Bridging the Diagnostic Gap in Chronic Hepatitis D: Implementing Reflex Testing and Standardized HDV RNA Assessment in the Therapeutic Era

Chronic hepatitis D virus (HDV) infection is the most severe form of viral hepatitis, yet it remains frequently underdiagnosed in routine clinical practice. With the recent availability of effective therapies such as bulevirtide, missed or delayed diagnosis has become an increasingly relevant clinical issue. This review aims to examine the main factors contributing to underdiagnosis and to discuss practical strategies to improve HDV detection and management. This is a narrative, non‐systematic review of the literature focusing on HDV epidemiology, diagnostic pathways, and laboratory aspects, with particular attention to reflex testing strategies and HDV RNA assessment. Current evidence suggests that HDV prevalence is strongly influenced by testing practices, and that the apparent decline observed in some settings may reflect insufficient screening rather than a true reduction in disease burden. In routine care, the diagnostic process is often incomplete, leading to missed opportunities for identification. Reflex testing approaches can help streamline the diagnostic pathway and improve case detection. At the same time, variability in HDV RNA quantification across assays and pre‐analytical conditions may affect clinical interpretation, particularly in the context of treatment monitoring. In the current therapeutic era, improving diagnostic pathways is essential to fully realize the benefits of available treatments. More systematic testing strategies, combined with greater standardization of HDV RNA measurement, may support earlier diagnosis and more appropriate clinical management.