Bedaquiline: finding the pores on the pot

From the authors:

We read with interest the correspondence by Prasanta Raghab Mohapatra commenting on our editorial [1], which was aimed at discussing the absence of adequate drug susceptibility protocol for the new drug bedaquiline.

Prasanta Raghab Mohapatra raised interesting comments on the limitation of the trials presently available on bedaquiline and on the possible consequences for the patients.

With reference to the article by Diacon et al. [2], the authors investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis (TB) were enrolled. We concur with the authors that multi-agent EBA studies can contribute to reducing the time needed to develop new anti-TB regimens.

Drug safety considerations are of outmost concerns for patients participating in clinical trials. In the case of bedaquiline, the risk of cardiological toxicity (prolongation of the QT interval in the electrocardiogram) and the unexplained higher toxicity in the treatment arm of the trial [3], pose additional queries that are still unanswered.

This necessary caution explains also why the World Health Organization (WHO), in absence of evidence on the simultaneous use of bedaquiline and delamanid, does not recommend the prescribing of these two drugs together [4] (table 1). In addition, WHO has developed the Policy Implementation Package for the introduction of new TB drugs (PIP document), underlining the minimum requirements that countries should have in place in order to use the new drugs safely, and with a reasonable low probability of developing further drug resistance (table 1).

We agree with Prasanta Raghab Mohapatra that properly designed trials are necessary to answer the numerous clinical queries that are still pending (table 1) [4].

In addition, there should be banking of Mycobacterium tuberculosis complex strains from patients participating in clinical trials, especially in those in whom therapy failed. Furthermore, novel compounds should be made available to the laboratory community in order to develop appropriate assays for minimal inhibitory concentrations (MIC), therapeutic drug monitoring, and molecular drug resistance assays [7].

Because of the new mechanism of action by bedaquiline (inhibition of ATP synthase), some clinicians may argue that antimicrobial susceptibility testing or analysis of the MIC may not be needed in patients who have never received bedaquiline [3]. However, it is important to have complete information when assessing novel compounds. It is imperative that for patients who are going to be treated with bedaquiline that antimicrobial susceptibility testing or analysis of the MIC of bedaquiline for TB strains should be performed, with these strains being further characterised with the use of molecular protocols.

Furthermore, it is of paramount importance to ensure a rational prescription of all regimens aimed at treating multidrug-resistant TB cases, particularly when the new drugs bedaquiline and delamanid are involved [8]. The European Respiratory Society (ERS) through the ERS/WHO TB Consilium (www.tbconsilium.org an e-platform aimed at providing a free-cost, language-sensitive clinical guidance to clinicians for their difficult-to-treat cases) is in the frontline to fight drug-resistance and to support rational use of drugs [9, 10].

On the other side we need also to balance the potential benefit of adding a new drug in patients who are, otherwise, very likely to die [11]. The success rate in the patients affected by severe forms of extensively drug-resistant strains of M. tuberculosis is, unfortunately, less than 20% [11].

As summarised in table 1, WHO recommends that the new drugs bedaquiline and delamanid are prescribed within sound TB control programmes on top of optimised background regimens designed as per WHO guidelines, at recommended dosages, having a pharmacovigilance system in place, and requesting the patient's informed consent and implementing proper monitoring (i.e. of the QT interval, specifically for bedaquiline) [4] (table 1).

In conclusion, additional evidence is needed to maximise safe and effective use of the new drugs while preventing development of drug resistance.