Hepatitis delta virus: From infection to new therapeutic strategies

Abstract

The hepatitis delta virus (HDV) is a small RNA virus that encodes a single protein and which requires the hepatitis B virus (HBV)-encoded hepatitis B surface antigen (HBsAg) for its assembly and transmission. HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations, specifically intravenous drug users, practitioners of high-risk sexual behaviours, and patients with cirrhosis and hepatocellular carcinoma. The chronic form of HDV-related hepatitis is usually severe and rapidly progressive. Patterns of the viral infection itself, including the status of co-infection or super-infection, virus genotypes (both for HBV and HDV), and persistence of the virus' replication, influence the outcome of the accompanying and manifested liver disease. Unfortunately, disease severity is burdened by the lack of an effective cure for either virus type. For decades, the main treatment option has been interferon, administered as mono-therapy or in combination with nucleos(t)ide analogues. While its efficacy has been reported for different doses, durations and courses, only a minority of patients achieve a sustained response, which is the foundation of eventual improvement in related liver fibrosis. The need for an efficient therapeutic alternative remains. Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle; the most promising among these are myrcludex B, which inhibits virus entry into hepatocytes, lonafarnib, which inhibits farnesylation of the viral-encoded L-HDAg large hepatitis D antigen, and REP-2139, which interferes with HBsAg release and assembly.

Keywords: Hepatitis B virus; Hepatitis delta virus; Lonafarnib; Myrcludex; REP 2139.

Figure 1

Schematic representation of the hepatitis D virus life cycle. New drugs interfere with the hepatitis B surface antigen at the viral entry or viral assembly level. HBsAg: Hepatitis B surface antigen; HDAg: Hepatitis D antigen; HDV: Hepatitis delta virus; L-HDAg: Large hepatitis D antigen; NTCP: Sodium tauro-cholate cotransporting polypeptide; RNP: Ribonucleoprotein complex; S-HDAg: Small hepatitis D antigen.