Randomized trial of posaconazole and benznidazole for chronic Chagas' disease.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.).
From the Infectious Disease Department (I.M., F.S., A.S.-M., A.P.), Microbiology Department (E.S.), the Drug Monitoring Unit, Clinical Laboratory (A.B.-G.), and the Clinical Pharmacology Service (X.V.), Vall d'Hebron Teaching Hospital, Special Program for Infectious Diseases, Vall d'Hebron Drassanes (J.G.P., B.T., N.S., D.P., J.C.), International Health Program of the Catalan Institute of Health (PROSICS) Barcelona (I.M., J.G.P., F.S., B.T., E.S., N.S., D.P., J.C., A.S.-M., A.P.), International Health Unit Metropolitana Nord, Infectious Disease Unit, Internal Medicine Department, Germans Trias i Pujol Teaching Hospital (S.R.), and International Health Unit Metropolitana Nord (L.V.), PROSICS Metropolitana Nord, and the Department of Pharmacology, Therapeutics, and Toxicology, Universitat Autònoma de Barcelona, and Fundació Institut Català de Farmacologia, WHO Collaborating Center for Research and Training in Pharmacoepidemiology (X.V.) - all in Barcelona.
Israel
I
Molina
Jordi
J
Gómez i Prat
Fernando
F
Salvador
Begoña
B
Treviño
Elena
E
Sulleiro
Núria
N
Serre
Diana
D
Pou
Sílvia
S
Roure
Juan
J
Cabezos
Lluís
L
Valerio
Albert
A
Blanco-Grau
Adrián
A
Sánchez-Montalvá
Xavier
X
Vidal
Albert
A
Pahissa
D000328:Adult; D014355:Chagas Disease / Q000188:drug therapy*; D002908:Chronic Disease; D016054:DNA, Protozoan / Q000032:analysis; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D000637:Transaminases / Q000097:blood; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects; D014344:Trypanocidal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000302:isolation & purification
D016054:DNA, Protozoan; D009593:Nitroimidazoles; D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D000637:Transaminases; C009999:benzonidazole