In this study, we found that 84.4% of patients experienced a successful treatment outcome under programmatic conditions in BC. Our treatment outcomes are consistent with those from other INH resistant treatment cohorts in high resource, low incidence settings [10,11,12, 16]. In resource-limited settings, where detailed individual level drug susceptibility results are not always accessible, the proportions of patients experiencing unsuccessful outcomes are often much higher. For example, in an INH resistance treatment cohort in rural South Africa, 15% of patients experienced treatment failure, of which 61% progressed to MDR-TB [17].While the differences in treatment outcomes may be reflective of differences in patient and health care resources rather than regimen efficacy, it is worth noting that in studies where resistance was detected early and drug regimens were modified, a higher proportion of patient’s experienced successful outcomes [11, 12]. This suggests that outcomes of treatment in INH resistant disease may be related to early detection of resistance and individualized therapy.
Within our cohort, over 30 different treatment regimens were prescribed; regimens were adjusted based on DST patterns, adverse events, severity of disease, and physician preference. Regimens were also often extended. However, similar to other studies [12], 12.7% of patients in our study were unable to tolerate PZA and the high incidence of drug toxicity suggests that new treatment regimens are needed to improve INH-resistant TB treatment outcomes.
In our cohort, 3 cases of relapse that occurred in patients who completed on a 9–12 month regiment of only RIF, PZA and EMB. Meanwhile, no cases of relapse developed in the 61 (37.0%) patients receiving an FQN-containing regimen. This finding, while not statistically significant, is in line with growing evidence suggesting that supplementation with FQNs may strength treatment regimens among patients with INH-resistant disease [16, 18, 19]. In a recent retrospective analysis of treatment outcomes with FQN containing regimens [18], the authors concluded that INH resistant pulmonary TB is associated with improved outcomes when FQNs are added to standard treatment regimens (97.3% vs. 84.6%, P = 0.007).
In 2011, Jenkins et al. reviewed the global burden and trends of INH resistant TB using surveillance data reported to the WHO [4]. The authors concluded that in several geographically disparate settings, the number of new TB cases with INH resistance is increasing [4]. This is consistent with routine surveillance data from BC and Canada, which show an increase in the prevalence of INH resistance [13]. As the burden of INH resistant disease increases, the need for a standard, cost-effective, evidence-based treatment regimen becomes more pressing. Prolonged, individualized courses for INH resistant TB are not practical, and would be difficult to implement in resource limited settings where the highest INH resistance burden exists [1, 4]. The WHO currently recommends two different treatment regimens for INH resistance; one for countries with an assumed ‘high’ level of INH resistance and another based on a setting of known first line drug susceptibility results [7, 20]. Unfortunately, the controversies regarding both of these treatment regimens outweigh the evidence [5, 6] and highlight the need for controlled trials to validate specific standardized recommendations.
Our study had several limitations. The most important was our inability to control for potential confounding variables and effect modification. Instead, we had to rely exclusively on univariate analysis for our analysis of outcomes due to the small sample size of unsuccessful outcomes. Whereas prior studies have identified characteristics of different treatment regimens associated with improved treatment outcomes, such as extending PZA duration [21], addition of fluoroquinolones [18], or use of four effective drugs in the intensive phase [5], these findings were not statistically evident in our cohort, possibly the result of the relatively small combined endpoint.
We were also limited by the variation in the composition and duration of treatment regimens. There was great variation in the composition and duration of treatment regimens making it impossible to identify superior or inferior regimens given the type of study and the sample size. Additionally, within each regimen group, there may have been clinically important differences that we could not account for. Highly heterogeneous treatment regimens are a widely recognized to be present in clinical practice, particularly when evidence behind treatment regimens is scarce [10,11,12, 16]. The wide variety of treatment regimens presented here reflects the uncertainty of clinicians in appropriate treatment of INH resistant disease.
Despite these limitations, our study raises important concerns about the currently recommended treatment regimens for INH resistant TB. It highlights the need for high quality studies to firmly establish standardized treatment regimens, with special consideration given to trials that utilize fluoroquinolones. Currently, there is little evidence and much controversy regarding the recommended treatment regimens, and given the global burden of INH resistance, solid evidence validating the various recommendations for treatment is urgently needed.