Author + information
- Julio A. Urbina, PhD∗ ()
- ↵∗Venezuelan Institute for Scientific Research, 200 Lakeside Drive, Apt. 503, Oakland, CA 94612-3503
The paper by Morillo et al. (1) describes the results of a clinical trial that evaluated the safety and efficacy of posaconazole, benznidazole, and their combination for the etiological treatment of chronic Chagas disease caused by the kinetoplastid parasite Trypanosoma cruzi, which is the largest parasitic disease burden in the American continent (2). The study was relevant for the management of this prevalent and long-neglected disease, and was well carried out, but several issues in the experimental design and interpretation of the findings deserve further discussion.
There is a most plausible explanation for the lack of sustained antiparasitic activity of posaconazole in this trial and a previous trial in humans (3), in contrast to the curative activity previously demonstrated in several murine models. Posaconazole was administered at the optimal dose for humans in its liquid suspension formulation (400 mg twice daily); systemic exposures in humans at that dose are 10% to 20% of those measured in mice at the curative anti−T. cruzi dose of 20 mg/kg per day [see references in (2)]. This indicates that the patients in both trials were underdosed with posaconazole as anti−T. cruzi therapy. The recent development of a delayed-release tablet formulation of the drug, with a 4-fold higher oral bioavailability than the liquid suspension formula, and no toxic side effects up to at least 400 mg/day (4), provides a way to assess the true efficacy of posaconazole for the anti−T. cruzi indication.
As the investigators acknowledged, the short follow-up time of 1 year did not permit the evaluation of the effect of the different treatments on the long-term clinical evolution of the patients, but it must be pointed out that it also impeded the assessment of their short-term effects on the patients’ parasite burdens. It would have been of critical interest in the current study to assess if the frequent and increasing number of relapses of parasitemia observed among chronic patients treated with benznidazole monotherapy 2 to 5 years after EOT (end of treatment) in the recently completed BENEFIT (Benznidazole Evaluation for Interrupting Trypanosomiasis) trial (5) disappeared or were significantly diminished in patients who received the combination of benznidazole plus posaconazole.
Please note: Dr. Urbina has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Morillo C.A.,
- Waskin H.,
- Sosa-Estani S.,
- et al.
- Urbina J.A.