Multidrug-resistant tuberculosis in Finland: treatment outcome and the role of whole-genome sequencing

Discussion

Regardless of the alarming MDR-TB situation in Finland's neighbourhood, the proportion of MDR-TB strains in Finland is still low, less than 2%. Treatment success rate was 74% in our national cohort study using individually tailored treatment regimens with directly observed treatment and treatment supervised by a national advisory group. We found that extensive drug resistance, meaning MDR with additional resistance to at least one fluoroquinolone and one injectable agent, and surprisingly also Finnish origin, predicted non-successful treatment outcome. Furthermore, our data show that MDR-TB is not transmitted inside Finland, reflecting cases being found and treatment started on time.

Phenotypic and genotypic drug resistance results were fully concordant for isoniazid, fluoroquinolones and amikacin. One isolate had contradictory results for rifampicin as a mutation was not found in the rpoB gene. On the other hand, more than half of phenotypically EMB-sensitive isolates were genotypically resistant. Most (90%) of the mutations found were high-confidence mutations at the positions 306, 406 or 497 of the embB gene, and based on earlier studies, the isolates should be assumed EMB resistant [18, 19]. The critical concentration of 5 mg·L⁻¹ for EMB may be too high and can mis-classify strains as susceptible [10]. One phenotypically streptomycin-sensitive isolate had a mutation in the gidB gene causing low-level resistance to streptomycin.

With current diagnostic tools, initial MDR treatment regimen is often based on NAAT results. However, NAAT from direct sample was requested by the treating clinician for only slightly more than half of the cases in our study, suggesting that MDR was not initially suspected by the physician. NAAT directly from sample has been recommended in Finnish guidelines for all TB suspects only since 2020 [12]. A need for faster and reliable DST methods exists. In our study, an effective MDR treatment regimen was started almost a median of 2 weeks before pDST results were reported for first-line drugs. WGS was performed retrospectively for the study cohort. Our data show that using WGS as a primary DST method would accelerate diagnosis of MDR-TB.

∼70% of our MDR cases are of foreign origin, and the different resistance mutation profiles in the otherwise similar isolates emphasise that the MDR cases detected in Finland are sporadic infections of MDR clusters very common elsewhere [20, 21]. Furthermore, most Finnish-born MDR cases had stayed for longer periods in countries with high MDR-TB incidences (data not shown), and active transmission of MDR-TB in Finland was not found. In this study, two Finnish-born patients could be suspected of being clustered, but the fairly long allelic distance (5) and different resistance mutations indicate that the patients most probably have not transmitted the isolate to each other but are likely to have been infected abroad.

Linezolid, a fluoroquinolone, and amikacin were each used for about 90% of our patients. Our results support earlier observations of a need for better tolerated treatment regimens [22]. With our treatment regimens, adverse events were extremely common; almost 90% of our cases had an adverse event for at least one drug. More than two-thirds of our patients receiving linezolid and more than half of our patients receiving amikacin had an adverse event for the drug, in contrast to an earlier meta-analysis showing that only 10% of patients using amikacin and 14% of patients using linezolid had an adverse event leading to permanent discontinuation of the drug [23]. Clofazimine caused adverse events very rarely, in line with results from earlier studies [7, 24]. As our study period ended a few years before WHO announced the new recommendations for bedaquiline-based treatment for all MDR patients [25], bedaquiline was used only for a minority of cases.

Our treatment success rate of almost 75% for MDR-TB cases is higher than in the WHO European region on average [3] and in line with a few studies from European low-incidence countries using individualised treatment [7, 8]. However, targeting even higher success rates is still warranted. We need to improve our treatment programme as for almost one-fifth of our cases MDR-TB treatment was interrupted or the patient transferred to another country during treatment resulting in high risk of treatment interruption. On the other hand, our treatment success rate of 71% among pulmonary MDR-TB cases is close to the rate published earlier for pulmonary non-MDR-TB cases in Finland [26]. Nevertheless, direct conclusions about MDR versus non-MDR cases cannot be made as demographics among these two cohorts differ substantially; MDR cases are much younger, have less comorbidities and are more often of foreign origin [26].

The rate of outcome cured using TBNET outcome definitions for pulmonary MDR-TB cases was not considerably higher compared to using WHO outcome definitions in our study, in contrast to earlier studies [27]. That is mainly caused by the high proportion of undeclared outcome due to deficiency of sputum samples at 6 months after treatment initiation and patients being transferred out during treatment or not showing up at post-treatment assessment. This calls for a special effort to collect sputum samples regularly during treatment, to improve the reliability of treatment outcome data. However, acquired drug resistance during MDR treatment and microbiologically confirmed relapses after treatment cessation were not found in our study. Earlier studies have shown that most relapses occur within 12 months of treatment completion [14, 28].

Our observation of extensive drug resistance as a clear predictor for non-successful outcome is in line with earlier studies [29, 30] even though some centres have published similar treatment success rates for patients with XDR- and MDR-TB [7]. Our finding is alarming, considering that most of our patients with XDR-TB were on bedaquiline-based regimens, and calls for a special effort on guiding treatment by the national advisory group each time XDR-TB is diagnosed. Surprisingly, Finnish origin was a risk factor for non-successful outcome mostly because treatments were interrupted, or patients died during treatment (data not shown). One explanation might be comorbidities, as 50% of cases with Finnish origin and only 21% of foreign-born cases had at least one comorbidity (p=0.048).

This study has several limitations. As this is a retrospective cohort study of 10 years, diagnostic methods and recommendations for treatment and treatment outcome evaluation have developed during the study period. We did not use the definition for (pre-)XDR recently announced by WHO [1]. The impact of different treatment regimens on treatment outcome could not be assessed as our cohort was small and especially the newer bedaquiline-based treatment regimen was infrequently used. Treatment success relied more often on patients completing treatment than on microbiologically confirmed cure, which is common also in other countries with a low incidence of TB [14]. Sampling of sputum becomes more difficult when a patient improves, and an intent to induce sputum samples, e.g. using nebulised hypertonic saline during TB treatment, is not mentioned in our national TB guidelines. The laboratory methods, especially DST for EMB and PZA, are challenging [31]. In this study, the concordance of phenotypic and genotypic DST was poor especially for EMB, as more than half of phenotypically EMB-sensitive isolates were genotypically resistant. Hopefully more comprehensive resistance mutation catalogues and refined pDST methods will clarify the field in the future [32].

In conclusion, our national cohort study of 10 years shows treatment success in three-quarters of cases when treatment regimens are individualised, and treatment is supervised by an advisory group. The high number of adverse effects supports the need for more tolerable treatment regimens partly adopted in new guidelines as well as through follow-up of patients. Reliable and early DST is a key element in composing adequate drug regimens. WGS most probably will speed up the selection of an optimal treatment regimen in the future.