BACKGROUND AND AIMS: A dichotomous separation of hepatitis B viral DNA and hepatitis B surface antigen (HBsAg) concentrations occurs during the natural history and treatment of chronic hepatitis B. We have evaluated the ability of hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) as surrogates of silencing of covalently closed circular DNA (cccDNA), to characterize this dissociation, and virological outcomes. APPROACH AND RESULTS: Three cohorts of hepatitis B e antigen (HBeAg)-negative patients were studied: cohort A: 66 HBeAg-negative patients on long-term nucleos(t)ide analogue (NA) therapy; cohort B: 23 antibodies against hepatitis B e antigen (anti-HBe)-positive patients who stopped treatment; and Cohort C: 19 anti-HBe-positive patients on long-term NA treatment who achieved HBsAg loss and in whom treatment was withdrawn. Concentrations of HBV serological/virological biomarkers (HBV DNA, HBsAg, HBcrAg, and HBV RNA) were measured in sequential samples at different time points on/off therapy. Cohort A: After 3 years of antiviral therapy, 33% and 30% had detectable HBcrAg and HBV RNA, respectively, despite all being HBV-DNA negative. After 5 years' therapy with NA, 27% and 14% had detectable HBcrAg and HBV RNA. Detectable HBcrAg and HBV RNA at the time of treatment withdrawal was only observed in those patients who developed a severe aminotransferase flare. Only those patients with HBV reactivation in cohort C had detectable HBV RNA at treatment withdrawal, but HBcrAg and HBV DNA were not detected. CONCLUSIONS: HBcrAg and HBV RNA are sensitive biomarkers of continued transcription of cccDNA in HBeAg-negative patients despite marked HBV-DNA suppression by NA. These markers were predictors of severe alanine transaminase flares, after treatment withdrawal, and HBV-DNA reactivation. Their measurement during the natural history of hepatitis B, and on treatment with current and new agents, could characterize residual HBV-RNA transcription from cccDNA and assist drug development and disease management.
BACKGROUND AND AIMS: A dichotomous separation of hepatitis B viral DNA and hepatitis B surface antigen (HBsAg) concentrations occurs during the natural history and treatment of chronic hepatitis B. We have evaluated the ability of hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) as surrogates of silencing of covalently closed circular DNA (cccDNA), to characterize this dissociation, and virological outcomes. APPROACH AND RESULTS: Three cohorts of hepatitis B e antigen (HBeAg)-negative patients were studied: cohort A: 66 HBeAg-negative patients on long-term nucleos(t)ide analogue (NA) therapy; cohort B: 23 antibodies against hepatitis B e antigen (anti-HBe)-positive patients who stopped treatment; and Cohort C: 19 anti-HBe-positive patients on long-term NA treatment who achieved HBsAg loss and in whom treatment was withdrawn. Concentrations of HBV serological/virological biomarkers (HBV DNA, HBsAg, HBcrAg, and HBV RNA) were measured in sequential samples at different time points on/off therapy. Cohort A: After 3 years of antiviral therapy, 33% and 30% had detectable HBcrAg and HBV RNA, respectively, despite all being HBV-DNA negative. After 5 years' therapy with NA, 27% and 14% had detectable HBcrAg and HBV RNA. Detectable HBcrAg and HBV RNA at the time of treatment withdrawal was only observed in those patients who developed a severe aminotransferase flare. Only those patients with HBV reactivation in cohort C had detectable HBV RNA at treatment withdrawal, but HBcrAg and HBV DNA were not detected. CONCLUSIONS: HBcrAg and HBV RNA are sensitive biomarkers of continued transcription of cccDNA in HBeAg-negative patients despite marked HBV-DNA suppression by NA. These markers were predictors of severe alanine transaminase flares, after treatment withdrawal, and HBV-DNA reactivation. Their measurement during the natural history of hepatitis B, and on treatment with current and new agents, could characterize residual HBV-RNA transcription from cccDNA and assist drug development and disease management.
Authors: Anna Kramvis; Kyong-Mi Chang; Maura Dandri; Patrizia Farci; Dieter Glebe; Jianming Hu; Harry L A Janssen; Daryl T Y Lau; Capucine Penicaud; Teresa Pollicino; Barbara Testoni; Florian Van Bömmel; Ourania Andrisani; Maria Beumont-Mauviel; Timothy M Block; Henry L Y Chan; Gavin A Cloherty; William E Delaney; Anna Maria Geretti; Adam Gehring; Kathy Jackson; Oliver Lenz; Mala K Maini; Veronica Miller; Ulrike Protzer; Jenny C Yang; Man-Fung Yuen; Fabien Zoulim; Peter A Revill Journal: Nat Rev Gastroenterol Hepatol Date: 2022-07-20 Impact factor: 73.082
Authors: Raymond T Chung; Wendy C King; Marc G Ghany; Mauricio Lisker-Melman; Amanda S Hinerman; Mandana Khalili; Mark Sulkowski; Mamta K Jain; Eun-Young K Choi; Michael A Nalesnik; Atul K Bhan; Gavin Cloherty; David K Wong; Richard K Sterling Journal: Clin Gastroenterol Hepatol Date: 2021-12-29 Impact factor: 13.576
Authors: Ashwin Balagopal; Tanner Grudda; Ruy M Ribeiro; Yasmeen S Saad; Hyon S Hwang; Jeffrey Quinn; Michael Murphy; Kathleen Ward; Richard K Sterling; Yang Zhang; Alan S Perelson; Mark S Sulkowski; William O Osburn; Chloe L Thio Journal: JCI Insight Date: 2020-10-02