Treatment options for chronic hepatitis B not responding to interferon

Abstract

Chronic hepatitis B (CHB) defined by the presence of hepatitis B surface antigen (HBsAg) in serum, high levels of circulating hepatitis B virus (HBV) DNA and chronic necroinflammation of the liver is separated into two forms based on the hepatitis B e antigen (HBeAg) and antibody (anti-HBe) status [1,2]. The HBeAg-positive CHB considered as the typical, prototype form of the disease, occurs in earlier phases of chronic HBV infection than HBeAgnegative CHB, it prevails in European and North American patients infected with HBV genotype A and is characterized by persistently high serum aminotransferases (ALT) and hepatitis B viraemia levels [1,3]. In perinatally acquired HBV infection, which is common in geographical areas of high HBV prevalence like Asia, it appears to follow a period of immune tolerance of HBV during which HBV DNA levels are high while ALT levels keep normal or nearly normal and liver necroinflammtion is minimal or absent [4]. When HBeAg-positive CHB develops serum ALT levels increase and liver damage progresses to severe necroinflammation with advancing fibrosis. If HBeAg-positive CHB is left untreated it may subside spontaneously terminating into loss of HBeAg, seroconversion to antiHBe, suppression of HBV replication to non-detectability by molecular hybridization techniques or to ,10–10 copies/ml by polymerase chain reaction, return of ALT to normal and resolution of liver disease activity. However, the probability of spontaneous resolution of HBeAg-positive CHB is limited to approximately 10–12% per year (ranging in the various studies from 2 to 24% [2]. Thus, a large number of untreated patients with HBeAg-positive CHB are left with severe liver necroinflammation which persists for several years and results in an increased likelihood of progression of liver damage to advanced stages of fibrosis, cirrhosis and even development of hepatocellular carcinoma (HCC), the most dire consequence in the natural history of CHB [2]. In a recent study, the relative risk of HCC among men positive both for HBsAg and HBeAg was 60.2 compared to 9.2 in those with only HBsAg [5]. The need, therefore, for early and effective therapeutic intervention in HBeAgpositive CHB is obvious, but unfortunately it has remained an unresolved issue of clinical hepatology for more than 20 years now. In the HBeAg-negative form of CHB, which prevails in the Mediterranean Area and Asia and is mostly due to precore HBV mutants, serum HBV DNA levels are lower than in HBeAg-positive CHB, generally between 10 and 10 copies/ml. Both HBV DNA and serum ALT levels are often fluctuating [1]. However, spontaneous remissions are extremely rare and prognosis is poor with frequent progression to cirrhosis and HCC. Therefore, similar to HBeAg-positive CHB, the need for effective therapeutic intervention is again obvious [6].