Hepatitis B core-related antigen: a strong indicator for cessation of nucleos(t)ide analog therapy in patients with chronic hepatitis B

Abstract

With successful nucleos(t)ide analog therapy, serum hepatitis B virus (HBV) DNA titer decreases to below detection limit, alanine aminotransferase (ALT) normalizes, and fibrosis of the liver may become improved [1][2][3][4]. The incidence of hepatocellular carcinoma can be decreased as well [5][6][7].However, withdrawal hepatitis frequently occurs after treatment cessation, even in patients with undetectable HBV DNA levels. As this complication is sometimes lethal [8][9][10], it is crucial to determine the optimal conditions for stopping nucleos(t)ide analog therapy, especially for young patients wishing to have children, the avoidance of hyper-resistant viral strains, and regulating medical expenses.Knowledge of intrahepatic HBV replication status is the key to defining the safe conditions for nucleos(t)ide analog therapy cessation. cccDNA level is a suitable indicator for this aim, although frequent liver biopsies are needed. Serum HBV DNA was believed to be a good estimator of cccDNA. However, the correlation of HBV DNA and intrahepatic cccDNA levels is lost under the nucleos(t)ide analog treatment and cannot therefore be adopted [11]. Alternative, non-invasive markers are desired.The possibility of discontinuation of nucleos(t)ide analogs is also affected by the clinical goal, such as no withdrawal hepatitis, no viral relapse, or long-term clinical response. The majority of patients experience viral recurrence during withdrawal, but some will not develop hepatitis or will achieve clinical remission after a hepatitis flare.In this issue, Jung KS et al.[12] report on virological remission (i.e., HBV DNA B2000 IU/ml) over 1 year following cessation of nucleos(t)ide therapy in patients HBeAg-positive or HBeAg-negative at the start of treatment. The virological relapse rate of each group was 57.8 and 54.4 %, respectively. Significantly and independently related factors for virological relapse were age [40 years at the start of nucleos(t)ide therapy and basal HBV DNA level[20,000,000 IU/ml in the HBeAg-positive group, and age [40 years at the start of nucleos(t)ide analog therapy and HB core-related antigen (HBcrAg) level[3.7 log U/ml in the HBeAg-negative group.HBcrAg is an established viral activity marker [13]. HBcrAg levels correlated closely with those of intrahepatic cccDNA, even when HBV DNA became undetectable, during nucleos(t)ide analog therapy [11]. Thus, HBcrAg may represent a non-invasive marker of cccDNA with or without nucleos(t)ide analog therapy. We have also reported that a combination of HBsAg and HBcrAg levels at the end of nucleos(t)ide analog therapy was useful to predict long-term clinical remission [14,15].According to APASL guidelines, the appropriate duration of nucleoside analog administration is unknown, although HBV DNA and HBsAg are suggested as estimators of treatment efficacy [16]. There are no precise criteria for the cessation of nucleos(t)ide analog therapy in the EASL guidelines as well [17]. In the AASLD guidelines, HBsAg loss is regarded as the best predictor of sustained remi...

Human immunodeficiency virus coinfection differentially impacts hepatitis B virus viral markers based on hepatitis Be antigen status in patients with suppressed viremia

“…HBV RNA levels are not substantially affected by NAs and interferon treatment, and they correlate with cccDNA levels among virally suppressed patients. [1][2][3][4][5][6][7] HBV RNA levels may be predictive of HBeAg seroconversion during treatment with NAs and be a helpful marker for the safe discontinuation of HBV therapy. [1][2][3][4] Hepatitis B core-related antigen (HBcrAg) also correlates in both treated and untreated patients with cccDNA levels.…”

“…HBcrAg level varies during the different phases of chronic HBV infection, is a useful marker of virus reactivation in occult viral carriers and re-infection after liver transplantation and predicts HBeAg seroconversion. [5][6][7] Measuring and comparing HBV RNA and HBcrAg levels, with other routine HBV serologic and molecular markers (HBV DNA, serum HBsAg/anti-HBs and HBeAg/anti-HBe) in patients with HBVonly and HBV-HIV co-infection receiving antiviral therapy may be relevant to better understanding viral expression and course of infection in the setting of HBV-only and HBV-HIV.…”

“…HBV RNA levels are not substantially affected by NAs and interferon treatment, and they correlate with cccDNA levels among virally suppressed patients 1–7 . HBV RNA levels may be predictive of HBeAg seroconversion during treatment with NAs and be a helpful marker for the safe discontinuation of HBV therapy 1–4 .…”

“…Hepatitis B core‐related antigen (HBcrAg) also correlates in both treated and untreated patients with cccDNA levels. HBcrAg level varies during the different phases of chronic HBV infection, is a useful marker of virus reactivation in occult viral carriers and re‐infection after liver transplantation and predicts HBeAg seroconversion 5–7 …”