Hepatitis b and c treatment in japan

A Special Report on Hepatology in Asia Akira Hayasaka

A Special Report on Hepatology in Asia
-Standardized treatment of hepatitis B and C
according to the annually revised guidelines in Japan-
Akira Hayasaka, MD
The President of Hayasaka Clinic
Correspondence address:
4-6-17 Hatazawaminami,
Kisarazu, Chiba,
JAPAN #2920826
hayasaka@hayasakaakira.com
Abstract
Hepatitis B and C virus infections cause chronic inflammation in the liver,
chronic hepatitis. These inflammatory diseases damage the liver and result
in cirrhosis, chronic liver failure and hepatocellular carcinoma. As an
example of “hepatology in Asia”, the excerpts are reported on the
guidelines for the treatment of chronic hepatitis B and C in Japan. One of
the characteristic features of the criteria for the treatment eligibility in
Japan to patients with chronic hepatitis B is slightly elevated serum
aminotransferase level (higher than 31 IU/L) than in the guidelines of the
different areas. Long-term interferon and the sequential treatment
(entecavir followed by interferon) are recommended for patients younger
than 35 years old to gain a “drug-free status”. Entecavir is also used as the
second choice, but for patients 35 years or older, entecavir is the first
choice for the treatment. Long-term interferon and the sequential treatment
are the second choice. The combination of peginterferon and ribavirin is
recommended for the treatment of patients with hepatitis C with a high
viral load. Interferon monotherapy (either standard interferon or
peginterferon) is indicated for the patients with a low viral load. Antiviral
treatment is also recommended for hepatitis C virus carriers with normal
serum aminotransferase if they have the fibrotic liver based on platelet
counts. This article will further discuss treatments specific within the
Japanese medical practice for hepatitis B and C.
Keyword: Hepatitis B, hepatitis C, guideline, interferon, ribavirin, entecavir, adefovir, lamivudine,
Japan Article word count (excluding references): 2350
Disclosure: The author has no conflicts of interest to declare

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Introduction
“Hepatology in Asia” is an interesting title given to me for a new section of
“Special Reports” in US Gastroenterology and Hepatology Review,
particularly to readers of the western hemisphere. Asia is the largest, most
populous and arguably the most diverse continent. “Hepatology” in this
area has been studied by a large number of basic and clinical researchers in
each country throughout Asia. Recently, a scan of hepatology research in
Asia pacific regions is presented by the Asian Pacific Association of the
Study of Liver Diseases (1).
Based on the title and the contents of the abstracts from various countries,
the control of viral hepatitis, especially hepatitis B (CHB) and hepatitis C
(CHC), must be the most urgent and important clinical issue in Asia
because these infections are highly prevalent in this area and lead to the
development of hepatocellular carcinoma (HCC) and chronic liver failure,
ultimately fatal to these patients. The importance is not only in Asia but all
over the world because these viruses constitute a major global health risk
with around 350 million people being chronically infected with hepatitis B
and around 170 million people being chronically infected with hepatitis C,
according to the World Health Organization (WHO) report (2).
Reported in this article, as an example of “hepatology in Asia”, there are
excerpts on the latest guidelines for the treatment of CHB and CHC by
“The Study Group for the Standardization of Treatment of Viral Hepatitis
Including Cirrhosis” (3), under the auspice of the Ministry of Health, Labor
and Welfare of Japan. The guidelines are revised annually by the member
of the study expert group. The guidelines are widely accepted by practicing
hepatologists who are treating patients with both hepatitis B and C in Japan.
The latest guidelines are seen on the web site of The Japan Society of
Hepatology (JSH) (3). The older one has been published recently by
Kumada et.al. (4,5).

CHRONIC HEPATITIS B

The importance of treatment of CHB in Japan
Approximately 1.5 million people are infected with the hepatitis B virus
(HBV) in Japan (6).Those that are infected could eventually develop HCC

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and cirrhosis leading to chronic liver failure. Treatment of patients with
chronic hepatitis B (CHB) is important because successful treatment results
in the suppression of the HBVDNA quantity, stabilizes or improves the
liver inflammation, cirrhosis, chronic liver failure, and some regression of
liver fibrosis and reduces the incidence of the development of HCC. Taken
all together, patients can live longer with a good quality of life.

The goals of the treatment of CHB in Japan
The present goal is to normalize serum levels of alanine aminotransferase
(ALT) by reducing the viral load through the various treatments. The
ultimate goal for the treatment of CHB is to prevent the progression of the
disease and the development of HCC by eliminating HBV from the
patients.

The available drugs for the treatment of CHB in Japan
Interferon (IFN) (standard interferon [α and β] and peginterferon α2a and
α2b) and nucleotide analogs (such as lamivudine, adefovir,
entecavir, telbivudine, and tenofovir) are the major drugs use for the
treatment of CHB. Currently, standard interferon (α and β) and three kinds
of nucleotide analogs (lamivudine, adefovir and entecavir) are approved in
Japan under the National Health Insurance system for the treatment of
patients with CHB. Peginterferon and tenofovir have not been approved for
the treatment of CHB by the Ministry of Health, Labor and Welfare of
Japan.

The newly approved diagnostic tests for the treatment of CHB
It is well known that HBV genotypes are closely related to the clinical
course and the response efficacy to the anti-viral therapy to HBV. Thus, it is
better to know the genotype of each patient to be treated before
determining the most effective treatment. The diagnostic test for the
genotypes was approved by the Ministry in Japan last May.

Guidelines for the treatment of patients with CHB separately by the
ages of the patients (Table 1)

In Japan, the guidelines for treatment were constructed separately for

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patients younger than 35 years old and over 35 years old. These guidelines
were constructed separately for these two groups because younger patients
have the possibility to stabilize the disease activity in their natural course as
seen in Table 1 (4).
Criteria for treatment eligibility are patients infected with HBV and have
serum aminotransferase (ALT) levels higher than 31 IU/L because those
infected patients are considered to have CHB. In the guidelines of other
countries/areas, treatments will be recommended in patients with the higher
levels of serum ALT. In addition, patients are selected for the treatment if
the HBV DNA titers are 5 log copies of more in HBeAg-positive patients, 4
log copies or more in HBeAg-negative patients and 3 log copies/mL or
more in the patients with cirrhosis due to HBV.
Guidelines for the treatment of patients younger than 35 years
Long-term interferon (IFN) and the sequential treatment (entecavir
followed by interferon) are recommended for patients younger than 35
years to gain a “drug-free status”. However, even for these young patients,
starting entecavir treatment is recommended if they are HBe antigen
negative and with platelet counts less than 150000/μL or with advanced
liver disease of stage F2 or higher. Details are described about “sequential
therapy” at the Japanese Society of Hepatology website (3).

Guidelines for the treatment of patients 35 years or older
For patients 35 years or older, entecavir is suggested as a first choice for
treatment. There are some differences in the recommendation for the
treatments depending on the extent of the viral load and HBe antigen status
(3).
Guidelines for the treatment with nucleoside analogs of patients with
CHB who are receiving lamivudine (Table 2)

Lamivudine is the first nucleotide analogs introduced to the treatment of
HBV infection in Japan. This drug has rapid and potent virus suppression
effects and has been used for many patients. The main disadvantage of the
drug is the high rate of drug resistance to the HBV mutant. Compared with
lamivudine, entecavir has potent antiviral activity and low rate of drug
resistance to the HBV mutant. Tenofovir is known to have much lower drug
resistance than entecavir, but, as noted above, this drug has not been

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approved in Japan. The basic rule is to switch lamivudine to entecavir to
reduce the emerging drug-resistant HBV mutants in patients treated with
lamivudine.
Guidelines for the patients with HBV DNA titers < 2.1 copies/mL
As patients with HBV DNA titers less than 2.1 copies/mL possess
entecavir-resistant mutants in low frequencies, they are recommended to
switch to entecavir as soon as possible shown in the upper part of Table 2.
Guidelines for the patients with HBV DNA titers ≧2.1 copies/mL
For patients with drug-resistant mutants and with virological breakthroughs,
adefovir add-on lamivudine is started for the purpose of stabilizing liver
function. Otherwise these patients with the high viral load may be switched
to entecavir as indicated in the lower part of Table 2.

Supplements to the guidelines for the treatment of CHB
Ten important supplementary comments are described additionally in the
latest guidelines (3). The following are two of the ten supplementary
comments; 1) the treatment should be chosen based on HBV genotypes
(Even in patients 35 years or older, IFN is recommended as the first
treatment if they have the genotype A or B because of the high response
efficacy of the genotypes to interferon) and 2) self-injection of IFN at home
is recommended to eligible patients, so as to improve their quality of life.
The other comments will be translated to English by the expert team who
made the guidelines.

HEPATITIS C
The importance of the treatment of CHC in Japan
As with the HBV infection, hepatitis C virus (HCV) infection is a major
public health problem. The infection, if not treated progressively worsens
over the course of many years and can ultimately result in cirrhosis and
HCC. More than 30,000 patients die from these resultant diseases in Japan
(8).

The goals of the treatment of CHC
The main goal of treatment for patients with CCH is to eradicate HCV
virus. The second goal, if eradication is not possible, is to prevent the
progressions of liver fibrosis and of the development of HCC.

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The available drugs for the treatment of CHC in Japan
At present, standard interferon (α, β), peginterferon (α2a, α2b) and
ribavirin can be used for the anti-viral treatment of patients with CHC in
Japan. Telaprevir, a potent protease inhibitor, has not yet been approved in
Japan, however, it will be used in the near future.

The predictors of a treatment response to patients with CHC
Some of the important predictors of a treatment response include: HCV
genotype (genotypes 2 and 3 are more responsive to treatment than
genotypes 1 and 4), baseline viral load (more responsive in <5.0 Log
IU/mL than more than 5.0 Log IU/mL) and host genetic factors (eg, IL28B
polymorphisms, ISDR mutations and Core aa70 mutations). There are six
major genotypes of HCV in the world, but genotype 1 (about 70%) and
genotype 2 (about 30%) are the major genotypes of HCV in Japan (8). The
other types are extremely rare in this country. Therefore, in the guidelines
there are discussions only about genotype 1 and genotype 2. The TaqMan
HCV test (Roche Molecular Systems) is available for highly sensitive
detection and reliable quantification of HCV in our clinical practice. IL28B
gene polymorphisms, the interferon sensitivity-determining region (ISDR)
mutations and Core aa70 mutations tests are not covered with the National
Health Insurance system. Hopefully, these tests will be approval in the near
future.
Guidelines for patients of CHC
Guidelines for the primary treatment of patients with CHC (Table 3)
As shown in Table 3, the guidelines are constructed based on the
difference in the genotypes of HCV and the levels of HCV RNA load.
Basically, for patients with a high viral load, the combination treatment of
peginterferon and ribavirin is recommended. The treatment lengths are set
for longer in patients with the genotype 1 (48-72 weeks) than in the
genotype 2 (24 weeks) because of the difference of the response efficiency
between the two genotypes. In the latest guidelines the combination
treatment of interferonβ and ribavirin is added for patients with mentaly
depressive state.
For patients with a low viral load, long-term standard interferon treatment
or peginterferon monotherapy is recommended.
Furthermore, the combination treatment with the telaprevir, ribavirin and

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peginterferon α2b (for 24 weeks) are recommended for the patients of CHC
with the genotype 1 and the high viral load when telaprevir is approved (3).

Guidelines for the treatment of patients with normal ALT levels
towards preventing the development of HCC (Table 4)
The interpretation of the “normal” upper level of ALT has been changing
recently. As several studies show, patients with the “normal” level of serum
ALT may have chronic hepatitis with several stages of fibrosis including
cirrhosis. To prevent the development of HCC, the guidelines have been
made for patients infected with HCV with normal ALT levels. In these
guidelines, patients with CHC with normal ALT levels are divided into
four groups by ALT levels and platelet counts. Patients with platelet counts
less than150,000/μL are recommended to receive liver biopsy, if possible,
to know the stage of their liver fibrosis.
Supplements to the guidelines for the treatment of CHC
Guidelines for re-treatment of CCH, for the treatment indication based on
the tests results of IL28B, ISDR and Core aa70 and for the criteria to stop
the treatments are also described in detail at the Japanese Society of
Hepatology website (3).

Discussion
This article reports only parts of the guidelines for the treatment of chronic
hepatitis B and C in Japan. The guidelines are well organized and described
the needed information in detail. They are accepted and used widely by
Japanese practicing hepatologists. In addition, these guidelines are revised
and improved annually, though, usually published only in Japanese with the
exception of the fiscal year, 2008 version (4, 5). Because of the language
barriers, it seems to be a little difficult to discuss them with non-Japanese
hepatologists right now. Since academic research from Japan is published
mainly in English now, this barrier will be resolved soon in clinical
practical work as well. Through this article-written in a common
language-such as English, “hepatology in Asia” is more known to the
western hepatologists.

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References
1 Special Chapter: A Scan of Hepatology in Asia Pacific Region, Hepatology Int.
2010 ;4 (Suppl 1):S94-S101.
2 The website of the World Health Organization :
( http://www.who.int/mediacentre/events/annual/world_hepatitis_day/en/index.html)
3 The website of the Japanese Society of Hepatology:
http://www.jsh.or.jp/medical/index.html [in Japanese]
4 Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronic
hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan.
Hepatology Research 2010; 40:1-7.
5 Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronic
hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan.
Hepatology Research 2010; 40:8-13.
6 Yokosuka O, Kurosaki M, Imazeki F, et al. Management of hepatitis B:
Consensus of the Japan Society of Hepatology 2009. Hepatology Research 2011;
41:1-21.
7 Namiki I, Nishiguchi S, Hino K, et al. Management of hepatitis C; Report of
the Consensus Meeting at the 45th Annual Meeting of the Japan Society of
Hepatology (2009). Hepatology Research 2010; 40:347-368.

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Author biography

Akira Hayasaka, MD, the President and CEO of the Hayasaka Clinic, is a Certified
Medical Doctor, and a liver disease expert in Japan. Akira’s mission is to help
patients recover from liver diseases, not only in Japan, but all over the world. With
more than 30 years of experience in the medical field, Akira is a Board Certified
Hepatologist of the Japan Society of Hepatology, a Board Certified
Gastroenterologist in Japan, and Board Certified Member of the Japanese Society
of Internal Medicine. He is also a Board Councilor of The Japan Society of
Hepatology, The Japanese Society of Gastroenterology and former Clinical
associated professor of medicine at Chiba University School of Medicine.

For more information, go to http://akirahayasaka.com

9

Table 1 Guideline for treatment of patients with chronic hepatitis B in Japan 2011 (modified from 4)
This guideline is used for patients with HBV infection who has ALT≧31IU/L and
HBVDNA≧5 log copies/mL in HBeAg(+) status
HBVDNA≧4 log copies/mL in HBeAg(-) status
HBVDNA≧3 log copies/mL in cirrhosis

Patients Age < 35 years old ≧35 years old
HBV DNA ≧7 log copies/mL < 7 log copies/mL ≧7 log copies/mL < 7 log copies/mL
① IFN (24w-48w) ① Entecavir
HBeAg(+) ② Entecavir
② Entecavir followed by
IFN* ① Entecavir
② IFN (24w-48w)
① Entecavir followed by IFN* ① Follow-up or Entecavir
HBeAg(-) ② Entecavir ② IFN (24w) Entecavir
Entecavir: PLT<150,000/μL or ≧F2 in liver biopsy

HBV, hepatitis B virus; HBeAg, hepatitis B e-antigen; IFN, interferon; PLT, platlet;.
*Sequential therapy with entecavir followed by interferon.

Table 2 Guideline for nucleos(t)ide analogues selection in patients with chronic
hepatitis B taking lamivudine in Japan 2011 (modified from 4)

HBV DNA Recommended Treatment
Constantly
Change to Entecavir
< 2.1 log copies/mL
Viral breakthrough (-) Changable to Entecavir
≧ 2.1 log copies/mL
Viral breakthrough (+) Add Adefovir

HBV, hepatitis B virus.

Table 3 Guideline of treatment of naïve patients with chronic hepatitis C in Japan 2011 (modified from 4)

HCVRNA Genotype 1 Genotype 2
Peg-IFNα2b + Ribavirin (48-72w) Peg-IFNα2b + Ribavirin (24w)
≧ 5.0 Log IU/mL Peg-IFNα2a + Ribavirin (48-72w)
IFNβ + Ribavirin (48-72w) IFNβ + Ribavirin (24w)
IFN (24w) IFN (8-24w)
< 5.0nLog IU/mL
Peg-IFNα2a (24-48w) Peg-IFNα2a (24-48w)

Table 4 Guideline of anti-viral treatment of patients with chronic hepatitis C with "normal" ALT levels in Japan 2011 ( for the
eradication of hepatitis C virus and/or the prevention of development of hepatocellular carcinoma) (modified from 4)

Platlet Count ≧150,000/μL ＜ 150,000/μL
Followup of ALT is needed every 2-4 month. Liver biopsy is recommended.
When ALT is elevated, consider anti-viral ① Consider anti-viral treatment: if the biopsy
treatment with the careful evaluation of the shows ≧F2A2.
hepatitis condition. ② Without liver biopsy, followup of ALT is
ALT ≦ 30IU/L
needed every 2-4 month. When ALT is elevated,
consider anti-viral treatment .

Consider anti-viral treatment Consider anti-viral treatment
ALT: 31-40IU/L ≦65 years old according to the guideline shown
according to the guideline shown in Table 3
in Table 3

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