Treatment to eradicate Hepatitis B- is there light at the end of the tunnel?

Abstract

HBsAg seroclearance before the age of 50 years of age is associated with decreased incidence of hepatocellular carcinoma. Studies of spontaneous HBsAg seroclearance select special population with low viral activities. However HBsAg seroclearance is only achievable in 8-11% of patients with the current treatment agents. The pattern of HBsAg level decline during NA treatment is variable. In contrast, permanent suppression of HBV DNA levels to below PCR detectability is achieved in 98- 100% of patients on long-term nucleoside analogues (NAs). Hepatitis B virus (HBV) covalently closed circular (ccc) DNA, a minichromosome essential for HBV replication, is supposed to be resistant to NA treatment. In a pioneering study of 43 subjects with three liver biopsies on long-term NAs with continuous viral suppression for a median of 126 months, at the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. Compared to baseline levels, there was reduction of HBsAg levels by 71.46%, ihHBV DNA levels by 99.84% and cccDNA levels by 99.89%, with 49% of patients having undetectable cccDNA. The median pregenomic RNA level, measured only in the third biopsy, was 0.021 copies per cell, with 40% of patients having undetectable pgRNA. Only one patient had undetectable HBsAg. With the low level of viral replication as indicated by the low cccDNA and pgRNA levels, it is likely that HBsAg is produced from integrated HBV DNA. There are several agents currently being investigated. These agents can be classified into two main subgroups, direct acting antiviral agents and host-immune-stimulating agents. The former group includes HBV entry-to-hepatocyte inhibitors, short interfering RNA (siRNA), nucleocapsid assembly inhibitors. The latter group includes therapeutic vaccine and toll-like receptor agonists. These upcoming agents may further optimize HBV control. For clearance of integrated HBsAg, siRNA is the most likely option.