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      Experimental and Clinical Treatment of Chagas Disease: A Review

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          Abstract.

          Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

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

          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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            Epidemiology of Chagas disease in non endemic countries: the role of international migration

            Human infection with the protozoa Trypanosoma cruzi extends through North, Central, and South America, affecting 21 countries. Most human infections in the Western Hemisphere occur through contact with infected bloodsucking insects of the triatomine species. As T. cruzi can be detected in the blood of untreated infected individuals, decades after infection took place; the infection can be also transmitted through blood transfusion and organ transplant, which is considered the second most common mode of transmission for T. cruzi. The third mode of transmission is congenital infection. Economic hardship, political problems, or both, have spurred migration from Chagas endemic countries to developed countries. The main destination of this immigration is Australia, Canada, Spain, and the United States. In fact, human infection through blood or organ transplantation, as well as confirmed or potential cases of congenital infections has been described in Spain and in the United States. Estimates reported here indicates that in Australia in 2005-2006, 1067 of the 65,255 Latin American immigrants (16 per 1000) may be infected with T. cruzi, and in Canada, in 2001, 1218 of the 131,135 immigrants (9 per 1000) whose country of origin was identified may have been also infected. In Spain, a magnet for Latin American immigrants since the 2000, 5125 of 241,866 legal immigrants in 2003 (25 per 1000), could be infected. In the United States, 56,028 to 357,205 of the 7,20 million, legal immigrants (8 to 50 per 1000), depending on the scenario, from the period 1981-2005 may be infected with T. cruzi. On the other hand, 33,193 to 336,097 of the estimated 5,6 million undocumented immigrants in 2000 (6 to 59 per 1000) could be infected. Non endemic countries receiving immigrants from the endemic ones should develop policies to protect organ recipients from T. cruzi infection, prevent tainting the blood supply with T. cruzi, and implement secondary prevention of congenital Chagas disease.
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              Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial.

              Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain. To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment. Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups. Chagas disease center in Buenos Aires, Argentina. 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure. The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity. Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients). Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034). Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted. Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.
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                Author and article information

                Journal
                Am J Trop Med Hyg
                Am. J. Trop. Med. Hyg
                tpmd
                tropmed
                The American Journal of Tropical Medicine and Hygiene
                The American Society of Tropical Medicine and Hygiene
                0002-9637
                1476-1645
                08 November 2017
                02 October 2017
                02 October 2017
                : 97
                : 5
                : 1289-1303
                Affiliations
                [ 1 ]Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil;
                [2 ]Infectious Diseases Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, PROSICS Barcelona, Barcelona, Spain;
                [3 ]Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
                Author notes
                [* ]Address correspondence to Policarpo Ademar Sales Junior, Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou–FIOCRUZ, Av. Augusto de lima 1715, Belo Horizonte 30190-009, Brazil. E-mail: policarpoasjunior@ 123456yahoo.com.br

                Authors’ addresses: Policarpo Ademar Sales Junior and Silvane Maria Fonseca Murta, Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, Brazil, E-mails: policarpoasjunior@ 123456yahoo.com.br and silvane@ 123456cpqrr.fiocruz.br . Israel Molina, Adrián Sánchez-Montalvá, and Fernando Salvador, Infectious Diseases Department, Vall d’Hebron University Hospital, Barcelona, Spain, E-mails: israelmolina@ 123456ymail.com , adrian.sanchez.montalva@ 123456gmail.com , and fmsalvad@ 123456vhebron.net . Rodrigo Corrêa-Oliveira, Centro de Pesquisas René Rachou - FIOCRUZ, Laboratório de Imunologia Celular e Molecular, Belo Horizonte, Minas Gerais, Brazil, E-mail: correa@ 123456cpqrr.fiocruz.br . Cláudia Martins Carneiro, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil, E-mail: claudiamartinscarneiro@ 123456gmail.com .

                Article
                tpmd160761
                10.4269/ajtmh.16-0761
                5817734
                29016289
                43ef6ad6-b02f-4b59-88b6-8c89a7cf0b1b
                © The American Society of Tropical Medicine and Hygiene

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 September 2016
                : 24 June 2017
                Page count
                Pages: 15
                Categories
                Review Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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