High-dose isoniazid in the shorter-course multidrug-resistant tuberculosis regimen in the Republic of Moldova

To the Editor:

Since May 2016 the World Health Organization (WHO) has recommended the treatment of multidrug-resistant tuberculosis (MDR-TB) patients with a standardised treatment regimen of 9–12 months duration if patients fulfil specific eligibility criteria [1]. This shorter-course MDR-TB treatment regimen consists of a combination of seven drugs (clofazimine, ethambutol, high-dose isoniazid, kanamycin, moxifloxacin, prothionamide and pyrazinamide) for 4–6 months, followed by four drugs (moxifloxacin, clofazimine, pyrazinamide and ethambutol) for 5 months. It is based on the results from recent observational cohort studies performed in Bangladesh [2], Cameroon [3] and Niger [4] where this or similar treatment regimens led to high cure rates for MDR-TB. Shortly after the WHO proposed the shorter-course MDR-TB regimen, substantial concerns were raised about the applicability of this regimen for patients with MDR-TB in Europe, where many circulating strains of Mycobacterium tuberculosis have additional resistance to 2nd-line anti-tuberculosis (anti-TB) drugs. Based on results from existing databases with comprehensive records of the drug-susceptibility patterns of M. tuberculosis strains in patients with MDR-TB, several groups reported independently that less than 10% of MDR-TB patients from the WHO European Region were likely to be eligible for this regimen [5–8].

We read with interest the correspondence by Heldal et al. [9], which suggested that exclusion criteria should be interpreted more liberally to allow more patients with MDR-TB to be treated with the shorter-course regimen in Europe. We are concerned that such suggestions are being made in the absence of clinical evidence applicable to the geographic region in question and we provide further evidence here as to why this shorter-course treatment regimen should be considered with caution for patients in Europe.

One of the components of the WHO-proposed, shorter-course MDR-TB regimen is high-dose isoniazid. This recommendation is made under the assumption that treatment with 15–20 mg·kg^–1 body weight of isoniazid may be effective in M. tuberculosis strains with low-level isoniazid resistance due to mutations in the inhA promotor at positions 8, 15 or 16. There is general consensus that high-level isoniazid resistance due to a mutation in the katG gene at position 315 cannot be overcome by high-dose isoniazid treatment [10]. At the National TB Reference Laboratory of the Phthisiopneumology Institute in Chişinău, Moldova, one of the high-burden countries for MDR-TB in Eastern Europe, we evaluated all the results of molecular drug-resistance testing on M. tuberculosis strains performed by GenoType MTBDRplus v.2 (Hain Lifescience GmbH, Nehren, Germany) line probe assay between 2010 and 2016. This analysis then allowed us to estimate the proportion of patients with MDR-TB that might benefit from high-dose isoniazid therapy as part of the short-course regimen.

From a total of 5368 line probe assay evaluations, 4570 gave valid results (table 1). In 2638 strains, mutations were identified that suggested resistance to both isoniazid and rifampicin, this being indicative of MDR-TB. In 2323 of these 2638 strains (88.1%), a mutation in the katG gene at position 315 was present, suggesting high-level isoniazid resistance. Only 20 out of 2638 strains (0.7%) had a mutation in the inhA promotor alone while in 295 out of 2638 strains (11.2%) the location of a mutation could not be identified by the line probe assay. This data demonstrates that almost 90% of M. tuberculosis strains from patients with MDR-TB in the Republic of Moldova have a high-level of resistance to isoniazid.

Results from this study strongly suggest that high-dose isoniazid should not be part of a standardised treatment regimen for patients with MDR-TB in the Republic of Moldova or other parts of Europe [11]. A one-size-fits-all solution, like the WHO recommendation for the short-course MDR-TB treatment regimen, is not applicable for many patients outside of Bangladesh, Niger and Cameroon where this regimen has been highly effective. In Europe (and probably in other parts of the world) it is time to move away from standardised treatment regimens towards individualised MDR-TB therapies. For the choice of an individualised MDR-TB treatment regimen, physicians should be guided by drug availability and by the results of comprehensive molecular drug resistance testing (e.g. by line probe assay). Now that these tools are affordable even in the poorest country in Europe, we can move away from solutions based on fixed drug combinations and towards tailor-made therapies (except when all drugs in a treatment combination are novel and the likelihood that M. tuberculosis is resistant to any of the compounds is low).

Disclosures