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.
Highlights
Hepatitis B virus (HBV) is a DNA virus that infects human liver and causes acute or chronic hepatitis B (CHB) of variable severity [1,2]
While challenges in detecting closed circular DNA (cccDNA) prevent it from being used for monitoring patients with CHB, HBV RNA has been recently proposed as a valuable alternative
We summarize recent advances in HBV virology and CHB pathogenesis, discuss pros and cons of cccDNA and HBV RNA monitoring in patients with CHB, and outline the need for a decisive leap to create diagnostic techniques that are capable of identifying complete viral clearance
Summary
Hepatitis B virus (HBV) is a DNA virus that infects human liver and causes acute or chronic hepatitis B (CHB) of variable severity [1,2]. Interferon-α (IFN) treatment can achieve sustained antiviral response in a small proportion of patients [24,25,26,27] These two options represent all the available therapeutics to date, but neither can they completely clear HBV infection in patients. These treatments represent valuable and very potent approaches for suppressing viral replication and help significantly to slow down liver disease progression and reduce the risks of adverse CHB outcomes, like cirrhosis and HCC [5,28]. While challenges in detecting cccDNA prevent it from being used for monitoring patients with CHB, HBV RNA has been recently proposed as a valuable alternative. We summarize recent advances in HBV virology and CHB pathogenesis, discuss pros and cons of cccDNA and HBV RNA monitoring in patients with CHB, and outline the need for a decisive leap to create diagnostic techniques that are capable of identifying complete viral clearance
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