Author information

¹Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.

²Excellence Cluster RESIST, Hannover Medical School, Hannover, Germany.

³D-SOLVE: EU-funded Network on individualized management of hepatitis D.

⁴German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany.

⁵Forum for Collaborative Research, University of California Berkeley, Washington, DC, USA.

⁶Gilead Sciences, Inc., Foster City, CA, USA.

⁷Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.

⁸Centre National de Référence pour les virus des hépatites B, C et Delta, Laboratoire de microbiologie clinique, Hôpital Avicenne Assistance Publique - Hôpitaux de Paris, Bobigny, France.

⁹Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA.

¹⁰Ex Quest Diagnostics, Secaucus, NJ, USA and currently affiliated HK Healthcare Consultant LLC.

¹¹Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria.

¹²Janssen Pharmaceutica NV, Beerse, Belgium.

¹³Institute for Mikrobiology, Virology and Hygiene, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany.

¹⁴German Center for Infection Research (DZIF), Partner Site Hamburg, Lübeck, Kiel, Germany.

¹⁵Roche Diagnostics Solutions, Clinical Development and Medical Affairs, Rotkreuz, CH, Switzerland.

¹⁶Division of Antivirals, US Food and Drug Administration, Silver Spring, MD, USA.

¹⁷Swedish Medical Products Agency, Uppsala, Sweden.

¹⁸Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

¹⁹Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

²⁰Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

²¹CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Abstract

Co-infection with hepatitis B virus (HBV) and hepatitis D virus (HDV) results in hepatitis D, the most severe form of chronic viral hepatitis, frequently leading to liver decompensation and hepatocellular carcinoma. Pegylated interferon alpha, the only treatment option for chronic hepatitis D for many years, has limited efficacy. New treatments are in advanced clinical development, with one recent approval. Diagnosis and antiviral treatment response monitoring are based on detection and quantification of HDV RNA. However, the development of reliable HDV RNA assays is challenged by viral heterogeneity (at least 8 different genotypes and several subgenotypes), intra-host viral diversity, rapid viral evolution, and distinct secondary structure features of HDV RNA. Different RNA extraction methodologies, primer/probe design for Nucleic Acid Tests, lack of automation, and overall dearth of standardization across testing laboratories contribute to substantial variability in performance characteristics of research-based and commercial HDV RNA assays. A WHO standard for HDV RNA, available for about 10 years, has been used by many laboratories to determine the limit of detection of their assays and facilitates comparisons of RNA levels across study centers. Here we review challenges for robust pan genotype HDV RNA quantification, discuss particular clinical needs and the importance of reliable HDV RNA quantification in the context of drug development and patient monitoring. We summarize distinct technical features and performance characteristics of available HDV RNA assays. Finally, we provide considerations for the use of HDV RNA assays in the context of drug development and patient monitoring.