Jurnal Reading

Present and Future Therapies of

Hepatitis B: From
Discovery to Cure
Preseptor: dr Ihsanil Husna, Sp.PD

Background

Hepatitis B virus (HBV) is a significant global

pathogen, infecting more than 240 million
people worldwide.

Moreover, the actual number of persons who

are chronically infected is estimated to have
increased slightly from 223 million to 240
million during this same period.

Natural history of chronic hepatitis B

The course of chronic HBV infection has been

grouped into four phases:

The immune tolerant phase

The immune active/hepatitis B e antigen
(HBeAg)positive chronic hepatitis phase,
The HBeAg-negative inactive phase
The immune active/HBeAg-negative chronic
hepatitis phase.

HBV Replication

Current therapies of hepatitis B and

mechanism of action

There are currently two classes of drugs

approved for the treatment of hepatitis B:
nucleos(t)ide reverse transcriptase inhibitors
(NRTIs) and interferon-a (IFN-a).

The first-line antiviral HBV medications include

a nucleoside analogue, entecavir; a nucleotide
analogue, tenofovir; and pegylated IFN-a
(PEG-IFN-a), used as monotherapy.

The second generation NRTIs such as

entecavir and tenofovir can potently suppress
the DNA synthesis step of HBV replication,
they have a little effect on the level and
activity of cccDNA, which has a long half life
and can persist for decades in the infected
liver despite successful antiviral treatment.

Entecavir and tenofovir can decrease the level

of HBV DNA by 6 logs within 1 year of
treatment and have low rates of antiviral drug
resistance.

For patients who do not have cirrhosis or do

not require immunosuppresive therapy,
profesional society guidelinesrecommend
treating those in the immune active phase.

Combination Studies of Current Therapies

Combinaton of PEG-IFN with an NRTI would be

more likely to result in synergy because the
drugs have different mechanism of action, the
concept being that inhibition of viral
replication with an NRTI may augment the
immune effect of PEG-IFN.

Patients receiving PEG-IFN and tenofovir had a

higher rate of HBsAg loss than those receiving
either drug along. They represent a small
increase (6%) in HBsAg loss over PEG-IFN
monotherapy.

HBV Entry Inhibitors

In particulr, small molecules and antibody

based treatments are quite effective in
treating acute viral infections.

Myrcludex B, cyclosporin A and other

substrate analogues inhibit bile salt transport
by NTCP.

Preliminary results suggested that Myrcludex

B is safe and well tolerated in HBsAg positive
patients with or without HDV coinfection.

HBV Capsid Inhibitors

They function to dysregulate or selectively

inhibit either pregenomic RNA encapsidation
or nucleocapsid assembly or both. The first of
these were the phenylpropenamide
derivatives AT-61 and AT-130.

The second group is the

heteroaryldihydropyrimidines.
In vitro studies have demonstrated strong
synergy when these inhibitors are used in
combination with currently approved NRTIs.

HBV Nonspesific Immunomodulatory

Agents

TLR Agonists
PDI and othe Coinhibitory Blockers

Therapeutic Vaccines

Induce sufficient anti HBV immune responses

to eliminate and/or cure infected heaptocytes
without undue host cell damage, prevent viral
spread to new heaptocytes and promote long
term viral control.

HBsAg based Vaccine

Cytotoxic T-Lymphocyte Epitope Vaccine
DNA Vaccination with or without
Immunomodulators
Other Therapeutic Vaccine Trials

Therapeutic pipeline and Conclusion

To achieve a more sustained and effective

control of HBV Infection , a combination of the
existing HBV therapies and one or more of the
above modalities, either small molecules
drugs or biologics will be necessary.

With growing interest in developing and

efforts to develop more effectie therapies for
HBV the challenging goal of a cure may be
well within reach in the near future.