Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?

Abstract

BackgroundHepatitis B virus (HBV) chronic infection affects up to 240 million people in the world and it is a common cause of cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) plays an essential role in HBV persistence and replication. Current pharmacological treatment with nucleos(t)ide analogues (NA) may suppress HBV replication with little or no impact on cccDNA, hence lifelong treatment is required in the vast majority of patients. Clearances of intrahepatic cccDNA and/or HBsAg are critical endpoints for future antiviral therapy in chronic HBV. Recent promising developments targeting different molecular HBV life cycle steps are being pre-clinically tested or have moved forward in early clinical trials.MethodsWe review the current state of the art of these pharmacological developments, mainly focusing on efficacy and safety results, which are expected to lay the ground for future HBV eradication. An inclusive literature search on new treatments of HBV using the following electronic databases: Pubmed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts and abstracts published over the last 12 years, from 2005 to March 2011 were reviewed for relevance and reference lists were crosschecked for additional applicable studies regarding new HBV antiviral treatment.ResultsHBV entry inhibitors, HBV core inhibitors, HBV cccDNA transcripts RNA interference, HBV cell apoptosis inducers, HBV RNA, viral proteins and DNA knock down agents, HBV release inhibitors, anti-sense nucleosides, exogenous interferon stimulation, interferon response stimulation and HBV therapeutic vaccines were reviewed.ConclusionThis review will provide readers with an updated vision of current and foreseeable therapeutic developments in chronic hepatitis B.

Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19

“…On the other hand, Birinapant and Dynasore from the category of the antiviral drug show a good binding affinity towards SARS-CoV-2 M pro . Antiviral activity of Birinapant against chronic hepatitis B virus (HBV) infection by induction of apoptosis by inhibiting cellular inhibitor of apoptosis proteins (cIAPs) has been reported in the literature (Alonso et al., 2017 ; Ebert et al., 2015). The second antiviral lead compound i.e.…”

Combination of a Latency-Reversing Agent With a Smac Mimetic Minimizes Secondary HIV-1 Infection in vitro

“…Birinapant is currently an investigational drug for a variety of cancers, and it is to be noted that the activity of birinapant to induce apoptosis can vary among different cell types, and cancer cells (or cell lines derived from cancer cells) are likely to be more sensitive to the drug ( Fulda and Vucic, 2012 ; Bai et al, 2014 ). However, it is noteworthy that birinapant is also currently being investigated for its use in the treatment of chronic HBV infection ( Ebert et al, 2015 ), and a phase II clinical trial is currently ongoing ( Alonso et al, 2017 ). Regarding the utility of birinapant for HIV-1 infection, especially to cure HIV-1, Pache et al (2015) reported that certain Smac mimetics reactivated latent HIV-1-infected cells and raised their HIV-1 mRNA expression ( Pache et al, 2015 ).…”

Molecular, Evolutionary, and Structural Analysis of the Terminal Protein Domain of Hepatitis B Virus Polymerase, a Potential Drug Target

“…Chronic HBV infections are currently treated with pegylated interferon-α, which increases immune activity, and/or with nucleoside analogs that block the RT domain from replicating viral DNA. Both of these main classes of drugs achieve hepatitis B surface antigen (HBsAg) loss only rarely; interferon is poorly tolerated, and nucleoside analogs are administered for life to achieve a reduction in viral load [2][3][4].…”

“…Although several hundred million people in the world are infected by HBV, an effective vaccine exists, as well as non-curative treatment [1]. Current antiviral drugs, except immunomodulatory drugs such as pegylated interferon α and thymalfasin, are all directed against the HBV polymerase (Pol) [2][3][4], though therapeutics for novel targets are in development [5]. Although there is no small animal model capable of infection with human HBV, informative studies have been performed using related HBV species that infect avian and mammalian hosts, such as duck HBV (DHBV) and woodchuck HBV [6].…”