Abstract
Future strategic choices in the clinical development of bedaquiline should be guided by the need to generate high-quality evidence and ultimately improve outcomes of tuberculosis treatment, while preventing the emergence of drug resistance https://bit.ly/3iAOCZr
Bedaquiline can probably be considered the biggest breakthrough in tuberculosis drug development of the past decades. The first compound of a new anti-tuberculosis drug class, diarylquinolines, bedaquiline binds the mycobacterial ATP synthase, inducing major conformational changes and ultimately impacting the bacterial respiration pathway [1, 2]. After being developed in 2005 [3], bedaquiline showed promising results in phase II trials [4, 5], and was granted accelerated approval in 2012 by the US Food and Drug Administration (FDA) and conditional approval in 2014 by the European Medicines Agency. In the following years, the access to bedaquiline has progressively increased, from compassionate to programmatic use [6, 7], although at an insufficient pace. Between July 2015 and December 2019, 51 098 patients received bedaquiline worldwide: although remarkable, this figure only represents 11% of those who are estimated to need it according to the most recent recommendations by the World Health Organization (WHO) [8].
In this issue of the European Respiratory Journal, Chesov et al. [9] elegantly describe the impact of the early years of programmatic bedaquiline implementation in the Republic of Moldova. In this retrospective cohort study, consecutive adult patients diagnosed with culture-confirmed pulmonary multidrug-resistant tuberculosis (MDR-TB) were identified through a nationwide database. Overall, 2069 MDR-TB patients were included in the study: 115 had received bedaquiline and 1954 had not. The study included patients who started treatment between 2016 and 2018, a period during which bedaquiline was reserved mainly for the most difficult-to-treat strains and for salvage treatment regimens: consequently, most bedaquiline-treated patients in the cohort have a history of treatment failure, positive sputum smear results and lung cavities at baseline, and harbour fluoroquinolone-resistant strains. In order to select a comparable population, propensity score matching was performed by age, sex, area of residence, presence of cavitary lesion, HIV status, sputum smear positivity at baseline, fluoroquinolone resistance, previous history of tuberculosis, and drugs included in the treatment regimen; this allowed the selection of two groups of 114 patients with similar baseline characteristics. Remarkably, favourable treatment outcome rates in the bedaquiline-treated group were higher using both WHO definitions (55.3% versus 24.6%) in all the cohort and TBnet definitions in the subgroup of patients who had at least 1 year post-treatment follow-up available (43.5% versus 19.6%). In addition, mortality rates were significantly lower in the bedaquiline-treated group. Despite limitations due to its retrospective nature, missing data in some of the matching variables, and potential unknown confounders not captured by propensity scoring, this study gives an excellent example of the impact of bedaquiline as part of conventional MDR-TB treatment regimens, supported by a sound methodological approach. However, outcomes achieved by bedaquiline-treated patients in the cohort are still far from optimal, as shown by high rates of treatment failure (27.2% and 39.2%, according to WHO and TBnet definitions). This finding, similar to results from previous studies performed in the same region [10, 11], may have multiple explanations: bedaquiline was, in most cases (82%), not part of the initial regimen and added subsequently to adapt to phenotypic drug susceptibility testing (DST) results; when bedaquiline was added, it was usually not accompanied by other effective drugs; bedaquiline was administered for a median of 34 weeks, and almost never for the full duration of treatment; and finally, other important drugs, such as clofazimine and delamanid, were used only in a few cases, due to limited availability in the Republic of Moldova.
The study reported by Chesov et al. [9] adds to an already rich body of observational evidence supporting the use of bedaquiline for MDR-TB [12]. Large, multinational cohort studies and a meta-analysis of individual patient data have confirmed the efficacy of this drug [13–16]. Similarly, initial safety concerns, in particular regarding QT interval prolongation, have been progressively dispelled [17–20]. WHO recommendations include bedaquiline among the “core drugs” of the individualised, conventional treatment regimen for MDR-TB, and recently also as part of an all-oral shorter MDR-TB regimen [21]. Moreover, latest WHO recommendations allow for increasing flexibility in establishing the duration of bedaquiline treatment beyond 24 weeks and in combining it with other QT-prolonging drugs, like delamanid.
Does this mean that the tale of bedaquiline is heading towards a happy ending? Unfortunately, we cannot say for sure (yet). All these recommendations are based on observational data, indirect comparisons (for the shorter regimen), and mostly very low quality evidence [22]. Indeed, results of a phase III clinical trial of bedaquiline are still awaited, despite engagements by the manufacturer at the moment of provisional approval by the FDA [23]. There are also reasons for concern that should not be underestimated. Over the past years, multiple reports have alerted on the selection of emerging drug resistance to bedaquiline [24–27]. Fears of increasing resistance rates have led some groups to advocate “restricting” the use of bedaquiline for fluoroquinolone-resistant strains [28]. In addition, reliable DST for bedaquiline (and other new and re-purposed drugs) is currently lacking in most medium- and high-incidence countries [29, 30].
Ultimately, major breakthroughs, and reliable data on the risk of acquired drug resistance, will only come from clinical research. Multiple clinical trials, summarised in table 1, are currently planned or ongoing [31]. The development path of bedaquiline is now at a crossroads leading to (at least) four main directions. First, bedaquiline may continue to be assessed as part of all-oral regimens for rifampicin-resistant tuberculosis: these drug combinations are tested as standardised options for all rifampicin-resistant strains (i.e. TB-PRACTECAL), or as part of a strategy where regimens can be adapted to results of rapid molecular testing for fluoroquinolone resistance (i.e. BEAT Tuberculosis). Second, bedaquiline may be included in regimens which specifically target fluoroquinolone-susceptible strains (i.e. STREAM Stage 2, endTB). Third, bedaquiline may be reserved for fluoroquinolone-resistant strains, as part of combinations of new and re-purposed drugs (i.e. endTB-Q). In all these cases, the overarching goal is to reduce the duration of treatment for such drug-resistant strains to 6 to 10 months, while preventing the selection of drug resistance, mantaining the efficacy rates of conventional treatment, and hopefully improving its safety profile. Finally, bedaquiline may be studied as a component of new efforts to improve first-line treatment for rifampicin-susceptible tuberculosis by reducing its duration to 2 to 4 months, as hinted by promising pre-clinical [32] and bactericidal activity studies [33]. Regardless of the development path, randomised phase III trials [34, 35], including a sufficient sample size and an internal, dynamic control arm, are needed to radically improve the evidence base for treatment of this disease [36]. Innovative trial designs may help accelerate this process [37, 38], but adequate funding and strong political commitment are more critical than ever in these times of the coronavirus disease 2019 pandemic [39].
Recent improvements in MDR-TB treatment with bedaquiline-containing regimens, as shown by Chesov et al. [9], are undeniable, and make a case for enhanced global access to bedaquiline and other new and re-purposed drugs. However, this may only be the beginning of the journey for bedaquiline. Strategic choices on priorities of clinical development of this drug will shape its role in tuberculosis treatment in coming years. We believe that these choices should be guided by the need to improve treatment outcome for each patient, and that all development directions are worthy of being explored. Implementation of bedaquiline-containing regimens based on high-quality evidence expected from clinical trials, together with widespread DST capacity, rather than restricted use for salvage therapy, may be the best way to prevent resistance and to ensure the grand finale that this story deserves.
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Footnotes
Author contributions: L. Guglielmetti made a substantial contribution to the conception of the manuscript, wrote the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. F. Varaine made a substantial contribution to the conception of the manuscript, critically revised the manuscript for important intellectual content, gave final approval of the current version to be published, and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflict of interest: L. Guglielmetti is the co-principal investigator of two MSF-sponsored clinical trials testing MDR-TB regimens including bedaquiline.
Conflict of interest: F. Varaine is the project leader of two MSF-sponsored clinical trials testing MDR-TB regimens including bedaquiline.
- Received January 9, 2021.
- Accepted January 18, 2021.
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