Trypanocidal treatment of Chagas disease

Chagas disease is an anthropozoonosis from the American continent that has spread from its original boundaries through migration. It is caused by the protozoan Trypanosoma cruzi, which was identified in the first decade of the 20th century. Once acute infection resolves, patients can develop chronic disease, which in up to 30-40% of cases is characterised by cardiomyopathy, arrhythmias, megaviscera, and, more rarely, polyneuropathy and stroke. Even after more than a century, many challenges remain unresolved, since epidemiological control and diagnostic, therapeutic, and prognostic methods must be improved. In particular, the efficacy and tolerability profile of therapeutic agents is far from ideal. Furthermore, the population affected is older and more complex (eg, immunosuppressed patients and patients with cancer). Nevertheless, in recent years, our knowledge of Chagas disease has expanded, and the international networking needed to change the course of this deadly disease during the 21st century has begun.

Current therapeutic options for Chagas' disease are limited to benznidazole and nifurtimox, which have been associated with low cure rates in the chronic stage of the disease and which have considerable toxicity. Posaconazole has shown trypanocidal activity in murine models. We performed a prospective, randomized clinical trial to assess the efficacy and safety of posaconazole as compared with the efficacy and safety of benznidazole in adults with chronic Trypanosoma cruzi infection. We randomly assigned patients to receive posaconazole at a dose of 400 mg twice daily (high-dose posaconazole), posaconazole at a dose of 100 mg twice daily (low-dose posaconazole), or benznidazole at a dose of 150 mg twice daily; all the study drugs were administered for 60 days. We assessed antiparasitic activity by testing for the presence of T. cruzi DNA, using real-time polymerase-chain-reaction (rt-PCR) assays, during the treatment period and 10 months after the end of treatment. Posaconazole absorption was assessed on day 14. The intention-to-treat population included 78 patients. During the treatment period, all the patients tested negative for T. cruzi DNA on rt-PCR assay beyond day 14, except for 2 patients in the low-dose posaconazole group who tested positive on day 60. During the follow-up period, in the intention-to-treat analysis, 92% of the patients receiving low-dose posaconazole and 81% receiving high-dose posaconazole, as compared with 38% receiving benznidazole, tested positive for T. cruzi DNA on rt-PCR assay (P<0.01 for the comparison of the benznidazole group with either posaconazole group); in the per-protocol analysis, 90% of the patients receiving low-dose posaconazole and 80% of those receiving high-dose posaconazole, as compared with 6% receiving benznidazole, tested positive on rt-PCR assay (P<0.001 for the comparison of the benznidazole group with either posaconazole group). In the benznidazole group, treatment was discontinued in 5 patients because of severe cutaneous reactions; in the posaconazole groups, 4 patients had aminotransferase levels that were more than 3 times the upper limit of the normal range, but there were no discontinuations of treatment. Posaconazole showed antitrypanosomal activity in patients with chronic Chagas' disease. However, significantly more patients in the posaconazole groups than in the benznidazole group had treatment failure during follow-up. (Funded by the Ministry of Health, Spain; CHAGASAZOL ClinicalTrials.gov number, NCT01162967.).

The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven.