Latest Treatment of Hepatitis B - Pegylated Interferon-α & Nucleoside Analogs

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Latest Treatment of Hepatitis B Pegylated Interferon-α & Nucleoside Analogs Hepatitis B virus (HBV) is a major public health threat worldwide, as nearly 300 million people have chronic HBV infection. The ideal readout that indicates the success of chronic HBV treatment is the clearance of the hepatitis B virus surface antigen (HBsAg or HBs) after the treatment is stopped. Currently, there are two treatments for hepatitis B virus infection, pegylated interferon-α (IFN-α) and nucleos(t)ide analogues (NAs).

Structure of Hepatitis B Virus HBV particles, also known as Dane particles, were first discovered by Dane and colleagues in 1970. They are spherical in shape and approximately 42 nm in diameter.

They consist of an outer envelope, which is a host-derived lipid bilayer, containing three different sizes of HBV surface antigens (HBsAg or HBs) around the virus nucleocapsid.

The nucleocapsid (approximately 27 nm diameter) is icosahedral and contains the HBV core protein (HBcAg), viral DNA genome, and viral DNA polymerase (P). The virus also secretes a variety of defective particles, including enveloped nucleocapsid particles that are empty or contain defective immature genomes and subviral lipid particles that contain virus surface antigens.

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Approved Treatment of Hepatitis B Interferon-α (IFN-α) was first approved in 1991 for the treatment of HBV infection.

However, the addition of polyethylene glycol chains to IFN-α resulted in a significant improvement in pharmacological properties. Therefore, IFN-α was replaced by its pegylated counterpart PEG IFN-α in 2005. There are currently two forms of PEG-IFN-α, PEG-IFN-α-2a (Pegasys©, Roche) and PEG-IFN-α-2b (Pegintron©, Merck). They improve the pharmacokinetics and allow a longer half-life and are administered once a week. PEG-IFN-α is administered subcutaneously and has direct antiviral and immunomodulatory activities.

Huateng Pharma, as a professional PEG derivative supplier, can provide high purity PEG derivatives with an extensive variety of functional groups for your research, in both non-GMP and GMP grade.

Compared with nucleoside analogs, PEG IFN-α therapy has advantages including a lack of drug resistance, a finite and defined treatment course, durable response posttreatment, and a higher likelihood for HBsAg clearance. However, PEG-IFN-α treatment can cause adverse reactions, including flu-like symptoms, bone marrow suppression, fatigue and depression, and it is contraindicated in patients with liver failure or cirrhosis. Due to subcutaneous administration, patient compliance is also low.

Nucleoside analogs inhibit HBV reverse transcriptase activity, thus blocking HBV DNA replication. The active form of most of these drugs is the triphosphate produced by the phosphorylation of hepatocyte kinases. Nucleoside triphosphate analogs are substrates for RT. During reverse transcription, they act as immediate or delayed transcription terminator and prevent the synthesis of (-) and (+) HBV DNA strands. They are administered orally, with acceptable pharmacokinetics and limited drug-drug interactions.

They effectively inhibit HBV DNA levels, and have been shown to prevent the disease from progressing to cirrhosis, reverse liver fibrosis and even cirrhosis, and reduce but not eliminate the risk of HCC. However, NAs have almost no effect on covalently closed circular DNA (cccDNA), a stable free form of the HBV genome with a very long half-life and can persist for decades in hepatocytes despite effective viral suppression. Therefore, NAs will not lead to the disappearance of HBsAg, but will only inhibit viral replication, requiring prolonged treatment (indefinitely) and associated costs. Currently, eight kinds of NAs (Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir, Clevudine, Tenofovir Disoproxil Fumarate, Tenofovir Exalidex, Tenofovir Alafenamide Fumarate, Besifovir Dipivoxil Maleate) have been approved for anti-HBV, of which currently recommended are Entecavir and two tenofovir prodrugs, desoproxil and alafenamide.

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Huateng Pharma is dedicated in pharma intermediates manufacturing, can provide entecavir intermediates with high quality.

Overall, achieving a “functional cure” of the infection remains a real challenge. New treatments are urgently needed to cure hepatitis B. Recent findings concerning the viral replication cycle have led to the development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. So chances are high that these strategies may be found that substantially improve treatment for HBV patients.

References Prifti, G.-M.; Moianos, D.; Giannakopoulou, E.; Pardali, V.; Tavis, J.E.; Zoidis, G. Recent Advances in Hepatitis B Treatment. Pharmaceuticals 2021, 14, 417. https://doi.org/10.3390/ph14050417