Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus

Abstract

Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.

A Phase 3 clinical trial validating the potency and safety of an innovative, extra‐long‐acting interferon in chronic hepatitis C

“…Ropeginterferon alfa‐2b could also be useful in combination therapies for CHB or CHD. Pegylated IFN therapy can lead to high rates of HbeAg and HbsAg seroconversion, which may be due to its ability to enhance the covalently closed circular DNA (cccDNA) degradation and have epigenetic modifications of the cccDNA transcription 31 . Nucleoside analogue (NA) therapy, especially the long‐term NA treatment, is also effective in depleting the cccDNA 32 .…”

Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis

“…Pegylated IFN alfa was approved for the CHB treatment [28] and serves as a backbone treatment in CHD patients as an off-label use [58]. Pegylated IFN treatment can lead to higher rates of HBeAg and HBsAg seroconversion in patients, compared to those receiving NAs, possibly due to its immune stimulation or ability to enhance the cccDNA degradation and exert epigenetic modifications of the cccDNA transcription [59]. Ropeginterferon alfa-2b therapy has been shown to cause higher HBeAg seroconversion rates than the conventional pegylated IFN alfa-2a given weekly in the phase 2 setting [12].…”

An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss

“…IFNα can act on cccDNA and is even regarded as one of the most promising drugs in the elimination of HBV cccDNA. 85 Additionally, IFNα regulates the transcription of cccDNA by the epigenetic modifications of the histones and indirectly targets cccDNA through APOBEC3 family proteins. [86][87][88]…”