In this study, after adjusting for patient classification and other important covariates, treatment success was significantly improved among patients in the TMTC era compared to the pre-TMTC era in several different models. The better treatment results at 36 months and the long-term follow-up highlighted the effectiveness of early intervention and a patient-centered DOTS-Plus project, irrespective of patient classifications of MDR-TB cases. The TMTC, with the objectives of combating the high default rate and the emerging number of MDR-TB cases by integrating medical resources and the DOTS-Plus project 
, improved the cure rate and decreased the incidence of default.
It is possible that the subgroup analysis of the 390 patients with available DSTs for second-line drugs did not represent the 651 patients included in the original cohort. However, a comparison between those with or without a DST for second-line drugs revealed that those with DSTs were typically cases with higher severity (Table S2
). Even so, the analysis in showed the same trend for TMTC effectiveness as the result in . This further suggests that TMTC was useful for advanced MDR-TB patients.
The duration of treatment was significantly longer in the pre-TMTC era patients (). Compared to the community-based MDR-TB management program at the Indus Hospital in Karachi, Pakistan, between January 2008 and June 2010, the median time of culture conversion in Karachi was 196 days, which was longer than the 160 days in the TMTC era but shorter than the 14.3 months in the pre-TMTC era 
. Because TMTC was implemented in May 2007, some patients who failed to complete treatment before that date were re-evaluated by therapeutic teams and retreated under supervision, leading to a longer duration of treatment. However, the significantly shorter duration of treatment in the TMTC era indicates that a patient-centered treatment program has potential benefits. Nevertheless, the effectiveness of TMTC improved when we excluded 311 patients from the pre-TMTC era who had treatment results in the TMTC era (Table S3
). Compared to a study analyzing the treatment outcomes of 1027 patients with MDR-TB in Latvia between 2000 and 2004 
, the duration of treatment for those categorized as treatment failure was longer in Taiwan than in Latvia (708 days versus 348 days, respectively), which could be the result of physician-dependent judgment to define treatment failure in Taiwan. Although standardized treatment outcome measures for MDR-TB have been proposed to allow international comparisons 
, the definition of treatment failure is still debated 
. Because ineffective treatment leads to the unnecessary expenditure of medical resources, a consensus for a more sophisticated definition of MDR-TB treatment failure is mandatory.
The best strategy to prevent MDR-TB transmission is to treat MDR-TB cases to prevent chronicity. Experiences in Peru, Russia and Lesotho revealed that the six elements for the successful implementation of MDR-TB programs are as follows: the performance of baseline assessments, the early identification of key collaborators, the identification of an initial locus of care, the minimization of patient-incurred costs, targeted interventions for vulnerable populations, and the importance of technical assistance and funding 
. Countries in the Asia-Pacific area, such as South Korea and Taiwan, have well-established medical care systems and sound public health infrastructures. However, only 45.3% of treatment successes in all registered MDR-TB patients in 2000–2002 were achieved in South Korea 
, similar to the 44% in all registered MDR-TB patients in the pre-TMTC era (2000–2006) in our study. There was an even worse report from South Korea in 2011, showing that only 37.1% had a successful outcome in a 2004 cohort receiving care in three public referral pulmonary hospitals 
. No DOT was specifically mentioned, and a high default rate (reaching 37.1%) in MDR-TB patients accompanied by a high proportion of XDR-TB (15%) cases was the cause of the lower rate of successful outcomes. In Shanghai, 53.1% of MDR-TB patients (excluding XDR-TB cases) enrolled from July 2007 to June 2009 in a pulmonary hospital had a successful outcome, which was much lower than the 81% observed in the TMTC era 
. The lack of a comprehensive TB control program including socioeconomic support, an adequate follow-up system, an infection control program, careful management of comorbidities, and proper case management could have caused the low success and high default rates in this area. Fluoroquinolones and other second-line drugs used without restriction in the private sector for TB patients and those with community-acquired pneumonia, raising the concern of very limited numbers of effective anti-XDR-TB medications in both countries. With a relatively stable public health infrastructure and an easily accessible medical care system 
, the identification of vulnerable populations and the initial locus of care became feasible in Taiwan. With the technical assistance of the NTP and their strong political will, the TMTC incorporated a good-quality private-public mix model to deliver creative care to MDR-TB patients. The TMTC model could be a solution for the NTP in this area to address the poor outcomes of MDR-TB patients and the emerging XDR-TB problem before there are no effective medications to block transmission in this area.
There were many limitations to our study. The TMTC was scaled up very fast in 2007; therefore, the high TMTC coverage of MDR-TB patients prevented us from using contemporary controls. The use of historical controls rather than contemporary controls introduced a temporal bias (e.g., patients treated more recently did better because the treating personnel were more experienced) and other factors (e.g., improved adherence to MDR-TB treatment guidelines, more medications available for MDR-TB treatment) that may have affected the difference in outcomes in a manner not related to the TMTC program. The median number of sputum examinations per month was 1.5 in the TMTC era compared to 1.0 in the pre-TMTC era. Individualized regimens were provided in both groups mainly by the private sector under the NHI. However, the MDR-TB treatment provided to patients in the TMTC era was required to meet the WHO MDR-TB treatment guidelines (). The improvement of the adherence to standard regimens and the increased frequency of sputum collections during treatment were considered as achievements of the TMTC program. Therefore, we did not use these covariates adjusted in analysis due to potential co-linearity. We also evaluated the evolution of treatment success in MDR-TB patients in Taiwan in the past two decades. Only 47% of 36 MDR-TB patients achieved sustained culture conversion at TB centers in Taipei City during 1987–1989 
. The treatment success of MDR-TB patients in 1992-1996 was 51.2% at a referral center in Taipei City 
, while it was 44% in all registered MDR-TB patients in 2000–2006 in this study. Ofloxacin had been utilized for MDR-TB patients in Taiwan since 1992 
, but the regimens for MDR-TB patients were not always adequate because TB patients could receive TB care in any NHI-contracted hospital. Some effective second-line anti-TB medications were not available for all MDR-TB patients until the TMTC was created. The TMTC itself therefore represented the designed regimens, the quality of the DOT and patient-centered care as the entirety of medical care and case management. Before the TMTC was created, we can conclude that treatment success was consistently poor even with the use of ofloxacin and newer generations of fluoroquinolones. The treatment outcome for MDR-TB patients in 2007–2008 (the TMTC era) achieved 81%. This study enrolled all the MDR-TB patients reported during the study period to prevent selection bias and provided strong evidence that better outcomes were achieved in the TMTC era.
In the TMTC era, each strain of MDR-TB was required to be transferred to the Reference Laboratory of Mycobacteriology, TCDC, where MDR-TB confirmation testing was performed 
. Rapid diagnostic tools, such as molecular line-probe assays, were not used in the study period. Before 2007, DSTs of second-line drugs were performed by the clinical microbiology laboratories of the hospitals using agar proportional methods only at the request of clinicians 
. Thus, a difference in the chance of misclassification of the DST results of second-line drugs may exist between the pre-TMTC era and the TMTC era. Moreover, the systemic DST surveillance of second-line drugs in MDR-TB patients was required after 2007. Therefore, 52% of patients in the pre-TMTC era underwent DSTs for second-line drugs, while 69% of those in the TMTC era had DSTs for second-line drugs. However, this difference would not affect the better treatment outcomes in the TMTC era in the analysis of the 651 patients ( and ). We acknowledged some challenges, but we also demonstrated the feasibility of using a weighted logistic analysis to adjust for covariates and demonstrate an overall improvement in MDR-TB case management.
In conclusion, the improved treatment success achieved in the TMTC era compared to the pre-TMTC era is encouraging. The detailed components of the TMTC that contributed the most to the better outcomes require confirmation in follow-up studies with larger numbers of MDR-TB patients.