The Japan
GastroenterologicalEndoscopy Society

The Japan
Society for
Portal Hypertension

The Japan
Society of
Hepatology

The JapaneseLiver Transplantation
Society

The Japanese Societyof Gastroenterological
SurgeryTokyo

The JapaneseSociety of
Gastroenterology

The LiverCancer Study
Group of JapanThe Organizationof JDDWWEDNESDAY, 24 February 2016

InsidePortal Vein Thrombosis in Cirrhotic
and Non-cirrhotic Liver
02
Achieving a Functional Cure for
Chronic Hepatitis B: Challenges andProgress
05
HCC and the Promise of Immune Therapy		
07
Serial AFP Assay Deserves Attentionin Acute Hepatitis Flare
08

Today

Hepatology Keeps Moving into the Future

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App 下载地址PASL has become one of the leading scientific conferences in hepatology. All of us, including the patients,
have been contributing to its development. Today, APASL2016 will come to a successful close. As the
President of APASL 2016, Dr. Osamu Yokosuka must have been the busiest but the happiest person during the 25th
APASL meeting. He told APASL Daily, “the APASL meeting is a very big meeting. The majority of the world’s
patients with liver disease live in the Asia-Pacific region, so for us, liver diseases are very important. We have toconquer hepatitis for our own Asian-Pacific population and to benefit everyone in the world.” This is what makes
APASL attractive and unique to him.
He also explained his reasoning for the theme of APASL2016 - “Modern Hepatology”. Technology and methodsof therapy have progressed and there are a lot of new developments. For hepatitis C, the direct-acting antiviral
agents have become available and many HCV patients are being cured and many more will be cured. With regard to
HBV, we have new agents together with interferon that allow us to control hepatitis B and we can stop the progressof disease. The other area is non-HBV/HCV NASH, which has increased in prevalence due to economic and socialchanges in the Asia-Pacific region. There are more patients developing NASH than was anticipated and we haveto conquer this condition. Lastly, although we have drugs like sorafenib for hepatocellular carcinoma, we have toconsider new therapeutics and new approaches to treatment of this cancer. That is why we have used the theme of“Modern Hepatology”.
As a wrap up of APASL2016, Dr. Yokosuka believed that we needed to get the message out to the Asian-Pacificcommunity that hepatitis C is curable. Also, we are accumulating new knowledge about HBV, so spreading the word
about new advances there is one of the tasks of APASL2016. Although it will be difficult for us to eradicate HBVdue to persistent cccDNA in the liver, it is very important that we continue to work to eliminate the virus entirely
from the body. Work in that area is a highlight and important message of this meeting.
At the end of the interview, Dr. Yokosuka expressed his best wishes for APASL2017 in Shanghai. “Dr. Jinlin Houwill be the President of the APASL2017 meeting in Shanghai. There are a lot of HBV infected patients in China, so
the treatment of HBV as well as HCV will be a focus of APASL2017. I hope the APASL2017 Annual Meeting will
be very successful under the leadership of Dr. Hou.”

16/2/23 下午3:16

Portal Vein Thrombosis in Cirrhotic and Non-cirrhotic LiverInterview with Dr. Shiv K. Sarin, President of APASL 2004

1

Shiv K. Sarin

3

APASL Daily: What are the major risk factors for thedevelopment of portal vein thrombosis (PVT) in cirrhosis
and non-cirrhosis?

APASL Daily: What is the role ofgrowth factors in the treatment ofliver failure?

Dr. Sarin: PVT in non-cirrhotics is mainly because of
hypercoagulable states which are genetically determined, likebeing procoagulant. Besides genetic factors, local factors andsystemic factors like dehydration or pancreatitis can precipitate
PVT in non-cirrhotics. But in cirrhotic patients, PVT is a resultof cirrhosis causing hepatic frugal flow (blood flowing awayfrom the liver). Sluggish flow and high pressure in the liver
leads to thrombosis. Also, tumor thrombi can occur. So the mostimportant cause is hemodynamics in patients with cirrhosis andin non-cirrhotics it is procoagulant factors. Thrombosis can beacute or chronic. Chronic thrombosis is generally because of
infections.

D r. S a r i n : I n l i v e r f a i l u r e ,regeneration is slow. Normally in acuteliver failure, the hepatocytes can replicate
by themselves. But in cirrhosis with liver
failure (acute-on-chronic liver failure),
the hepatocyte regeneration is very weak,so progenitor or resident stem cells are
required. To stimulate them, we give
growth factors which work on the bonemarrow, like G-CSF or erythropoietin,
and they mobilize cells from bonemarrow like CD33-positive or CD34positive cells, and those work in the liver
to stimulate regeneration. In two large
studies published by our group in 2012,in acute-on-chronic liver failure, patients
given G-CSF every day for five days
and every alternate day for the rest of themonth (a twelve-dose schedule), showed
improved survival compared to placebo(69% vs. 30%). A second study used two
growth factors, G-CSF plus darbepoetin,
in cirrhotics who were on transplant lists.
Giving growth factors decreased thechance of infection from about 35% to
5% and also improved survival. This was
published last year in Gastroenterology.
So growth factors are very important for
managing liver failure and improving
liver regeneration.

2

APASL Daily: What progress has been made in the
diagnosis and treatment of PVT in recent years?

Dr. Sarin: The diagnosis of PVT has improved with the useof ultrasound Doppler and contrast-enhanced CT scans. With the
Doppler, you can see where there is no or sluggish flow, and with
the CT scan you will see causative material in the portal vein.
There are also certain blood tests which indicate procoagulant
factors. Sometimes myelodysplastic syndrome is present anda bone marrow biopsy is needed to find out if the patient has a
hypercoagulable state.
In treatment also, there are many advances. If patients havea procoagulant state (i.e. hypercoagulable), they are given
continuous lifelong anticoagulation starting with drugs likeenoxaparin and continuing with oral drugs. In those patients withno procoagulant factors, we give them three to six months oftherapy and try to recanalize. In acute thrombosis of the portal
veins, it may be required to implant a stent. The stent can extend
from the portal vein to the hepatic vein. A catheter can also beplaced in the portal vein by instilling urokinase. There are new
drugs called inhibitors of thrombin, which are very effective andcan be used in all liver disease patients, but have not been fully
evaluated. If the PVT is recognized early, prognosis is improved.
The most important thing is, in cirrhotics who are on atransplant list, 50% of these patients will have thrombosis of theportal vein. If we dissolve this thrombus, the patient’s ascites
and jaundice may improve to the point of perhaps not requiring atransplant.
It has been shown that long-term survival improves if you
give anticoagulants. Our own group has shown that giving
anticoagulants is safe. If a patient has varices and portal veinthrombosis, I would suggest first blocking the varices anderadicate them and then start with enoxaparin and later switch
to Acitrom (nicoumalone) or warfarin to resolve the thrombus.
These patients need to be monitored every three to six months.
At the end of one year, about 50% resolution of thrombosis canbe achieved.

4

APASL Daily: Next year’s APASL
annual conference will be held in
Shanghai, China. What are your hopes
for that meeting?
Dr. Sarin: China is the most populated
country in the world with a very heavy
burden of liver disease and consequently
the best liver experts are in China. With
Professors Jinlin Hou, Lai Wei and JiDong Jai, you have the best three people
in Asia to lead the liver disease field. The
2017 meeting has my fullest support andI am sure attendance in Shanghai will
exceed 6000 people and I would predictthat it will be a most memorable congress.
In 2018, APASL will be in New Delhi and
we invite all the Chinese hepatologists toattend our meeting also. My best wishes
to Jinlin Hou and to China.

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New Endpoints in
HBV Drug Development

Robert G. Gish

Chronic hepatitis B (CHB) is
the world’s most common serious
liver infection and is a widespread
global health issue that is underdiagnosed and under-treated.
Although hepatitis B virus (HBV)
infection is not currently curable, it
can be effectively controlled using
pegylated IFN-α (PegIFN-α) and/or nucleos(t)ide analogue antivirals(NUCs). The next steps in the HBVtherapeutic strategy are towards thecure of HBV infection according
to Prof. Robert G. Gish, Stanford
University, USA.

Right now, the antiviralregimens are limited
for the strategy of HBVelimination.
PegIFN-α has the advantage ofa fixed duration of therapy with theoption of response-guided therapy
based on HBsAg levels and can be
an ideal option for some patientswith high ALT and medium to low
HBV DNA, but the rate of HBsAg
seroconversion is lower than 20%.
Entecavir and tenofovir treatment
is indefinite for most patientsbut maintains extended virologic
control over several years resulting
in histologic improvement. There isalso evidence that hepatic cccDNA
levels can be modestly decreased
with NUC therapy but withoutachieving cccDNA clearance.

The success of long-term
NUC treatment prompts
new questions for future
HBV treatment strategies.
We can say “yes” to all thesequestions, Prof. Robert G. Gishsaid optimistically. It is possible
to permanently eliminate HBV
infection with therapies thatspecifically target the cccDNA
pathway and we be aiming toachieve a “functional cure”
using HBsAg elimination as an
endpoint and thus, the ultimate
maker that we are changing
outcomes. We will have a newrole for HBV RNA and HBcrAg
testing and there will be newtechnologies for FNA and liver
sampling for cccDNA andintracellular intermediates of
HBV replication, including HBVpregenomic RNA (pgRNA) andmRNA testing.

The next step for antiviraltherapy: new technologies
and new anti-viral tools.
The new technologies andanti-viral tools include: iRNA,
anti-sense, blocking viral entry,
inhibiting viral release, using
cellular mechanisms of viral
replication such as cyclophilins,
capsid inhibitors, and immune
m o d u l a t o r s i n c l u d i n g P D - L1
antagonists, TLR-7 agonists,
Ta r m o g e n - b a s e d v a c c i n e s ,vaccines with adjuvants ande x t e n d e d p r e S1 e p i t o p e s ; a swell as attacking the virus in the
n u c l e u s u s i n g C R I S P R / C a s9,changing histones, and acylation
patterns are all new milestones
towards the elimination of HBV
infection.

The steps towards
eliminating HBV.
“For the strategy of HBVelimination with anti-viral therapy,
we are on the path and next need toclear HBsAg, then clear cccDNA,and finally clear all cells withHBV DNA integration and prevent
HBV integration from occurring in
those patients with early phases of
disease”, said Prof. Gish.

The new concept of HBVtherapy is usage of new
combination therapeutic
tools in combination andsequence.
The new Guidelines from
APASL, AASLD and EASL will
guide current therapy, but we needto further suppress the virus, stop
the regeneration of cccDNA andawaken the host immune system
so it will ultimately have thefinal “word” in viral control andclearance. The new therapies needto target multiple sites in the HBVgenome and/or the immune system.
The major concept moving forwardwith HBV therapeutics is the use of
new combination therapies, and/or
new therapies in sequence.
Prof. Gish concluded that it will
be very exciting that we will havethe chance to achieve a cure for
HBV infection in our lifetime.

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Screening, Novel Treatment Modalities
and Multidisciplinary Teams for HCC

Massimo Colombo

Dr. Massimo Colombo isProfessor of Gastroenterology
at the University of Milan,
Italy. Yesterday, he addressedt h e i s s u e o f Tr e a t m e n t o fAdvanced HCC in BCLC B/CPatients. After that, he shared
his opinions on some interesting
topics in the management of
HCC with APASL Daily.

1

APASL Daily: What are the main difficulties thatcurrently exist in HCC research?

Prof. Colombo: First of all, I think that we need todevelop screening methods that can be used in the generalcommunity. Currently, we screen patients for the risk ofcancer that are represented either in the patient populations
or attending hospitals. We need to bring surveillance forliver cancer into the community and to do this we needto develop predictors of liver cancer that can be obtained
through urinalysis or blood tests.

2

A PA S L D a i l y : W h e n w e t a l k a b o u t c a n c e rtargeted therapy, we must first be clear about its
pathogenesis. In recent years, what important progresshas there been in the field of the pathogenesis of HCC?
Prof. Colombo: Currently, we have only one targeted
therapy that works in patients with advanced cancer andprovides a survival benefit of three months only on average.
The next step would be to develop treatment modalities,
possibly by looking better at the stratification of our patient
populations and, in this respect, I believe the studies in themolecular analysis of tumor compositions and possibly
also development of combined treatment modalities mightprovide us with stronger medical therapies compared to what
we have currently.

3

APASL Daily: Several studies found that some types of commonlyused prescription drugs have the function of protecting against
and preventing HCC, such as statins, metformin, and aspirin. What isyour opinion in this regard? What kinds of patients would be likely toobtain benefit from these prescription drugs?
Prof. Colombo: Data indicating that these drugs might reduce the risk of livercancer to some extent are flawed by many methodological problems. First there
are several biases. Patients were recruited based on a diagnosis different from livercancer or cancer risk. Secondly, treatment was not homogeneously pursued in all
patients. And thirdly, most of these patient populations have received multiple
drugs that might interact with each other, so the data presented in the literatureprovides an insight that some of these molecules may have an anticancer effectbut there is no robust evidence that these drugs should be entering the therapeuticarmamentarium of the hepatologists to prevent liver cancer in patients at risk.

4

APASL Daily: One of your talks is on the topic of treatment of advanced HCC
in BCLC B/C patients. In recent years, more and more experts recommend
multidisciplinary treatment (MDT), including systemic drug therapy. Can you
introduce some important progress in the study of chemotherapy for HCC?
Prof. Colombo: Our own experience tells us that the multidisciplinary teams are essential
to improve the management of the patient with liver cancer. They provide a more precise
location of the patient populations to these specific treatment modalities and they also speed up theprocess of treatment allocation and delivery. As far as medical therapy of liver cancer is concerned,
currently sorafenib is the only licensed drug and in our own experience, treatment with sorafenib
requires expertise. So first of all, doctors should be trained to pursue therapy and to continue therapy
even in the presence of adverse events and doctors should be trained to stratify patients according
to the pattern of adverse events and reactions that may identify a subpopulation of patients who are
refractory to sorafenib and need to consider second-line therapies.

5

APASL Daily: Are there any other experiences in HCC treatment you would sharewith the Asian-Pacific physicians and researchers?

Prof. Colombo: Frankly, most of what we learn about liver cancer comes from Asia - China
and Japan particularly. I think that the multidisciplinary team is what our Asian colleagues should
start and build up as a strategy to improve management of patients with liver cancer. Secondly,
here in the Asian-Pacific region, there is still a long-standing tradition of hepatic resection
to treat patients with liver cancer. By comparison, in Europe we switched to local ablativetechniques. Resection of liver cancer is not only a very effective treatment modality, but also
allows for the recovery of liver cancer tissue to undergo appropriate investigations, particularlyin the area of molecular biology.

What to Watch Out for Today
CEV-HAP Symposium
8:30-10:00

Viral Hepatitis Policy Symposium

Room 1BC-Hepatitis in the UN Sustainable Development Goals: How Can the SDGs Help Clinicians Advance Hepatitis Policy and Core in Asia Pacific?
WHO Symposium
10:20-12:20

Early Release of New Recommendations from Updated Guidelines for the Treatment of Persons with Hepatitis C Infection
Closing Ceremony
12:20-12:40

Room 1BC

Room 1BC

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Achieving a Functional Cure for Chronic
Hepatitis B: Challenges and ProgressA r o u n d 240 m i l l i o n p e o p l eworldwide have been persistently
infected with hepatitis B virus(HBV) and are at risk of end-stage
liver diseases such as liver cirrhosis,
liver failure and hepatocellular
carcinoma (HCC). Currently
available therapeutics for chronic
hepatitis B (CHB) are mainly
limited to nucleoside analogues(NAs) and interferon-α (IFN-α).
These drugs reduce viral load andimprove long-term outcomes, butrarely lead to a functional cure of
CHB, currently defined as HBsAg
seroconversion together withresidual cccDNA existence. Failure
to achieve such a “functional cure”
of chronic HBV infection is linked
with an inability to elicit an effective
immune response that resembles
acute resolved infection. Therefore,a “cure” strategy for chronic HBV
infection has been proposed which
would be dependent on the full
restoration of an efficient immune
response against HBV. The list of
immunotherapeutic strategies against
CHB under active investigation
keeps increasing.

Cure of HBV infection isclosely associated with HBsAg
clearance

Drugs specific to the clearanceof viral cccDNA are not yet
available and are difficult to assay
clinically. Therefore, clearance of
HBsAg becomes one of the criticalissues for the functional cure of
CHB patients. HBsAg, a milestone
discovery that was identified around50 years ago by Nobel laureate, Dr.
S Blumberg, is the hallmark of overt
HBV infection.
Functional cure of CHB isdependent not only on the cccDNA/
HBsAg inhibitors, but also on
restoration of host anti-HBV
immunity.
Basic and clinical studies haveprovided evidence to support thenotion that the functional cure ofchronic HBV infection is mostly
dependent on the host immune

responses against HBV.
The ideal host anti-HBV immune
responses include rapid viral control,
HBeAg seroconversion and HBsAg
seroconversion. However, functional
cure occurs in only 1-3% of patients
per year with current NA or IFN
antiviral treatment, which impliest h a t e ff i c i e n t c c c D N A / H B s A g
inhibitors need to be identified ordeveloped in future.

Current immunotherapies for
CHB and unmet issues

Based on the most recent
understanding of the immune
mechanisms of chronic HBV
infection, several immunotherapeuticstrategies have been underinvestigation (Table 1). These
immunotherapies target various
immune components and present
promising data for the future. They
include as follows: (1) Targeting
innate immune responses. GS9620 working selectively with
TLR-7, has the potential to induce
prolonged HBV suppression andanti-HBV innate immune responses
in chronically infected chimpanzees.
Current data demonstrates thatshort and finite duration treatment
with the oral TLR7-agonist GS9620 c a n i n d u c e a s u s t a i n e dantiviral response in chronic HBV
infection. (2) Targeting adaptive

immune responses. Optimal immune
activation of naive CD8 T-cells
requires signal 1 mediated by the
T-cell receptor, signal 2 mediated byco-stimulation and signal 3 provided
by pro-inflammatory cytokines. Ongoing studies have indicated that
increasing the three signals may
rescue HBV-specific T-cell responses
and could be clinically beneficial.
Although engineering HBV-specific
T cells through transfer of HBVspecific T cell receptors or HBVspecific CAR showed encouraging
results in vitro and in animalmodels and might have potential,
safety concerns, cost, and ethicalissues related to viral vector use
need to be addressed. (3) Blockadeof co-inhibitory pathway. Some
immunotherapeutic approaches,such as the blockade of co-inhibitory
PD-1 and CTLA-4 pathways, havebeen put into clinical trials although
their long-term efficacy needs to be
confirmed.

Removing the HBV antigens or
cccDNA in vivo

Both circulating HBeAg and
HBsAg are postulated as possible
immune-suppressing agents against
host anti-HBV immunity. Therefore,
efficient drugs that can clarify the
HBsAg or cccDNA urgently need tobe identified or developed.

Fusheng Wang
Challenges and prospectives

There are still many challenges
in the field, even if efficient immune
therapeutic approaches wereavailable. For example, the optimal
therapeutic approaches (how to
combine different antiviral drugs
and immunotherapies), the optimal
timing and indications (which patient
population is optimal for addingon immunotherapy) and the optimal
immunotherapeutic combination(boosting innate and adaptive
immune responses particularly, thedouble-swords of immune responses)
remain unknown.
( F ro m : F u - S h e n g Wa n g ,Tre a t m e n t a n d R e s e a rc h C e n t e r
for Infectious Diseases, Beijing 302

Hospital, Beijing, China. Email:fswang302@163.com)

Table 1. The current immunotherapeutic strategies on HBV infection
Immune Targets
Innate immune
responses

Adaptive T cell
responses

Adaptive B
cell responses

Immune strategy
TLR-7 agonist
NK cell adoptive transfer
IFN-α
IL-12
GM-CSF
Envelope-specific T cells-expressing chimeric antigen receptor
TCR-electroporated T cells
TCR-like antibody targeting IFN-α
HBV-specific CD8 T cell reconstitution: blockade of Bim,
modulation of co-inhibitory receptors (PD-1, CTLA-4, Tim-3)
and modulation of inhibitory cytokines (TGF-β, IL-10)
Therapeutic vaccine
Cytokine induced killer cells
DC vaccine
GM-CSF+HBV Vaccine
Antibody (anti-HBs)

Phase
phase I
preclinicalclinicallabclinical
HBV transgenic miceclinical HCC
lablabclinicalclinical HCC
clinicalclinicalclinical

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Chronic Hepatitis B “Cure” - Still A DreamThe majority of HBV patientslive in a chronic carrier statewith
the risk of flaring up to progressive
disease and hepatocellular
carcinoma. Currently, the available
approved treatment drugs are
Peg-IFN-α and a few nucleoside/
nucleotide analogues.
If the goal is to cure(functionally) chronic hepatitis B,
then not only does there need to benormalization of a patient’s ALTlevels and reduction of serum HBVDNA levels, but also clearance of
HBeAg and achievement of HBsAg
seroclearance, ideally with antiHBs antibody production. So canwe achieve this “cure” with current
drugs?
Fumitaka Suzuki, MD,
Toranomon Hospital, Japan, tried touse data from four clinical trials to
address that question.
The first clinical trial involved
615 Japanese CHB patients treatedwith IFN, with a median follow-

up period of 8.1 years. The resultss h o w n t h a t 11% (69 p a t i e n t s )achieved HBsAg seroclearance, andthat status continued after more than
20 years follow up in some of thesepatients. According to Dr. Suzuki, it
seemed that age >30 years, genotype
A and male were all independent
factors predictiveof achievement of
HBsAg seroclearance.
The second trial concerned 22
CHB patients treated with Peg-IFN
for either 24 weeks or 48 weeks andfollowed up for 5 years. In HBeAgpositive patients, 13%, 14% and
21% patients achieved HBeAg
seroconversion at the end of 1, 3 and5 years treatment respectively. In
HBeAg-negative patients, the ALT
normalization rates were 0%, 20%
and 20%, respectively. One patientachieved HBsAg clearance at 3.5
years.
The third trial was 791 patientstreated with LAM over a period of
12 years. Later on, 299 patients had

ADV added on andpatients could
also choose to switch from LAM to
ETV. Five percent (38) of patientscleared HBsAg successfully. The
overall cumulative rates of HBsAg
clearance was 0.2% at 1 year, 1.2%
at 2 years, 2.6% at 5 years and 6.4%
at 9 years in the HBeAg-positive
cohort. According to Dr. Suzuki,
patients with previous IFN treatment
and HBV genotype A baselinecharacteristics showed morefavorable outcomes.
The last trial was 556 nucleos(t)ide naïve CHB patients treatedwith entecavir, and the results
demonstrated that the cumulative
HBsAg clearance rate was 3.4% at 5
years. The independent predictors of
HBsAg seroclearance were genotype
A patients and HBsAg level<500
IU/ml.
From the above convincing data,
Dr. Suzuki has concluded that for
majority of patients, clinical cure ofchronic hepatitis B is not a reality yet.

Treatment of HCV in Developing Countries, Way to Go!
“Bangladesh is
now on its way to
becoming an example
for other developing
countries to overcome
the challenge of
eradicating HCV
infection.”

Globally, it is estimated that130-170 million people are infectedwith HCV through different modesof transmission. With the populationbase in Asian-Pacific regions andwith prevalence in certain countries
r a n g i n g f r o m 0.56% -11% , t h eabsolute figures are still strikingly
large in many developing countries
in this region. The HCV prevalencein Bangladesh is 0.8%.
“HCV increases the risk ofdeveloping HCC 25-fold, causes 3-4
times more liver-related death than
HBC and no vaccine is available,
which makes HCV a silent killer inmany developing countries”, said
Prof. Salimur Rahman, Presidentof the South Asian Association forStudy of the Liver and Chairmanof the Viral Hepatitis Foundation
Bangladesh.
The goal and endpoint of HCV
tre a tme nt is to e ra dic a te H C V
virus, delay disease progression,and prevent complications andrecurrence after liver transplant.
In Asian-Pacific regions, the main
HCV genotypes are 1 and 3, withgenotype 3 the most difficult to treat.
In recent years, the treatment
choice for HCV has evolved from
peg-interferon alfa with ribavirin
as the gold standard treatment todirect antiviral agents (DAAs),
which has created the potential tocure the majority of HCV patients,
even patients with decompensatedcirrhosis.
The caveat to the newly
established DAA drugs are their highcost; so high that even in developed
countries there are accessibility andaffordability problems, let alone forpatients in developing countries.
Fortunately, from 2015, thegeneric versions of DAAs became
available in some developing
countries and Bangladesh is oneof these lucky countries. FromF e b r u a r y o f 2015, s o f o s b u v i r,
daclatasvir and ledipasvir have been
made available in Bangladesh at
much lower prices, according toProf. Rahman.
For treating HCV patients
without cirrhosis, there is the
choice of sofosbuvir/daclatasvir (allgenotypes), or ledipasvir/sofosbuvir(genotypes 1, 4, 5, 6) for 12 weeks
without ribavirin. For treating
HCV patients with cirrhosis, thechoices are sofosbuvir/daclatasvir
or ledipasvir/sofosbuvir withoutribavirin for 24 weeks; or bothregimens with ribavirin just for 12
weeks. For genotype 2, the choice issofosbuvir/ribavirin for 16-20 weeks
in Bangladesh.
For some special subgroups,
such as patients co-infected with
HBV or HIV, there is no need tochange the regimen. And there isno need to change DAA dosages
for patients with renal creatinine
clearance between 30-80ml/min.
With most of the other developing
countries still struggling with accessto affordable DAA drugs, “Bangladesh
is drawing focus worldwide withthe availability of daclatasvir andledipasvir most recently,” stated Prof.
Rahman. “Bangladesh is now on its
way to becoming an example for otherdeveloping countries to overcome
the challenge of eradicating HCV
infection.”

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HCC and the Promise of Immune Therapy
Every thirty seconds, one person
dies from liver cancer in the world
and most people with HCC are notcandidates for curative therapy
when they are diagnosed. The
recent success of immune-based
therapies for other solid tumorso ff e r s n e w h o p e f o r t a rg e t i n gprocesses related to immune
responses for the treatment of HCC.
This was reported by Prof. Tushar
Patel, Mayo Clinic, Florida, USA,at a lecture on the application of
genome research for HCC treatment
at 25th APASL conference on Feb
23rd.
The current treatments for
HCC include surgery, local andregional therapies and systemic
therapies. However, the available
therapeutic options for advanced
HCC treatment have limited
efficacy. We need more effective
treatments.

The immune system and HCC

The incidence of HCC isincreased in immunocompromised
individuals such as transplantpatients or HIV infected patients,
indicating the immune system playsa critical role in the carcinogenesis
of HCC. However, because of its
tolerogenic effects and uniquei m m u n o b i o l o g y, t h e u s e o fconventional immunotherapy ischallenging in the liver. PD-1/
PD-L1 interactions maintain the
immune tolerance in HCC. Adaptive
immune responses can occur during
the formation of HCC, including
DC, APC, etc. and adoptive
immunotherapy can improveoutcomes in HCC, Prof. Patel stated.

Future therapeutic strategies
for HCC: the immunotherapeuticstrategies

The immunotherapeuticstrategies for HCC include cancer
vaccines, monoclonal antibodies,checkpoint inhibitors, growth factors
and cytokines. Immunotherapy trials
for HCC conducted so far have hadcontrasting results. The results for
the PD-1 inhibitor, nivolumab, in
advanced HCC in promising with
62% overall survival at 12 months.
The potential approaches for
HCC therapies could target both
tumor cell specific antigens andimmune cells. Synergistic antitumor activity may be observed
when immunotherapy is used in
combination with conventional
treatment such as immunotherapy plus
systemic therapies, or immunotherapy
plus local regional therapies.
Prof. Patel concluded thattargeting immunity offers new
potential therapeutic approaches for
HCC, and is very promising as a
future treatment strategy for HCC.

Welcome Message

Jinlin Hou
Dear Colleagues,
We are delighted and honored to
introduce you to the 26th Conferenceof the Asian Pacific Association for
the Study of the Liver (APASL),
which will take place in Shanghai,
China. We will bring together adistinguished faculty of renowned
specialists from the Asia-Pacificregion and from around the world tothis conference.
The APASL Annual Meetinghas grown as the leading conference
focusing on remarkable advancesin liver disease, aimed at providing
the latest scientific and evidence-

based research results that will
be applicable to everyday clinicalpractice. It provides an excellent
opportunity to share and exchange
experiences especially from theviewpoint of Asian-Pacific countries.
These elements are essential to pave
the way for the further developmentof hepatology.
We plan to have a three-day coreprogram to provide an overview
of various liver diseases with theState-of-the-Art Lectures on hotoff-the-press issues. Additionally,
Postgraduate Courses and Morning
Sessions will be designed for the indepth discussion of particular topics.
Free paper and poster presentations
are always the soul of the conference toshare research findings and there will
be several awards available aimed at
supporting young scientists to attend
the conference and encourage scientificresearch.
We thus enthusiastically invite
you to submit abstracts and join us
at this conference as well as ourblooming city, Shanghai.
We look forward to welcoming
you in Shanghai!
Jinlin Hou, M.D., PhD
President, APASL 20177

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Serial AFP Assay Deserves Attention in
Acute Hepatitis FlareIn chronic HBV patients withepisodes of acute hepatitis flare(defined as an event with an abrupt
rise of ALT >5 times ULN), patients
may progress to remission or may
experience severe hepatitis or
hepatic decompensation. According
to APASL guidelines, patientss h o u l d b e m o n i t o r e d w i t h 1-2
weekly measurements of serum
ALT, bilirubin and prothrombin
time.
So what kind of laboratory
tests or prognostic factors could
be effectively used to guide themanagement strategy? According toProf. Yun-Fan Liaw, Liver Research
Unit, Chang Gung Memorial
Hospital, Taipei, China, serial AFP(alpha-fetoprotein) assays are theanswer.
As early as 1974, Prof. Liaw
had pioneeredthe monitoring of

AFP levels in “chronic progressive
hepatitis” and carried out studies todiscover the relationship between
AFP levels and what was once called“acute hepatitis-like” episodes, now
acute hepatitis flare.
Prof. Liaw and other researchers
found that when AFP was above
100 n g / m l w i t h H B V p a t i e n tflare, it reflected bridging necrotic
hepatitis(BNH), which correlated
to the extent of hepatolysis. But
unlike ALT, AFP>100 ng/ml was
significantly superior to ALT topredict HBeAg loss.
When HBV DNA and HBsAg
declined before the peak of ALT,
it suggested that the patient had
effective immune clearance in aflare, and that the patient could justbe observed for the next 3-6 months.
If HBV DNA and HBsAg was stable
or increasing, it suggested that thepatient had ineffective immune
clearance, and the patient may haveliver function decompensation soneeded treatment right away.
Recently, regardless of whether
Peg-IFN, TDF/ADV, Peg-IFN/TDF
or ETV/TDF antiviral regimens
were used to treat HBV patients,
studies have confirmed that hepatitis
flares enhanced HBsAg decline.
During a newly published ETV
treatment study, it was found that
HBsAg decline was dependent on
AFP and ALT levels, with a stronger
correlation to changes in AFP.
In short, AFP>100 ng/ml may
serve as a surrogate marker for
BNH, and AFP is superior to ALT
as a factor for HBeAg loss, rapid
HBsAg decline and possible HBsAg
loss, according to Prof. Liaw.
“We used to rely on liver biopsy,
an invasive method, to find out what

Yun-Fan Liawis going on with the patient, but
now we can just do an AFP test to
see whether the patient has BNH, tofind out if AFP>100 ng/ml, and thencomes down. Otherwise, we need
to be concerned about the patient’s
HCC risk, as AFP is also a livercancer marker,” said Prof. Liaw.

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