Etiological treatment in asymptomatic patients infected with Trypanosoma cruzi . Experience in South-American countries – Argentina

SOSA-ESTANI S

Valencia, España

Simposio; Symposium “Trypanosomes, Triatomines and Chagas Disease: Basic Knowledge and Applied Research”; 2004

IX European Multicolloquium of Parasitology

In the Americas, there are approximately 16 million patients undergoing the indeterminate (IP) and chronic (CP) phases of Chagas´ disease. Patients with Chagas’ infection documented by a positive T. cruzi serology test have a 20%- 30% chance of progressing to dilated cardiomyopathy. At the end of the 1960s several authors have suggested the convenience of administering the treatment with Nifurtimox in the IP and CP (Cerisola 1969, Boca Tourres 1969, Cançado et al. 1969, Cichero et al. 1969). Twenty years of silence passed, because of the recommendation by several authors, about the useless of these drugs to treat patients in IP. Coinciding with the beginning of the control of T. cruzi transmission in the Southern Cone of America, several authors, have worked in south America countries, and have demonstrated through clinical trials, the effect of the specific treatment in the IP and CP.  The trials’ results have shown a decrease of serological titers when using total antigens (Del Barco 1993, Viotti 1994, de Andrade 1996, Fabro 1997, Blanco 1997, Sosa-Estani 1998, 2000); negative serological results using recombinant antigen (Krautz 1995, Sosa-Estani 1998) or a purified mucin-like glycoconjugate from cell-cultured trypomastigotes like antigen (de Andrade 1996, Almeida 1999); negative xenodiagnosis (Cerisola 1977, Del Barco 1993, Coura 1997, Sosa-Estani 1998, 1999, Solari 2001) or PCR (Britto 1999, Solari 2001, Schijman 2003); and a significant decrease of the plasmatic concentration of p-Selectin (Adhesion Molecule) (Laucella 1999). When trypanocidal treatment is used for patients with the late chronic phase, a very slow decrease in antibody titers is observed. Decline in titers may start after 5 or more years, and it depend of age of patients when received the treatment, and how long is the period between the treatment and the control. “Cure” rates (negative serology) between 8% and 70% have been reported in the late chronic phase by investigators who were able to follow this group of patients for such a long period of time (10~20 years) (Sosa-Estani 2000, Cancado 2002, Rassi & Luquetti 2003), and described that the rate of nagativization were higher in children than adults. Villar et al (2002) conducted a meta-analysis of 5 randomized clinical trials, and concluded that antitrypanosomal drugs have a beneficial effect on sero-conversion of patients with chronic CD. Overall, benznidazole reduced the proportion of positive xenodiagnosis in both children and adults by about 80%, and led to a 11-fold increase in the rate of negative sero-conversion. Among the several observational trials evaluating the effect of trypanocidal therapy, some have described ECG changes and clinical progression of cardiac disease he results of such studies are discordant, due to differences in populations, methods of evaluation, therapeutic schemes, duration of follow up, cure evaluation criteria, interpretation of results, and/or posibles regional differences (host, T. cruzi strain, etc), as were described on ’70 (Cerisola 1977). Several authors found that patients treated had a better evolution using as outcome ECGs changes (Viotti 1994, Miranda 1994, Fragata Filho 1995, de Andrade 1996, Fabro 2000, Catalioti & Acquatella 2000, Lauria-Pires 2000, Gallerano-Sosa R 2001, Apt 2003). Meanwhile that others did not abserved differences among treated and untreated patients (Macedo 1987). During the treatment, patients always must be under medical supervision. In our experience the tolerance during the treatment was good and the patients did not show serious side effects (Sosa-Estani 1998, 2004). The side effects observed, included dermal or gastrointestinal manifestations, and less frequently we observed peripheral neurotoxicy. Laboratory tests showed normal bilirrubin values, while rarely elevation of transaminases was observed. We have observed leucopenia once among 600 patients treated. Side effects are more frequently observed in adolescents and adults than in children and babies. In all cases, side effects disappear when the dose is diminished or the treatment is suspended. Ten years later children patients did not show any pathologic sign and symptom for the cardiovascular, digestive, neurological and locomotive system associated to the specific treatment in the clinical examination. These results permitted to the Public Health Authorities from Argentina and Brazil to introduce changes in the guidelines of the specific treatment of T. cruzi infection, after the meeting of Southern American specialists (Brazil: Diaz Gontijo & Costa Rocha, 1998, Argentina: Sosa-Estani & Segura 1999) and after in a PAHO meeting at Rio de Janeiro (PAHO/WHO 1999). Nifurtimox (1972) and Benznidazol (1974) have been accepted by almost all the Latin American Ministries of Health as the specific chemotherapy against T. cruzi. These drugs began to be assessed for the acute phase, and later for the IP of the disease. The goals of specific treatment against T. cruzi infection are to eliminate the parasite from the infected people, to diminish the probability of developing illness (Chagas’ Disease), and to hinder the chain of T. cruzi transmission (Sosa-Estani 1993). The efficacy measured of the specific treatment in the IP or CP of Chagas´ disease, must considerer i. the age of the patient at the moment he/she received the treatment, ii. The time lapsed between treatment and follow-up, iii. The diagnostic tools used, and iv. the region where the patients were infected. Based on the hypothesis that Chagas’ cardiomyopathy may indeed be triggered by persistent parasitic infection (Tarleton 2003) it appears plausible that trypanocidal therapy may delay, reduce or prevent the progression to the disease. This hypothesis needs to be tested in a randomized clinical trial. The search for better drugs than the ones available at this time to find a solution for the 16 million infected people is a challenge for the researchers of America. Meanwhile, Benznidazol and Nifurtimox continue to be the best-studied alternative.