5 XDR-TBor excluding XDR-TBre.

Values are n (%).

Statistical analyses were performed using chi-square test.

Bonferroni-corrected P, 0.05.

* XDR-TBre vs. non-XDR MDR-TB. XDR-TBor vs. non-XDR MDR-TB.

XDR-TB(or-re) vs. non-XDR MDR-TB.

Kim, Kim, Park, et al.: Outcomes and Survival in MDR-TB Patients 115


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Treatment Outcomes and Survival Based on Resistance

to OFX and SLIDTreatment success rates were 29.3, 35.8, 47, and 47.6% in thegroups with XDR-TBre, preXDR-TBo, preXDR-TBs, and theother form of MDR-TB (non-XDR and nonpre-XDR), re-

spectively, and success rates in patients with XDR-TBre andpreXDR-TBo were significantly lower than in patients with theother form of MDR-TB (P, 0.001 and P5 0.018, respectively)(Table 4).

With respect to long-term survival, patients with XDR-TBre(61.7 months) showed the worst survival compared with patientswith preXDR-TBo (75.7 months), patients with preXDR-TBs(78.3 months), and patients with the other form of MDR-TB(91.1 months) (P , 0.001, P 5 0.032, and P , 0.001, re-

spectively). Although the survival of patients with preXDR-TBo seemed to be worse than that of those with preXDR-TBs,the difference was not significant (P 5 0.062) (Figure 2). Inmultivariate analyses, the presence of any of XDR-TBre, preXDR-TBo, or preXDR-TBs was also a significant predictor ofpoor long-term survival. Compared with the survival of patientswith the other form of MDR-TB, HR values were 3.76 (95% CI,2.435.83; P, 0.001), 1.62 (95% CI, 1.092.40; P5 0.018), and1.57 (95% CI, 1.012.44; P5 0.048), respectively.

Treatment Outcomes and Survival Based on SM Susceptibility

in Patients with PreXDR-TB

In the group with XDR-TBre, neither treatment success rate(nor other outcomes) differed between patients who had SM-

susceptible disease (15/48; 31.2%) and those with SM-resistantdisease (7/27; 25.9%) (P5 0.627). When treatment outcomecategories were compared among the four subgroups with preXDR-TB, the treatment failure rate was significantly lower inpatients with SM-susceptible preXDR-TBs (4/80; 5%) than inthose with SM-resistant preXDR-TBo (13/56; 23.2%) (P 50.009) (Table 5). However, cumulative survival was significantlyhigher in the group with SM-susceptible preXDR-TBs than inthe other three groups with preXDR-TB by univariate analysis(P, 0.05 for each comparison) (Figure 3), and SM-resistancewas associated with relatively poor long-term survivalin patients with preXDR-TB irrespective of OFX- or SLID-resistance status by multivariate analyses. Compared withpatients with the other form of MDR-TB (those with non-

XDR and nonpre-XDR disease), the HR was 1.22 (95% CI,0.692.17; P 5 0.497) in patients with SM-susceptible preXDR-TBs, 1.43 (95% CI, 0.872.35; P5 0.158) in those withSM-susceptible preXDR-TBo, 2.17 (95% CI, 1.223.84; P5

Figure 1. Kaplan-Meier survival analysis estimates of long-term survivalbased on various definitions of XDR-TB. Mean survival time was 61.7,68, 72.2, and 89.2 months in patients with XDR-TBre, XDR-TBor, XDR-

TB(or-re), and non-XDR MDR-TB, respectively. All three XDR-TB groupsshowed poorer long-term survival than did the non-XDR MDR-TBgroup (P, 0.05 for each comparison), but there was no significantdifference among the three XDR-TB groups (XDR-TBre vs. XDR-TBor,P 5 0.240; XDR-TBre vs. XDR-TB(or-re), P 5 0.066; XDR-TBor vs.XDR-TB(or-re), P 5 0.347). Black solid line 5 XDR-TBre, black dashedline5 XDR-TBor, gray dashed line5 XDR-TB(or-re), gray solid line5 non-XDR MDR-TB. MDR 5 multidrug-resistant; TB 5 tuberculosis; XDR 5extensively drug-resistant; XDR-TBre 5 revised definition of XDR-TB;XDR-TBor 5 original definition of XDR-TB; XDR-TB(or-re) 5 XDR-TBorexcluding XDR-TBre.

TABLE 3. PREDICTORS OF LONG-TERM SURVIVAL BY XDR-TB DEFINITION

Univariate Analysis Multivariate Analysis

Variables No. of Deaths, n (%) HR* (95% CI) P Value HR* (95% CI) P Value

Age .40 years 329/833 (39.5) 2.45 (2.012.99) ,0.001 2.49 (1.893.28) ,0.001

Male sex 362/1,139 (31.8) 1.36 (1.091.69) 0.006

BMI ,18.5 kg/m2 115/224 (51.3) 2.46 (1.993.04) ,0.001 2.08 (1.492.91) ,0.001

Previous TB t reatment with second-line drugs 113/231 (57.6) 2.65 (2.103.35) ,0.001 2.29 (1.683.11) ,0.001

or more previous TB treatments 182/424 (42.9%) 2.03 (1.682.46) ,0.001

Far advanced disease 250/479 (52.2) 3.33 (2.754.04) ,0.001 1.98 (1.522.58) ,0.001

Hb ,10 g/dl 48/84 (57.1) 3.11 (2.294.21) ,0.001 1.58 (1.042.41) 0.032

Positive AFB smear at treatment initiation 338/1,060 (31.9) 1.29 (1.051.58) 0.015

Mean No. of TB drugs used before 6 SD 3.75 6 2.90 (04) 1.12 (1.081.17 ) ,0.001

Mean No. of potentially effective TB drugs 6 SD 3.00 6 1.75 (24) 0.82 (0.780.87 ) ,0.001

Surgical treatment 9/76 (11.8) 0.35 (0.180.67) 0.002 0.43 (0.171.05) 0.062

Definitions of XDR-TB

XDR-TBre 43/75 (57.3) 2.87 (2.083.94) ,0.001 3.15 (2.064.83) ,0.001

XDR-TBor 72/149 (48.3) 2.29 (1.772.95) ,0.001 2.15 (1.493.09) ,0.001

XDR-TB(or-re) 35/84 (41.7) 1.89 (1.332.68) ,0.001

Non-XDR MDR-TB 315/1,248 (25.2) 1

Definition of abbreviations: AFB 5 acid-fast bacilli; BMI 5 body mass index; CI 5 confidence interval; Hb 5 hemoglobin; HR 5 hazard ratio; TB 5 tuberculosis; XDR 5

extensively drug-resistant; XDR-TBre 5 revised definition of XDR-TB; XDR-TBor5 original definition of XDR-TB; XDR-TB(or-re) 5 XDR-TBor excluding XDR-TBre.

Values are n ( %), means 6 SDs, and ranges.

* Hazard ratio for all-cause mortality.



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0.008) in patients with SM-resistant preXDR-TBo, and 2.69(95% CI, 1.405.16; P5 0.003) in those with SM-resistant preXDR-TBs (see Table 5E in the online supplement).

DISCUSSION

The effects of drug-resistance on MDR-TB treatment outcomeshave varied in previous studies (49, 18), and it is often difficultto compare data because of relatively small patient numbers inprevious studies. Moreover, no study has compared treatmentoutcomes among patients classified using both the revised andoriginal definitions of XDR-TB. In the present work, both long-term survival after 5 to 8 years of follow-up and initial treatmentoutcomes were analyzed using the second-largest MDR-TBcohort ever studied, exceeded only by the 1,989 patients withMDR-TB examined in Peru (19). Outcomes were comparedwith respect to both the original and revised definitions of

XDR-TB to investigate the appropriateness of the two classi-fications, and were also analyzed among groups of patients withXDR-TBre, preXDR-TBo, preXDR-TBs, and the other form(OFX-susceptible/SLID-susceptible) of MDR-TB to determinethe impact of preXDR-TB status on outcomes in patients withMDR-TB. In addition, results were separately examined withrespect to SM susceptibility to determine the impact of SMstatus on outcomes of patients with XDR-TBre and preXDR-TB. Our results confirmed that the revised XDR-TB definitionwas optimal to define a subset of patients with MDR-TB withthe poorest treatment outcome and the worst long-termsurvival. Moreover, the results showed that the definition ofpreXDR-TB was an independent prognostic factor of pooroutcomes and survival in patients with MDR-TB and also

showed that SM susceptibility was an important predictor offavorable long-term survival in patients with preXDR-TB.

In previous studies, the presence of XDR-TB was found tobe the most serious obstacle to successful treatment of MDR-TB (4, 1013, 15). In the present work, 57.3% (43/75) of patientswith XDR-TBre eventually died during follow-up, and thisgroup had the poorest long-term survival rate. Since publicationof the revised definition of XDR-TB (3), no report has com-pared treatment outcomes and long-term survival relative to thenew and old criteria. As a new category of drug-resistant TB,XDR-TB should be clearly distinguished from non-XDR MDR-TB because patients with the former condition have particularlypoor prognosis. Although treatment success rates and survivalof patients with XDR-TBre and XDR-TBor did not differ

significantly in the present study, patients with XDR-TBre

tended to have a poorer treatment success rate than those withXDR-TB(or-re) (29.3 vs. 44%; P5 0.331), and the success rate ofpatients with XDR-TB(or-re) was about the same as the 46.3%

success rate of those with non-XDR MDR-TB. These findingsindicate that XDR-TBor includes a subgroup of patients witha relatively favorable prognosis (XDR-TB(or-re)). In addition,patients with XDR-TBre showed the worst cumulative survivalby Kaplan-Meier analysis, and compared with patients with

TABLE 4. TREATMENT OUTCOMES OF PATIENTS WITH XDR-TBRE AND preXDR-TB

XDR-TBre PreXDR-TBo PreXDR-TBs Other MDR-TB Total

P ValueTreatment Outcomes (n 5 75) (n 5 159) (n 5 117) (n 5 1,056) (n 5 1,407)

Cure* 9 (12) 34 (21.4) 34 (29.1) 348 (33) 425 (30.2) ,0.001

Treatment completion 4 (5.3) 9 (5.7) 13 (11.1) 67 (6.3) 93 (6.6) 0.222

Short-term treatment completion 9 (12) 14 (8.8) 8 (6.8) 88 (8.3) 119 (8.5) 0.646

Failure 12 (16) 22 (13.8) 7 (6) 24 (2.3) 65 (4.6) ,0.001

Transfer out 9 (12) 12 (7.5) 11 (9.4) 76 (7.2) 108 (7.7) 0.421

Default 12 (16) 36 (22.6) 31 (26.5) 374 (35.4) 453 (32.2) ,0.001

Death* 20 (26.7) 32 (20.1) 13 (11.1) 79 (7.5) 144 (10.2) ,0.001

Treatment success 22 (29.3) 57 (35.8) 55 (47) 503 (47.6) 637 (45.3) 0.001

For definition of abbreviations, see Table 2.

Values are n (%).



* XDR-TBre vs. preXDR-TBs. XDR-TBre vs. other MDR-TB. preXDR-TBo vs. other MDR-TB.

Figure 2. Kaplan-Meier survival analysis estimates of long-term survivalbased on the resistance to either ofloxacin or at least one of second-lineinjectable drugs. Mean survival time was 61.7, 75.7, 78.3, and 91.1months in patients with XDR-TBre, preXDR-TBo, preXDR-TBs, and theother form of MDR-TB, respectively. Patients with XDR-TBre showed theworst long-term survival (XDR-TBre vs. preXDR-TBo, P5 0.032; XDR-TBre vs. preXDR-TBs, P , 0.001; XDR-TBre vs. other MDR-TB, P ,0.001). Long-term survival of patients with preXDR-TBo and preXDR-TBs did not differ (P5 0.062), but was poorer than that of those withthe other form of MDR-TB (preXDR-TBo vs. other MDR-TB, P, 0.001;preXDR-TBs vs. other MDR-TB, P5 0.041). Black solid line5 XDR-TBre,black dashed line 5 preXDR-TBo, gray dashed line 5 preXDR-TBs,gray solid line 5 other MDR-TB. MDR 5 multidrug-resistant; TB 5tuberculosis; XDR 5 extensively drug-resistant; XDR-TBre 5 reviseddefinition of XDR-TB; XDR-TBor5 original definition of XDR-TB; XDR-

TB(or-re) 5 XDR-TBor excluding XDR-TBre.



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non-XDR MDR-TB, the HR for all-cause mortality of thosewith XDR-TBre was higher than that of patients with XDR-

TB(or-re) (3.15 vs. 1.38, respectively). Thus, the revised definitionof XDR-TB seems to be more appropriate than the originaldefinition in identifying the subgroup with MDR-TB with theworst prognosis.

Various drug-resistance patterns, such as resistance toFQNs (5, 6), kanamycin (7), capreomycin (8), SM (9), and ad-ditional first-line drugs (4), have been previously analyzed toidentify factors predictive of unsuccessful MDR-TB treatment.We found that treatment success rate and long-term survivaldid not differ between patients with preXDR-TBo and preXDR-TBs, and that the long-term survival of both groups withpreXDR-TB was poorer than those with OFX-susceptible/SLID-susceptible MDR-TB. In addition, the high HR values(1.62 and 1.57, respectively) for all-cause mortality in patients

with preXDR-TBo and preXDR-TBs showed that suchdisease status was independently important in determining poorlong-term survival in patients with MDR-TB. Thus, the currentdefinition of preXDR-TB also seems to be appropriate fordefining an intermediate risk group lying between XDR-TBreand OFX-susceptible/SLID-susceptible patients with MDR-TBin terms of disease severity.

Although SM is a first-line injectable anti-TB drug witha mechanism of action similar to that of other SLIDs, SM-resistance has not been included in the current definition ofXDR-TB or preXDR-TB (3), and few studies have investi-gated the impact of SM susceptibility on the outcomes ofpatients with XDR-TB and preXDR-TB. Although one studyfound that SM-resistance was associated with adverse treatment

outcomes in HIV-negative patients with XDR-TB (9), anotherstudy showed that patients with MDR-TB, resistant to bothFQN and SM but susceptible to all three SLIDs, had bettertreatment outcomes than did patients with XDR-TB (18). In thepresent study, neither treatment outcomes nor long-term sur-vival was affected by SM susceptibility within the group withXDR-TBre. However, when that group was compared withpatients with preXDR-TB, SM susceptibility was an importantpredictor of favorable long-term survival, irrespective of thepresence of either OFX- (preXDR-TBo) or SLID-resistance(preXDR-TBs). Collectively, these findings indicate that SM-resistance does not need to be included in the current definitionof XDR-TB and SM use may be helpful to improve treatmentoutcomes in patients with preXDR-TB. Considering the

importance of SM susceptibility in MDR-TB treatment, judi-

cious use of SM seems to be prerequisite in improving treatmentoutcomes in patients with MDR-TB. In accordance with this

finding, recently revised WHO guidelines restricted the Cate-gory II regimen (inclusion of SM) only for recurrent patientswith TB at medium to low likelihood of MDR-TB, because theCategory II regimen has a possibility to amplify drug-resistanceincluding SM-resistance in patients with high risk of MDR-TB(21).

TABLE 5. TREATMENT OUTCOMES BY SM SUSCEPTIBILITY IN PATIENTS WITH pre-XDR-TB

PreXDR-TBo PreXDR-TBs

P Value

SM-Resistant SM-Susceptible SM-Resistant SM-Susceptible

Treatment Outcomes (n 5 56) (n 5 103) (n 5 37) (n 5 80)

Cure 12 (21.4) 22 (21.4) 8 (21.6) 26 (32.5) 0.290

Treatment completion 5 (8.9) 4 (3.9) 3 (8.1) 10 (12.5) 0.199

Short-term treatment completion 4 (7.1) 10 (9.7) 4 (10.8) 4 (5) 0.605

Failure* 13 (23.2) 9 (8.7) 3 (8.1) 4 (5) 0.005

Transfer out 4 (7.1) 8 (7.8) 5 (13.5) 6 (7.5) 0.678Default 8 (14.3) 28 (27.2) 10 (27) 21 (26.2) 0.280

Death 10 (17.9) 22 (21.4) 4 (10.8) 9 (11.2) 0.227

Treatment success 21 (37.5) 36 (35) 15 (40.5) 40 (50) 0.211

Definition of abbreviations: SM 5 streptomycin; TB 5 tuberculosis; XDR 5 extensively drug-resistant; preXDR-TBo 5 ofloxacin-resistant non-XDR MDR-TB; preXDR-

TBs 5 second-line injectable drug-resistant non-XDR MDR-TB.

Values are n ( %).



* SM-resistant preXDR-TBo vs. SM-susceptible preXDR-TBs.

Figure 3. Kaplan-Meier survival analysis estimates of long-term survivalbased on SM-resistance in patients with preXDR-TB. Mean survivaltime was 73.4, 74.8, 67, and 82.4 months in SM-resistant preXDR-TBo, SM-susceptible preXDR-TBo, SM-resistant preXDR-TBs,and SM-susceptible preXDR-TBs patients, respectively. Patients withSM-susceptible preXDR-TBs showed more favorable long-term survivalthan did those with SM-resistant preXDR-TBo (P5 0.041), SM-sus-ceptible preXDR-TBo (P5 0.013), or SM-resistant preXDR-TBs (P50.026), respectively. Black solid line5 SM-resistant preXDR-TBo, blackdashed line 5 SM-susceptible preXDR-TBo, gray solid line 5SM-resistant preXDR-TBs, gray dashed line 5 SM-susceptible preXDR-TBs. SM 5 streptomycin; TB 5 tuberculosis; XDR 5 extensivelydrug-resistant; preXDR-TBo 5 ofloxacin-resistant non-XDR MDR-TB;

preXDR-TBs5 second-line injectable drug-resistant non-XDR MDR-TB.



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This study has several limitations inherent to retrospectivestudies, as already described (10). Because DST results foramikacin and FQNs other than OFX were not obtained, thedefinition of XDR-TB used in this study was suboptimal andthe impact of FQN cross-resistance on treatment outcomes wasnot evaluated. Long-term survival was analyzed only for all-cause mortality, not for TB-related mortality, because of therecently amended rules of the Korea National Statistical Office.In addition, the high default rate may have affected the

accuracy of treatment outcome analysis. However, despite theselimitations, the large number of patients studied and the carefulassessment of fatal outcomes facilitate accurate subset analysis.

Conclusion

We found that the revised definition of XDR-TB was optimalfor defining the subset of patients with MDR-TB with the worsttreatment outcomes and long-term survival. PreXDR-TB,irrespective of OFX- or SLID-resistance, was independentlyassociated with poor outcomes in patients with MDR-TB, andSM-resistance affected treatment outcomes of patients withpreXDR-TB.

Conflict of Interest Statement: D.H.K. does not have a financial relationship witha commercial entity that has an interest in the subject of this manuscript. H.J.K.

does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript. S-K.P. does not have a financialrelationship with a commercial entity that has an interest in the subject of thismanuscript. S-J.K. does not have a financial relationship with a commercial entitythat has an interest in the subject of this manuscript. Y.S.K. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. T-H.K. does not have a financial relationship with a commer-cial entity that has an interest in the subject of this manuscript. E.K.K. does nothave a financial relationship with a commercial entity that has an interest in thesubject of this manuscript. K.M.L. received up to $1,000 from Pfizer Korea, up to$1,000 from Bayer Korea, and up to $1,000 from LG Life Sciences in lecture fees.S-S.L. does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript. J.S.P. received up to $1,000 from PfizerKorea, up to $1,000 from Bayer Korea, and up to $1,000 from LG Life Sciences inlecture fees. W.J.K. does not have a financial relationship with a commercial entitythat has an interest in the subject of this manuscript. C-H.L. does not havea financial relationship with a commercial entity that has an interest in the subjectof this manuscript. T.S.S. received up to $1,000 from Pfizer Korea, up to $1,000

from Bayer Korea, and up to $1,000 from LG Life Sciences in lecture fees.

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