Chronic hepatitis B: A wave of new therapies on the horizon

Abstract

This year marks the 50th anniversary of the discovery of the Australia antigen (Blumberg, Alter and Visnich, 1965), which in 1968 was identified to be the hepatitis B virus (HBV) surface antigen. Even though several antiviral medications have been in use for the management of chronic HBV infection for more than 20 years, sustained clearance of HBsAg, similar to the sustained viral response (SVR) or cure in chronic hepatitis C (HCV), occurs in only a minority of treated patients. Moreover, even after 10 years of effective suppression of HBV viremia with current therapy, there is only a 40-70% reduction in deaths from liver cancer. Recent success in developing antivirals for hepatitis C that are effective across all genotypes has renewed interest in a similar cure for chronic HBV infection. In this article, we review a wave of newly identified drug targets, investigational compounds and experimental strategies that are now under clinical evaluation or in preclinical development. The paper forms part of a symposium in Antiviral Research on “An unfinished story: From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”

New horizon for radical cure of chronic hepatitis B virus infection

“…However, complete suppression of HBV polymerase can result in the complete elimination of cccDNA through the death of cccDNAcontaining hepatocytes after one natural lifespan of these cells [92] . Among the agents being tested are prodrugs of HBV polymerase inhibitors [93] . These include prodrugs of tenofovir, such as AGX1009 (Agenix) and TAF (GS7340, Gilead Sciences), which have been evaluated in phase 3 trials [93,94] , and CMX157, a lipid conjugate of tenofovir, which has been evaluated in phase 1/2 trials [93,95] .…”

“…Among the agents being tested are prodrugs of HBV polymerase inhibitors [93] . These include prodrugs of tenofovir, such as AGX1009 (Agenix) and TAF (GS7340, Gilead Sciences), which have been evaluated in phase 3 trials [93,94] , and CMX157, a lipid conjugate of tenofovir, which has been evaluated in phase 1/2 trials [93,95] . RNase H inhibitors are also being tested, based on the specificity of HBV replication, which depends on the RNase H activity of HBV polymerase to degrade pgRNA [10] .…”

“…RNase H inhibitors are also being tested, based on the specificity of HBV replication, which depends on the RNase H activity of HBV polymerase to degrade pgRNA [10] . Evaluations of selective inhibitors of HBV polymerase RNase H activity [96] suggest that they might be more effective when combined with NAs [93] . [97] .…”

“…Radical treatment for HBV the HBV life cycle in hepatocytes, including inhibitors of HBVDNA polymerase, virus entry, core assembly and HBsAg secretion (Table 2) [93,95,120,121] . Especially Myrcludex B, a synthetic lipopeptide that targets NTCP, has been shown to efficiently prevent viral spread and has been applied in clinical trials [15,17,122,123] .…”

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

“…Actualmente, existen múltiples frentes de investigación sobre una potencial cura para la HBC y una gran variedad de medicamentos dirigidos a nuevos blancos moleculares se encuentran en estudio (16,17), los cuales se exponen en este artículo.…”