Hepatology. 2019 Nov 7. doi: 10.1002/hep.31026. [Epub ahead of print]
Pre-genomic HBV RNA and HBcrAg predict outcomes in HBeAg negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy.
Carey I1, Gersch J2, Wang B1, Moigboi C1, Kuhns M2, Cloherty G2, Dusheiko G1, Agarwal K1.
Author information
1
Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom.
2
Department of Infectious Diseases, Abbott Laboratories, North Chicago, Illinois, United States of America.
Abstract
BACKGROUND AND AIMS:
A dichotomous separation of hepatitis B viral DNA and HBsAg concentrations occurs during the natural history and treatment of chronic hepatitis B. We have evaluated the ability of HBV RNA and HBcrAg as surrogates of silencing of cccDNA, to characterise this dissociation, and virological outcomes.
METHODS:
3 cohorts of HBeAg-negative patients were studied: Cohort A: 66 HBeAg-negative patients on long-term nucleos(t)ide analogue (NA) therapy. Cohort B: 23 anti-HBe positive patients who stopped treatment. Cohort C: 19 anti-HBe-positive patients on long-term NA treatment who achieved HBsAg loss and in whom treatment was withdrawn. The concentrations of HBV serological/virological biomarkers (HBV DNA, HBsAg, HBcrAg, HBV RNA) were measured in sequential samples at different time-points on/off therapy.
RESULTS:
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.
CONCLUSION:
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 ALT 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 new drug development and disease management.