Abstract
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 patients with MDR-TB newly diagnosed or retreated in 2000 to 2002 were retrospectively analyzed based on drug-resistance patterns after 5–8 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 pre–XDR-TB (pre–XDR-TBo); and 117 (8.3%) had second-line injectable drug (SLID)–resistant pre–XDR-TB (pre–XDR-TBs). Patients with XDR-TBre showed the lowest treatment success rate (29.3%) and the poorest long-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], 2.06–4.83; P < 0.001 vs. HR, 2.15; 95% CI, 1.49–3.09; P < 0.001). Patients with either form of pre–XDR-TB showed poorer cumulative survival than those with ofloxacin-susceptible/SLID-susceptible MDR-TB (P < 0.05 for each comparison). Although streptomycin susceptibility did not affect the treatment outcomes of patients with pre–XDR-TB, streptomycin-resistant pre–XDR-TB was more strongly associated with long-term mortality than ofloxacin-susceptible/SLID-susceptible MDR-TB (HR, 2.17; 95% CI, 1.22–3.84; P < 0.008 for pre–XDR-TBo; and HR, 2.69; 95% CI, 1.40–5.16; P = 0.003 for pre–XDR-TBs).
Conclusions: The revised XDR-TB definition is appropriate for defining patients with MDR-TB with the poorest outcomes. Both pre–XDR-TBo and pre–XDR-TBs were independently associated with poor long-term survival in patients with MDR-TB. SM susceptibility was linked to better survival in patients with pre–XDR-TB.
Treatment outcomes and long-term survival with respect to the original and revised definitions of extensively drug-resistant (XDR-TB) have not been compared in previous studies, and the impact of pre–XDR-TB (multidrug-resistant tuberculosis [MDR-TB] resistant to either any fluoroquinolones or at least one second-line injectable drug, but not to both) on MDR-TB treatment outcomes has also not received attention.
Our results confirmed that the revised XDR-TB definition was adequate to define a subset of MDR-TB patients with the poorest treatment outcome and the worst long-term survival. Moreover, the presence of pre–XDR-TB was an independent prognostic factor of poor outcomes and survival in patients with MDR-TB. Streptomycin susceptibility was an important predictor of favorable long-term survival in patients with pre–XDR-TB.
A total of 1,407 Korean patients with MDR-TB were enrolled from January 2000 to December 2002; their details have been described previously (10). Medical records were retrospectively reviewed for demography, TB treatment history, comorbidities, acid-fast bacilli (AFB) cultures and drug susceptibility test (DST) results, chest radiographs, treatment modalities, and outcomes. All patients were followed-up for 5–8 years after commencement of treatment, and information on vital status as of December 2007 was obtained from the death registry of the Korea National Statistical Office; however, this registry does not provide information on cause of death. This study was approved by the Institutional Review Board of the Asan Medical Center, Seoul, South Korea, and other institutions.
AFB were examined by Ziehl-Neelsen staining, and were cultured on egg-based Ogawa medium. DSTs for isoniazid, rifampicin, ethambutol, pyrazinamide, SM, kanamycin, cycloserine, p-aminosalicylic acid, prothionamide, and ofloxacin (OFX) were performed at all participating laboratories. Enviomycin-capreomycin susceptibility was determined at the Korean Institute of Tuberculosis, the Supranational TB Reference Laboratory, Seoul, South Korea, and one private laboratory. The proportion method and the pyrazinamidase test were used for DST at the Korean Institute of Tuberculosis. Of the FQNs and second-line aminoglycosides, only OFX and kanamycin susceptibility tests, respectively, were routinely performed during the study period. Thus, DSTs of amikacin and other FQNs were not evaluated.
Four groups were defined as follows: (1) XDR-TBre (revised definition), MDR-TB with bacillary resistance to OFX and at least one of the SLIDs (kanamycin, capreomycin, or enviomycin); (2) XDR-TBor (original definition), MDR-TB with bacillary resistance to at least three of the six main classes of second-line drugs (2); (3) XDR-TB(or-re), XDR-TBor excluding XDR-TBre; and (4) pre–XDR-TB, MDR-TB resistant to either OFX (pre–XDR-TBo) or at least one SLID (pre–XDR-TBs), but not to both drugs.
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, including 12 months after culture conversion. Short-term treatment completion was defined as follows: (1) inadequate treatment duration, but more than 6 months; (2) three consecutive negative cultures before treatment completion; and (3) treatment completion assessed by a physician based on favorable response. Treatment success was defined as the sum of cure, treatment completion, and short-term treatment completion. All outcomes were the initial treatment outcomes during the study period, and were analyzed based on AFB culture results.
Chi-square and one-way analysis of variance tests were used in univariate analyses. Bonferroni correction was used if multiple comparisons were performed, and all P values evaluated in chi-square tests were Bonferroni-corrected. Cumulative survival was estimated by the Kaplan-Meier method and compared by the log-rank test. Cox regression was used to define the predictors of long-term survival by multivariate analysis using the backward elimination procedure. SPSS software, version 13.0 (SPSS Inc., Chicago, IL), was used for all analyses, with P < 0.05 indicating significance.
Of 1,407 patients with MDR-TB, 75 (5.3%) were diagnosed with XDR-TBre; 159 (11.3%) with pre–XDR-TBo; 117 (8.3%) with pre–XDR-TBs; and 1,056 (75.1%) with the other form of MDR-TB (susceptible to both OFX and SLID). The mean age of the study patients was 42.9 years (range, 13–89 years); the male to female ratio was 2.8:1; and the mean body mass index was 19.2 kg/m2 (range, 12–32 kg/m2). HIV-ELISA tests were conducted on 66 (4.7%) patients, with only one found to be seropositive. Patient demographic characteristics are shown in Table 1.
XDR-TBre | Pre–XDR-TBo | Pre–XDR-TBs | Other MDR-TB | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Characteristics | (n = 75) | (n = 159) | (n = 117) | (n = 1,056) | (n = 1,407) | |||||
| Mean age, y ± SD (range)*† | 47.8 ± 15.5 (16–80) | 44.8 ± 14.4 (17–79) | 41.7 ± 16 (13–80) | 42.4 ± 14.7 (13–89) | 42.9 ± 14.9 (13–89) | |||||
| Male sex‡ | 53 (70.7) | 112 (70.4) | 75 (64.1) | 799 (75.7) | 1,039 (73.8) | |||||
| Mean BMI ± SD (range) | 18.5 ± 2.7 (13.2–23.7) | 19.1 ± 3.3 (12.7–27) | 18.7 ± 3 (13.9–25.2) | 19.4 ± 3.3 (12–32) | 19.2 ± 3.2 (12–32) | |||||
| Previous history of TB treatment (n = 1,359) | (n = 73) | (n = 150) | (n = 114) | (n = 1,022) | (n = 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 only†§ | 33 (45.2) | 62 (41.3) | 65 (57) | 631 (61.7) | 791 (58.2) | |||||
| History of TB treatment with second-line drugs*†§‖ | 26 (35.6) | 48 (32) | 20 (17.5) | 89 (8.7) | 183 (13.5) | |||||
| No. of previous TB treatment: ≥2 times (n = 1,335)*†‡§ | 31/65 (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 = 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 = 1,251)** | (n = 67) | (n = 143) | (n = 107) | (n = 934) | (n = 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 advanced†§ | 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 = 1,190) | 51/67 (76.1) | 103/130 (79.2) | 71/104 (68.3) | 655/889 (73.7) | 880/1,190 (73.9) | |||||
A previous history of treatment with second-line TB drugs was more common in patients with XDR-TBre (35.6%) and pre–XDR-TBo (32%) than in those with pre–XDR-TBs (17.5%) or the other form of MDR-TB (8.8%) (P < 0.05 for each comparison), and a history of at least two previous TB treatments was more common in patients with XDR-TBre (47.7%), pre–XDR-TBo (38.4%), and pre–XDR-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 was higher in patients with XDR-TBre and pre–XDR-TBo than in the other patients with MDR-TB (50.7%, 45.5%, and 29%, respectively; P < 0.05 for each comparison).
The overall treatment success rate of the 1,407 study participants was 45.3% (cure 30.2%, treatment completion 6.6%, and short-term treatment completion 8.5%). Treatment success rates for patients with XDR-TBre (n = 75), XDR-TBor (n = 149, including 65 patients with XDR-TBre), and XDR-TB(or-re) (n = 84) were 29.3, 38.9, and 44%, respectively, and these rates did not significantly differ among groups (P > 0.05 for each comparison). However, the success rate of the group with XDR-TBre was significantly higher than that of those with non-XDR MDR-TB (n = 1,248; success rate 46.3%) (P = 0.025) (Table 2).
XDR-TBre | XDR-TBor | XDR-TB(or-re) | Non-XDR MDR-TB | ||
|---|---|---|---|---|---|
| Treatment outcomes | (n = 75) | (n = 149) | (n = 84) | (n = 1,248) | P Value |
| Cure*† | 9 (12) | 31 (20.8) | 22 (26.2) | 394 (31.6) | <0.001 |
| Treatment 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 |
Mean survival times were 61.7, 68, and 72.2 months in patients with XDR-TBre, XDR-TBor, and XDR-TB(or-re), respectively, and were thus lower than that (89.2 months) in patients with non-XDR MDR-TB (P < 0.001 for each comparison) (Figure 1). Among the three groups with XDR-TB, presence of XDR-TBre was the strongest predictor of poor long-term survival in multivariate analyses. Compared with the presence of non-XDR MDR-TB, the hazard ratio (HR) was 3.15 (95% confidence interval [CI], 2.06–4.83; P < 0.001) in patients with XDR-TBre; 2.15 (95% CI, 1.49–3.09; P < 0.001) in those with XDR-TBor; and 1.38 (95% CI, 0.80–2.39; P = 0.252) in patients with XDR-TB(or-re), respectively (Table 3).
Figure 1. Kaplan-Meier survival analysis estimates of long-term survival based 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 groups showed poorer long-term survival than did the non-XDR MDR-TB group (P < 0.05 for each comparison), but there was no significant difference among the three XDR-TB groups (XDR-TBre vs. XDR-TBor, P = 0.240; XDR-TBre vs. XDR-TB(or-re), P = 0.066; XDR-TBor vs. XDR-TB(or-re), P = 0.347). Black solid line = XDR-TBre, black dashed line = XDR-TBor, gray dashed line = XDR-TB(or-re), gray solid line = non-XDR MDR-TB. MDR = multidrug-resistant; TB = tuberculosis; XDR = extensively drug-resistant; XDR-TBre = revised definition of XDR-TB; XDR-TBor = original definition of XDR-TB; XDR-TB(or-re) = XDR-TBor excluding XDR-TBre.
[More] [Minimize]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 (2.01–2.99) | <0.001 | 2.49 (1.89–3.28) | <0.001 | |||||
| Male sex | 362/1,139 (31.8) | 1.36 (1.09–1.69) | 0.006 | |||||||
| BMI <18.5 kg/m2 | 115/224 (51.3) | 2.46 (1.99–3.04) | <0.001 | 2.08 (1.49–2.91) | <0.001 | |||||
| Previous TB treatment with second-line drugs | 113/231 (57.6) | 2.65 (2.10–3.35) | <0.001 | 2.29 (1.68–3.11) | <0.001 | |||||
| or more previous TB treatments | 182/424 (42.9%) | 2.03 (1.68–2.46) | <0.001 | · | · | |||||
| Far advanced disease | 250/479 (52.2) | 3.33 (2.75–4.04) | <0.001 | 1.98 (1.52–2.58) | <0.001 | |||||
| Hb <10 g/dl | 48/84 (57.1) | 3.11 (2.29–4.21) | <0.001 | 1.58 (1.04–2.41) | 0.032 | |||||
| Positive AFB smear at treatment initiation | 338/1,060 (31.9) | 1.29 (1.05–1.58) | 0.015 | · | · | |||||
| Mean No. of TB drugs used before ± SD | 3.75 ± 2.90 (0–4) | 1.12 (1.08–1.17) | <0.001 | · | · | |||||
| Mean No. of potentially effective TB drugs ± SD | 3.00 ± 1.75 (2–4) | 0.82 (0.78–0.87) | <0.001 | · | · | |||||
| Surgical treatment | 9/76 (11.8) | 0.35 (0.18–0.67) | 0.002 | 0.43 (0.17–1.05) | 0.062 | |||||
| Definitions of XDR-TB | ||||||||||
| XDR-TBre | 43/75 (57.3) | 2.87 (2.08–3.94) | <0.001 | 3.15 (2.06–4.83) | <0.001 | |||||
| XDR-TBor | 72/149 (48.3) | 2.29 (1.77–2.95) | <0.001 | 2.15 (1.49–3.09) | <0.001 | |||||
| XDR-TB(or-re) | 35/84 (41.7) | 1.89 (1.33–2.68) | <0.001 | · | · | |||||
| Non-XDR MDR-TB | 315/1,248 (25.2) | 1 | · | · | · | |||||
Treatment success rates were 29.3, 35.8, 47, and 47.6% in the groups with XDR-TBre, pre–XDR-TBo, pre–XDR-TBs, and the other form of MDR-TB (non-XDR and non–pre-XDR), respectively, and success rates in patients with XDR-TBre and pre–XDR-TBo were significantly lower than in patients with the other form of MDR-TB (P < 0.001 and P = 0.018, respectively) (Table 4).
XDR-TBre | Pre–XDR-TBo | Pre–XDR-TBs | Other MDR-TB | Total | ||
|---|---|---|---|---|---|---|
| Treatment Outcomes | (n = 75) | (n = 159) | (n = 117) | (n = 1,056) | (n = 1,407) | P Value |
| 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 |
With respect to long-term survival, patients with XDR-TBre (61.7 months) showed the worst survival compared with patients with pre–XDR-TBo (75.7 months), patients with pre–XDR-TBs (78.3 months), and patients with the other form of MDR-TB (91.1 months) (P < 0.001, P = 0.032, and P < 0.001, respectively). Although the survival of patients with pre–XDR-TBo seemed to be worse than that of those with pre–XDR-TBs, the difference was not significant (P = 0.062) (Figure 2). In multivariate analyses, the presence of any of XDR-TBre, pre–XDR-TBo, or pre–XDR-TBs was also a significant predictor of poor long-term survival. Compared with the survival of patients with the other form of MDR-TB, HR values were 3.76 (95% CI, 2.43–5.83; P < 0.001), 1.62 (95% CI, 1.09–2.40; P = 0.018), and 1.57 (95% CI, 1.01–2.44; P = 0.048), respectively.
Figure 2. Kaplan-Meier survival analysis estimates of long-term survival based on the resistance to either ofloxacin or at least one of second-line injectable drugs. Mean survival time was 61.7, 75.7, 78.3, and 91.1 months in patients with XDR-TBre, pre–XDR-TBo, pre–XDR-TBs, and the other form of MDR-TB, respectively. Patients with XDR-TBre showed the worst long-term survival (XDR-TBre vs. pre–XDR-TBo, P = 0.032; XDR-TBre vs. pre–XDR-TBs, P < 0.001; XDR-TBre vs. other MDR-TB, P < 0.001). Long-term survival of patients with pre–XDR-TBo and pre–XDR-TBs did not differ (P = 0.062), but was poorer than that of those with the other form of MDR-TB (pre–XDR-TBo vs. other MDR-TB, P < 0.001; pre–XDR-TBs vs. other MDR-TB, P = 0.041). Black solid line = XDR-TBre, black dashed line = pre–XDR-TBo, gray dashed line = pre–XDR-TBs, gray solid line = other MDR-TB. MDR = multidrug-resistant; TB = tuberculosis; XDR = extensively drug-resistant; XDR-TBre = revised definition of XDR-TB; XDR-TBor = original definition of XDR-TB; XDR-TB(or-re) = XDR-TBor excluding XDR-TBre.
[More] [Minimize]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-resistant disease (7/27; 25.9%) (P = 0.627). When treatment outcome categories were compared among the four subgroups with pre–XDR-TB, the treatment failure rate was significantly lower in patients with SM-susceptible pre–XDR-TBs (4/80; 5%) than in those with SM-resistant pre–XDR-TBo (13/56; 23.2%) (P = 0.009) (Table 5). However, cumulative survival was significantly higher in the group with SM-susceptible pre–XDR-TBs than in the other three groups with pre–XDR-TB by univariate analysis (P < 0.05 for each comparison) (Figure 3), and SM-resistance was associated with relatively poor long-term survival in patients with pre–XDR-TB irrespective of OFX- or SLID-resistance status by multivariate analyses. Compared with patients with the other form of MDR-TB (those with non-XDR and non–pre-XDR disease), the HR was 1.22 (95% CI, 0.69–2.17; P = 0.497) in patients with SM-susceptible pre–XDR-TBs, 1.43 (95% CI, 0.87–2.35; P = 0.158) in those with SM-susceptible pre–XDR-TBo, 2.17 (95% CI, 1.22–3.84; P = 0.008) in patients with SM-resistant pre–XDR-TBo, and 2.69 (95% CI, 1.40–5.16; P = 0.003) in those with SM-resistant pre–XDR-TBs (see Table 5E in the online supplement).
Figure 3. Kaplan-Meier survival analysis estimates of long-term survival based on SM-resistance in patients with pre–XDR-TB. Mean survival time was 73.4, 74.8, 67, and 82.4 months in SM-resistant pre–XDR-TBo, SM-susceptible pre–XDR-TBo, SM-resistant pre–XDR-TBs, and SM-susceptible pre–XDR-TBs patients, respectively. Patients with SM-susceptible pre–XDR-TBs showed more favorable long-term survival than did those with SM-resistant pre–XDR-TBo (P = 0.041), SM-susceptible pre–XDR-TBo (P = 0.013), or SM-resistant pre–XDR-TBs (P = 0.026), respectively. Black solid line = SM-resistant pre–XDR-TBo, black dashed line = SM-susceptible pre–XDR-TBo, gray solid line = SM-resistant pre–XDR-TBs, gray dashed line = SM-susceptible pre–XDR-TBs. SM = streptomycin; TB = tuberculosis; XDR = extensively drug-resistant; pre–XDR-TBo = ofloxacin-resistant non-XDR MDR-TB; pre–XDR-TBs = second-line injectable drug-resistant non-XDR MDR-TB.
[More] [Minimize]Pre–XDR-TBo | Pre–XDR-TBs | ||||||
|---|---|---|---|---|---|---|---|
| SM-Resistant | SM-Susceptible | SM-Resistant | SM-Susceptible | ||||
| Treatment Outcomes | (n = 56) | (n = 103) | (n = 37) | (n = 80) | P Value | ||
| 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) | 0.678 | ||
| Default | 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 | ||
The effects of drug-resistance on MDR-TB treatment outcomes have varied in previous studies (4–9, 18), and it is often difficult to compare data because of relatively small patient numbers in previous studies. Moreover, no study has compared treatment outcomes among patients classified using both the revised and original definitions of XDR-TB. In the present work, both long-term survival after 5 to 8 years of follow-up and initial treatment outcomes were analyzed using the second-largest MDR-TB cohort ever studied, exceeded only by the 1,989 patients with MDR-TB examined in Peru (19). Outcomes were compared with respect to both the original and revised definitions of XDR-TB to investigate the appropriateness of the two classifications, and were also analyzed among groups of patients with XDR-TBre, pre–XDR-TBo, pre–XDR-TBs, and the other form (OFX-susceptible/SLID-susceptible) of MDR-TB to determine the impact of pre–XDR-TB status on outcomes in patients with MDR-TB. In addition, results were separately examined with respect to SM susceptibility to determine the impact of SM status on outcomes of patients with XDR-TBre and pre–XDR-TB. Our results confirmed that the revised XDR-TB definition was optimal to define a subset of patients with MDR-TB with the poorest treatment outcome and the worst long-term survival. Moreover, the results showed that the definition of pre–XDR-TB was an independent prognostic factor of poor outcomes and survival in patients with MDR-TB and also showed that SM susceptibility was an important predictor of favorable long-term survival in patients with pre–XDR-TB.
In previous studies, the presence of XDR-TB was found to be the most serious obstacle to successful treatment of MDR-TB (4, 10–13, 15). In the present work, 57.3% (43/75) of patients with XDR-TBre eventually died during follow-up, and this group had the poorest long-term survival rate. Since publication of the revised definition of XDR-TB (3), no report has compared treatment outcomes and long-term survival relative to the new 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 particularly poor prognosis. Although treatment success rates and survival of 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 with XDR-TB(or-re) (29.3 vs. 44%; P = 0.331), and the success rate of patients with XDR-TB(or-re) was about the same as the 46.3% success rate of those with non-XDR MDR-TB. These findings indicate that XDR-TBor includes a subgroup of patients with a relatively favorable prognosis (XDR-TB(or-re)). In addition, patients with XDR-TBre showed the worst cumulative survival by Kaplan-Meier analysis, and compared with patients with non-XDR MDR-TB, the HR for all-cause mortality of those with XDR-TBre was higher than that of patients with XDR-TB(or-re) (3.15 vs. 1.38, respectively). Thus, the revised definition of XDR-TB seems to be more appropriate than the original definition in identifying the subgroup with MDR-TB with the worst prognosis.
Various drug-resistance patterns, such as resistance to FQNs (5, 6), kanamycin (7), capreomycin (8), SM (9), and additional first-line drugs (4), have been previously analyzed to identify factors predictive of unsuccessful MDR-TB treatment. We found that treatment success rate and long-term survival did not differ between patients with pre–XDR-TBo and pre–XDR-TBs, and that the long-term survival of both groups with pre–XDR-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 pre–XDR-TBo and pre–XDR-TBs showed that such disease status was independently important in determining poor long-term survival in patients with MDR-TB. Thus, the current definition of pre–XDR-TB also seems to be appropriate for defining an “intermediate risk group” lying between XDR-TBre and OFX-susceptible/SLID-susceptible patients with MDR-TB in terms of disease severity.
Although SM is a first-line injectable anti-TB drug with a mechanism of action similar to that of other SLIDs, SM-resistance has not been included in the current definition of XDR-TB or pre–XDR-TB (3), and few studies have investigated the impact of SM susceptibility on the outcomes of patients with XDR-TB and pre–XDR-TB. Although one study found that SM-resistance was associated with adverse treatment outcomes in HIV-negative patients with XDR-TB (9), another study showed that patients with MDR-TB, resistant to both FQN and SM but susceptible to all three SLIDs, had better treatment outcomes than did patients with XDR-TB (18). In the present study, neither treatment outcomes nor long-term survival was affected by SM susceptibility within the group with XDR-TBre. However, when that group was compared with patients with pre–XDR-TB, SM susceptibility was an important predictor of favorable long-term survival, irrespective of the presence of either OFX- (pre–XDR-TBo) or SLID-resistance (pre–XDR-TBs). Collectively, these findings indicate that SM-resistance does not need to be included in the current definition of XDR-TB and SM use may be helpful to improve treatment outcomes in patients with pre–XDR-TB. Considering the importance of SM susceptibility in MDR-TB treatment, judicious use of SM seems to be prerequisite in improving treatment outcomes in patients with MDR-TB. In accordance with this finding, recently revised WHO guidelines restricted the Category II regimen (inclusion of SM) only for recurrent patients with TB at medium to low likelihood of MDR-TB, because the Category II regimen has a possibility to amplify drug-resistance including SM-resistance in patients with high risk of MDR-TB (21).
This study has several limitations inherent to retrospective studies, as already described (10). Because DST results for amikacin and FQNs other than OFX were not obtained, the definition of XDR-TB used in this study was suboptimal and the impact of FQN cross-resistance on treatment outcomes was not evaluated. Long-term survival was analyzed only for all-cause mortality, not for TB-related mortality, because of the recently 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 these limitations, the large number of patients studied and the careful assessment of fatal outcomes facilitate accurate subset analysis.
We found that the revised definition of XDR-TB was optimal for defining the subset of patients with MDR-TB with the worst treatment outcomes and long-term survival. Pre–XDR-TB, irrespective of OFX- or SLID-resistance, was independently associated with poor outcomes in patients with MDR-TB, and SM-resistance affected treatment outcomes of patients with pre–XDR-TB.
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