Multidrug-resistant tuberculosis (MDRTB), defined as TB resistant to at least isoniazid and rifampin, represents an obstacle to TB control, especially in areas where MDRTB prevalence is high ( 1 ). New World Health Organization (WHO) estimates suggest that 424,203 MDRTB cases occurred in 2004 (95% confidence interval 376,019–620,061), or 4.3% of all new and previously treated TB cases. More than half of the estimated MDRTB cases were in China and India, while the highest estimated prevalences were in countries of the former Soviet Union and certain provinces of China ( 2 ). DOTS is the internationally recommended strategy for TB control and is based on a 6-month treatment regimen with first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) for new patients and an 8-month treatment regimen with isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin for re-treatment patients ( 3 ). While DOTS prevents the emergence of drug resistance in drug-susceptible cases, in patients with MDRTB, this treatment yields inadequate cure rates ( 4 – 7 ). A retrospective cohort study of treatment of MDRTB with this regimen in 6 countries showed treatment success rates of 52% (range 11%–60%) in new cases and 29% (range 18%–36%) in previously treated cases ( 5 ). In addition, the frequency of TB recurrence among MDRTB patients previously considered to be cured after this treatment has been reported at 28% ( 6 ). Treating MDRTB with second-line drugs may cure >65% of patients and stop ongoing transmission ( 8 – 10 ). However, most of the evidence of successful MDRTB management is generated from high-income countries where treatment is provided in referral hospitals ( 10 ). In 1999, WHO and partner agencies launched DOTS-Plus to manage MDRTB in resource-limited settings, a term that was recently abolished since it was used for the piloting of the management of MDRTB within the context of DOTS programs. Effective MDRTB control builds on the 5 tenets of the DOTS strategy ( 3 ) and expands each of these areas to address the complexities associated with treating MDRTB ( 11 ). As part of this strategy, a novel partnership known as the Green Light Committee (GLC) was created to foster access to, and rational use of, second-line drugs ( 11 – 13 ). The second-line drugs included in the WHO Model List of Essential Medicines are amikacin, capreomycin, ciprofloxacin, cycloserine, ethionamide, kanamycin, levofloxacin, ofloxacin, p-aminosalicylic acid, and prothionamide ( 11 ). GLC reviews applications from projects that wish to integrate MDRTB management into a DOTS-based TB control program. If the applicant proposes a strategy consistent with international recommendations and agrees to the monitoring procedures of GLC, then access to reduced-price, quality-assured second-line drugs is granted. Some of the requirements for GLC endorsement include a well-functioning DOTS program, long-term political commitment, rational case-finding strategies, diagnosis of MDRTB through quality-assured culture and drug susceptibility testing (DST), treatment strategies that use second-line drugs under proper management conditions, uninterrupted supply of quality-assured second-line drugs, and a recording and reporting system designed for MDRTB control programs that enables monitoring and evaluation of program performance and treatment outcome ( 11 , 13 , 14 ). These conditions represent the MDRTB control framework. Projects must be tailored to site-specific epidemiologic and programmatic conditions within this framework. As a result, MDRTB control programs may differ substantially between settings ( 11 ). Some aspects in which MDRTB control programs may vary include whether all TB patients are tested with culture and DST or only patients with an increased risk for MDRTB, use of standardized or individualized second-line treatment regimen, and hospitalization of MDRTB patients or provision of treatment on an ambulatory basis. This analysis of the first 5 GLC-endorsed MDRTB control programs provides, for the first time, results on management of MDRTB under DOTS-based program conditions in multiple resource-limited countries by using standardized treatment outcome definitions. Methods This is a study of MDRTB patients enrolled in Estonia, Latvia, Lima (Peru), Manila (the Philippines), and Tomsk Oblast (Russian Federation). The data were collected prospectively. The enrollment period started in 1999 for Lima and Manila, 2000 for Latvia and Tomsk, and 2001 for Estonia and ended December 31, 2001. All patients evaluated were managed under GLC-approved protocols and had the opportunity to receive >24 months of treatment. In addition, follow-up data on successfully treated patients were collected at the beginning of 2006, two years after the last patient's treatment ended (December 31, 2003). A new MDRTB patient was defined as a patient who had never received TB treatment or who had received TB treatment for 1 month with only first-line anti-TB drugs. An MDRTB patient previously treated with second-line drugs was defined as an MDRTB patient who had been treated for >1 month with >1 second-line anti-TB drug (with or without first-line drugs). Six standard and mutually exclusive categories were used to define treatment outcome: cure, treatment completed, death, default, failure, and transfer out ( 14 ) (Table 1). The treatment success percentage was obtained by adding the percentage of cured patients to the percentage of patients who completed treatment. Table 1 Treatment outcome definitions for multidrug-resistant tuberculosis (MDRTB) patients ( 14 ) Category Definition Cure Completed treatment according to country protocol and been consistently culture-negative (>5 results) for final 12 mo of treatment. If only 1 positive culture is reported during that time with no concomitant clinical evidence of deterioration, patient may still be considered cured, provided that positive culture is followed by >3 consecutive negative cultures taken >30 d apart. Treatment completed Completed treatment according to country protocol but does not meet definition for cure or treatment failure because of lack of bacteriologic results (i.e., 2 consecutive months for any reason. Treatment failure >2 of 5 cultures recorded in the final 12 mo are positive or if any of the final 3 cultures is positive. Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early due to poor response or adverse events. Transfer out Transferred to another reporting and recording unit and the treatment outcome is unknown. Outcome data were recorded by the individual projects in centralized electronic registers. International standards for core data collection in MDRTB control programs were developed in 2000 ( 11 ). Projects developed their own standardized forms and electronic databases that included all of the core data elements. Aggregated program and patient data were collected from each project with a data collection form developed by GLC. The accuracy of laboratory methods was verified though regular quality assurance exercises performed by a network of WHO/International Union Against Tuberculosis and Lung Disease supranational TB reference laboratories, as previously described ( 1 ). For each project, data submitted to WHO were checked for completeness and consistency; all errors or discrepancies were corrected in consultation with the project's investigators. Statistical tests were performed with the Fisher exact test for 2×2 comparisons and the χ2 test for the other tables. For all statistical tests, we regarded a p value 4 drugs, and most patients received >4 drugs initially. All regimens included an injectable agent (amikacin, capreomycin, kanamycin, or streptomycin) and a fluoroquinolone (ciprofloxacin, levofloxacin, or ofloxacin). Nearly all drugs were administered for the duration of treatment except for the injectable agent, which was given for a specified interval after the patient's specimens were culture negative. Treatment duration was 18–24 months, and the exact length was usually determined individually for each patient. The frequency of drugs used in the regimens is shown in Table 3. The median duration of patient follow-up after a patient's having been declared cured or treatment completed was 24 months (range 12 months [Lima and Tomsk] to 36 months [Estonia]). Table 3 Frequency of drugs used in multidrug-resistant tuberculosis control program treatment regimens Drug Estonia, n (%) Latvia, n (%) Lima, n (%) Manila, n (%) Tomsk, n (%) Total, n (%) Ethambutol 44 (95.7) 117 (47.8) 102 (20.1) 43 (41.0) 28 (19.6) 334 (31.9) Pyrazinamide 1 (2.2) 99 (40.4) 146 (28.7) 88 (83.8) 84 (58.7) 418 (39.9) Streptomycin 1 (2.2) 9 (3.7) 104 (20.5) 51 (48.6) 0 165 (15.8) Capreomycin 11 (23.9) 115 (46.9) 199 (39.2) 23 (21.9) 94 (65.7) 442 (42.2) Cycloserine 45 (97.8) 189 (77.1) 316 (62.2) 100 (95.2) 142 (99.3) 792 (75.6) Ciprofloxacin 0 0 257 (50.6) 18 (17.1) 0 275 (26.3) Clofazimine 0 0 13 (2.6) 0 0 13 (1.2) Kanamycin 7 (15.2) 129 (52.7) 167 (32.9) 91 (86.7) 47 (32.9) 441 (42.1) Levofloxacin 1 (2.2) 0 0 30 (28.6) 0 31 (3.0) Ofloxacin 35 (76.1) 242 (98.8) 44 (8.7) 87 (82.9) 142 (99.3) 550 (52.5) p-Aminosalicylic acid 26 (56.5) 71 (29.0) 323 (63.6) 98 (93.3) 118 (82.5) 636 (60.7) Prothionamide or ethionamide 38 (82.6) 154 (62.9) 244 (48.0) 104 (99.0) 94 (65.7) 634 (60.6) Augmentin 4 (8.7) 7 (2.9) 325 (64.0) 0 2 (1.4) 338 (32.3) Clarithromycin 4 (8.7) 1 (0.4) 67 (13.2) 46 (43.8) 3 (2.1) 121 (11.6) Sparfloxacin 0 0 0 14 (13.3) 0 14 (1.3) Thiacetazone 0 164 (66.9) 0 0 0 164 (15.7) Drugs were administered under direct observation. In Lima, Tomsk, and Manila, drugs were administered 6 days per week; in Estonia and Latvia, drugs were given 7 days during the hospital phase and then 5 or 6 days a week after discharge. Monitoring of treatment regimens was based on the results of monthly sputum smear and culture. Chest radiographs were also performed every 3 months in Estonia, Latvia, and Tomsk and every 6 months in Lima and Manila. All projects except that in Manila had access to adjunctive surgery for major interventions such as lung resection. Each project provided patients with ancillary drugs to manage adverse events. MDRTB program cohort characteristics are shown in Table 4. Among 1,047 MDRTB patients, 119 (11%) were new, and 928 (89%) were previously treated. Among the 919 previously treated patients from whom details could be obtained, 438 (48%) had received only first-line drugs and 481 (52%) first and second-line drugs. Few patients' isolates were resistant to only rifampin and isoniazid (2.6%); most (65%) were resistant to first- and second-line drugs. HIV coinfection was identified in 0% (Estonia and Tomsk) and 4.5% (Latvia) of patients. (In Lima and Tomsk, all MDRTB patients were tested for HIV; in Estonia and Latvia, 67% and 90% of MDRTB patients were tested; and in Manila HIV testing was not performed.) Frequency of hospitalization varied from 5.0% (Manila) to 100% (Latvia), and duration of hospitalization ranged from 29 days (Manila) to 267 days (Tomsk). Table 4 Multidrug-resistant tuberculosis control program cohort characteristics* Characteristic Estonia, n (%) Latvia, n (%) Lima, n (%) Manila, n (%) Tomsk, n (%) Total, n (%) Total no. cases 46 (100.0) 245 (100.0) 508 (100.0) 105 (100.0) 143 (100.0) 1,047 (100.0) New cases 22 (47.8) 91 (37.1) 1 (0.2) 5 (4.8) 0 119 (11.4) Previously treated cases 24 (52.2) 154 (62.9) 507 (99.8) 100 (95.2) 143 (100.0) 928 (88.6) Cases previously treated with first-line drugs 19 (79.2) 132 (85.7) 125 (25.0)† 53 (54.6)† 109 (76.2) 438 (47.7) Cases previously treated with first- and second-line drugs 5 (20.8) 22 (14.3) 376 (75.0)† 44 (45.4)† 34 (23.8) 481 (52.3) Resistance to only H and R 0 7 (2.9) 11 (2.2) 9 (8.6) 0 27 (2.6) Resistance to only H, R, and other first-line drugs 0 78 (31.8) 182 (35.8) 26 (24.8) 55 (38.5) 341 (32.6) Resistance to first- and second-line drugs 46 (100.0) 160 (65.3) 315 (62.0) 70 (66.7) 88 (61.5) 679 (64.9) Treatment cessation because of adverse events 3 (6.5) 5 (2.0) NA 9 (8.6) 0 17 (3.2) HIV coinfection 0 11 (4.5) 5 (1.0) NA 0 16 (1.7) Surgery performed 1 (2.2) 18 (7.3) 78 (15.4) 0 17 (11.9) 114 (10.9) No. patients hospitalized 41 (89.1) 245 (100.0) NA 5 (5.0) 71 (49.7) 362 (67.2) Average no. drugs in treatment regimen 5.4 5.5 NA 6.28 5.3 *H, isoniazid; R, rifampin; NA, not applicable.
†Information is lacking from 6 patients (Lima) and 3 patients (Manila) on previous treatment with first-line drugs only or with first- and second-line drugs. The treatment outcomes of new, previously treated, and all MDRTB patients are shown in Table 5 and Figure 1. Treatment was successful in 70% of 1,047 patients (range 59%–83%). Failure occurred in 3.3% to 11% of patients, default in 6.3% to 16%, and death in 3.7% to 19%. In Estonia and Latvia, MDRTB patients not previously treated for TB had a higher treatment success rate (80% vs. 61%, odds ratio [OR] 2.54, 95% confidence interval [CI] 1.47–4.37, p 21,000 MDRTB patients were approved for treatment. The number of GLC-approved MDRTB control programs is increasing rapidly, both as a result of more funding for TB control from the GFATM and mainstreaming of MDRTB management into general TB control efforts. However, with the estimated incidence of 424,203 MDRTB cases, most cases remain undiagnosed and untreated. Expanding projects and accelerating evidence gathering are necessary to further develop international policies. The future success of MDRTB management in resource-limited settings will depend on the ability of the donor community and technical agencies, as well as TB-endemic countries themselves, to expand and strengthen MDRTB control programs.
