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Targeting Viral cccDNA for Cure of Chronic Hepatitis B
Gaëtan Ligat1,2, Kaku Goto1,2, Eloi Verrier1,2
1Université de Strasbourg, 67000 Strasbourg, France.
Insights
Novel therapies are emerging to combat chronic hepatitis B (CHB) by targeting the persistent hepatitis B virus (HBV) covalently closed circular DNA (cccDNA). These strategies aim for a functional or curative cure beyond current nucleos(t)ide analogue limitations.
Area of Science:
- Hepatology
- Virology
- Drug Discovery
Background:
- Chronic hepatitis B (CHB) is a global health concern, leading to liver disease and cancer.
- Current treatments suppress hepatitis B virus (HBV) but do not eliminate its persistent cccDNA form.
- Patients on therapy remain at risk for hepatocellular carcinoma (HCC).
Purpose of the Study:
- To review recent advancements in novel therapeutic strategies for CHB.
- To explore the impact of these strategies on cccDNA biology.
- To discuss the progression of these therapies from discovery to clinical development.
Main Methods:
- Review of current literature on cccDNA biology and therapeutic targets.
- Analysis of emerging strategies including genome editing, host factor targeting, and immune-based approaches.
- Assessment of the clinical development status of novel CHB therapies.
Main Results:
- Significant progress in understanding cccDNA biology, including host factors and epigenetic regulation.
- Multiple strategies targeting cccDNA are in preclinical or early clinical development.
- Clinical trials are evaluating capsid assembly modulators and immune-based therapies for CHB.
Conclusions:
- Novel therapies show promise for achieving functional or curative CHB treatment.
- Combination therapies may offer enhanced efficacy.
- Further research and clinical trials are crucial to overcome limitations and achieve HBV eradication.
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.
