Medical Advances in Hepatitis D Therapy: Molecular Targets

Abstract

An approximate number of 250 million people worldwide are chronically infected with hepatitis B virus, making them susceptible to a coinfection with hepatitis D virus. The superinfection causes the most severe form of a viral hepatitis and thus drastically worsens the course of the disease. Until recently, the only available therapy consisted of interferon-α, only eligible for a minority of patients. In July 2020, the EMA granted Hepcludex conditional marketing authorization throughout the European Union. This first-in-class entry inhibitor offers the promise to prevent the spread in order to gain control and eventually participate in curing hepatitis B and D. Hepcludex is an example of how understanding the viral lifecycle can give rise to new therapy options. Sodium taurocholate co-transporting polypeptide, the virus receptor and the target of Hepcludex, and other targets of hepatitis D therapy currently researched are reviewed in this work. Farnesyltransferase inhibitors such as Lonafarnib, targeting another essential molecule in the HDV life cycle, represent a promising target for hepatitis D therapy. Farnesyltransferase attaches a farnesyl (isoprenyl) group to proteins carrying a C-terminal Ca1a2X (C: cysteine, a: aliphatic amino acid, X: C-terminal amino acid) motif like the large hepatitis D virus antigen. This modification enables the interaction of the HBV/HDV particle and the virus envelope proteins. Lonafarnib, which prevents this envelopment, has been tested in clinical trials. Targeting the lifecycle of the hepatitis B virus needs to be considered in hepatitis D therapy in order to cure a patient from both coexisting infections. Nucleic acid polymers target the hepatitis B lifecycle in a manner that is not yet understood. Understanding the possible targets of the hepatitis D virus therapy is inevitable for the improvement and development of a sufficient therapy that HDV patients are desperately in need of.

Keywords: Hepcludex; antivirals; farnesyl transferase; hepatitis B; hepatitis D; viral entry mechanisms.

Figure 1

Comparison of HBV and HDV. Both viral envelopes consist of small, medium, and large HBsAg. HBcAg forms the HBV capsid which encloses the reverse transcriptase and the HBV genome. In the HDV particle, the envelope proteins enclose the ribonucleoprotein consisting of the genome and the small and large HDAg.

Figure 2

Global distribution of HDV genotypes. Genotype 1 is spread globally. Genotypes 2 and 4 are found in Taiwan and Japan. Genotype 2 is also found in parts of Russia. Genotype 3 dominates in the Amazon region. Genotypes 5 to 8 are located on the African continent.

Figure 3

Hepatitis D virus life cycle. The hepatitis D virus enters hepatocytes via the NTCP. HBsAg and RNP separate and the genome migrates into the nucleolus. Inside the nucleus, several copies of the antigenome are produced from the genome via a rolling circle mechanism. These serve as a template for mRNA synthesis from which the small HDAg is translated. In addition, the antigenome is edited by adenosine deaminase I. The edited antigenome serves as a template for mRNA synthesis from which the large HDAg is translated. Subsequently, the large HDAg is farnesylated by the human farnesyltransferase. Several copies of the genome are produced from the antigenome via a rolling circle mechanism. Together with the two HDAg these form an RNP, which is enveloped by HBsAg in an early Golgi compartment and secreted.