Efficacy and safety of 9-month oral treatment for rifampicin-resistant tuberculosis with WHO group A/B drugs

Tuberculosis (TB) is the leading cause of death worldwide in connection with antibiotic resistance [1]. In particular, multidrug-resistant (MDR) or rifampicin-resistant (RR) TB (MDR/RR-TB) poses a significant threat to public health, accounting for an estimated 4% of all TB cases (approximately 410,000 cases) [1, 2]. Treatment success for MDR/RR-TB is only about 64% worldwide [2]. The WHO European Region accounts for only 2% of the global TB disease burden. Nevertheless, it recorded 16% of all new MDR/RR-TB cases in 2022, with Eastern Europe, Central Asia and the Baltic States particularly affected [2, 3].

In 2020, the WHO primarily recommended a 9- to 12-month, oral, bedaquiline-based fixed combination for suitable patients with MDR/RR-TB without fluoroquinolone resistance [4]. However, due to frequent resistance to the components, this regimen could hardly be used in Europe and was only subordinately recommended in Germany [5]. An individualized therapy adapted to the pathogen resistance, primarily with the drugs of WHO groups A and B, was considered more suitable by the authors of the S2k guideline 2022 [6]. However, this must be carried out over 18 months and is often associated with treatment discontinuation [7]. In order to evaluate a modified, shorter MDR-TB therapy based on group A and B drugs (modified shorter treatment regimen [mSTR]), the WHO initiated a prospective cohort study in 13 countries in the European WHO region in 2020-2023 [8].

In the single-arm prospective study, the majority of the 2636 participants aged over six years received bedaquiline, linezolid, levofloxacin, clofazimine and cycloserine (96%) for 9 months. In case of intolerance or resistance to cycloserine, this was replaced by delamanid (3%). In contrast, children under six years of age were given delamanid, linezolid, levofloxacin and clofazimine (1%) [8]. After a 12-month follow-up period, the time to an unsuccessful treatment outcome (treatment discontinuation, non-appearance of the participant(s) during the follow-up period, death or recurrence of TB) was primarily evaluated. In addition, the frequency of adverse drug reactions (ADRs) was observed [8].

The probability of a successful treatment outcome through the use of mSTR was 79% at the end of the follow-up. In comparison, a treatment success rate of 70% was achieved in a South African cohort with the 9- to 12-month bedaquiline-based fixed combination recommended by the WHO up to that point [9]. At 4%, the mortality rate of mSTR was lower in the mSTR cohort than in the South African cohort used for comparison (17%). Co-infection with HIV, smoking, alcohol consumption, older age, malnutrition, anemia, liver damage and bilateral caverns were associated with a non-successful treatment outcome, as was unemployment.

At 9%, more severe ADRs of mSTR were similarly frequent as in comparable studies. As expected, the most common ADRs included myelosuppression, QT prolongation and peripheral neuropathy. Recurrence of TB was observed in less than 1% of participants during the follow-up period. As described in other cohorts, there was an increase in mortality to 6% during the follow-up period due to excess mortality [7, 8].

According to the authors of the WHO study, the high treatment success and the low relapse rate within 12 months of treatment speak for the potential of mSTR. This modified, shorter MDR/RR-TB therapy with the known WHO group A/B drugs can therefore complement existing treatment options [8].

Since 2022, the WHO and in 2023 also the German S2k guideline recommend the 6-month oral BPaLM regimen for the treatment of MDR/RR-TB, consisting of bedaquiline, pretomanid and linezolid and moxifloxacin [10, 11]. For pregnant or breastfeeding women and children under 14 years of age, there are currently still indication restrictions for pretomanid as an essential component of BPaLM. There is more experience with the mSTR drugs for these patient groups. The study results are therefore particularly important for these patient groups [8, 10]. The inclusion of socio-medical factors in the risk factor analysis and the efforts to contribute to the improvement of treatment structures in a region particularly affected by MDR/RR-TB during the study should also be emphasized.

On August 23, a further update of the recommendations for the treatment of resistant tuberculosis was announced by the WHO in a "rapid communication" for the first quarter of 2025. We will report on the planned changes and categorize them together with the authors of the guideline for the German treatment context.

Literature used

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