nifurtimox and Chronic-Disease

People with Chagas disease may develop progressive and lethal heart conditions. Drugs to eliminate the parasite Trypanosoma cruzi (T cruzi) currently carry limited therapeutic value and are used in the early stages of the disease. Extending the use of these drugs to treat chronic chagasic cardiomyopathy (CCC) has also been proposed.. To assess the benefits and harms of nitrofurans and trypanocidal drugs for treating late-stage, symptomatic Chagas disease and CCC in terms of blood parasite reduction or clearance, mortality, adverse effects, and quality of life.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS databases on 12 November 2019. We also searched two clinical trials registers, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), on 3 December 2019.. We included randomised controlled trials (RCTs) assessing trypanocidal drugs versus placebo or no treatment for late-stage, symptomatic Chagas disease and CCC.. We conducted the reporting of the review according the standard Cochrane methods. Two review authors independently retrieved articles, performed data extraction, and assessed risk of bias. Any disagreements were resolved by a third review author. We contacted study authors for additional information.. We included two studies in this review update. One RCT randomly assigned 26 participants to benznidazole 5 mg/kg/day; 27 participants to nifurtimox 5 mg/kg/day; and 24 participants to placebo for 30 days. The second RCT, newly included in this update, randomised 1431 participants to benznidazole 300 mg/day for 40 to 80 days and 1423 participants to placebo. We also identified one ongoing study. Benznidazole compared to placebo At five-year follow-up, low quality of the evidence suggests that there may be a benefit of benznidazole when compared to placebo for clearance or reduction of antibody titres (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.14 to 1.37; 1 trial; 1896 participants). We are uncertain about the effects of benznidazole for the clearance of parasitaemia demonstrated by negative xenodiagnosis, blood culture, and/or molecular assays due to very limited evidence. Low quality of the evidence suggests that when compared to placebo, benznidazole may make little to no difference in the risk of heart failure (RR 0.89, 95% CI 0.69 to 1.14; 1 trial; 2854 participants) and ventricular tachycardia (RR 0.80, 95% CI 0.51 to 1.26; 1 trial; 2854 participants). We found moderate quality of the evidence that adverse events increase with benznidazole when compared to placebo (RR 2.52, 95% CI 2.09 to 3.03; 1 trial; 2854 participants). Adverse effects were observed in 23.9% of patients in the benznidazole group compared to 9.5% in the placebo group. The most frequent adverse effects were: cutaneous rash, gastrointestinal symptoms, and peripheral polyneuropathy. No data were available for the outcomes of pathological demonstration of tissue parasites and quality of life. Nifurtimox compared to placebo Data were only available for this comparison for the outcome clearance or reduction of antibody titres, and we are uncertain about the effect due to very limited evidence. Regarding adverse events, one RCT mentioned in a general manner that nifurtimox caused intense adverse events, without any quantification.. There is insufficient evidence to support the efficacy of the trypanocidal drugs benznidazole and nifurtimox for late-stage, symptomatic Chagas disease and CCC.

Topics: Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Placebos; Randomized Controlled Trials as Topic; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease has become a global health problem due to migration of infected people out of Latin America to non-endemic countries. For more than 40 years, only the nitroimidazole compounds Benznidazole and Nifurtimox, have been used for specific treatment of Trypanosoma cruzi infection with disappointing results, specially due to the long duration of treatment and adverse events in the chronic phase. In the last years, ergosterol inhibitors have been also proposed for specific treatment. Different randomized clinical trials were performed for evaluating their treatment efficacy and safety. One of the greatest concerns in clinical trials is to provide an early surrogate biomarker of response to trypanocidal chemotherapy. Serological response is slow and the classical parasitological tests have poor sensitivity and are time-consuming. Nowadays, PCR is the most helpful tool for assessing treatment response in a short period of time. Different protocols of PCR have been developed, being quantitative real time PCR based on amplification of repetitive satellite or minicircle DNA sequences plus an internal amplification standard, the mostly employed strategies in clinical trials. Standardized protocols and the use of an external quality assessment ensure adequate technical procedures and reliable data. Clinical trials have shown a significant reduction in parasite loads, reaching undetectable DNA levels in bloodstream after specific treatment, however events of treatment failure have also been reported. Treatment failure could be due to inadequate penetrance of the drugs into the affected tissues, to the presence of primary or secondary drug resistance of the infecting strains as well as to the existence of dormant parasite variants reluctant to drug action. The early diagnosis of drug resistance would improve clinical management of Chagas disease patients, allowing dictating alternative therapies with a combination of existing drugs or new anti-T. cruzi agents. The aim of this review was to describe the usefulness of detecting T.cruzi DNA by means of real time PCR assays, as surrogate biomarker in clinical trials for evaluating new drugs for CD or new regimens of available drugs and the possibility to detect treatment failure.

Topics: Biomarkers; Chagas Disease; Chronic Disease; Drug Resistance; Humans; Nifurtimox; Nitroimidazoles; Nucleic Acids; Parasite Load; Real-Time Polymerase Chain Reaction; Treatment Failure; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease (CD) is caused by the protozoan parasite

Topics: Animals; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Disease Models, Animal; Drug Compounding; Humans; Incidence; Latin America; Nanoparticles; Nifurtimox; Nitroimidazoles; Observational Studies as Topic; Randomized Controlled Trials as Topic; Tissue Distribution; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). It is endemic in Latin American countries outside the Caribbean. The current criterion for cure in the chronic phase of the disease is the negativization of at least two serological tests such as enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IIF) and indirect hemagglutination assay (IHA). The serological evolution of treated subjects with chronic T. cruzi infection is variable. Treatment failure is indicated by a positive parasitological and/or molecular test (persistence of parasitemia).. To summarize the pattern of response to treatment of parasitological, molecular and serological tests performed during the follow-up of subjects with chronic T. cruzi infection.. Electronic searches in relevant databases and screening of citations of potentially eligible articles were accomplished. Organizations focusing on neglected infectious diseases were asked for help in identifying relevant studies. Included studies were randomized controlled trials (RCTs), quasi-RCTs, and cohort studies involving adults and children with chronic infection who received trypanocidal treatment (benznidazole or nifurtimox) and were followed over time. The assessment of risk of bias was performed separately for each study design. The Cochrane Collaboration's tool and the guidelines developed by Hayden et al. were used. Two reviewers extracted all data independently. A third review author was consulted in case of discordant opinion. Additional analyses were defined in ad-hoc basis. Scatter plots for percentage of positive parasitological and molecular tests and for negative serological tests were developed by using the lowess curve technique. Heterogeneity was measured by I2. The protocol was registered in PROSPERO, an international prospective register of systematic review protocols (Registration Number CRD42012002162).. Out of 2,136 citations screened, 54 studies (six RCTs and 48 cohort studies) were included. The smoothed curves for positive xenodiagnosis and positive polymerase chain reaction (PCR) were characterized by a sharp decrease at twelve month posttreatment. Afterwards, they reached 10-20% and 40% for xenodiagnosis and PCR, respectively. The smoothed curves for negative conventional serological tests increased up to 10% after 48 months of treatment. In the long-term, the rate of negativization was between 20% and 45%. The main sources of bias identified across cohort studies were the lack of control for confounding and attrition bias. In general, RCTs were judged as low risk of bias in all domains. The level of heterogeneity across included studies was moderate to high. Additional analysis were incomplete because of the limited availability of data. In this regard, the country of origin of study participants might affect the results of parasitological and molecular tests, while the level of risk of bias might affect serological outcomes. Subgroup analysis suggested that seronegativization occurs earlier in children compared to adults.. We acknowledge that there is a dynamic pattern of response based on parasitological, molecular and serological tests in subjects chronically infected with T. cruzi after treatment. Our findings suggest a trypanocidal effect in the long-term follow-up. Further research is needed to explore potential sources of heterogeneity and to conduct reliable subgroup analysis.

Topics: Adult; Antibodies, Protozoan; Chagas Disease; Child; Chronic Disease; Cohort Studies; Disease Progression; DNA, Protozoan; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Hemagglutination Tests; Humans; Nifurtimox; Nitroimidazoles; Parasitemia; Randomized Controlled Trials as Topic; Treatment Failure; Trypanocidal Agents; Trypanosoma cruzi; Xenodiagnosis

Most Chagas patients belong to the chronic indeterminate stage, in which pharmacological treatment has an inconclusive outcome.. To evaluate the efficacy of nifurtimox treatment in chronic asymptomatic Trypanosoma cruzi infection.. We performed a systematic review and meta-analysis of electronically published literature, with no language, type of study, age or gender restrictions, until September 2010. Studies of chronic asymptomatic Chagas disease patients treated exclusively with nifurtimox were included in the analysis. Treatment efficacy was evaluated using parasitological or serological parameters.. Of 463 identified studies, 7 were finally selected: 6 observational studies and 1 randomized clinical trial; 4 of the studies were in adults, 3 in children < 14 years. In 6 studies, outcomes were defined by serological techniques. Summary estimate (log odds) was 0.37 (CI9 -1.32 - 2.07).. The analyzed studies gave discordant results. Those might be explained by differences in the populations studied, follow-up periods, diagnostic techniques, and sample size. More studies are necessary to obtain conclusive results about treatment efficacy of nifurtimox in this clinical phase of T. cruzi infection.

Topics: Adult; Chagas Disease; Child; Chronic Disease; Humans; Nifurtimox; Treatment Outcome; Trypanocidal Agents

Chagas disease, also known as American trypanosomiasis, is a chronic infection caused by Trypanosoma cruzi, a protozoan parasite. It is transmitted to human beings mainly through the feces of infected triatomine bugs. The disease affects an estimated 8 to 10 million people in the Americas, putting them at risk of developing life-threatening cardiac and gastrointestinal complications. This article provides a brief update on the epidemiology, clinical manifestations, diagnosis, and treatment of Chagas disease.

Topics: Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Topics: Adult; Animals; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Disease Progression; Electrocardiography; Female; Humans; Life Cycle Stages; Nifurtimox; Nitroimidazoles; Practice Guidelines as Topic; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease must be treated in all its stages: acute, indeterminate, chronic, and initial and middle determinant chronic, due to the fact that DNA of the parasite can be demonstrated by PCR in chronic cases, where optical microscopy does not detect parasites. Nifurtimox (NF) and benznidazole (BNZ) are the drugs accepted to treat humans based upon ethical considerations and efficiency. However, both the drugs produce secondary effects in 30% of the cases, and the treatment must be given for at least 30-60 days. Other useful drugs are itraconazole and posaconazole. The latter may be the drug to treat Chagas disease in the future when all the investigations related to it are finished. At present, there is no criterion of cure for chronic cases since in the majority, the serology remains positive, although it may decrease. In acute cases, 70% cure with NF and 75% with BNZ is achieved. In congenital cases, 100% cure is obtained if the treatment is performed during the first year of life. In chronic acquired cases, 20% cure and 50% improvement of the electrocardiographic changes are obtained with itraconazole.

Topics: Acute Disease; Animals; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Time Factors; Treatment Outcome; Trypanocidal Agents

There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.

Topics: Acute Disease; Animals; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Humans; Mice; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease, an infection caused by a protozoan parasite and previously endemic to Mexico and Central and South America, is becoming more prevalent in the United States and Canada. Because nurses and physicians in health care settings may be the first to encounter undiagnosed cases of Chagas disease, it is essential that public health personnel and health care providers in general become more familiar with the disease, including its incidence and prevalence, clinical manifestations, diagnostic criteria, treatment options, and implications for nursing.

Topics: Acute Disease; Animals; Canada; Chagas Disease; Chronic Disease; Emigration and Immigration; Hispanic or Latino; Humans; Immunologic Tests; Incidence; Insect Control; Insect Vectors; Nifurtimox; Nitroimidazoles; Nurse's Role; Prevalence; Primary Prevention; Risk Factors; South America; Travel; Triatoma; Trypanocidal Agents; United States

People with Chagas disease (American Trypanosomiasis) may develop progressive and potentially lethal heart conditions. Drugs to eliminate the causative parasite, Trypanosoma cruzi, currently in use have limited therapeutic value and are used in early stages of the disease. Extending the use of these drugs to treat symptomatic chronic parasitism with chronic Chagasic cardiopathy (CCC) and progressive dilated cardiomyopathy has been proposed.. To assess the effects (harms and benefits) of nitrofurans and imidazolic trypanocidal drugs for treating late stage chronic Chagas disease and CCC.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3, 2004), MEDLINE (1985-2004), EMBASE (1985-2004), BIREME (1985-2004), LILACS (1985-2004), ARTEMISA (1985-2004), SCIELO (1985-2004). Indexing terms in English and Spanish were used. References obtained were assessed for relevance by two reviewers independently.. We included randomized controlled clinical trials (RCTs), single or double blind using trypanocidal drugs versus placebo or no treatment in CCC.. All articles retrieved were assessed using a predefined check list to determine if they met the inclusion criteria. Two independent reviewers collected data using a pre-designed form piloted on three articles before the review process started. Disagreements were resolved by a third reviewer. If the information was unavailable the articles were excluded. We planned a quantitative analysis of reduction of parasite load whether recorded as a categorical variable or the reduction of specific antibody titers. However insufficient data were available for quantitative analysis. We prepared a qualitative description of data identified.. We found only one randomized double blind placebo controlled trial. We also found six uncontrolled or non-randomized studies which were of some relevance and were therefore described. We found insufficient evidence to define the effects of drug treatment for people with CCC.. There is insufficient evidence to support the efficacy of nitrofurans or imidazolic drugs as recommended treatment in CCC and chronic T.cruzi infections, specifically if overt heart disease is present. A well designed randomized controlled trial is necessary to establish if new drugs are suitable for treatment of cardiac patients with CCC.

Topics: Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Humans; Imidazoles; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Chagas disease, a vector-borne parasitosis caused by Trypanosoma cruzi, is endemic to Latin America and has spread to other countries due to immigration of infected persons. It is estimated that 160,000 people are infected in Chile, most of them in the chronic phase and without etiological treatment. The infection is confirmed by conventional serological methods while molecular methods have become in valuable tools to evaluate parasitemia in treated and non-treated chronic Chagas disease patients. The objective of this study was to determine, by conventional Polymerase Chain Reaction, the presence of T. cruzi kinetoplastid DNA in peripheral blood samples from 114 adult individuals with confirmed chronic Chagas disease, before and 6.6 years (average) after treatment with nifurtimox. The samples were received and preserved in guanidine-EDTA until DNA purification. Conventional PCR assays were performed in triplicate with T. cruzi kinetoplastid DNA primers 121 and 122. The amplified products were fractionated by electrophoresis in 2% agarose gels. A 330 bp product represented a positive assay. 84.2% (96 cases) and 6.1% (7 cases) of the samples taken before and after the treatment, respectively, were positive. The McNemar test showed a statistically significant difference between the groups of samples (p<0.001). Since serological negativization (the current cure criterion) delay many years after therapy and positive parasitological results represent a treatment failure, the conversion of pre-therapy positive conventional PCR is a qualitative and complementary tool that could be included in protocols of prolonged follow-up.

Topics: Adolescent; Adult; Aged; Chagas Cardiomyopathy; Chile; Chronic Disease; DNA, Protozoan; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nifurtimox; Polymerase Chain Reaction; Treatment Failure; Trypanosoma cruzi

Laboratory and animal studies have demonstrated that pyrazolopyrimidines have significant activity against Trypanosoma cruzi. This clinical investigation was to ascertain the efficacy of allopurinol in the treatment of chronic Chagas' disease. Of 307 patients studied, 91 were untreated; the remaining 216 were divided into 4 treatment groups. These corresponded to 600 or 900 mg/day of allopurinol for 60 days and benznidazole or nifurtimox at conventional dosage regimens. Patients were evaluated clinically, serologically, and parasitologically. Allopurinol was found to be as efficacious as the conventional therapeutic modalities in eliminating the parasitemia and rendering patients seronegative. Adverse reactions occurred in 11% of patients who received allopurinol and in 30% of those receiving nitrofurans. Reactions with the conventional therapy were more frequent and of a more serious nature. Oral allopurinol is as effective as the nitrofurans, but has none of the side effects.

Topics: Adult; Allopurinol; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Allopurinol; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

A drawback in the treatment of chronic Chagas disease (American trypanosomiasis) is the long time required to achieve complete loss of serological reactivity, the standard for determining treatment efficacy.. Antibody-secreting cells and memory B cells specific for Trypanosoma cruzi and their degree of differentiation were evaluated in adult and pediatric study participants with chronic Chagas disease before and after etiological treatment.. T. cruzi-specific antibody-secreting cells disappeared from the circulation in benznidazole or nifurtimox-treated participants with declining parasite-specific antibody levels after treatment, whereas B cells in most participants with unaltered antibody levels were low before treatment and did not change after treatment. The timing of the decay in parasite-specific antibody-secreting B cells was similar to that in parasite-specific antibodies, as measured by a Luminex-based assay, but preceded the decay in antibody levels detected by conventional serology. The phenotype of total B cells returned to a noninfection profile after successful treatment.. T. cruzi-specific antibodies in the circulation of chronically T. cruzi-infected study participants likely derive from both antigen-driven plasmablasts, which disappear after successful treatment, and long-lived plasma cells, which persist and account for the low frequency and long course to complete seronegative conversion in successfully treated participants.

Topics: B-Lymphocytes; Chagas Disease; Chronic Disease; Humans; Nifurtimox; Nitroimidazoles; Persistent Infection; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox is indicated in Chagas disease but determining its effectiveness in chronic disease is hindered by the length of time needed to demonstrate negative serological conversion. We manually reviewed long-term follow-up data from hospital records of patients with chronic Chagas disease (N = 1,497) in Argentina diagnosed during 1967-1980. All patients were aged ≥18 years at diagnosis and were either treated with nifurtimox (n = 968) or received no antitrypanosomal treatment (n = 529). The primary endpoint was negative seroconversion (the "event"), defined as a change from positive to negative in the serological or parasitological laboratory test used at diagnosis. Time to event was from baseline visit to date of endpoint event or censoring. The effectiveness of nifurtimox versus no treatment was estimated with Cox proportional hazard regression using propensity scores with overlap weights to calculate the hazard ratio and 95% confidence interval. The nifurtimox group was younger than the untreated group (mean, 32.4 vs. 40.3 years), with proportionally fewer females (47.9% vs. 60.1%), and proportionally more of the nifurtimox group than the untreated group had clinical signs and symptoms of Chagas disease at diagnosis (28.9% vs. 14.0%). Median maximum daily dose of nifurtimox was 8.0 mg/kg/day (interquartile range [IQR]: 8.0-9.0) and median treatment duration was 44 days (IQR: 1-90). Median time to event was 2.1 years (IQR: 1.0-4.5) for nifurtimox-treated and 2.4 years (IQR: 1.0-4.2) for untreated patients. Accounting for potential confounders, the estimated hazard ratio (95% confidence interval) for negative seroconversion was 2.22 (1.61-3.07) favoring nifurtimox. Variable treatment regimens and follow-up duration, and an uncommonly high rate of spontaneous negative seroconversion, complicate interpretation of this epidemiological study, but with the longest follow-up and largest cohort analyzed to date it lends weight to the benefit of nifurtimox in adults with chronic Chagas disease. Trial registration: The study protocol was registered at ClinicalTrials.gov: NCT03784391.

Topics: Adult; Antibodies, Protozoan; Argentina; Chagas Disease; Chronic Disease; Female; Humans; Male; Middle Aged; Nifurtimox; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Chagas disease remains a significant public health problem in Latin America. There are only two chemotherapy drugs, nifurtimox and benznidazole, and both may have severe side effects. After complete chemotherapy of acute cases, seropositive diagnosis may revert to negative. However, there are no definitive parasitological or serological biomarkers of cure.. Following a pilot study with seven Bolivian migrants to Spain, we tested 71 serum samples from chronic patients (mean age 12.6 years) inhabiting the Argentine Chaco region. Benznidazole chemotherapy (5-8 mg/kg day, twice daily for 60 days) was administered during 2011-2016. Subsequently, pre-and post-chemotherapy serum samples were analysed in pairs by IgG1 and IgG ELISA using two different antigens and Chagas Sero K-SeT rapid diagnostic tests (RDT). Molecular diagnosis by kDNA-PCR was applied to post-treatment samples.. Pilot data demonstrated IgG1 antibody decline in three of seven patients from Bolivia 1 year post-treatment. All Argentine patients in 2017 (averaging 5 years post-treatment), except one, were positive by conventional serology. All were kDNA-PCR-negative. Most (91.5%) pre-treatment samples were positive by the Chagas Sero K-SeT RDT, confirming the predominance of TcII/V/VI. IgG1 and IgG of Argentine patients showed significant decline in antibody titres post-chemotherapy, with either lysate (IgG, P = 0.0001, IgG1, P = 0.0001) or TcII/V/VI peptide antigen (IgG, P = 0.0001, IgG1, P = 0.0001). IgG1 decline was more discriminative than IgG. Antibody decline after treatment was also detected by the RDT. Incomplete treatment was associated with high IgG1 post-treatment titres against lysate (P = 0.013), as were IgG post-treatment titres to TcII/V/VI peptide (P = 0.0001). High pre-treatment IgG1 with lysate was associated with Qom ethnicity (P = 0.045). No associations were found between gender, age, body mass index and pre- or post-treatment antibody titres.. We show that following chemotherapy of early chronic Chagas disease, significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure. We show that following chemotherapy of early chronic Chagas disease, a significant decline in IgG1 antibody suggests cure, whereas sustained or increased IgG1 is a potential indicator of treatment failure. Due to restricted sensitivity, IgG1 should not be used as a diagnostic marker but has promise, with further development, as a biomarker of cure.

Topics: Adolescent; Antibodies, Protozoan; Chagas Disease; Chronic Disease; Cohort Studies; Female; Humans; Immunoglobulin G; Immunologic Tests; Male; Molecular Diagnostic Techniques; Nifurtimox; Nitroimidazoles; Pilot Projects; Time Factors; Trypanocidal Agents; Trypanosoma cruzi

The immunodominant B13 protein of Trypanosoma cruzi is found on the surface of trypomastigotes and exhibits cross-reactivity with the human cardiac myosin heavy chain; for which antibodies against this parasitic antigen may be involved in the development of disease pathology. In a cohort of chronically T. cruzi-infected adults, undergoing trypanocidal treatment, or not, we, therefore, decided to evaluate the levels of anti-B13 antibodies (ELISA-B13) and its eventual relationship with heart complaints. Two hundred twenty-eight serum samples from 76 chronically infected adults with an average follow-up of 24 years were analyzed. Thirty of them had received trypanocidal treatment. Among treated patients, anti-B13 Ab levels in successive samples showed a significant decrease in reactivity as the years after treatment increased (ANOVA test, p = 0.0049). At the end of the follow-up, 36.7% became non-reactive for ELISA B13. Untreated patients did not have significant variations in the level of anti-B13 antibodies during follow-up. None of the treated patients had electrocardiographic changes compatible with chronic chagasic cardiomyopathy, whereas 21.7% of those undergoing no treatment did show such kind of pathological electrocardiogram tracings. ELISA-B13 was reactive in all cases with heart involvement. Among untreated patients, there were no significant differences in anti-B13 antibodies when comparing individuals without proven pathology with those with chronic chagasic cardiomyopathy. Although treatment with trypanocidal drugs was followed by decreased anti-B13 antibody levels, such assessment was unhelpful in differentiating the evolution of chronic chagasic heart disease.

Topics: Adult; Animals; Antibodies, Protozoan; Antigens, Protozoan; Argentina; Chagas Disease; Chronic Disease; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Nifurtimox; Nitroimidazoles; Retrospective Studies; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Current options for Chagas' disease treatment are restricted to benznidazole and nifurtimox. To the best of our knowledge, no study has ever compared their tolerance in adults in a non-endemic country.. To compare the completion rates and drug tolerance in a cohort of patients treated according to current guidelines.. We analysed the medical records of all Chagas' disease patients aged 18 years or over who started antiparasitic treatment at the Geneva University Hospitals, Switzerland, from 2008 to 2016. We recorded treatment duration and all adverse events.. We included 176 patients, 92 and 84 of whom received benznidazole or nifurtimox, respectively. The overall treatment completion rate was 62.5%, without a significant difference between the groups (P=0.436). Most patients (89.8%) suffered at least one adverse event. Those receiving nifurtimox had more events (6.2 versus 3.5, P<0.001). Mucocutaneous symptoms predominated in the benznidazole group, whereas digestive symptoms were most frequent with nifurtimox. Neuropsychiatric events frequently occurred in both groups, most notably in patients receiving nifurtimox. Arthralgia, dyspnoea, sensitive neuropathy and pruritus were independent predictors of treatment interruption.. Currently recommended drug regimens for Chagas' disease are not well tolerated and entail frequent treatment discontinuation irrespective of the drug used. This highlights the need to improve treatment tolerance in adults with Chagas' disease with new therapeutic options.

Topics: Adult; Chagas Disease; Chronic Disease; Drug Tolerance; Humans; Nifurtimox; Nitroimidazoles; Switzerland; Trypanocidal Agents; Trypanosoma cruzi

Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects. Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no tests-of-cure either, which greatly undermines patients follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite- and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

Topics: Biomarkers; Chagas Disease; Chronic Disease; Gastrointestinal Tract; Heart; Host-Parasite Interactions; Humans; Nifurtimox; Nitroimidazoles; Prognosis; Treatment Outcome; Trypanosoma cruzi

In the indeterminate chronic period of Chagas disease (ChD) the treatment has not been conclusive, because the serological negativization requires many years. This study aims to evaluate the efficacy of nifurtimox (NF) in the treatment of chronic ChD in prolonged follow-up by serological techniques of indirect immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA) IgG comparing 2 groups of patients, treated and non treated. Mann-Whitney test was performed for ELISA and IFA, with significant difference between the groups (P < 0.05). IgG levels were lower in individuals treated compared with untreated patients, indicating chemotherapeutic efficacy in prolonged follow-up.

Topics: Antibodies, Protozoan; Chagas Disease; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Humans; Immunoglobulin G; Male; Middle Aged; Nifurtimox; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole.. We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs.. A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths.. Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.

Topics: Adult; Chagas Disease; Chronic Disease; Cohort Studies; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Prospective Studies; Retreatment; Trypanosoma cruzi

Chagas disease is a parasite infection primarily transmitted to humans via the bite of triatomine insect vectors. Up to 8 million people are estimated to be infected with Chagas disease in the Americas. Patients who do not receive treatment can develop severe cardiac debility, gastrointestinal organ dysfunction, and may die. The changing demographics of the United States, a consequence of changing immigration patterns, means that healthcare providers are more likely to encounter patients with Chagas disease, and must understand its cause, pathogenesis, diagnosis, and treatment.

Topics: Acute-Phase Reaction; Cardiomyopathies; Chagas Disease; Chronic Disease; Diagnosis, Differential; Female; Humans; Male; Megacolon; Nifurtimox; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi; United States

Nifurtimox (NFX) is one of the approved drugs used to treat Chagas disease. Safety profile studies and models on risk factors for treatment interruption in adults are scarce in Latin America. This study evaluated retrospectively the medical records of adult Chagas disease patients treated with NFX between 2007 and 2012 in Bogotá, Colombia. An accelerated failure time model was used, and associations were expressed as time ratio (TR). In total, 76 adult patients with NFX were included: 60 (79.0%) completed 60 days of treatment, 61 (80.3%) presented adverse drug reactions (ADRs), and 16 (21.0%) required treatment interruption. The predominant symptoms were epigastric pain (23.7%), nauseas (18.4%), sleep disturbances (18.4%), loss of appetite (17.1%), and temporary loss of memory (15.2%). ADRs were classified as mild (64.5%), moderate (30.4%), and severe (5.1%). Time of treatment was significantly longer when presenting ≤ 3 ADRs (TR: 1.78; 95% CI: 1.04-3.03), presence of non-severe ADRs (TR: 6.52; 95% CI: 3.24-13.1), doses of NFX ≤ 8 mg/kg/day (TR: 1.78; 95% CI: 0.90-3.49), and age < 48 years (TR: 1.57; 95% CI: 0.90-2.74). Treatment with NFX in adults caused a high frequency of ADRs, but most of the cases were mild and did not require treatment interruption. Severity and number of ADRs were the main predictors for treatment interruption.

Topics: Adolescent; Adult; Aged; Antiprotozoal Agents; Chagas Disease; Chronic Disease; Colombia; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Nifurtimox; Retrospective Studies; Time Factors; Young Adult

Treatment for Chagas disease with currently available medications is recommended universally only for acute cases (all ages) and for children up to 14 years old. The World Health Organization, however, also recommends specific antiparasite treatment for all chronic-phase Trypanosoma cruzi-infected individuals, even though in current medical practice this remains controversial, and most physicians only prescribe palliative treatment for adult Chagas patients with dilated cardiomyopathy. The present opinion, prepared by members of the NHEPACHA network (Nuevas Herramientas para el Diagnóstico y la Evaluación del Paciente con Enfermedad de Chagas/New Tools for the Diagnosis and Evaluation of Chagas Disease Patients), reviews the paradigm shift based on clinical and immunological evidence and argues in favor of antiparasitic treatment for all chronic patients. We review the tools needed to monitor therapeutic efficacy and the potential criteria for evaluation of treatment efficacy beyond parasitological cure. Etiological treatment should now be mandatory for all adult chronic Chagas disease patients.

Topics: Adolescent; Adult; Antibodies, Protozoan; Chagas Cardiomyopathy; Child; Chronic Disease; Disease Management; Drug Administration Schedule; Humans; Nifurtimox; Nitroimidazoles; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

With declining vectorial transmission, Chagas disease predominantly affects adults nowadays. The efficacy of nifurtimox in the chronic phase in adult patients is poorly known, particularly in regions where there is no risk of reinfection. Recommendations for treatment outcome assessment rely on serological follow-up. We evaluated the serological and parasitological response to nifurtimox in a cohort of adult patients three years post-treatment in Switzerland.. Patients treated with nifurtimox in 2008 during a cross-sectional study in Geneva, Switzerland, were contacted for follow-up in 2011. Two ELISAs and a rapid immunochromatographic test were used to test 2008 and 2011 serum samples simultaneously. In addition, conventional and real-time PCR were performed on 2011 samples.. Thirty-seven (84.1%) of 44 eligible patients, predominantly female, middle-aged, Bolivians at the indeterminate stage, were enrolled. All 2011 ELISA and immunochromatographic tests were positive. Twenty-eight (75.7%) patients presented a lower optical density (OD) in 2011 compared to 2008. This OD difference was significant in both commercial (P < 0.001) and in-house (P = 0.002) ELISAs. Agreement between the two ELISAs was low (Kappa = 0.469). All patients had negative conventional PCR results but one (2.7%) was positive with real-time PCR.. Our results highlight the inadequacy of serology for assessing response in adults, three years after treatment. In our cohort, 97.3% had results that could either indicate treatment failure or persistant humoral response despite treatment. The lack of accurate early post-treatment tests of cure prevents appropriate patients information and councelling. New follow-up tests are needed to assess treatments efficacy given the large adult population in need of antiparasitic therapy.

Topics: Adult; Chagas Disease; Chronic Disease; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nifurtimox; Real-Time Polymerase Chain Reaction; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

This work compared the time at which negative seroconversion was detected by conventional serology (CS) and by the ELISA-F29 test on a cohort of chronic chagasic patients treated with nifurtimox or benznidazole. A retrospective study was performed using preserved serum from 66 asymptomatic chagasic adults under clinical supervision, and bi-annual serological examinations over a mean follow-up of 23 years. Twenty nine patients received trypanocide treatment and 37 remained untreated. The ELISA-F29 test used a recombinant antigen which was obtained by expressing the Trypanosoma cruzi flagellar calcium-binding protein gene in Escherichia coli. Among the untreated patients, 36 maintained CS titers. One patient showed a doubtful serology in some check-ups. ELISA-F29 showed constant reactivity in 35 out of 37 patients and was negative for the patient with fluctuating CS. The treated patients were divided into three groups according to the CS titers: in 13 they became negative; in 12 they decreased and in four they remained unchanged. ELISA-F29 was negative for the first two groups. The time at which negativization was detected was significantly lower for the ELISA-F29 test than for CS, 14.5 ± 5.7 and 22 ± 4.9 years respectively. Negative seroconversion was observed in treated patients only. The results obtained confirm that the ELISA-F29 test is useful as an early indicator of negative seroconversion in treated chronic patients.

Topics: Adolescent; Adult; Antibodies, Protozoan; Antigens, Protozoan; Case-Control Studies; Chagas Disease; Chronic Disease; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Nifurtimox; Nitroimidazoles; Retrospective Studies; Time Factors; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; Young Adult

Currently, evaluation of drug efficacy for Chagas disease remains a controversial issue with no consensus. In this work, we evaluated the parasitological efficacy of Nifurtimox treatment in 21 women with chronic Chagas disease from an area of endemicity in Chile who were treated according to current protocols. Under pre- and posttherapy conditions, blood (B) samples and xenodiagnosis (XD) samples from these patients were subjected to analysis by real-time PCR targeting the nuclear satellite DNA of Trypanosoma cruzi (Sat DNA PCR-B, Sat DNA PCR-XD) and by PCR targeting the minicircle of kinetoplast DNA of T. cruzi (kDNA PCR-B, kDNA PCR-XD) and by T. cruzi genotyping using hybridization minicircle tests in blood and fecal samples of Triatoma infestans feed by XD. In pretherapy, kDNA PCR-B and kDNA PCR-XD detected T. cruzi in 12 (57%) and 18 (86%) cases, respectively, whereas Sat DNA quantitative PCR-B (qPCR-B) and Sat DNA qPCR-XD were positive in 18 cases (86%) each. Regarding T. cruzi genotype analysis, it was possible to observe in pretherapy the combination of TcI, TcII, and TcV lineages, including mixtures of T. cruzi strains in most of the cases. At 13 months posttherapy, T. cruzi DNA was detectable in 6 cases (29.6%) and 4 cases (19.1%) by means of Sat DNA PCR-XD and kDNA PCR-XD, respectively, indicating treatment failure with recovery of live parasites refractory to chemotherapy. In 3 cases, it was possible to identify persistence of the baseline genotypes. The remaining 15 baseline PCR-positive cases gave negative results by all molecular and parasitological methods at 13 months posttreatment, suggesting parasite response. Within this follow-up period, kDNA PCR-XD and Sat DNA qPCR-XD proved to be more sensitive tools for the parasitological evaluation of the efficacy of Nifurtimox treatment than the corresponding PCR methods performed directly from blood samples.

Topics: Adult; Animals; Chagas Disease; Chronic Disease; DNA, Protozoan; Female; Genotyping Techniques; Humans; Middle Aged; Nifurtimox; Polymerase Chain Reaction; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

American Trypanosomiasis or Chagas Disease is a major public health problem, endemic in the American continent since prehistoric times. Its natural course is towards chronicity in the immunocompetent host, often leading to severe cardiopathy or bowel involvement. Pharmacologic therapy is restricted to two drugs and only one of them is currently available in Chile. Both have poor effectiveness in the chronic stages of the disease and cause frequent adverse reactions. Many physicians avoid their use, despite published evidences about the usefulness. We herein report the experience of our Center in the treatment of Chronic Chagas Disease in adults using the drug nifurtimox, emphasizing its degree of acceptability and its secondary effects.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chagas Disease; Chile; Chronic Disease; Female; Humans; Male; Medication Adherence; Middle Aged; Nifurtimox; Trypanocidal Agents; Young Adult

We investigated the relationship between potentially pathogenic antibodies against a Trypanosoma cruzi ribosomal protein (P2β) and the evolution of Chagas disease and the effect of trypanocidal treatment on these variables. Seventy-eight patients with chronic Chagas disease who were followed-up for more than 20 years were divided into three groups: 30 asymptomatic persons undergoing specific treatment (group A), 37 asymptomatic persons not undergoing specific treatment (group B), and 11 patients with chronic chagasic cardiomyopathy (CCC) who were not treated. Five patients in group B showed evolution to myocardial abnormalities. Among persons with CCC, six showed no changes; the remaining persons showed progression of cardiac involvement. Levels of antibodies to P2β in persons in group A decreased from their initial values. This finding was not observed in persons in groups B and C. Comparisons at the end of the follow-up showed lower amounts of antibodies to P2β in groups A and C. These findings support the benefits of specific treatment during chronic infection.

Topics: Animals; Antibodies, Protozoan; Cardiomyopathies; Chagas Disease; Chronic Disease; Female; Humans; Immunity, Humoral; Male; Nifurtimox; Nitroimidazoles; Protozoan Proteins; Ribosomal Proteins; Trypanocidal Agents; Trypanosoma cruzi

Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity.. This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0.. Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5).. Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced.

Topics: Adolescent; Adult; Aged; Chagas Disease; Chronic Disease; Female; Humans; Kaplan-Meier Estimate; Latin America; Longitudinal Studies; Male; Medication Adherence; Middle Aged; Nifurtimox; Switzerland; Trypanocidal Agents

Topics: Antiparasitic Agents; Chagas Disease; Child; Chronic Disease; Humans; Nifurtimox

With the exception of assays for the detection of antibodies promoting complement-mediated lysis of Trypanosoma cruzi, serologic tests have generally failed to assess the effectiveness of chemotherapy for Chagas' disease. Conventional serology, although useful for the diagnosis of infection, is not capable of determining which patients have been cured. Here we demonstrate that a high proportion of antibodies detected by conventional serology (using fixed epimastigotes or trypomastigotes or crude extracts obtained therefrom) are directed against the carbohydrate residue galactosyl alpha 1- > 3 galactose (Gal alpha 1- > 3 Gal), a determinant also recognized by antibodies from noninfected healthy volunteers. In a study of 14 cured patients with long-term followup, we found that the persistently positive reactions detected using conventional serology were largely eliminated following immunoadsorption with melibiose. Because of their wide distribution among microorganisms of intestinal and pulmonary microflora, these carbohydrate determinants may keep stimulating lymphocytes previously primed by T. cruzi Gal alpha 1- > 3 Gal epitopes, thereby accounting for false-positive results in cured patients. Consistent with this proposition, enzyme-linked immunosorbent assays performed with two distinct T. cruzi antigen preparations that lack the Gal alpha 1- > 3 Gal epitope, namely purified GP57/51 and trypomastigote-shed antigens, were indeed capable of determining a cure after chemotherapy, albeit to a different degree. Collectively, the data indicate that conventional immunoassays prepared with highly specific T. cruzi antigens can be useful in the assessment of a cure after chemotherapy.

Topics: Acute Disease; Adsorption; Adult; Animals; Antibodies, Protozoan; Antibody Specificity; Antigens, Protozoan; Chagas Disease; Child; Chronic Disease; Cross Reactions; Cysteine Endopeptidases; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Follow-Up Studies; Glycoproteins; Humans; Middle Aged; Nifurtimox; Nitroimidazoles; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi

Topics: Animals; Chagas Disease; Chronic Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Mice; Nifurtimox; Protozoan Infections; Toxoplasmosis; Trypanosoma cruzi

Topics: Animals; Antiprotozoal Agents; Choroid Plexus; Chronic Disease; Diminazene; Mice; Nifurtimox; Trypanosoma brucei brucei; Trypanosomiasis, African

Topics: Adult; Aged; Antineoplastic Agents; Chagas Disease; Chronic Disease; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Neoplasms; Nifurtimox; Prednisone