Drugs against parasites for prevention of Chagas heart disease

Background

Chagas disease is a form of heart disease that develops after decades of infection with a parasite called Trypanosoma cruzi. In addition to avoiding transmission of the parasites (through contact with insects in rural areas of many central and south American countries, blood transfusion, organ transplants from infected individuals or vertical transmission to newborns), one of the actions for prevention of Chagas disease is treating the estimated seven to 12 million infected individuals with medications against the parasites (trypanocidal therapy, or TT for short).

Despite the enthusiasm for using TT, there are limitations including uncertainty on its efficacy, poor tolerance and limited production of the conventional drugs. This review presents data from the studies evaluating the impact of TT on the tests looking at the presence of the parasites, the outcome of the infected individual and the tolerance to this short term (i.e. two to three months) treatment.

Study characteristics

We searched scientific databases for studies comparing TT versus a placebo (an inactive or pretend treatment) or no treatment in people with Trypanosoma cruzi infection. The search is current to February 2014.

Key results

We identified 13 studies comparing the outcomes of 4229 people after receiving TT or placebo. Five of these studies were from Argentina, five from Brazil, one from Venezuela, one from Chile and one from Bolivia.

Receiving TT was associated with a 50% to 90% smaller chance of having circulating antibodies or parasitic material, as compared with non-treated people. However, the results on progression towards Chagas disease or death indicate smaller benefits. Furthermore, the results were also statistically inconclusive, did not rule out potential harm and had substantial variation across studies conducted in different countries or testing different drugs. About one in five individuals treated abandoned the treatment and one in 40 treated individuals had a severe reaction (needing hospitalisation, additional treatments or interruption of this treatment).

We conclude that although TT may reduce the progression of Chagas disease, better quality studies are warranted before its use can be generally recommended for chronically infected individuals. New data should bring more certainty of the efficacy of TT and provide a precise evaluation of the balance between benefits and harms. Because of the variations across studies, these studies should include populations from more regions and test newer drugs.

Quality of the evidence

Only 25% of these data came from good-quality studies. Although most studies were published since 2000, all studies tested drugs developed in the 1960s.

Authors' conclusions: 

Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.

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Background: 

Prevention of chronic chagasic cardiomyopathy (CCC) by treating infected populations with trypanocidal therapy (TT) remains a challenge. Despite a renewed enthusiasm for TT, uncertainty regarding its efficacy, concerns about its safety and limited availability remain barriers for a wider use of conventional drugs. We have updated a previous version of this review.

Objectives: 

To systematically search, appraise, identify and extract data from eligible studies comparing the outcome of cohorts of seropositive individuals to Trypanosoma cruzi exposed to TT versus placebo or no treatment.

Search strategy: 

We sought eligible studies in electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), Issue 1, 2014); MEDLINE (Ovid, 1946 to January week 5 2014); EMBASE (Ovid, 1980 to 2014 week 6) and LILACS (up to 6 May 2010)) by combining terms related with the disease and the treatment. The search also included a Google search, handsearch for references in review or selected articles, and search of expert files. We applied no language restrictions.

Selection criteria: 

Review authors screened the retrieved references for eligibility (those dealing with human participants treated with TT) and then assessed the pre-selected studies in full for inclusion. We included randomised controlled trials (RCTs) and observational studies that provided data on either mortality or clinical progression of CCC after at least four years of follow-up.

Data collection and analysis: 

Teams of two review authors independently carried out the study selection, data extraction and risk of bias assessment, with a referee resolving disagreement within the pairs. Data collection included study design, characteristics of the population and interventions or exposures and outcome measures. We defined categories of outcome data as parasite-related (positive serology, xenodiagnosis or polymerase chain reaction (PCR) after TT) and participant-related (including efficacy outcomes such as progression towards CCC, all-cause mortality and side effects of TT). We reported pooled outcome data as Mantel-Haenszel odds ratios (OR) or standardised mean differences (SMD) along with 95% confidence intervals (CI), using a random-effects model. I2 statistics provided an estimate of heterogeneity across studies. We conducted an exploratory meta-regression analysis of the relationship between positive-serology and progression of CCC or mortality.

Main results: 

We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela.

TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I2 = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I2 = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I2 = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I2 = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I2 = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I2 = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events).

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