Tis, the main AE to EMB, is rare in the doses and exposure times commonly used for TB treatment.32 Despite the potential for providing the highest level of evidence in therapeutic intervention research, RCTs have been criticized because of their limited generalizability. RCTs are often conducted under optimal medical care and may underestimate the potential benefit of using 4-FDC formulations to enhance adherence in settings where malpractice or unmonitored therapies are common. Important differences in adherence have been found in many RCTs.33 Therefore, pragmatic clinical trials, which are conducted in a way that more closely resembles typical clinical practice, may be more appropriate to obtain a better estimate of treatment effectiveness.34,35 At the beginning of 2013, a systematic review was published in Canada to evaluate the risk of treatment failure or disease relapse, acquired drug resistance, bacterial conversion after 2 months of treatment, AEs, adherence, and treatment satisfaction associated with treatment of active TB using FDC or SD formulations.36 This study concluded that, although FDC formulations simplify TB therapy, the current evidence did not indicate that these formulations improve treatment outcomes among patients with active TB. However, that systematic review included studies of both four-drug and two-drug combinations and, therefore, differs from the present one in the number of retrieved articles. These differences justify the need for a revision to compare precisely the effect of 4-FDC versus SD formulations. The World Health Organization has recommended 4-FDC treatments since 1999. Combined treatments prevent drug selection by the patient (monotherapy) by providing all of the drugs in the same tablet.12,34,35,37 Due to their simplified and standardized nature, 4-FDC regimens facilitate dosage calculation and prevent prescription errors. However, one of the most relevant MS-275 custom synthesis features of 4-FDC formulations, the prevention of drug resistance, was not addressed in those studies. Nevertheless, based on their similar efficacies, user-friendliness, lower costs, and operational and logistical advantages, generalized use of 4-FDC formulations should continue to be recommended. One limitation of this meta-analysis is that the included studies did not investigate adherence to the prescribed treatment. Moreover, the impact of the Directly Observed Treatment Short-Course (DOTS) strategy on the outcomes of TB treatment was not assessed, which resulted in less precise estimates. Another limitation is the inconsistency in ascertainment of the time of relapse in the different studies; because of the heterogeneous methods, we did not pool the study results for this variable. We could not assess mortality as an outcome because this term was defined differently in the studies (all-cause vs. TB-specific mortality), measured over different follow-up periods and, in some studies, was not reported or not attributed to the treatment group. Finally, small differences in drug concentrations existed between studies. Regardless of these limitations, this systematic reviewhas several strengths. Lack of significant heterogeneity of the Nutlin (3a) msds estimates of sputum conversion in the initial and final phases of therapy and of default in the different trials permitted pooling and increased the precision of our results regarding treatment efficacy. By the end of 2009, Brazil was the only country with a high burden of TB to use a three-drug treatment regi.Tis, the main AE to EMB, is rare in the doses and exposure times commonly used for TB treatment.32 Despite the potential for providing the highest level of evidence in therapeutic intervention research, RCTs have been criticized because of their limited generalizability. RCTs are often conducted under optimal medical care and may underestimate the potential benefit of using 4-FDC formulations to enhance adherence in settings where malpractice or unmonitored therapies are common. Important differences in adherence have been found in many RCTs.33 Therefore, pragmatic clinical trials, which are conducted in a way that more closely resembles typical clinical practice, may be more appropriate to obtain a better estimate of treatment effectiveness.34,35 At the beginning of 2013, a systematic review was published in Canada to evaluate the risk of treatment failure or disease relapse, acquired drug resistance, bacterial conversion after 2 months of treatment, AEs, adherence, and treatment satisfaction associated with treatment of active TB using FDC or SD formulations.36 This study concluded that, although FDC formulations simplify TB therapy, the current evidence did not indicate that these formulations improve treatment outcomes among patients with active TB. However, that systematic review included studies of both four-drug and two-drug combinations and, therefore, differs from the present one in the number of retrieved articles. These differences justify the need for a revision to compare precisely the effect of 4-FDC versus SD formulations. The World Health Organization has recommended 4-FDC treatments since 1999. Combined treatments prevent drug selection by the patient (monotherapy) by providing all of the drugs in the same tablet.12,34,35,37 Due to their simplified and standardized nature, 4-FDC regimens facilitate dosage calculation and prevent prescription errors. However, one of the most relevant features of 4-FDC formulations, the prevention of drug resistance, was not addressed in those studies. Nevertheless, based on their similar efficacies, user-friendliness, lower costs, and operational and logistical advantages, generalized use of 4-FDC formulations should continue to be recommended. One limitation of this meta-analysis is that the included studies did not investigate adherence to the prescribed treatment. Moreover, the impact of the Directly Observed Treatment Short-Course (DOTS) strategy on the outcomes of TB treatment was not assessed, which resulted in less precise estimates. Another limitation is the inconsistency in ascertainment of the time of relapse in the different studies; because of the heterogeneous methods, we did not pool the study results for this variable. We could not assess mortality as an outcome because this term was defined differently in the studies (all-cause vs. TB-specific mortality), measured over different follow-up periods and, in some studies, was not reported or not attributed to the treatment group. Finally, small differences in drug concentrations existed between studies. Regardless of these limitations, this systematic reviewhas several strengths. Lack of significant heterogeneity of the estimates of sputum conversion in the initial and final phases of therapy and of default in the different trials permitted pooling and increased the precision of our results regarding treatment efficacy. By the end of 2009, Brazil was the only country with a high burden of TB to use a three-drug treatment regi.
