Novel Therapeutics for Hepatitis B

Hepatitis B virus (HBV) infects around 257 to 291 million people worldwide.

The liver is vital to the health of the human body. Excessive drinking, drugs, medicines, and other viruses can cause damage to the liver. Once the liver is damaged, it will not function properly and people will become abnormally weak.

Four major symptoms that may appear in the early stage of Hepatitis B:

• Fatigue: feeling fatigue is related to liver metabolic dysfunction caused by hepatitis, loss of appetite, difficulty in digestion and absorption, resulting in insufficient energy supply.
• Loss of appetite and annoying grease: hepatitis B causes the necrosis of liver cells that reduce the function of secreting bile, and thereby fat digestion will be affected.
• Yellow urine
• Pain or swelling in the liver area: the overtight liver capsule coupled with gallbladder inflammation and intestinal bloating causes the pain in the liver area.

Current treatments for Hbv

Currently, the FDA has approved seven antiviral therapies for the treatment of chronic HBV infection. Among them, interferon and nucleoside analogs (NAs) can reduce liver inflammation and fibrosis, and reduce the incidence of liver cirrhosis and HCC. The goal of antiviral therapy is mainly defined by virological and biochemical indicators. Virological response and biochemical response are related to the improvement of clinical outcomes. However, the limitation of current treatment methods is the low serum clearance rate of HBeAg and HBsAg in the early stage of hepatitis B. Current HBV therapies can inhibit HBV replication, but cannot eliminate the virus.

Therapeutic response

Blood

Liver

ALT

HBV DNA

HBsAg

Anti-HBs

cccDNA

Virologic

N/A

Undetectable

Detected

Undetectable

Present

Biochemical

Normal

N/A

Detected

Undetectable

Present

Function cure

Normal

Undetectable

Undetectable

Detected

Present

Complete/sterilizing cure

Normal

Undetectable

Undetectable

Detected

Undetectable

Abbreviations: ALT, alanine aminotransferase; anti-HB, HBV surface antibody; cccDNA, covalently closed circular DNA; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

Novel HBV treatments

1. Targeted antiviral drugs

Some new drugs for different stages of the HBV life cycle are currently in phase II clinical trials.

HBV entry inhibitor: It can prevent HBV and hepatitis D virus (HDV) from entering and prevent infection of the initial liver cells, thereby preventing further infection. Some of these drugs (such as cyclosporin A) can bind to sodium ion-taurocholic acid cotransporter (NTCP) and have antiviral activity.

Nucleocapsid assembly regulator: HBV core protein is essential for HBV pregenomic RNA (pgRNA) packaging and reverse transcription. According to the chemical structure of core protein allosteric modulators (CpAMs), two types of dysfunctional capsids may be formed, which are unstable abnormal capsids or empty capsids. Theoretically, a dysfunctional capsid reduces the production of infectious virus particles and reduces the replenishment of cccDNA in the nucleus of liver cells. There are currently 10 CpAMs in phase I or II studies.

Post-transcriptional regulatory inhibitors (RNAi or oligonucleotides): RNAi can directly target HBV transcripts and induce their degradation, leading to gene silencing. Single-stranded oligonucleotides (SSOs) are small nucleic acids that are complementary to the target transcript, which can also induce degradation after binding.

HBsAg release inhibitor: the mechanism of action is the same as that of RNAi and oligonucleotides, namely blocking the release of subviral HBsAg particles that are considered to have immunosuppressive properties and blocking the natural immune response.

cccDNA target: small molecules that can inhibit the formation of cccDNA or destroy the stability of the existing cccDNA are currently being explored, but clinical trials have not yet been conducted.

2. Immunomodulatory therapy

The use of immunomodulatory therapy to restore HBV-specific immune response may be the key to achieving durable virus clearance.

Interferon: interferon plays an important role in the natural immune response to viral infection. Interferon binds to receptors on the cell surface and stimulates response elements stimulated by IFN in the nucleus. These elements have a variety of downstream effects, including virus recognition and clearance. Peg-IFN can inhibit the encapsidation of pgRNA, promote the degradation of cccDNA, and make epigenetic modification of cccDNA transcription. A variety of investigative HBV therapies are used in combination with Peg-IFN to produce a combination therapy. However, the side effects of Peg-IFN are a challenge.

Toll-like receptor agonists: TLRs are essential in initial perception of human viral infections, which initiates the intracellular pathway of inducing antiviral mediators, including interferons, cellular immune mediators, and antiviral cytokines. Early studies show that the activation of TLR-mediated pathways can inhibit HBV replication in vivo and in vitro. There are currently TLR-7, -8, and -9 agonists in Phase I and Phase II trials.

Checkpoint inhibitors: by reversing T cell failure and restoring anti-tumor immunity, checkpoint inhibitors against PD-1 and PD-L1 are shown to be effective in a variety of malignancies. Corresponding clinical trials are ongoing.

Therapeutic vaccines: therapeutic vaccines are developed to stimulate the host's immune response to inhibit HBV replication and ultimately HBsAg, thereby restoring HBV-specific immune control. So far, the results of therapeutic vaccines in early human studies are not ideal, and combined methods with other antiviral or immunomodulatory therapies should be deployed to achieve a functional cure of HBV.

In summary, HBV has caused severe morbidity and mortality worldwide. At present, there are a variety of new drugs with unique mechanisms of action in the research, but attention needs to be paid to the safety and effectiveness of these drugs.

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