Abstract
BackgroundChagas disease, a neglected tropical disease endemic to Latin America caused by the parasite Trypanosoma cruzi, currently affects 6–7 million people and is responsible for 12,500 deaths each year. No vaccine exists at present and the only two drugs currently approved for the treatment (benznidazole and nifurtimox), possess serious limitations, including long treatment regimes, undesirable side effects, and frequent clinical failures. A link between parasite genetic variability and drug sensibility/efficacy has been suggested, but remains unclear. Therefore, we investigated associations between T. cruzi genetic variability and in vitro benznidazole susceptibility via a systematic article review and meta-analysis.Methodology/Principal findingsIn vitro normalized benznidazole susceptibility indices (LC50 and IC50) for epimastigote, trypomastigote and amastigote stages of different T. cruzi strains were recorded from articles in the scientific literature. A total of 60 articles, which include 189 assays, met the selection criteria for the meta-analysis. Mean values for each discrete typing unit (DTU) were estimated using the meta and metaphor packages through R software, and presented in a rainforest plot. Subsequently, a meta-regression analysis was performed to determine differences between estimated mean values by DTU/parasite stage/drug incubation times. For each parasite stage, some DTU mean values were significantly different, e.g. at 24h of drug incubation, a lower sensitivity to benznidazole of TcI vs. TcII trypomastigotes was noteworthy. Nevertheless, funnel plots detected high heterogeneity of the data within each DTU and even for a single strain.Conclusions/SignificanceSeveral limitations of the study prevent assigning DTUs to different in vitro benznidazole sensitivity groups; however, ignoring the parasite’s genetic variability during drug development and evaluation would not be advisable. Our findings highlight the need for establishment of uniform experimental conditions as well as a screening of different DTUs during the optimization of new drug candidates for Chagas disease treatment.
Highlights
Chagas disease (CD) or American trypanosomiasis, a neglected tropical disease, affects 6–7 million people worldwide [1]
Data for a total of 59 T. cruzi strains belonging to 6 different discrete typing units (DTUs) were analyzed (40 TcI, 6 TcII, 3 TcIII, 1 TcIV, 5 TcV and 4 TcVI strains)
Why a systematic review and meta-analysis is relevant to address the question of the impact of genetic variability of T. cruzi strains over drug sensitivity?
Summary
Chagas disease (CD) or American trypanosomiasis, a neglected tropical disease, affects 6–7 million people worldwide [1]. During the acute phase, which comprises the first ~8 weeks after the initial infection, trypomastigotes are present in the blood of infected individuals. ~5% of those infected, especially children, may die during the acute phase [5]. Around 8 weeks post-infection, the immune response clears most parasites, and the chronic phase ensues. Patients seroconvert; the vast majority of those infected (~60–70%) remain asymptomatic and without visceral involvement, i.e. in the indeterminate form of the disease [6]. A neglected tropical disease endemic to Latin America caused by the parasite Trypanosoma cruzi, currently affects 6–7 million people and is responsible for 12,500 deaths each year. A link between parasite genetic variability and drug sensibility/efficacy has been suggested, but remains unclear. We investigated associations between T. cruzi genetic variability and in vitro benznidazole susceptibility via a systematic article review and meta-analysis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
