Characteristics of MDR/RR-TB patients
2,395 electronic records and 1,913 paper-based records were available and 2,266 MDR/RR-TB cases were included (Figure 1). Of these patient diagnosed between 2011-2015, eight patients relapsed, 13 were re-treated after loss to follow-up, and two were re-treated after treatment failure. Baseline characteristics are presented in table 1. Median age among the 2,266 cases was 43 years (IQR: 33-53 years) and did not change between 2011-2015 (p = 0.481). A total of 204 patients (9.6% of tested patients) were HIV co-infected; of these, 33 (16.1%) were registered as new TB patients and 21 (10.3%) had extra-pulmonary MDR-TB, including 10 (4.9%) patients with MDR-TB meningitis. MDR-TB meningitis was more common than in patients without HIV co-infection (p<0.001). Eighty four of 204 HIV co-infected patients (41.2%) were established on antiretroviral therapy (ART) before starting MDR-TB treatment. The remaining HIV co-infected patients (58.8%) started ART at least two weeks after starting MDR-TB treatment. Among 1,815 cases for whom BMI data were available, 57.8% was classified as underweight and 25.1% severely underweight. Median BMI did not change over 5 years (p = 0.966). DM status was available for 1,189 patients (52.5%), 359 of whom (30.2%) had DM. Median BMI among patients with DM (20.0 kg/m2) was higher than among patients without DM (17.8 kg/m2) (p<0.001) and HIV co-infection in patients with DM (0.9%) was lower than among patients without DM (9.8%) (p<0.001).
Drug resistance pattern
Table 2 outlines the observed drug resistance patterns. DST results were retrieved for 502 isolates from 490 patients. Ten patients had results for two isolates at different time points, and one patient had results for three isolates. Among the 490 patients with a DST result, 55.0% and 63.1% had resistance to pyrazinamide and ethambutol, respectively. Resistance to fluoroquinolones and injectable agents was seen in 12.7% and 8.1% of isolates, respectively. Among 378 patients with DST to second-line drugs, 63 (16.7%) had pre extensively drug-resistant (XDR) TB and 8 (2.1%) had XDR-TB.
Figure 2 shows an increasing temporal trend from 2011 to 2015 for both the absolute number of cases diagnosed and the notification rate per 100,000 population. Numbers of notified MDR/RR-TB patients decreased by 9% between 2011-2012, and increased an average of 15.9% annually from 2012 to 2015. The number of MDR-TB cases and the notification rate increased 41.0% and 24.7% from 2011-2015, respectively.
Table 3 summarizes the treatment outcomes of 2,240 MDR-TB patients whose treatment outcomes were retrievable. Successful outcomes were achieved in 1,641 (73.3%) patients, including 55.6% who were cured and 17.7% who completed treatment but for whom data on cure were unavailable. Among those with unsuccessful outcomes, 10.1% died, 5% failed treatment and 11.6% were lost to follow-up. Patient characteristics by treatment outcome are further described in the supplementary material (Table C). 49/204 patients with HIV died (23.0%), 8 (3.9%) failed treatment and 42 (20.5%) were lost to follow-up. Ten of 21 (47.6%) patients with TB meningitis had successful outcomes, nine (42.6%) died and two (9.5%) were lost to follow-up. Among the 64 patients with pre-XDR-TB, 53.1% had a successful outcome, 14.1% died, 23.4% failed treatment and 7.8% were lost to follow-up. Of 8 XDR-TB patients, 1 (12.5%) was cured with a bedaquiline-containing regimen, 2 (25%) died, including 1 who received a bedaquiline-containing regimen, and 5 (62.5%) failed.
Of 259 patients lost to follow-up, median treatment duration was 200 days (IQR: 60-340) with 56% lost during intensive phase. 17.3% had HIV co-infection, 32% had a positive AFB smear and 35.9% had a positive culture prior to being lost to follow-up.
Risk factors for poor outcomes
We evaluated the association between poor treatment outcome and HIV co-infection, history of previous MDR-TB treatment, AFB smear grade and BMI. Male gender, age and DM status were included as in the multivariate logistic regression model as potential risk factors. Further analysis failed to show the interaction between HIV co- infection and other risk factors (age, gender, AFB smear grade, BMI, DM status and history of previous MDR-TB treatment) (p=0.93). Since MDR-TB patients received standardized treatment in 24 different DTUs, we did not include treatment site covariate in our final logistic regression model.
There were only small differences in the results between complete case and multiple imputation analysis (Table 4). Therefore, we presented the Forrest plot of results from the imputed data analysis (Figure 3).
Independent risk factors for poor outcomes were older age (OR for every increase of 5 years when patients are older than 60: 1.45, 95% CI: 1.14-1.79, p<0.001), HIV co-infection (OR: 2.94, 95% CI: 2.07-4.16, p<0.001), a history of MDR-TB treatment (OR: 5.53, 95% CI: 2.85-10.72, p<0.001), AFB positive (OR: 1.47 for low smear grade (1+ and <1+), 95%CI: 1.08-2.00, p=0.01 and OR: 2.06 for high smear grade (2+ and 3+), 95%CI: 1.49-2.87, p<0.001), and low BMI (OR: 0.83 for every increase of 1kg/m2 for patients with BMI<21, 95%CI: 0.79-0.87, p<0.001) (Figure 3).