Chronic hepatitis B infection is a major global health issue, affecting around 248 million people. Current treatments like nucleoside analogues and interferon are not curative and have limitations. New therapies targeting the hepatitis B virus directly or the host immune response are in development. Direct-acting antivirals in clinical trials inhibit the viral polymerase, capsid formation, HBsAg secretion, and RNase H. Host-targeting approaches trial immune enhancers, viral entry inhibitors, vaccines, and pro-apoptotic drugs. Promising preclinical candidates additionally modulate immunity, epigenetics, interferons, and cyclophilins. These novel therapies aim to achieve functional cures for chronic hepatitis B.

1. HBV Therapeutic Advances
Direct antiviral drugs
Dr.Mohammed A. Aboelmagd MD
Endemic and Infectious diseases department

2. Introduction
• Chronic hepatitis B infection remains a major
disease burden globally, and leads to high risk
of hepatocellular carcinoma development.
• Although effective vaccines have been
available for more than three decades,
hepatitis B virus (HBV) infection remains a
global public health issue. It is estimated
around 248 million people are chronically
infected by HBV, and most of them are
residing in the Asia-Pacific region

3. Clinical relevance of chronic hepatitis B
and the need for therapeutic advances
• About 4 % of the global population, are
chronically infected with hepatitis B virus
(HBV).
• is the dominant risk factor for development
of hepatocellular carcinoma (HCC) in Asia
and sub-Saharan Africa

4. Clinical relevance of chronic hepatitis B
and the need for therapeutic advances
• Vaccination coverage remains low in many
countries and a low percentage of individuals
have no or low development of antibody
response upon vaccination
• HBV infection occurs during birth or during
adolescence, the likelihood of
development into chronic hepatitis B is
estimated at 90 % and 20–30 %
respectively.

5. Overview of hepatitis B viral life cycle
• HBV is a DNA virus that belongs to the
family of Hepadnaviridae, and has a 3.2 kD
double stranded genome surrounded by
nucleocapsid and envelope proteins.
• All four of the open reading frames (ORFs)
overlap and are present on the minus
strand, encoding for the viral polymerase
and reverse transcriptase, envelope,
precore and X proteins.

6. Overview of hepatitis B viral life cycle
• HBV is highly hepatotrophic and species-
specific, which means that HBV replicates
exclusively within human hepatocytes.
• The viral replication cycle can be divided
into early and intermediate events (reverse
transcriptase-independent) and late events
(reverse transcriptase-dependent).

7. Overview of hepatitis B viral life cycle
• Early events:
- Attachment
- Penetration
- Uncoating
• Intermediate events:
- Replication ( cccDNA)
• Late events:
- Assembly
- Release

9. Overview of the immune response to acute
and chronic hepatitis B
• It remains strongly debated whether the
lack of innate response within the infected
hepatocytes is due to active suppression
by HBV or defective immune sensing
mechanisms.
• Even though HBV lacks the ability to
trigger a strong innate immune response, it
remains susceptible to the effects of innate
antiviral cytokines.

10. Overview of the immune response to acute
and chronic hepatitis B
• CD4 T cells produce cytokines that help in
the CD8 T cell response, and the CD8 T
cell response clears HBV infected
hepatocytes through cytolytic and non-
cytolytic mechanisms.
• Functional HBV specific CD4 and CD8 T
cell responses are required for HBV
control in both chimpanzees and humans

12. Overview of the immune response to acute
and chronic hepatitis B
• Importantly, the immunological profiles
between acute and chronic hepatitis B
patients are different. During chronic HBV
infection, unlike acute HBV infection, the T
cell response is characterized by exhaustion,
where HBV specific T cells upregulate
expression of inhibitory molecules ,and T
cells are physically deleted through
apoptosis

13. Overview of the immune response to acute
and chronic hepatitis B
• The importance of adaptive immunity in
effective control of HBV infection stems from
observations that transplantation of bone
marrow from HBV immunized individuals,
which contain HBV-specific memory T and B
cells, into chronic hepatitis B patients
achieves control of chronic HBV infection

14. Current treatments against chronic hepatitis B
and development into HCC
• Current treatments for chronic hepatitis B
have developed in two main directions.
1- Nucleot(s)ide analogues that target reverse
transcription during the HBV life cycle and
prevent infectious virion release.
However, because nucleot(s)ide analogues do
not directly target cccDNA,the chance of relapse
after drug withdrawal is high and lifelong
nucleot(s)ide treatment is costly.
Resistance.

15. Current treatments against chronic hepatitis B
and development into HCC
2- conventional or pegylated IFNa, which
stimulates the antiviral immune response in
patients.(finite therapy,loss of HbsAg for long
duration, side effects,contraindicated in
advanced cirrohosis)

17. New waves of HBV therapies

19. Direct-acting antivirals
A.New investigational agents now in clinical trials
1. Prodrugs of HBV polymerase inhibitors:
chemical or molecular precursors of active
drugs Typically, a prodrug is designed to
improve the performance of the active drug
substance, usually by decreasing toxicity,
improving solubility, enhancing tissue
absorption and/or increasing the half-life, so
that the agent can be dosed no more
frequently than once daily.
Prodrugs of tenofovir are in the most advanced stages of development
Tenofovir disproxil fumarate,,tenofovir alafenamide

20. Direct-acting antivirals
• AGX1009 and TAF. AGX1009 (Agenix) and TAF
(Gilead), are prodrugs of tenofovir in Phase 3
clinical trials.
2- small interfering RNA :In principle, siRNA-acting
drugs, which target HBV transcripts,should be able to
shut down all HBV gene product production. This
approach has had great promise, but has been
frustrated by the inefficiency in delivery of the nucleic
acid oligomers to human hepatocytes, despite
extremely compelling results in experimental animal
(ARC-520 Inhibit HBsAg, HBeAg and HBV DNA
levels).

21. Direct-acting antivirals
3- HBsAg-reducing agents:
RepA9, from Replicor, is a nucleic acid-based
polymer(NAP) ,comprised of phosphorothioated
nucleic acids The mechanism of action is
unclear, but the sponsor reports it acts on
HBsAg. As stated, compounds that act on
HBsAg are particularly interesting because they
also have the potential for direct activity against
hepatitis delta virus (HDV)

22. Direct-acting antivirals
4- Inhibitors of capsid formation:
Capsid formation is an essential viral process that
does not occur in the uninfected cell, and thus
would be expected to provide a virus-selective
target. Moreover,capsid proteins are readily
detected in the nucleus of infected cells, far from
the site of nucleocapsid formation in the cytoplasm.
This is consistent with evidence that capsid proteins
play a role in regulating HBV cccDNA expression and
stability.
Three capsid inhibitors have reached clinical phase development:
BAY4109 (AiCuris), NV1221 (Novira) and GLS 4 (Sunshine).

23. Direct-acting antivirals
B-New investigational agents now in clinical trials
1-Inhibitors of capsid morphogenesis:
All these capsid inhibitors are small molecules that
interfere with HBV capsid morphogenesis, but not
necessarily at the same step. CpAMs are HBV core
protein allosteric modulators that accelerate a
dysfunctional capsid protein dimerization.
DVRs prevent the association of HBV pregenomic RNA
with the capsid

24. Direct-acting antivirals
2- Inhibitors of HBsAg secretion:
is a small molecule that has been shown to
prevent the secretion of HBsAg and viral DNA in
vitro,possibly by interfering with the ability of
HBsAg to associate with the LDL secretion
machinery .

25. Direct-acting antivirals
3-RNase H inhibitors
Unlike other DNA viruses HBV replication depends
upon the RNAseH activity of HBV polymerase to
degrade pregenomic RNA. RNAseH enzymatic
activity should, in principle, be a viable antiviral
target as is the reverse transcriptase/DNA
polymerase activity of HBV polymerase.

26. Direct-acting antivirals
4-CRISPR/Cas9 system:
The bacterial clustered regularly interspaced short
palindromic repeats associated systems
(CRISP/Cas9) loci encode RNA guided
endonucleases, derived from bacterial immune
response against foreign genetic elements such as
bacteriophages. they can be used to target
destruction of specific DNA sequences, and thus
hold a great potential for specific degradation of
HBV cccDNA.

27. Host-targeting antivirals
A-Products in clinical development:
1-Viral entry inhibitors(Myrcludex B)
2- Immune enhancers
3- Therapeutic vaccines
4-Birinapant (small molecule that is believed to mimic
second mitochondrial activator of caspases (SMAC). SMAC
normally binds to IAP (inhibitor of apoptosis), pushing the cell
towards apoptosis
5-Zadaxin:natural polypeptide from the thymus

28. Host-targeting antivirals
B-HTAs in the preclinical stage:
1- Immune checkpoint inhibitors
2-Epigenetic modifiers
3- interferon gene stimulator
4- Cyclophilin inhibitors