NEJM Blockbuster of the Year! A comprehensive review of recent developments in the treatment of hepatitis B

▎WuXi AppTec content team editor

Chronic hepatitis B infection remains a significant global public health burden
.
Globally, an estimated 296 million people live with chronic hepatitis B, of whom 221 million live in countries or regions
with medium/low levels of economic development.
Without effective intervention for patients with chronic hepatitis B, it is expected that by 2035, the number of deaths due to hepatitis B virus infection may peak
at 1.
14 million.

Recently, the New England Journal of Medicine (NEJM), a top international medical journal, published its annual blockbuster review "Innovative Therapies for Hepatitis B", detailing the latest progress
in the research of new biomarkers and innovative drugs in the field of hepatitis B diagnosis and treatment.

Screenshot source: NEJM

Novel diagnostic markers

At present, the commonly used markers for the diagnosis and treatment of patients with chronic hepatitis B include hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B core antibody (anti-HBc) and hepatitis B virus DNA.

The review notes that the persistence of intrahepatic covalently closed circular DNA (cccDNA) is the main cause of chronicization of HBV infection, however, HBsAg testing such as HBsAg does not distinguish between HBsAg derived from cccDNA and HBsAg
derived from integrated viral genomes.

At present, there is still a lack of recognized quantitative detection standards for cccDNA, but a variety of liver tissue cccDNA quantitative detection technologies are in the research and development stage
.
In addition, two novel serum markers, HBV RNA and hepatitis B core-associated antigen (HBcrAg), have been used to assess the transcriptional activity
of cccDNA.

• HBV RNA：

During HBV replication, a small number of pregenomic RNAs (pgRNAs) release HBV-containing capsids into serum
.
At present, scientists have developed two high-throughput detection methods for the quantitative detection of pgRNA
.
It should be pointed out that HBeAg-positive patients have significantly increased HBV RNA levels; In HBeAg-negative patients, there was a poor correlation between HBV RNA levels and HBsAg levels (because HBsAg was derived from the integrated genome).

Because nucleoside analogues of standard therapy for hepatitis B have minimal effect on cccDNA transcription to pgRNA, HBV RNA can be detectable for years
during hepatitis B treatment.

• HBcrAg：

HBcrAg testing involves HBeAg, HBcAg, and p22cr proteins (i.
e.
, the detection component is only from HBV cccDNA).

At present, scientists have developed a more sensitive serum HBcrAg detection technology, which has a detection limit of 2.
1 log₁₀U/ml
.

The review notes that both HBV RNA and HBcrAg assays identify active cccDNA transcription, so these two tests may identify patients at higher risk of disease progression and predict the likelihood
of relapse after discontinuation of drug therapy.
These two markers are expected to overcome the limitations of quantitative HBsAg, HBV DNA, and HBeAg detection, and effectively distinguish HBeAg-negative patients from patients with less active infection
.

▲ Hepatitis B virus survival cycle (Image source: Reference [1]).

Innovative therapies for hepatitis B

The goal of treatment for hepatitis B is to achieve a functional cure, i.
e.
, persistent loss of HBsAg (below the detection limit of 0.
05 IU/ml) after discontinuation of drug therapy, and no detectable
presence of HBV DNA in serum.
The review highlights that three goals need to be achieved to truly cure hepatitis B infection:

• eradication, degradation or silencing of cccDNA;

• silencing integrated viral genomes;

• Corrects antigen-specific immune dysfunction
  .
  

At present, the frontier of hepatitis B treatment includes viral entry inhibitors, RNA disruptors (siRNA), HBsAg assembly agents, capsid protein assembly modulators (CAM) and immunomodulatory therapies.

• Viral entry inhibitors:

Bulevirtide is an HBV/HDV viral entry inhibitor that binds to and inactivates sodium taurocholate co-transporting polypeptides, thereby inhibiting hepatitis B virus and hepatitis D virus entry into hepatocytes
.
At present, the therapeutic effect of this drug in chronic hepatitis B is still in
the early stage of clinical exploration.

• Nucleic acid polymers:

Nucleic acid polymers such as REP 2139 block the assembly and secretion
of HBV subviral particles.
Scientists have evaluated the efficacy
of REP 2139 in combination therapies such as tenofovir or peginterferon.
The study showed that after 48 weeks of follow-up, 14 of the 40 patients treated with REP 2139 tested negative for HBsAg
.

• Capsid protein assembly regulator (CAM):

A variety of oral small molecule CAMs are currently in the research and development stage
.
These drugs disrupt pgRNA capsidization
by interfering with capsid assembly.
Studies have shown that these drugs can reduce serum HBV DNA levels by up to 4 log 10 IU/ml and HBV RNA levels by up to 3 log₁₀copies/ml
within 28 days.

• RNA interferents:

RNA disruptors include siRNA and antisense oligonucleotides (ASOs).

Among them, siRNA lasts longer
than ASO.

The results of phase 1 and phase 2 trials showed that 60%~75% of patients receiving siRNA treatment had a reduction of HBsAg of more than 2.
0 log 10 IU/ml within 24~48 weeks, and the HBsAg level was less than₁₀₀IU/ml, while the rebound after treatment was relatively slow
.

ASO are synthetic single-stranded oligonucleotides that bind to complementary HBV RNA transcripts to form hybrid ASO-RNA
complexes.
Results from a recent Phase 2b b-Clear study showed that 10% of patients with chronic HBV infection who received monotherapy with the antisense oligonucleotide bepirovirsen met the primary endpoint (i.
e.
, HBsAg levels below the detection limit of 0.
05 IU/ml within 24 weeks of discontinuation; HBV DNA levels below 20 IU/ml).

Image source: 123RF

Although these innovative therapies have not yet achieved the primary goal of functional cure, data from these clinical studies also show that most patients are on track to achieve the goal
of reducing HBsAg levels to less than 100 IU/ml with these innovative therapies.
Based on the current treatment progress, many experts have proposed the concept of "partial functional cure" (that is, the HBsAg level drops to <100 IU/ml within 6 months of limited treatment).
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The review points out that there are still a number of innovative therapies in the preclinical research stage, including hepatitis B X gene targeted therapy, cccDNA destabilization therapy, CRISPR-Cas9 gene editing therapy (edit cccDNA), etc
.
In addition, early research data suggest that the use of novel antivirals alone is not sufficient to restore effective immunomodulatory capacity
in patients with hepatitis B.
Therefore, in the field of hepatitis B treatment, the research of immunomodulatory drugs (such as peginterferon α, oral selective toll-like receptor agonists) is also a hot spot
.