Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure

Abstract

. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.

Keywords: chronic hepatitis B; covalently closed circular DNA; hepatitis B virus; interferon; liver disease; monitoring; nucleot(s)ide analogues; pre-genomic RNA; prediction; splice variants; treatment end-points.

Figure 1

Hepatitis B virus (HBV) life cycle. Hepatocytes are infected by HBV virions containing the relaxed circular form of the DNA genome (rcDNA) or possibly pre-genomic RNA (pgRNA). Viral particles are uncoated and the HBV genome is converted into covalently closed circular DNA (cccDNA), which serves as a template for transcription of all viral RNAs, including spliced RNAs. The major transcript of HBV RNA is pgRNA (3.5 kb), which is reverse-transcribed within nucleocapsids to rcDNA. Hepatitis B virus cccDNA pool is replenished by rcDNA re-imported into the nucleus or by de novo infection. Infected hepatocytes release virions containing rcDNA and RNA, empty virions, and naked capsids (the last two are not shown in this picture). Abbreviations: ER: endoplasmid reticulum; RT: reverse transcription; HBsAg: hepatitis B virus surface antigen; HBcAg: hepatitis B virus core antigen.