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Meta-Analysis
. 2014 May 27;2014(5):CD003463.
doi: 10.1002/14651858.CD003463.pub2.

Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection

Affiliations
Meta-Analysis

Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection

Juan Carlos Villar et al. Cochrane Database Syst Rev. .

Abstract

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 methods: 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. I(2) 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, I(2) = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I(2) = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I(2) = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I(2) = 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, I(2) = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I(2) = 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).

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.

PubMed Disclaimer

Conflict of interest statement

Dr. Riarte is the principal investigator of TRAENA, one of the studies included in this review. Dr. Marin‐Neto is one of the co‐principal investigators of the BENEFIT trial. All other authors declare having no conflict of interest.

Figures

1
1
Quality assessment of the studies other than RCTs included.
2
2
Study flow diagram.
3
3
Main characteristics of the included studies.
4
4
Quality assessment of randomised controlled trials included.
5
5
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. *Non‐randomised experiment **Observational study
6
6
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
7
7
Meta‐regression analysis. Relationship between effect of TT on progression of CCC and serology.
8
8
Meta‐regression analysis. Relationship between effect of TT on mortality and serology.
1.1
1.1. Analysis
Comparison 1 Parasite‐related outcomes, Outcome 1 Positive serology.
1.2
1.2. Analysis
Comparison 1 Parasite‐related outcomes, Outcome 2 Positive PCR: nitroderivatives.
1.3
1.3. Analysis
Comparison 1 Parasite‐related outcomes, Outcome 3 Positive xenodiagnosis: all populations, all tested drugs.
1.4
1.4. Analysis
Comparison 1 Parasite‐related outcomes, Outcome 4 Mean reduction of antibodies titres: all populations, all tested drugs.
2.1
2.1. Analysis
Comparison 2 Patient‐related outcomes: efficacy, Outcome 1 ECG abnormalities ‐ RCT data ‐ benznidazole.
2.2
2.2. Analysis
Comparison 2 Patient‐related outcomes: efficacy, Outcome 2 Progression of cardiomyopathy: non‐RCT data ‐ adults, nitroderivatives.
2.3
2.3. Analysis
Comparison 2 Patient‐related outcomes: efficacy, Outcome 3 Mortality: non‐RCT data ‐ adults, all tested drugs.
3.1
3.1. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 1 BZD mild‐to‐moderate ‐ RCT data only.
3.3
3.3. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 3 BZD severe side effects.
3.5
3.5. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 5 ALLOP ‐ mild‐to‐moderate ‐ RCT data only.
3.6
3.6. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 6 ALLOP ‐ severe side effects.
3.7
3.7. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 7 NFTMX ‐ severe side effects.
3.8
3.8. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 8 ITRA ‐ severe side effects.
3.9
3.9. Analysis
Comparison 3 Patient‐related outcomes: safety, Outcome 9 Drug discontinuation ‐ all populations, all drugs.

Update of

References

References to studies included in this review

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References to other published versions of this review

Villar 2002
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