What will it take to cure hepatitis B?

Abstract

The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.

Graphical abstract

FIGURE 1

HBV life cycle and targets for direct-acting antiviral agents. Direct-acting antiviral drugs in development or clinical use include (1) Entry inhibitors targeting sodium taurocholate cotransporting polypeptide; (2) capsid assembly modulators (CAM) primarily interfering with capsid assembly but may also interfere with capsid disassembly and recycling; (3) translation inhibitors: small interfering RNA (siRNA), ASO, RNA destabilizers, locked nucleic acid (LNA)s that decrease viral protein and virion production; (4) cccDNA epigenetic modifiers, destabilizers, endonucleases; (5) HBx inhibitors that may decrease cccDNA transcription; (6) HBsAg release inhibitors such as nucleic acid polymers; (7) HBV DNA replication inhibitors such as nucleos(t)ide analogs (NAs), RNase H inhibitors. Numbers in the figure indicate the sites of action of each class of direct-acting antiviral agents. Abbreviations: cccDNA, covalently closed circular DNA; NTCP, sodium taurocholate cotransporting polypeptide; rcDNA, relaxed circular DNA.

FIGURE 2

Immunomodulatory therapies aimed to restore innate and adaptive immune responses against HBV. Innate immunity modulators or activators include TLR7, 8 agonists, and IFN. Therapeutic vaccines, checkpoint inhibitors (anti-PD-1, Anti-PD-L1, PDL1 LNA, apoptosis inducer), and anti-HBV T-cell receptors (IMC-1109V) aim to restore or to stimulate the adaptive immune response to HBV by reversing T-cell exhaustion or triggering a new T-cell immune response. HBV pre-S/S antibodies aim to restore B-cell immune response by neutralizing circulating HBV virions/SVPs and may also prevent de novo infection of the hepatocyte. Abbreviations: IFN, interferon; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed death receptor-1; TGF, transforming growth factor; TLR, toll-like receptor.

FIGURE 3

Strategies to achieve functional HBV cure and the current hurdles in developing novel agents against CHB. De novo or sequential combination of different classes of direct-acting antiviral drugs with or without immune modulatory therapies to inhibit HBV replication, decrease viral antigen production or release, and stimulate or restore immune response to HBV will be required to achieve functional HBV cure. NAs will remain the backbone for HBV replication inhibition. The addition of CAMs may provide more complete suppression of viral replication, the addition of entry inhibitors may prevent de novo infection of uninfected hepatocytes, and the addition of siRNA/ASO may further decrease viral replication. Translation inhibitors, siRNA, and ASO will be pivotal in decreasing viral protein production. PegIFNα can also decrease viral protein production in addition to its immunomodulatory effects. HBsAg release inhibitors, NAP and STOP, can decrease circulating HBsAg. Inhibition of HBV replication and viral protein production may be sufficient in restoring immune response to HBV in some patients while others will need immune modulatory therapies to stimulate/restore innate and/or adaptive immune response to achieve functional HBV cure. The availability of tests that can reliably determine when cccDNA transcription is completely silenced, the source of circulating HBsAg from cccDNA versus integrated HBV DNA, and patient’s immune response to HBV would be crucial to the development of HBV cure. The current major hurdles in drug development for CHB include incomplete or nondurable inhibition of cccDNA transcriptional activity, lack of effect on HBsAg production from integrated HBV DNA, and inconsistent effect on restoring HBV-specific immune response even when HBsAg level is markedly decreased. The knowledge gap and inadequate tools in assessing individual patient’s immune response to HBV hinder strategies to target immunomodulation. Safety is also a concern, as the development of several drugs was terminated because of drug-induced toxicity. Another safety concern relates to potential hepatitis flare during treatment and when treatment is discontinued. Drug delivery poses a concern for patient acceptance and global uptake, given that NAs are administered orally. New drugs that need to be given parenterally have to show significant incremental efficacy and comparable safety for patients to replace oral therapy with parenteral therapy. Drug resistance so far have been less of a concern because most trials extending for 12 or more weeks have been in combination with NA. Abbreviations: CAM, capsid assembly modulators; cccDNA, covalently closed circular DNA; NA, nucleos(t)ide analog; PD-1, programmed death receptor-1; siRNA, small interfering RNA.