The efficacy and safety of benznidazole in adults with seropositive indeterminate form, Trypanosoma cruzi infection: a systematic review and meta-analysis

BACKGROUND: Chagas disease (CD)-a parasitic infection caused by Trypanosoma cruzi, affects ~7 million people worldwide. Current first line therapies like Benznidazole and Nifurtimox have significant side effects, and limited data to support their efficacy when used to treat CD in its chronic indeterminate (asymptomatic) phase. This study aimed to critically assess and meta-analyze all clinical trials to date that address this specific phase of CD. METHODS: PubMed, Cochrane, ClinicalTrials.gov, EBSCOhost, and SciELO (inception - December 2024) were searched for randomized, controlled trials (RCTs) including the efficacy or safety of treatment in adults with indeterminate form, chronic CD. English abstracts were required, with full text in English, Spanish or Portuguese. Studies had to have the potential to report disease progression (primary) or parasitological cure and adverse events (secondary) by treatment regimen. We define parasitological cure as T. cruziPCR negativity. Meta-analysis was conducted using random effects models with inverse-variance weighting of study-specific risk ratios (95% CI). Publication bias was assessed via funnel plots. RESULTS: Five out of 132 studies were unique RCTs that met the inclusion criteria. Inter-rater agreement on study selection was high (κ=0.83). Of all participants, most were female (428/653 or 66%). Summary estimates revealed significant benefit for achieving parasitological cure in treatment versus control groups (overall RR 5.93 [95% CI: 3.96, 8.86, p < 0.001]). A direct comparison of adverse events (AEs) experienced across trials was challenging (overall RR 1.47 [(95% CI: 0.90, 2.38), p <0.12]). Among all participants, 8.1% (53/653) discontinued treatment for various reasons after treatment initiation. Notably, no prospective RCTs of indeterminate form CD were identified that assessed for development of long-term cardiac or gastrointestinal complications. CONCLUSION: Antitrypanosomal treatment can significantly improve parasitological cure rates in indeterminate (asymptomatic) form, chronic phase CD, despite high risk of bias and aggregated data limitations. Our analysis underscores the need for more rigorous, standardized randomized controlled trials with consistent inclusion criteria based on indeterminate form, chronic phase CD and clinical endpoints. This study provides a focused, clinically relevant perspective by emphasizing randomized trial data, complementing broader CD research. PROSPERO REGISTRATION: CRD42024512886.