Shorter regimens for multidrug-resistant tuberculosis should also be applicable in Europe

From the authors:

In response to our manuscript on the eligibility for shorter treatment of multidrug-resistant tuberculosis (MDR-TB) in the European Union (EU) [1], Heldal and co-workers highlight the limitations of the surveillance data that were used to estimate the proportion of MDR-TB cases eligible for the shorter regimen, and they question the criteria that we used to define eligibility.

The World Health Organization (WHO) criteria for eligibility state that patients exposed to second-line medicines included in the shorter MDR-TB regimen for ≥1 month are not eligible. As information on exposure is not available in our surveillance data, we excluded all cases with previous treatment, realising that this was a conservative approach. The data from Latvia (V. Riekstina, Centre of Tuberculosis and Lung Diseases, Riga, Latvia; personal communication) provide an indication that our approach was indeed conservative. Taking this criticism into account, readers are able to ascertain from the data provided in figure 1 in our published study [1], that 524 (16.9%) of the 3103 new cases were eligible for the shorter MDR-TB treatment, given the exclusion of extrapulmonary TB and those resistant to kanamycin/amikacin, moxifloxacin/ofloxacin or ethambutol.

Heldal and colleagues question our decision to consider ofloxacin-resistant cases as moxifloxacin-resistant. They argue that only 7% of ofloxacin-resistant strains have been found to be resistant to moxifloxacin. The data to which they refer are from Azerbaijan, Bangladesh, Belarus (Minsk city), Pakistan and South Africa (Gauteng and Kwazulu Natal). In our EU/European Economic Area (EEA) data, 816 rifampicin-resistant TB cases were tested for both ofloxacin and moxifloxacin. Out of 208 ofloxacin-resistant cases, 169 (81.2%) were also resistant to moxifloxacin. Thus, in our setting, cross-resistance between ofloxacin and moxifloxacin is frequent, supporting our choice of using ofloxacin resistance as a proxy for moxifloxacin resistance to cover missing data (1768 out of 1774 cases were tested for ofloxacin and 386 out of 1774 for moxifloxacin).

The authors also challenge the fact that we considered MDR-TB cases with resistance to ethambutol as ineligible for the shorter MDR-TB regimen. We based our exclusion on the WHO criteria that for patients “who have documented or are likely to have strains resistant to medicines in the [shorter MDR-TB] regimen” [2] the new regimen should not be used [3]. As ethambutol is part of the shorter regimen, cases with reported resistance to ethambutol were considered ineligible in our analysis. It is questioned by Heldal and co-workers whether ethambutol resistance should be an exclusion criterion since the test for ethambutol resistance is unreliable, according to the WHO. In the EU/EEA, the growth-based (liquid) drug-susceptibility test (DST) methods (e.g. the mycobacteria growth indicator tube system) are widely used, especially in high-income countries. These methods have been found to be reliable for most of the anti-TB drugs [4]. Discrepancies amongst DST results obtained using the growth-based tests have been reported for ethambutol, in comparison with proportion methods (e.g. agar proportion) and embB mutation analysis. Proportion methods and embB mutation analysis more frequently indicate ethambutol resistance compared with growth-based methods [5]. Thus, ethambutol resistance may be underdiagnosed in the EU/EEA due to the preferred use of growth-based methods. Therefore, we believe that we were conservative in considering ethambutol-resistant MDR-TB cases ineligible. If ethambutol resistance had not been an exclusion criterion, 602 of the 1774 MDR-TB cases who only had additional resistance to ethambutol would have been eligible for the shorter MDR-TB regimen.

The authors also remark on the reliability of pyrazinamide resistance. However, information on pyrazinamide resistance is not available in our database and was therefore not considered.

We agree with Heldal and colleagues that the shorter MDR-TB regimen is also likely to be effective in extrapulmonary TB cases. However, as discussed, we followed the WHO eligibility criteria and therefore excluded extrapulmonary TB cases. It is hoped that data will soon be available to support the use of the shorter regimen in extrapulmonary MDR-TB cases.

We applaud the fact that Norway included the shorter regimens in their MDR-TB treatment options and we would welcome data from operational research in a European setting on the effectiveness of the shorter regimen in patients who are currently excluded.

Several papers have recently been published on this topic [6–11]. This is an indication of the increased interest in shorter MDR-TB treatment regimens. It is hoped that this interest will result in further studies that might provide evidence for the revised criteria, meaning more MDR-TB patients will be eligible for the shorter regimen.