--- title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Pathophysiology" description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Pathophysiology. Topics: Immune-mediated liver injury by a non-cytopathic virus, Covalently closed circular DNA: the nuclear transcriptional template and long-lived reservoir, Integrated HBV DNA: a source of HBsAg independent of viral replication, Limited effect of nucleos(t)ide analogues on cccDNA and HBsAg production, and 3 further topics. 7 evidence topics quoted from 9 sources." canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description/pathophysiology" published: "2026-10-21T22:39:04-04:00" modified: "2026-10-22T19:07:03-04:00" --- # Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Pathophysiology ## 2.2.1.4 Pathophysiology ### Immune-mediated liver injury by a non-cytopathic virus > “As HBV is not directly cytopathic, host responses to the virus-infected hepatocytes are believed to mediate liver cell injury and, with long-term chronic liver inflammation and ineffective immune-mediated viral clearance, contribute to the development of cirrhosis and liver cancer (92), (93).” Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/) > “Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease.” Source: [Iannacone and Guidotti (2022)](https://pubmed.ncbi.nlm.nih.gov/34002067/) ### Covalently closed circular DNA: the nuclear transcriptional template and long-lived reservoir > “The host DNA repair machinery9 converts the incoming DNA to covalently closed circular DNA (cccDNA) molecules that are packaged into chromatin-like minichromosomes by histone and non-histone proteins,10,11 whereupon it acts as the HBV transcriptional template and long-lived reservoir in the hepatocyte nucleus.” Source: [Revill et al. (2019)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6732795/) > “A major hurdle to HBV “cure” is the presence of cccDNA in the hepatocyte nucleus in a non-integrated form or episome. cccDNA serves as the template for transcription of all viral RNAs including pregenomic RNA and thus plays a key role in the viral lifecycle.” > “The half-life of cccDNA is long thus explaining why it is difficult to cure HBV infection and why HBV can reactivate either spontaneously or following immune suppression, many years after clearance of HBsAg.” Source: [Lok et al. (2017)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6294322/) > “Current therapies (pegylated interferon alfa [pegIFNa] and nucleos(t)ide analogues [NAs]) are not curative due to persistence of covalently closed circular DNA (cccDNA), a stable, non-integrated form of viral DNA located in the hepatocyte nucleus, as well as HBV DNA that is directly integrated into the host genome.” Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/) ### Integrated HBV DNA: a source of HBsAg independent of viral replication > “Integrated HBV DNA is derived from linear genomic DNA present in viral particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of hepatitis B surface antigen (HBsAg) and HBx. DNA integration events accumulate over the course of viral infection, ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infections.” > “Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection, which rely on HBsAg as a diagnostic marker.” Source: [Zoulim et al. (2024)](https://pubmed.ncbi.nlm.nih.gov/38971531/) > “Hindering the goal of functional cure as a treatment endpoint is the fact that HBsAg in serum originates from two sources, cccDNA and integrated HBV DNA. Although novel treatments in development may potentially eliminate or silence cccDNA, they may not abolish ongoing RNA transcription from integrated viral genomes, and HBsAg would remain detectable in serum.” Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/) > “Although qHBsAg reflects covalently closed circular DNA and intrahepatic DNA levels, it also measures HBsAg that arises from integrated DNA, thereby reducing its specificity as a biomarker for viral replication.” Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/) ### Limited effect of nucleos(t)ide analogues on cccDNA and HBsAg production > “Since NAs do not directly affect the HBV cccDNA transcriptional template, a modest decrease in cccDNA is observed after long-term NA therapy, most likely due to the indirect impact of NAs on de novo infections and intracellular replenishment coupled with the gradual dilution of the cccDNA pool through cell division.253,254 Low rates of HBsAg loss on NA treatment are ascribed to the limited effect of NAs on the cccDNA template and to the significant contribution of HBV integration to HBsAg production, especially in HBeAg-negative individuals.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) > “By contrast, nucleos(t)ide analogues only inhibit HBV genome replication; they have minimal effects on the immune response or the cccDNA minichromosome reservoir, and are not curative.” Source: [Revill et al. (2019)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6732795/) > “Continued transcription from cccDNA and integrated viral genomes may explain the relatively minor decrease in serum HBsAg levels during NA therapy despite undetectable serum HBV DNA levels.” Source: [Lok et al. (2017)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6294322/) ### HBsAg and T-cell exhaustion > “HBV-specific T cells necessary for HBV control (and may also play a role in hepatic inflammation) are dysfunctional and may be depleted or deleted in chronic HBV.53,54 Their exhausted phenotype has been attributed to persistent antigen exposure and increased expression of T cell inhibitory responses,3,52,55 providing the basis for the focus on reducing HBsAg production.” Source: [Lok et al. (2017)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6294322/) > “Chronic exposure to high levels of HBV antigens, especially HBsAg, results in host immune dysfunction. Multiple immune signaling pathways are influenced by HBV antigens, which ultimately result in virus-specific and global T-cell dysfunction [43, 44].” Source: [Hui et al. (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11750937/) > “For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology.” Source: [Iannacone and Guidotti (2022)](https://pubmed.ncbi.nlm.nih.gov/34002067/) > “More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response.” Source: [Zoulim et al. (2024)](https://pubmed.ncbi.nlm.nih.gov/38971531/) > “During acute infection, cccDNA can be silenced and/or degraded through immune mechanisms, however in chronic infection the immune responses are dysfunctional and not easily restored by current treatments.” Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/) ### Integration and hepatocarcinogenesis > “HBV DNA integration events have primarily been investigated in the context of hepatocellular carcinoma development as they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and, presumably, induce epigenetic alterations, promoting tumour growth.” Source: [Zoulim et al. (2024)](https://pubmed.ncbi.nlm.nih.gov/38971531/) > “Antiviral therapy may decrease HCC risk by suppressing viral replication, thereby decreasing clonal expansion and integration of HBV DNA into the host genome.” Source: [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) ### Rationale for HBsAg loss as the treatment goal > “Of all these surrogate endpoints, HBsAg loss is considered to be the most relevant because HBsAg seroclearance is associated with sustained off-treatment improvement in clinical outcomes.(1, 2) Additionally, HBsAg loss has been shown to have an additional clinical benefit (lower rates of HCC and hepatic decompensation) over HBV DNA suppression alone, particularly in patients with cirrhosis.(3, 4) Moreover, HBsAg seroclearance is easy to measure with standardized and widely available assays.” > “Nonetheless, a sustained seroclearance of HBsAg, (i.e., rendering HBsAg to levels below the currently accepted detection enzyme immune assays, <0.05 IU/ml), plausibly implies profound suppression of replication of HBV, and suggests reduced overall expression from cccDNA and integrated viral genomes.” Source: [Ghany et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12373085/) > “Increasingly, there is emphasis on the achievement of HBsAg loss as the desired endpoint for treatment (functional cure), because of its association with reduction in clinical outcomes and long-term durability, though it is recognized that functional cure is infrequent with current approved therapies, albeit higher with peginterferon than for NAs.” Source: [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) > “Loss of HBsAg (post therapy) is the ultimate goal of treatment, is the defining feature of functional cure of HBV infection,55 and is associated with an improved prognosis.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ## Related pages - [Hibsago (bepirovirsen): Chronic hepatitis B virus infection in adults without cirrhosis](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Terms and abbreviations](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/terms-and-abbreviations) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/terms-and-abbreviations.md) - [Hibsago (bepirovirsen): Chronic hepatitis B virus infection in adults without cirrhosis](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/executive-summary) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/executive-summary.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Product information and disease description](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Clinical evidence](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Economic information and modeling report](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/economics) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/economics.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: References](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/references) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/references.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: new drug review](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/monograph/review) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/monograph/review.md) - [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: cost-effectiveness analyses and utility weights](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/cost-effectiveness-analyses) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/cost-effectiveness-analyses.md)