Bedaquiline: finding the pores on the pot
- Prasanta Raghab Mohapatra⇑
- Prasanta Raghab Mohapatra, Dept of Pulmonary Medicine, All India Institute of Medical Sciences, Bhubaneswar-751019, India. E-mail: prmohapatra{at}hotmail.com
Abstract
We need a better drug to control drug resistant tuberculosis (MDR TB) http://ow.ly/MTcSu
To the Editor:
Salfinger and Migliori [1] discussed some important issues of bedaquiline, the most promising drug for treating multidrug-resistant (MDR) tuberculosis (TB) in the early twenty-first century. I am afraid of some issues that could be detrimental to the future of TB control. Bedaquiline should be used with caution, bacause of some methodological flaws in a few of the published landmark studies. In one study, Diacon et al. [2], the authors, without doing drug-sensitivity testing on isoniazid and rifampicin (criteria of MDR-TB), firmly concluded the effectiveness of their new regimen on MDR-TB patients. By using a regimen containing bedaquiline for susceptible patients to the tested drug does not predict bedaquiline's effectiveness in MDR-TB patients, as the pharmacokinetics and probability of pharmacodynamic target attainment (area under the time curve minimum inhibitory concentration ratio) are likely to be altered in MDR patients [3].
In another recent study by Diacon et al. [4], the efficacy analyses were performed in the modified intention-to-treat (ITT) population and selectively excluded patients after randomisation in their study. Some of the participants received the drug-resistant treatment, including bedaquiline, without confirmation of drug resistance and some with negative mycobacterial cultures. There is no clear definition of what is modified ITT. Modified ITT analysis has potential bias, due to the inappropriate exclusion of patients after including them in the trial. Post-randomisation exclusions is treated as deviations from protocol, destined for biased effect and strongly associated with industry funding [5]. So the real outcome is likely to be different in pragmatic trials or in the study outside of the trial conditions. ITT remains the best method that preserves randomisation. Well designed, randomised control trials follow strictly to the ITT principle, which is the best method for preserving randomisation irrespective of completing treatment in the group they were originally allocated.
Yet again, after a decade, there is still no study, to the best of my knowledge, on the: 1) impact of bedaquiline on clinical failure, 2) rate of relapse or survival, and 3) clinical resolution of TB. Drug toxicity can lead to decrease adherence and compliances of bedaquiline containing regimens in realistic conditions.
Footnotes
Conflict of interest: None declared.
- Received February 9, 2015.
- Accepted February 11, 2015.
- Copyright ©ERS 2015