Virological Events During Immune Checkpoint Inhibitor Therapy: A Multi-Source Evaluation

Background/Objectives: Virological findings during immune checkpoint inhibitor (ICI) therapy may represent viral loss of control, pre-existing infection, tumour biomarkers, or infection after immune-related adverse event (irAE)-directed immunosuppression. Distinguishing these possibilities is important for treatment and diagnostic decisions. We evaluated virus-specific patterns across complementary data sources. Methods: We evaluated HBV, HCV, HIV, EBV, CMV, HSV, and VZV using FAERS disproportionality analysis (2011Q1-2026Q1), PubMed evidence mapping and appraisal, EBV endpoint verification, and review of ClinicalTrials.gov protocols by start era. Findings were interpreted in relation to prevention, monitoring, endpoint interpretation, and infectious mimic evaluation. Results: Among 200,699 primary suspect ICI reports, only HBV reactivation met the prespecified reporting criterion (226 reports; reporting odds ratio 1.20, 95% CI 1.06-1.37); this estimate did not persist with an oncology-restricted comparator (0.81, 0.71-0.94). Same report overlap of HBV with hepatic events and CMV with enterocolitis or pneumonitis identified diagnostically ambiguous settings without establishing event sequence. EBV DNA reflected viral inflammatory activity in some conditions but tumour burden in EBV-associated cancers. The evidence map included 198 publications, with design-specific appraisal of 84. Among 164 trials, conditional viral eligibility appeared in 49.0-57.1% across start eras, whereas longitudinal monitoring appeared in 8.2-19.6%. Conclusions: Reporting patterns were virus-specific and comparator-sensitive. The findings support HBV prevention, confirmation of HCV and HIV control, disease-specific interpretation of EBV markers, and CMV evaluation when inflammation or irAE-directed immunosuppression raises concern for infection. Context-specific assessment may help avoid unnecessary ICI interruption while identifying viral loss of control and infectious mimics.