The ergosterol-synthesis inhibitor posaconazole proved ineffective at eliminating Trypanosoma cruzi DNA from the blood of patients with chronic Chagas’ disease, according to a report published online May 14 in the New England Journal of Medicine.
"Posaconazole has shown considerable activity in murine models of acute and chronic Chagas’ disease, and this effect was expected to be reproducible in humans; unfortunately, however, only suppressive activity was shown," said Dr. Israel Molina of the infectious disease department, Vall d’Hebron Teaching Hospital, Barcelona, and his associates.
They assessed two oral doses of posaconazole against standard-dose benznidazole in an open-label clinical trial involving 78 treatment-naive patients with chronic Chagas’ disease, which is also known as American trypanosomiasis. At present, there are only two agents available for treating the chronic form of the disorder – benznidazole and nifurtimox – and both have daunting toxicity profiles. Up to 30% of patients withdraw from these drugs because of adverse events, and their cure rates are unsatisfactory at only 15%-35%.
Like other ergosterol-synthesis inhibitors, posaconazole was particularly promising because it showed antiprotozoal activity. It also has been used to treat invasive fungal infections and has an established safety profile in humans.
Chagas’ disease is endemic in Latin America but was rare in North America and Europe until recently, when population shifts caused the incidence in some countries, including the United States and Spain, to eclipse that in many endemic areas.
Dr. Molina and his colleagues performed the clinical trial at three public health centers in Spain. Seventy-five of the 78 patients were originally from Bolivia. There were 47 women and 31 men, and the mean age was 39.9 years. A total of 22% had cardiac involvement, 6% had gastrointestinal involvement, and 6% had involvement of multiple organ systems.
These participants were randomly assigned in equal numbers to receive 100-mg posaconazole twice daily, 400-mg posaconazole twice daily, or 150-mg benznidazole twice daily for 60 days. They were followed for 40 weeks after the conclusion of treatment.
All patients responded to all the drugs during active treatment, showing negative results on assays to detect T. cruzi DNA from serial blood samples by day 14. However, parasitic DNA began to be detected in many participants after treatment ended, by day 60, and continued to be found throughout follow-up.
The primary end point of the study was consistently negative results on the T. cruzi DNA assays throughout follow-up. This was achieved by only 2 of 26 patients receiving low-dose posaconazole and only 5 of 26 receiving high-dose posaconazole. In comparison, the primary end point was achieved by 16 of 26 patients receiving benznidazole, the investigators said (N. Engl. J. Med. 2014 May 14 [doi:10.1056/NEJMoa1313122]).
In an intention-to-treat analysis, 92% of patients in the low-dose posaconazole group and 81% in the high-dose posaconazole group tested positive for T. cruzi DNA during follow-up, compared with only 38% of the benznidazole group.
Serious adverse effects forced the withdrawal of treatment in five patients, all of whom were receiving benznidazole. These included severe allergic dermatitis (with anaphylaxis in one patient), other cutaneous reactions, dysgeusia, and leukopenia.
Despite these disappointing results, with posaconazole failing to eliminate T. cruzi DNA in the blood, the drug did show suppressive activity, even at the low dose, throughout the active treatment period. So "it is possible that ergosterol inhibitors could be useful as a partner drug in future combination therapies," the researchers said.
This study was supported by the Ministry of Health, Spain. Dr. Molina and his associates reported no potential conflicts of interest.