Targeting Viral cccDNA for Cure of Chronic Hepatitis B

Abstract

Purpose of Review Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a major cause of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. HBV replication is characterized by the synthesis of covalently closed circular (ccc) DNA which is not targeted by antiviral nucleos(t)ide analogues (NUCs) the key modality of standard of care. While HBV replication is successfully suppressed in treated patients, they remain at risk for developing HCC. While functional cure, characterized by loss of HBsAg, is the first goal of novel antiviral therapies, curative treatments eliminating cccDNA remain the ultimate goal. This review summarizes recent advances in the discovery and development of novel therapeutic strategies and their impact on cccDNA biology. Recent Findings Within the last decade, substantial progress has been made in the understanding of cccDNA biology including the discovery of host dependency factors, epigenetic regulation of cccDNA transcription and immune-mediated degradation. Several approaches targeting cccDNA either in a direct or indirect manner are currently at the stage of discovery, preclinical or early clinical development. Examples include genome-editing approaches, strategies targeting host dependency factors or epigenetic gene regulation, nucleocapsid modulators and immune-mediated degradation. Summary While direct-targeting cccDNA strategies are still largely at the preclinical stage of development, capsid assembly modulators and immune-based approaches have reached the clinical phase. Clinical trials are ongoing to assess their efficacy and safety in patients including their impact on viral cccDNA. Combination therapies provide additional opportunities to overcome current limitations of individual approaches.

Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication

“…7,8 As an episomal minichromosome, cccDNA serves as a stable replication template for the transcription of viral RNA in infected human hepatocytes. Therefore, along with inhibitors targeting cccDNA, 9,10 different antiviral strategies, including the suppression of viral replication or the stimulation of the host immune response, have been introduced to control HBV infections. 11−13 In the exploration of promising antiviral targets among HBV proteins translated from mRNA transcripts, capsid protein (core protein, HBc) has been identified to be key in the regulation of viral infectivity.…”

Viral hepatitis in 2021: The challenges remaining and how we should tackle them

“…A number of new treatments are being investigated for HBV and these are aiming to achieve clearance of HBsAg rather than just suppressing HBV DNA[ 36 ]. A detailed description of these treatments is beyond the scope of this review, but these include the development of new NAs (besifovir and metacavir), cccDNA silencers ( e.g., lymphotoxin beta receptor agonist) and HBV entry inhibitors (Myrcludex B)[ 28 , 38 , 56 ]. There may also be a role for immunomodulatory therapies such as toll-like receptor agonists (acting via activating the innate immune response), check point inhibitors (helping to restore T-cell dysfunction) or therapeutic vaccines such as TherVacB[ 56 , 57 ].…”

“…There may also be a role for immunomodulatory therapies such as toll-like receptor agonists (acting via activating the innate immune response), check point inhibitors (helping to restore T-cell dysfunction) or therapeutic vaccines such as TherVacB[ 56 , 57 ]. Gene editing strategies and RNA interference may be other potential treatment strategies[ 56 ]. Where eligible, patients should be considered for entry into clinical trials of novel therapies.…”

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

“…The main goal of treatment is to prevent the progression of severe liver disease to cirrhosis, liver failure and HCC through a reduction in viral replication, resulting in less liver damage and ultimately a lower risk of severe disease outcomes [ 18 ]. Current HBV treatments do not cure CHB (i.e., resulting in complete elimination of cccDNA [ 26 ]) and so the optimal outcome of treatment is functional cure. Functional cure is described as loss of serum HBsAg, undetectable serum HBV DNA and low intrahepatic persistence of HBV DNA [ 27 ].…”