Endpoints of Hepatitis B Treatment
The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies.
The ultimate goal of chronic infectious disease treatment is the eradication of the infectious agent; however, eradication of hepatitis B virus (HBV) is not a realistic goal of hepatitis B treatment. Currently available nucleos(t)ide analogues (NUCs) act mainly as inhibitors of the reverse transcription of the pregenomic RNA to HBV DNA and have no direct effect on the covalently closed circular DNA (cccDNA) – the template for the transcription of the pregenomic RNA as well as for the translation of viral proteins. This accounts for the high rate of viral relapse when treatment is stopped. Indeed, even in persons who have serological recovery from an acute HBV infection, HBV DNA remains detectable in the liver and reactivation of HBV replication can occur when those persons receive immunosuppressive therapy. Recent studies suggest that clearance of cccDNA relies on the turnover of infected hepatocytes. This may explain the higher rate of sustained off-treatment response to interferon (IFN) therapy even though IFN has weaker antiviral activity compared to NUCs.
Abstract and Introduction
Abstract
The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies.
Introduction
The ultimate goal of chronic infectious disease treatment is the eradication of the infectious agent; however, eradication of hepatitis B virus (HBV) is not a realistic goal of hepatitis B treatment. Currently available nucleos(t)ide analogues (NUCs) act mainly as inhibitors of the reverse transcription of the pregenomic RNA to HBV DNA and have no direct effect on the covalently closed circular DNA (cccDNA) – the template for the transcription of the pregenomic RNA as well as for the translation of viral proteins. This accounts for the high rate of viral relapse when treatment is stopped. Indeed, even in persons who have serological recovery from an acute HBV infection, HBV DNA remains detectable in the liver and reactivation of HBV replication can occur when those persons receive immunosuppressive therapy. Recent studies suggest that clearance of cccDNA relies on the turnover of infected hepatocytes. This may explain the higher rate of sustained off-treatment response to interferon (IFN) therapy even though IFN has weaker antiviral activity compared to NUCs.
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