Randomized Trial of Posaconazole and Benznidazole for Chronic Chagas' Disease

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Abstract

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.).

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Development of a real-time PCR assay for Trypanosoma cruzi detection in blood samples.

Jordi i Prat, Roser Fisa, Natalia Casamitjana … (2007)

The aim of this study was to develop a real-time PCR technique to detect Trypanosoma cruzi DNA in blood of chagasic patients. Analytical sensitivity of the real-time PCR was assessed by two-fold serial dilutions of T. cruzi epimastigotes in seronegative blood (7.8 down to 0.06 epimastigotes/mL). Clinical sensitivity was tested in 38 blood samples from adult chronic chagasic patients and 1 blood sample from a child with an acute congenital infection. Specificity was assessed with 100 seronegative subjects from endemic areas, 24 seronegative subjects from non-endemic area and 20 patients with Leishmania infantum-visceral leishmaniosis. Real-time PCR was designed to amplify a fragment of 166 bp in the satellite DNA of T. cruzi. As internal control of amplification human RNase P gene was coamplified, and uracil-N-glycosylase (UNG) was added to the reaction to avoid false positives due to PCR contamination. Samples were also analysed by a previously described nested PCR (N-PCR) that amplifies the same DNA region as the real-time PCR. Sensitivity of the real-time PCR was 0.8 parasites/mL (50% positive hit rate) and 2 parasites/mL (95% positive hit rate). None of the seronegative samples was positive by real-time PCR, resulting in 100% specificity. Sixteen out of 39 patients were positive by real-time PCR (41%). Concordance of results with the N-PCR was 90%. In conclusion, real-time PCR provides an optimal alternative to N-PCR, with similar sensitivity and higher throughput, and could help determine ongoing parasitaemia in chagasic patients.

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Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches.

Julio Urbina (2009)

A critical review of the development of specific chemotherapeutic approaches for the management of American Trypanosomiasis or Chagas disease is presented, including controversies on the pathogenesis of the disease, the initial efforts that led to the development of currently available drugs (nifurtimox and benznidazole), limitations of these therapies and novel approaches for the development of anti-Trypanosoma cruzi drugs, based on our growing understanding of the biology of this parasite. Among the later, the most promising approaches are ergosterol biosynthesis inhibitors such as posaconazole and ravuconazole, poised to enter clinical trials for chronic Chagas disease in the short term; inhibitors of cruzipain, the main cysteine protease of T. cruzi, essential for its survival and proliferation in vitro and in vivo; bisphosphonates, metabolic stable pyrophosphate analogs that have trypanocidal activity through the inhibition of the parasite's farnesyl-pyrophosphate synthase or hexokinase; inhibitors of trypanothione synthesis and redox metabolism and inhibitors of hypoxanthine-guanine phosphoribosyl-transferase, an essential enzyme for purine salvage in T. cruzi and related organisms. Finally, the economic and political challenges faced by development of drugs for the treatment of neglected tropical diseases, which afflict almost exclusively poor populations in developing countries, are analyzed and recent potential solutions for this conundrum are discussed. 2009 Elsevier B.V. All rights reserved.

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Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease.

Betina Porcel, E. Segura, S Sosa … (1998)

A double-blind, randomized, clinical field trial was designed to test the efficacy and tolerance of a specific drug treatment in children in the indeterminate phase of infection by Trypanosoma cruzi. Children were treated with benznidazole at a dose of 5 mg/kg/day for 60 days or placebo and followed-up for 48 months. The treated children showed a significant decrease in geometric mean titers of antibodies against T. cruzi measured by indirect hemagglutination, indirect immunofluorescence, and ELISA. After a four year follow-up, 62% of the benznidazole-treated children and no placebo-treated child were seronegative for T. cruzi when tested by an ELISA using a T. cruzi flagellar calcium-binding protein (F29). Xenodiagnosis carried out after 48 months of follow-up was positive in 4.7% of the benznidazole-treated children and in 51.2% of the placebo-treated children. These results show the tolerance to and efficacy of benznidazole against T. cruzi in seropositive children six to 12 years of age. We used an early serologic marker of cure after treatment, consisting of a recombinant antigen implemented in a rapid, conventional serologic procedure.