Targeting Covalently Closed Circular DNA (cccDNA): Emerging Therapeutic Strategies Toward a Functional Cure for Chronic Hepatitis B

Abstract

Chronic HBV won't be resolved in the immediate future. Almost 300 million individuals live with it [1], as well as it causes roughly 820,000 deaths annually [1]—mainly due to conditions such as cirrhosis, liver failure, or liver cancer. The usual therapies, such as nucleos(t)ide analogues and pegylated interferon-alpha, effectively manage the virus. However, conventional therapies fail to achieve complete viral eradication due to the persistence of covalently closed circular DNA (cccDNA) [2], an episomal viral reservoir residing in host hepatocytes. It hangs around within liver cells as a persistent minichromosome [2], silently acting as the template for each viral RNA required by the virus. Recently, though, there has been significant progress in addressing this virus reservoir directly. Scientists have begun testing CRISPR/Cas-based gene editing [18], RNAi (RNA interference) [23], ASOs (antisense oligonucleotides) [27], CAMs (capsid assembly modulators) [28], epigenetic suppression [31], as well as various forms of immunotherapy [33]. Among these, bepirovirsen, a type of ASO, has drawn notice—it succeeded in eliminating HBsAg in approximately 9–10% of patients in a Phase IIb clinical trial [27], which is highly significant in this area. The present review examines current knowledge of the biology of cccDNA [2] and outlines the top emerging therapeutic approaches. It also looks at the biggest hurdles left—like how to deliver these treatments safely—and evaluates what is actually required before we are able to classify CHB as curable [17].