The Japan
GastroenterologicalEndoscopy Society

The Japan
Society for
Portal Hypertension

The Japan
Society of
Hepatology

The JapaneseLiver Transplantation
SocietyTokyo

The Japanese Societyof Gastroenterological
Surgery

The JapaneseSociety of
Gastroenterology

The LiverCancer Study
Group of JapanThe Organizationof JDDWMONDAY, 22 February 2016

InsideNew Threat to Developed Countries:
NAFLD-related HCC
03
Hepatitis B Treatment:
Yesterday, Today and Tomorrow

04

Nucleos(t)ide or Interferon toPrevent HBV-related HCC?

07

Innate Immunity in Hepatitis B:
Killer and Protector

08

Today

Changes of APASL in 9 Years

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As the President of APASL 2007, Professor Masao Omata hosted the 17th
APASL in Kyoto. He told APASL Daily: “when I hosted APASL 2007 in
Kyoto, the number of participants was 3000. But now we are expecting 4500
participants, and of course the main progress at this meeting is the treatment
or the complete cure of hepatitis C virus infections. For HBV, we now havemore drugs and we have more choices that may produce a very long lasting
suppression of the virus without showing resistance. So over the last 9 years,
there have been developments and drug discoveries, but we still struggle totreat hepatocellular carcinoma…“See More on Page 2

The Situation of Liver
Diseases in AsianPacific Countries

For HBV/HCV Co-infection
Patients in DAA Era, Treat
the Viruses both!

Asian-Pacific countries are the major
regions where various liver diseases,
especially HBV and HCV associated liverdiseases, occur and prevail. This area hasgathered more than 75% of HBV and HCV
carriers all over the world. And with thedevelopment of the economy situation in
APASL countries, the prevalence of NASH
(nonalcoholic steatohepatitis) and alcoholic
liver disease may increase further.

Now hepatitis B and hepatitis C are the mostimportant cause of chronic liver diseases in Asiapacific region, especially China. Due to the similarmode of transmission, co-infection with HBV and
HCV is common, especially in high-risk populations
and in HBV endemic area. For example, co-infection of
HBV in patients with chronic HCV infection has been
estimated to be as high as 8.4% in Chinese. To date, nostandard-of-care recommendation exists for HBV/HCV
co-infection.

See More on Page 4

See More on Page 5

16/2/20 下午1:16

Changes of APASL in 9 Years

Interview with Honor President Masao Omata

1

APASL Daily: As the Presidentof APASL 2007, you hostedt h e 1 7 t h A PA S L i n K y o t o .
What are your comments on
the progress in liver disease
treatment in that time and how
will this conference be different
from the 17th, both held inJapan?

Masao Omata

Prof. Omata: When I hosted
APASL 2007 in Kyoto, the numberof participants was 3000. But now
we are expecting 4500 participants,
and of course the main progress at
this meeting is the treatment or thecomplete cure of HCV infections.
For HBV, we now have more drugs
and choices which may produce avery long lasting suppression of thevirus without resistance. So overthe last 9 years, there have beendevelopments and drug discoveries,
but we are still struggling to treat
hepatocellular carcinoma. There
are some advances, but in the areaof hepatocellular carcinoma, there
are a couple of features that havenot necessarily changed. We lookforward to developments in immune
modulatory cancer therapy which
we can expect to come very soon.
So I think there are some differences
between 2007 in Kyoto and 2016 in
Tokyo.

2

APASL Daily: Many studies have shown that treating patients withinterferon-free direct-acting antivirals is cost-effective. However,
all of those studies were performed in developed countries. Whatis the cost-effectiveness of interferon-free regimens compared withinterferon-based regimen in low- or middle-income countries?

Prof. Omata: Regardingt h e c o s t - e ff e c t i v e n e s s s t u d i e sof interferon-free direct-acting
antivirals, it is true that thesewere mainly done in developed
countries. However, because of
the generic license, some of theunderdeveloped countries can havevery discounted or cheap drugs.
So the very expensive drugs thatcosts $6000/year in Japan compares

3

APASL Daily: With highly potent oral antivirals available, could we
expect an opportunity for the eradication of HCV worldwide?

Prof. Omata: Yes, of course.
The company Gilead already has
generic licenses in 91 countries
which could not afford these
expensive drugs. In countries
like the United States, European
countries and Japan, we are treating
patients and getting very successful
eradication rates. In other countries
like China, the drugs are very
expensive and beyond the average

income of Chinese patients. So
maybe there are two extremes:
one is the Western countries andJapan which can afford to buy
these expensive drugs; and on theother hand, the countries like India,
Indonesia or Egypt, where they aresupplied with heavily discounted
prices. So for China, I understandthat it is facing a problem in termsof the cost of the drugs.

4

APASL Daily: What’s the most significant barrier of HCV treatmentin the Asia-Pacific area? How can we improve the accessibility of
direct-acting antivirals in low- or middle-income countries?
Prof. Omata: Of course, thecost can be the barrier for the
Asia-Pacific regions. But more
importantly, the HCV infection is
insidious, or it is a silent killer. In that
context, many patients came to theclinics in the late stage with obvious
symptoms, such as jaundice, bleedingor hepatic cirrhosis. So the screeningof patients can be a barrier for the
Asian-Pacific regions. In addition,
education about the natural causes
and transmission of HCV infection
is lacking. Therefore, APASLaretrying to update the APASL HCV
guidelines at this meeting.

5

APASL Daily: What is the biggest highlight in the upcoming revisionof the APASL HCC Guideline compared with prior ones?

Prof. Omata: There are several features in many HCC guidelines that
do not necessarily fit the Asian patients. Amongst many of the guidelines,
especially those from the Western countries, the treatment modalities differ
due to economic reasons. Therefore, we are trying to revise guidelines tosuit the Asian situation. Also, treatments like TACE are now becoming very
popular amongst Asian countries. Therefore, we have more precise or more
specific guidelines for treatments like TACE in Asian countries.

to only a few (20 to 30) dollars inother countries like Egypt or India.
The cost-effectiveness calculationis very complex. There are somestudies indicate that despite thehigh price, because it is a very
efficacious treatment with nearly
100% cure of HCV infection, it
has been concluded that it is costeffective compared to the standardsof developing countries.

2

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New Threat to Developed Countries: NAFLD-related HCC
As a Professor at the Departmentof Medicine, University ofIndonesia, Jakarta, and the Presidentof APASL2005 (15th, Bali), Dr.
Laurentius A. Lesmana has madea significant contribution to thedevelopment of hepatology in the
Asia-Pacific region. At APASL2016,
he will share his experience on thetreatment of HBV in Indonesia
and will show us the emerging
relationship between non-alcoholic
fatty liver disease (NAFLD) andhepatocellular carcinoma (HCC).
He told APASL Daily that in2007, the prevalence of hepatitis
B in Indonesia was around 9.4%,
involved about 230 million people.
A significant number of patientswith chronic hepatitis B (CHB)
received the infection via verticaltransmission. HBV infection is
also the most common etiologyof hepatocellular carcinoma inIndonesia. Most physicians inIndonesia treating patients with
CHB follow the guidelines of
APASL, EASL or AASLD. The

majority of patients with CHB
p refe rre d to us e nuc le os (t)ide
analogues (NAs) in Indonesia ,because the cost is significantly
cheaper (especially the potent
NA, tenofovir as a generic drug)
compared to pegylated interferon
and with far fewer side effects. In
private practice, generic tenofoviris the most commonly used drug.
Telbivudine is the only NA coveredby the government. Combination of
NAs and pegylated IFN is rarely used.

"In our experience, mostpatients who received
pegylated IFN for 48
weeks relapsed at the posttreatment."
On the other hand, worldwide,liver cancer is the fifth mostcommon cancer and the third
leading cause of cancer death.
Recently, HCC has been correlated
to NAFLD. The exact prevalence of

HCC in cirrhotic NAFLD remains
unknown. According to Prof.
Lesmana, about 6-13% of NAFLD
cases may progress to cirrhosis and
HCC. For NAFLD patients, diabetes
and obesity are major risk factors
for developing cirrhosis and HCC.
NAFLD can develop directly to HCC
probably through different pathways
compared to cryptogenic cirrhosis.
Studies by Prof. Lesmana and others
collectively showed that in cirrhotic
and non-cirrhotic NAFLD patients,
the dimensions of HCC were larger
in non-cirrhotic livers.

Laurentius A. Lesmana"The association between
NAFLD and HCC isalarming due to theglobally high prevalenceof these conditions andmay contribute to therising incidence of HCC
encountered in many
developed countries."

What to Watch out for Today
Presidential Lecture
Room 1BC

08:45 - 09:00

The Situation of Liver Diseases in APASL Countries/HCV and HBVOsamu Yokosuka

Room 1BC

10:45 - 11:05

Hepatitis B Treatment

Anna S. Lok

Room 1BC

11:05 - 11:25

Hepatitis B in EU

Patrick Marcellin

LectureRoom 1BC
11:25 - 11:45
Serum HBsAg and AFP Levels during Acute Hepatitis Flare of Chronic Hepatitis B:
		
A New Look in the Natural Course and Antiviral Therapy
Symposium 6. Novel Therapeutic Strategies for HBVRoom 1BC

13:50 - 14:10

		

Yun Fan Liaw

Curing Chronic Hepatitis B Depends on the Restorationof Integrative Immunity against HBVFu-Sheng Wang

Room 1BC
14:10 - 14:30
Innate Immunity in Hepatitis B
General Session 4. Treatment Towards HBsAg Clearance

Stephen Locarnini

Room 1D

11:05 - 11:25

New Endpoints in HBV Drug Development

Robert G. Gish

Room 1D

11:25 - 11:45

Curing HBV-New Therapeutic Approaches

Alexander Thompson

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The Situation of Liver Diseases in Asian-Pacific Countries
and the Urgent Tasks for Beating HCV and HBVAsian-Pacific countries are the major

virus propagation inside the cell nucleus

especially HBV- and HCV-associated

HBV can also lead to hepatocellularregions where various liver diseases,
liver diseases, occur and prevail. This

area accounts for more than 75% of HBVand HCV carriers globally. And with thedevelopment of the economic situationin APASL countries, the prevalence of
NASH (non-alcoholic steatohepatitis)

and alcoholic liver disease may increase
further.

Major progress has been made in

Osamu Yokosuka

and these may remain there permanently.
carcinoma through the integration of

its own DNA into the human genome.
Although we have been able to control

the inflammation of the liver cells after
HBV infection as well as the replicationof HBV, it is still difficult to eradicate

the integrated viral DNA and the leftover
cccDNA inside the liver cells.

In his presidential lecture, Dr. Osamu

the study of HCV in recent years, andYokosuka, the President of APASL2016

treatments have shown sustained viralliver disease in Asian-Pacific countries

patients receiving those novel improved

responses. These inspiring results let
us believe that HCV infection will be

eradicated in the near future. However,contrary to the upbeat progress in HCV

will give his insights on the situation ofand the urgent matters we are facing
nowadays in the fight against HCV and
HBV infection, and related liver diseases.

study, research in the field of HBV isquite different. Although the applicationof nucleotide analogues for suppressing
HBV replication has exhibited optimistic

results, the potential for complete

eradication of HBV infection is still
unlikely. After infecting the liver cells, theHBV virus can make cccDNA, which are

special DNA structures that arise during

Presidential Lecture “The Situation of Liver
Diseases in APASLCountries / HCV and HBV”
Room 1BC
9:30 - 10:30

Hepatitis B Treatment: Yesterday, Today and Tomorrow
This morning, Professor Anna

challenge in the management of patients

Michigan, Ann Arbor, USA will give awhen to start and when to stop antiviral

Suk-Fong Lok from the University oflecture on the state-of-the-art of hepatitis
B treatment.

therapy.

Wi t h i m p r o v e d u n d e r s t a n d i n g

Currently available therapies withof HBV biology and host immune

effective in suppressing HBV replication

immunomodulatory therapies are being

nucleos(t)ide analogues (NAs) are
and decreasing hepatic inflammationand over time can result in reversal offibrosis and reduction in risk of HCC.

However, they could not eradicate HBVAnna Suk-Fong Lok

with chronic hepatitis B is to determine

and completely eliminate the risk of HCC.
Thus, most patients need to remain on

treatment for years and often for life toresponse, numerous new antiviral anddeveloped and some are in early phaseclinical trials. The challenge is to design
efficient clinical trials to prove which ofthese new therapies is safe, efficacious

and acceptable for patients with chronic
hepatitis B.

prevent virologic relapse and to derive
continued benefit.

While the new NAs, entecavir andtenofovir are associated with very low

risk of drug resistance, long-term therapy
is expensive and associated with risks ofadverse events and non-adherence. Given

the limitations of NAs therapies, a major

Lecture 1 "Hepatitis B Treatment"
10:45 - 11:05
Room 1BC

4

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For HBV/HCV Co-infection Patients in DAA Era, Treat Bothof the Viruses!
of the brand name DAAs treatment of

hepatitis C in China), HBV reactivation in

HBV/HCV co-infected patients after cureof HCV should not be neglected anymore.
At APASL2016, Professor George Lau,
Humanity & Health Medical Centre,

Hong Kong, Hong Kong SAR, China andhis colleagues present a breakthroughfinding of increased incidence of hepatitis

due to HBV reactivation in HBV/HCV
co-infected patients treated with pan-oral

DAA therapy. Professor Lau told APASL

George K. K. Lau

Daily: “We see a phenomenon which has

not been observed previously and that is
HBV reactivation when the patients who

Currently, hepatitis B and hepatitis C

are the most important causes of chronic

liver disease in the Asia-Pacific region,
especially China. Due to the similar modeof transmission, co-infection with HBVand HCV is common, especially in highrisk populations and in HBV endemicareas. For example, co-infection of HBVin patients with chronic HCV infection
has been estimated to be as high as 8.4%
in Chinese patients. To date, no standard-of-care recommendation exists for HBV/HCV co-infection.

In general, HCV can suppress thereplication of HBV, probably via indirect

immune mechanisms. Hence, eradicationor suppression of HCV could lead to HBVreactivation. This has not been a big
issue in the past when IFN was the maintherapy for hepatitis C, because IFN caninhibit HCV and HBV simultaneously.

However, successful treatment of chronic
hepatitis C infection with pegylated

interferon-α and ribavirin has been related
to HBV reactivation in patients coinfected with both viruses.

“Up to 30% of patients coinfected with HBV/HCV
might experience hepatitis
flare after their HCV
infections are controlled by
DAAs.”
But now with the use of pan-oral

DAAs that solely target HCV (Professor
George Lau and his colleagues are among
the first and the largest group to make useare co-infected with both viruses andtreated with DAAs for hepatitis C, thepatient can have reactivation of hepatitis

B. This is a novel observation and it isimportant that we notice this phenomenon
and manage it appropriately.”

Another thing Professor Lau will

small molecules which block the viralwith 8-24 weeks of pan-oral DAAs.

to move forward beyond 2016 in terms ofas the entry site, capsid and assembly, andHBsAg-positive. Eleven (3.1%) CHC

A cure would mean either a functional

They prospectively studied 355

consecutive CHC Chinese patients treateddiscuss in his lectures is how we are going

Among these patients, 10(2.8%)werea cure for hepatitis B.

patients suffered from hepatitis duringcure or a complete cure. A functional cure

HBV reactivation (one of them developed

then these patients can still be reactivated.

treating HBsAg-positive patients withelimination of all viral DNA, even thatfactor associated with hepatitis in CHC

DNA, so the patient will be completely

DAA therapy at week 8, with three due tomeans HBsAg seroconversion or loss but

liver failure). They also identified that not

A complete cure means a complete

anti-HBV NAs is the most significant

which has integrated with the normal

patients treated with pan-oral DAAs

cured.

(HR : 12.28, P =0.001).

The current management for hepatitis

replication cycles at different steps, suchto prevent the formation of cccDNA. On

the other hand, we also have miRNA tointerfere with the replication cycle. Also

we have immune modulation methods,
such as Toll-like receptors and therapeutic
vaccinations, and there is also the very

exciting TCR engineering of the T-cells

because a functional cure can only happen
when we restore the immune control ofthe viral replication gene. This is based on
my paper published in Gastroenterology

Prof. Lau noted that up to 30% of

B only controls but not cures the disease.

with HBV/HCV might experiencevirus with prolonged medication, such as

are controlled by DAAs. In severe cases,

we cannot take the patients off the drugs.

failure. He thinks it is reasonable that inis achieved, the therapy can be stopped

with hepatitis C get tested for HBV

problem any more. In this regard, the

5 to 10 years, we will be able to see new

For patients with confirmed co-infection,therapy is HBsAg loss or HBsAg

same time, they are working on achieving

start at the same time as DAA therapy.

is very difficult to achieve HBsAg loss

“With HBsAg loss or
seroconversion, it meansthat we are able to restore
the host immune control ofthe virus.”therapies with the nucleoside analogues oruntreated (by NAs) patients co-infected

Most patients can get control of thehepatitis flare after their HCV infections

treatment with entecavir and tenofovir, but

hepatitis flare can even lead to liver

However, when a functional curehigh HBV prevalence areas, all patientssafely and the patient will not have theinfection before DAA therapy is initiated.

only certain indicator to stop a patient’s

anti-HBV therapy with potent NAs should

seroconversion. The problem is that itin 1994. We were the first group to makethe observation that restoration of the hostimmune control of hepatitis B can resultin a functional cure but these patients

can still have reactivations because they

still have cccDNA and this will be a very
difficult task.”

Professor Lau believes that in the next

molecules coming into practice. At theimmune control of viral replication.

or HBsAg seroconversion using current

with interferon-based therapy. In order toimprove this, many different approaches

are under study, such as combinations ofinterferon plus entecavir or tenofovir andmore promising new therapies.

Professor Lau said: “ We have

Symposium 7:Treatment of HBV for aCure - “Nucleotide”
15:10 - 15:30
Room 1BC

5

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Discovering Tokyo - Vintage & Natural
Tokyo ( 东京 , Tōkyō) is Japan's capital and the world's most populous metropolis.
Prior to 1868, Tokyo was known as Edo. A small castle town in the 16th century, Edobecame Japan's political center in 1603 when Tokugawa Ieyasu established his feudal
government there. A few decades later, Edo had grown into one of the world's mostpopulous cities. With the Meiji Restoration of 1868, the emperor and capital moved from
Kyoto to Edo, which was renamed Tokyo ("Eastern Capital"). Large parts of Tokyo weredestroyed in the Great Kanto Earthquake of 1923 and in World War II. However, Tokyo
was able to achieve a remarkably rapid recovery both times.
Today, Tokyo is one of the most populous cities in the world and a thriving center of
economy, culture and industry. The city's history can be appreciated in districts such as
Asakusa, and in many excellent museums, historic temples and gardens.

Senso-ji temple( 浅草寺 )Meiji Jingū ( 明治神宫 )Nakamise ( 仲见世 )Sensō-ji is Tokyo's largest ancient
Buddhist temple and a major Tokyo
attractions for Japanese and foreigners
located in Asakusa.

Meiji Shrine is the Shinto shrine thatis dedicated to the deified spirits ofEmperor Meiji and his wife, Empress
Shōken.

The temple is dedicated to theBodhisattva Kannon, also known as
Guan Yin or the Goddess of Mercy.

To pay respect:

Located just before Sensoji after
Kaminarimon or “Thunder Gate”,
a massive paper lantern dramaticallypainted in vivid red-and-black tones tosuggest thunderclouds and lightning,
Nakamise is one of the oldest shopping
centers in Japan.

I t i s T o k y o’s o l d e s t t e m p l e , a n d
one of its most significant. Formerly
associated with the Tendai sect, it
became independent after World WarII.

At a Torii (shrine archway): Bow once
when entering and leaving.
At Temizuya (water well): Rinse yourleft hand then right hand. Then Rinse
your mouth with your left hand before
rinse your left hand again. Lastly rinse
the dipper (allow the remaining water torun down the handle of the dipper).

Apart from typical Japanese souvenirs
such as yukata, keychains and folding
fans, various traditional local snacks
from the Asakusa area are sold along
the Nakamise.

Cherry blossom viewing( 花见 )
10 minute walk from Shinjuku Station,
200 yen, 9:00 to 16:30
Shinjuku Gyoen ( 新宿御苑 ) is one ofTokyo's largest and most popular parks.
In spring Shinjuku Gyoen becomes
one of the best places in the city to
see cherry blossoms. Shinjuku Gyoen
features more than one thousandcherry trees of over a dozen varieties.

At the Main Shrine building: Bow twice.
Clap your hands twice. Make a wish if
you like & Bow once again.

6

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Nucleos(t)ide or Interferon to Prevent HBV-related HCC?

Deepak Amarapurkar

Hepatitis B virus (HBV)
infection is associated with thedevelopment of hepatocellular
carcinoma (HCC) worldwide, andmany studies have shown thatthe HBV DNA level is one of themost significant risk factors for thedevelopment of HCC in patientswith chronic HBV infection.
Nucleos(t)ide analogues (NAs)and interferons (IFN), the current
standard of care for chronic HBV
infection, could decrease the riskof HCC. This morning, Professor
Deepak Amarapurkar from Bombay
Hospital and Medical ResearchCentre, India will give a lecture
entitled “Nucleotide or Interferon for
the Treatment of HBV (Preventionof HCC)”.
Currently there are 7 approved
agents: two formulations of IFN(IFN, PEG-IFN) and five NAs

including lamivudine, telbivudine,
entecavir, adefovir and tenofovir.
Advantages of IFN include a finite
treatment duration associated witha higher percentage of HBsAg
clearance compared with NAtherapy, and it is especially effectivein genotype A or B HBV infectedpatients with low viral load.
The main disadvantages of IFN
treatment are significant side effects
and administration by injection, andit cannot be used in decompensatedpatients. Compared with IFN
treatment, NAs can be administeredorally without significant side effects
and can be used in decompensatedp a t i e n t s . H o w e v e r, t h e r a t e o f
HBsAg clearance with NAs isvery low, so long-term treatment isnecessary in most patients and theefficacy is significantly reduced with
development of viral resistance.

Systemic reviews and metaanalysis have shown approximately
50-60% risk reduction for HCC
with IFN or NA antiviral therapy.
However, the risk of HCC couldn’t
be completely eliminated in patientswith chronic HBV infection.
Therefore, the patients need to befollowed up for HCC surveillance
lifelong.

General Session 1：
HBV Treatment in Various
Countries 1 - "Nucleotide
or IFN for the Treatment of
HBV (Prevention of HCC)"
09:00 - 09:20
Room 1A

Don't Miss Tomorrow
8:50 - 10:30
Room 1BC
Symposium 9. Current Situation of HCC and ICC in Asian Pacific
8:50 - 10:30
Room 1A
Symposium 10. Application of Genome Research for HCC Treatment
8:50 - 10:30
Room 1D
Symposium 11. Update of HCC Treatment
08:50 - 11:45
Room 2
General Session 7. Update of NASH/ASH Research
08:50 - 10:30
Room 3
APASL-AASLD Joint meeting
8:50 - 10:50
Room 3
ICA (International Club of Asscites)
10:45 - 11:45
Room 1A
Symposium 12. Liver Regeneration
10:45 - 11:05
Room 1BC
Lecture 4. Future Perspective of Hepatology
10:45 - 11:45
Room 1D
Symposium 13. Recent Trend in HCC Treatment
15:15 - 15:35
Room 1BC
Lecture 5. Disorders of Iron and Copper in the Asian Pacific Region
11:05 - 11:45
Room 1BC
Okuda Oration - Acute on Chronic Liver Failure: APASL ACLF ResearchConsortium (AARC) - A Proud Asian Initiative
13:35 - 15:35
Room 1A
General Session 8. Emerging Trends in NASH
13:35 - 15:15
Room 1D
General Session 9. Mechanism of Liver Fibrosis
13:35 - 15:15
Room 1BC
Symposium 14. Complication of Cirrhosis and the Treatment
13:35 - 15:25
Room 7
CEVHAP-Delivering Health Services to Indigenous and Remote Communities
15:50-17:10
Room 1BC
Critical Care in Hepatology
15:50 - 17:30
Room 3
APASL-EASL Joint Meeting
15:50- 17:10
Room 1A
General Session 10. Current Management of NASH
15:50-17:30
Room 1D
Symposium 15. Cancer Stem Cell

7

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Innate Immunity in Hepatitis B: Killer
and Protector
HBV has evolved a unique life
cycle that results in the productionof enormous viral loads as wellas antigen loads during active
replication without actually killingthe infected cell directly, and theliver damage in chronic hepatitis
B (CHB) is the result of the host’s
cellular immune response to HBVinfected hepatocytes as part of
the “immune clearance” phaseof the disease. This afternoon,
Professor Stephen Locarnini fromthe Victorian Infectious DiseaseR e f e r e n c e L a b o r a t o r y, N o r t hMelbourne, Australia will givea lecture on the topic of innate
immunity in hepatitis B.
HBV has developed a numberof strategies to ensure its persistencein the infected host, including the
production of excess HBsAg andthe expression of HBeAg. The
HBeAg is a powerful modulatorof the innate immune responseby downregulation of Toll-likereceptors (TLR), allowing viralpersistence within the host. The
N-terminal 10 amino acids of the
HBeAg (precore protein) contains
a Toll/interleukin-1 receptor (TIR)
motif, blocking not only TLR2, but also TLR-3, Mal, TRIF and
TRAM signaling, thereby inhibiting
both NF-κβ and interferon(IFN)-β activation. Likewise,
HBsAg inhibits TLR-9 mediatedactivation and IFN-α production inplasmacytoid dendritic cells. Thus,
HBV could effectively suppress
type I IFN responses in hepatocytes.
The cccDNA is found only
in infected hepatocytes and as aminichromosome. The HBcAg

protein is a key structural component
and positive regulator of theminichromosome. Both IFN-α andlymphotoxin β-agonists can activate
APOBEC 3A/3B and results inselective (APOBEC-HBV coreinteraction) HBV cccDNA degradation
following cytidine deamination.
Because HBV uses reverse
transcription to copy its genome,m u t a n t v i r a l g e n o m e s e m e rg efrequently. Particular selection
pressures, both endogenous (hostimmune clearance) and exogenous(vaccines and antiviral drugs),
readily select out these escapevariants. Therefore, further
studies are needed to identify thepathogenesis and clinical sequelae
arising from the selection of theseparticular mutants as well as to the“wild-type” HBV infections.

Stephen Locarnini

Symposium 6:
Novel Therapeutic
Strategies for HBV - "Innate
Immunity in Hepatitis B"
14:10 - 14:30
Room 1BC

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