--- title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Long-term morbidity" description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: Long-term morbidity. Topics: Chronic liver disease in 15% to 25% of persons with chronic infection; Cirrhosis, decompensation, and survival; Hepatocellular carcinoma: viral load as a risk factor; Residual cirrhosis and hepatocellular carcinoma risk on antiviral therapy in non-cirrhotic U.S. Veterans; 6 further topics. 10 evidence topics quoted from 12 sources." canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description/long-term-morbidity" 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: Long-term morbidity ## 2.2.1.7 Long-term Morbidity ### Chronic liver disease in 15% to 25% of persons with chronic infection > “Approximately 15%–25% of people with chronic infection develop chronic liver disease, including cirrhosis, liver failure, or liver cancer.” Source: [CDC Clinical Overview of Hepatitis B (2025)](https://www.cdc.gov/hepatitis-b/hcp/clinical-overview/index.html) > “Chronic HBV infection is a significant risk factor for the development of cirrhosis, end-stage liver disease, and HCC, and it may also be associated with extrahepatic manifestations.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ### Cirrhosis, decompensation, and survival > “The cumulative incidence of cirrhosis increased with the HBV-DNA level” > “Patients with cirrhosis are estimated to progress to decompensated cirrhosis at a rate of 3% annually.13 In cirrhotic patients, the presence of HBeAg (reflecting active viral replication) increases the risk for liver decompensation.14 The 5-year survival rate is 84% among compensated cirrhosis patients and 14%–28% in decompensated cirrhosis patients.” Source: [Iloeje et al. (2006)](https://doi.org/10.1053/j.gastro.2005.11.016) ### Hepatocellular carcinoma: viral load as a risk factor > “Elevated serum HBV DNA level (≥10 000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.” Source: [Chen et al. (2006)](https://doi.org/10.1001/jama.295.1.65) > “HBV DNA >2,000 IU/ml is associated with an increased risk of developing liver cirrhosis, end-stage liver disease and HCC.109,110 The relationship between serum HBV DNA level and HCC risk is a non-linear dose-response relationship, with a more significant increase in HCC risk at serum HBV DNA levels >200,000 IU/ml compared to the risk observed between 2,000 IU/ml and 200,000 IU/ml, while the risk is very low at levels <2,000 IU/ml.” > “An HBsAg level of ≥1,000 IU/ml was associated with an increased risk of HCC in both HBeAg-negative individuals with HBV DNA <2,000 IU/ml and those with HBV DNA between 2,000 and 20,000 IU/ml.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ### Residual cirrhosis and hepatocellular carcinoma risk on antiviral therapy in non-cirrhotic U.S. Veterans > “Among 2,496 patients with non-cirrhotic CHB (39.1% African American, 38.4% non-Hispanic White, 18.8% Asian, mean age 58.0 ± 13.4 years), the overall incidences of cirrhosis and HCC were 3.99 per 100 person-years (95% CI 3.66-4.35) and 0.43 per 100 person-years (95% CI 0.33-0.54), respectively. The highest incidences of cirrhosis and HCC were observed in non-Hispanic White patients (5.74 and 0.52 per 100 person-years, respectively), which were significantly higher than in Asian patients (1.93 and 0.17 per 100 person-years, respectively, p <0.0001).” Source: [Yang et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10494462/) ### Residual hepatocellular carcinoma risk beyond 10 years of entecavir or tenofovir > “Of 1,644 patients, 903 were followed beyond year 10 (mean:14 ± 2 years). The 10- and 15-year cumulative incidences of HCC were 10.9% and 13.2%, respectively. The HCC IR was 1.25 before year 10 and 0.55/100 PYs after year 10 (p <0.001), with similar findings after inverse probability weighting.” > “Despite >10 years of NA therapy, patients with CHB remain at risk of HCC, although the incidence rate declines significantly. HCC remains the main determinant of mortality.” Source: [Papatheodoridis et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42409322/) > “HCC risk remains after viral suppression” > “In patients without cirrhosis, longitudinal studies have also shown that long-term viral suppression reduces the risk of HCC,118,119 but the evidence in this case is less conclusive, mainly due to short follow-up and the low incidence rate in this setting.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ### Residual hepatocellular carcinoma risk after HBsAg loss > “For individuals who have cleared HBsAg, one study reported an annual HCC incidence of 0.86% overall, 2.42% in those with cirrhosis, 0.43% in those without cirrhosis, 1.07% for males, 0.57% for females, 1.21% if ≥50 years, and 0.33% if <50 years,113 while another reported a rate of 0.4% for males and 0% for females without cirrhosis.114 In a meta-analysis of 24 studies of 33,838 persons who cleared HBsAg, the pooled proportions of HCC occurrence ranged from 0.35% to 0.78% per year following treatment-induced or spontaneous HBsAg loss, respectively.” > “Taken together, following HBsAg loss whether spontaneous or with antiviral therapy, significant HCC risk remains for those with established cirrhosis and for those without cirrhosis who were 45-50 years or older at the time of HBsAg loss.” Source: [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) > “Patients who experienced HBsAg seroclearance had significantly lower HCC incidence than HBsAg‐positive (RR = 0.41, p < .001). The pooled HCC incidence after HBsAg seroclearance was 1.88%; this rate was reduced to 0.76% among patients without baseline cirrhosis.” > “The results showed that HBsAg seroclearance was durable, with a pooled recurrence rate of 6.19% (95% CI: 4.10%–8.68%).” Source: [Song et al. (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7986681/) > “Although progression of liver disease to cirrhosis or hepatic decompensation generally stops when patients lose HBsAg unless other causes of liver injury are present (eg, heavy alcohol consumption or nonalcoholic fatty liver), the risk of HCC persists, particularly if HBsAg loss occurred in patients older than 50 years or in those with cirrhosis or coinfection with HCV or hepatitis D virus (HDV) (128, 130–132).” Source: [Terrault et al. (2018)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5975958/) > “A systematic review also showed that HBsAg loss correlates with lower rates of incident cirrhosis, hepatic decompensation, and overall and liver-related mortality, though there was substantial heterogeneity across studies for all outcomes.” Source: [EASL (2025)](https://doi.org/10.1016/j.jhep.2025.03.018) ### Liver transplantation and end-stage outcomes among U.S. decedents with chronic hepatitis B > “Compared to survivors, decedents were older, more likely to be White (40.6%), African-American (27.1%), or male (74.2%); and more likely to have had cirrhosis (59.8%), diabetes (27.2%), alcohol abuse (17.7%), hepatocellular carcinoma (17.5%), or a liver transplant (5.7%); whereas survivors were more likely to be Asian (48.8%; all P < .001).” Source: [Bixler et al. (2019)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11230463/) > “The IR of death or LT was lower before vs. after year 10 (1.50 vs. 1.95/100 PYs, p = 0.069), whereas the IR was similar for liver-related death/LT between the two periods (0.74 vs. 0.70/100 PYs, p = 0.840).” Source: [Papatheodoridis et al. (2026)](https://pubmed.ncbi.nlm.nih.gov/42409322/) ### Projected U.S. decompensated cirrhosis and hepatocellular carcinoma, 2019 to 2030 > “New decompensated cirrhosis, hepatocellular carcinoma, and liver related deaths are expected to increase by 20%, 31% and 25% respectively from 2019 to 2030 at current diagnosis and treatment rate.” Source: [Razavi-Shearer et al. (2023a)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10239007/) ### Hepatitis D coinfection: prevalence and hepatocellular carcinoma risk in the United States > “A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%).” Source: [Gish et al. (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11020024/) > “For persons with HDV co-infection, a U.S. study of 4817 persons with HBV including 158 with HDV found an HCC incidence per 1,000 person-years of 18.65 in HBV/HDV versus 4.84 in HBV mono-infected individuals.115 The large majority of both mono-infected (92.3%) and co-infected (87.3%) participants in this study did not have cirrhosis.” Source: [Ghany et al. (2026)](https://doi.org/10.1097/HEP.0000000000001549) ### Extrahepatic disease: immune-complex manifestations and extrahepatic malignancies > “Antiviral therapy not only prevents disease progression but also helps reduce transmission, improve extrahepatic manifestations, and lower the risk of viral reactivation. Additionally, chronic HBV infection has been associated with a higher risk of developing extrahepatic malignancies.” > “Immunomodulatory and immunosuppressive agents (such as high-dose IgG, rituximab, high-dose corticosteroids and plasmapheresis) are usually required (in addition to antiviral therapy) to treat the major renal, neurologic and haematologic manifestations observed.” 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)