Abstract and Introduction Abstract

Approximately 350 million people worldwide are chronically infected with hepatitis B virus (HBV), representing a significant public health challenge. Nucleos/tide analogues (NUCs) and interferon alpha (IFNα), the current standard of care for chronic infection, aim at preventing progression of the disease to cirrhosis, hepatocellular carcinoma (HCC) and death. However, in contrast to the case of hepatitis C virus infection, in which novel antiviral drugs cure the vast majority of treated patients, in regard to HBV, cure is rare due to the unusual persistence of viral DNA in the form of covalently closed circular DNA (cccDNA) within the nucleus of infected cells. Available therapies for HBV require lifelong treatment and surveillance, as reactivation frequently occurs following medication cessation and the occurrence of HCC is decreased but not eliminated, even after years of successful viral suppression. Progress has been made in the development of new therapeutics, and it is likely that only a combination of immune modulators, inhibitors of gene expression and replication and cccDNA-targeting drugs will eradicate chronic infection. This review aims to summarize the state of the art in HBV drug research highlighting those agents with the greatest potential for success based on in vitro as well as on data from clinical studies.

Introduction

Chronic HBV (CHB) infection is a major global public health problem^[1] posing the risk of cirrhosis, HCC and death.^[2] Viral suppression is associated with reduced rates of liver complications and greater long-term survival,^[3–5] hence is a major goal in HBV therapy.

To date, there are two main classes of antiviral drugs for CHB; the immunomodulator agent interferon alpha (IFNα), and nucleos/tide analogues (NUCs).^[6,7] Current therapies suppress viral replication, resulting in normalization of serum Alanine transaminase (ALT) and improvement in liver histology.^[8,9]

IFNα has multiple mechanisms of action, including antiviral, antiproliferative and immunomodulatory effects. Importantly, IFNα treatment offers the opportunity for a finite duration of treatment with better chances for off-treatment virological response and HBV surface antigen (HBsAg) loss as compared to NUCs therapy.^[10,11] However, its use is vastly limited by side effects.

NUCs, on the other hand, inhibit the viral polymerase/reverse transcriptase activity that is obligatory for HBV replication. Their major shortcoming is the need for prolonged and often lifelong treatment due to their limited effect on the viral covalently closed circular DNA (cccDNA) pool.

Combination therapy with IFNα and NUCs may have a synergistic effect, resulting in a better control on the virus, at least theoretically. Earlier studies have failed to show a significant difference in major treatment outcomes with such a combination^[12] although more recent studies using a sequential therapy strategy (i.e. Peg-IFNα added to newer generation NUCs) holds some promise for better outcomes.^[13]

HBV is a DNA virus that replicates through an RNA intermediate. The viral genome consists of a small partially double-stranded relaxed circular DNA (rcDNA), which translocates to the nucleus, where it is converted into cccDNA that persists in the form of a mini-chromosome and serves as a template for viral transcription.^[14] Subsequently, one could expect that once viral suppression is achieved and no replication occurs, new molecules of cccDNA would not be created, and after several cycles of cell division and hepatocyte natural death, all infected cells would disappear. In practice, however, the pool of cccDNA molecules seems to be highly stable as viral DNA persists even after many years of NUCs treatment.^[15]

This is in a sharp contrast to HCV, an RNA virus that can be efficiently eliminated with current direct antiviral agents (DAAs), resulting in a complete cure among more than 95% of treated patients.

Given the high potency, safety and excellent resistance profile of the newer NUCs, some scholars argue that HBV treatment need not aspire much further. Nevertheless, given the low percentage of treated patients who achieve clinical cure on the current medications (only 5–8% of patients treated with the newer NUCs for 3 years will achieve HBsAg loss),^[16,17] the vast majority of patients will have to be treated with NUCs indefinitely. This poses the risk of emerging mutants and exposure of patients to potential long-term side effects. Furthermore, even long-standing viral suppression with NUCs significantly reduces, but does not eliminate, the risk of HCC.^[5] Accordingly, there is much rational in developing better therapies, but it is uncertain which therapy goal should be set; whereas clinical cure, defined as HBsAg loss, seems to be a realistic goal, a virological cure defined as total clearance of the virus and its genome from infected cells, seems to be much harder to achieve. Given that treatment with IFNα can substantially reduce cccDNA levels^[18] and clearance of cccDNA by non-cytopathic mechanisms has been shown to occur naturally in chimpanzees acutely infected with HBV,^[19] complete viral clearance is theoretically possible.

This review joins other recent publications,^[20,21] providing an overview and future perspectives regarding major developments in HBV research, focusing on the greatest obstacle to cure, the viral reservoir of cccDNA.

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