Hepatitis B virus infection in Indonesia

Abstract

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV-infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia.

Full text

Hepatitis B virus infection in Indonesia
Yoshihiko Yano, Takako Utsumi, Maria Inge Lusida, Yoshitake Hayashi
Yoshihiko Yano, Takako Utsumi, Yoshitake Hayashi, Center
for Infectious Diseases, Kobe University Graduate School of
Medicine, Kobe 650-0017, Japan
Takako Utsumi, Maria Inge Lusida, Indonesia-Japan Collabo-
rative Research Center for Emerging and Re-emerging Infectious
Diseases, Institute of Tropical Disease, Airlangga University,
Surabaya 60115, Indonesia
Author contributions: All the authors made a substantial
contribution to the conception and design of the study, data
acquisition, and to drafting and critically revising the manuscript;
the authors approved the nal version.
Supported by Japan Initiative for Global Research Network
on Infectious Diseases (J-GRID) program from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Conict-of-interest statement: All the authors declare that they
have no conict of interest.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Co rresponde nc e to : Tak ako Ut sumi, PhD, Center for
Infectious Diseases, Kobe University Graduate School of
Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017,
Japan. tutsumi@people.kobe-u.ac.jp
Telephone: +81-78-3825700
Fax: +81-78-3825719
Received: April 28, 2015
Peer-review started: May 6, 2015
First decision: June 23, 2015
Revised: July 14, 2015
Accepted: September 15, 2015
Article in press: September 15, 2015
Published online: October 14, 2015
TOPIC HIGHLIGHT
Submit a Manuscript: http://www.wjgnet.com/esps/
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DOI: 10.3748/wjg.v21.i38.10714
World J Gastroenterol 2015 October 14; 21(38): 10714-10720
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2015 Baishideng Publishing Group Inc. All rights reserved.
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2015 Advances in Hepatitis B virus
Abstract
Approximately 240 million people are chronically
infected with hepatitis B virus (HBV), 75% of whom
reside in Asia. Approximately 600000 of infected
patients die each year due to HBV-related diseases or
hepatocellular carcinoma (HCC). The endemicity of
hepatitis surface antigen in Indonesia is intermediate
to high with a geographical difference. The risk of
HBV infection is high in hemodialysis (HD) patients,
men having sex with men, and health care workers.
Occult HBV infection has been detected in various
groups such as blood donors, HD patients, and HIV-
infected individuals and children. The most common
HBV subg enotype in Indonesia is B3 followed by
C1. Various novel subgenotypes of HBV have been
identified throughout Indonesia, with the novel HBV
subgenotypes C6-C16 and D6 being successfully
isolated. Although a number of HBV subgenotypes
have been d iscov ere d in Ind one sia, geno type-
related pathogenicity has not yet been elucidated
in detail. Therefore, genotype-related differences in
the prognosis of liver disease and their effects on
treatments need to be determined. A previous study
conducted in Indonesia revealed that hepatic steatosis
was associated with disease progression. Pre-S2
mutations and mutations at C1638T and T1753V in
HBV/B3 have been associated with advanced liver
diseases including HCC. However, drug resistance to
lamivudine, which is prominent in Indonesia, remains
obscure. Although the number of studies on HBV in
Indonesia has been increasing, adequate databases
on HBV infection are limited. We herein provided an
overview of the epidemiology and clinical characteristics
of HBV infection in Indonesia.
Key words: Hepatitis B virus; Epidemiology; Prevention;
Clinical characteristics; Indonesia
© The Author(s) 2015. Published by Baishideng Publishing
Group Inc. All rights reserved.

in different areas of the world and the prevalence
of chronic HBV infection can be categorized as high,
intermediate, or low endemicity. Table 1 shows the
prevalence of the HBsAg in not only the general
population, but also risk groups such as commercial sex
workers (CSW) and men having sex with men (MSM).
The prevalence of HBV in the general population in
Indonesia is higher than that of HCV (2%)[12], with the
highest rates being reported in Makassar (7.1%)[13] in
Sulawesi Island and the lowest rates being reported
in Jakarta (4.0%)[14] in Java Island; however, another
study reported that the prevalence of HBV in Jakarta
was 5.8% in the general population[15]. Hasan
previously reported that the prevalence of HBV infection
in the general population was the highest in Pontianak
(9.1%) in the Kalimantan Island[5]. Furthermore, the
prevalence of HBsAg was markedly higher in habitants
in the highland of Papua (12.8%) and North Sulawesi
(33.0%)[16]. The prevalence of HBsAg in pregnant
women was found to be the same as that in the
general population in Indonesia[17,18]. These findings
demonstrated that the endemicity of HBsAg among the
general population in Indonesia is intermediate to high,
as reported previously[2,19].
HBV infection was not detected in children in
Tahuna, North Sulawesi, and Surabaya, East Java,
suggesting the efcacy of Hepatitis B (HB) vaccinations
in pre-school children[11,20].
The highest risk group of HBV infection was
previously reported to be hemodialysis (HD) patients
(11.2%) in Yogyakarta[12], followed by MSM (9.8%)[21]
in Solo in the Java Island (Table 1). The prevalence
of HBV/HIV co-infection was found to be higher than
that of HBV infection alone in Indonesia[22-24] as well
as in neighboring countries such as Vietnam and
India. The incidence of HIV and HBV burden are
currently increasing in Indonesia[22,23,25]; however, no
HBV/HIV co-infection cases have been identified in
CSW[26]. The prevalence of HBsAg has been classied
as high endemicity (8.8%) in health care workers[27]
and intermediate endemicity in staff in HDU (5.7%)
throughout Indonesia (Table 1). A previous study
also revealed that the prevalence of HBsAg was
high among medical employees in Padang (11.2%),
Mataram (13.3%), and Irian Jaya (13.3%)[5].
Many unique animals exist in Indonesia because
of its specic ecosystem. Gibbons in Kalimantan were
previously reported to be infected with HBV having
their own genotype[28].
OCCULT HBV INFECTION
Occult HBV infection (OBI) is dened as the presence
of HBV DNA in the serum and/or liver tissue of
individuals with HBV core antibodies (anti-HBc) without
HBsAg[29]. Several studies have been conducted on
OBI in Indonesia. OBI was detected in 8.1% of blood
donors with amino acid mutations (T123A, M133L,
and T143M) in the a determinant of HBsAg, which
Yano Y
et al
. Hepatitis B virus
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Core tip: Hepatitis B virus (HBV) infection is an
important public concern and its prevalence varies
greatly in different parts of the world. The high
prevalence of HBV in Indonesia highlights the need
to improve prevention and control measures because
few evidence-based prevention strategies are currently
available. Although studies on HBV in Indonesia are
increasing, it is still not fully understood. We herein
reviewed epidemiologically important aspects of HBV
infection in Indonesia.
Yano Y, Utsumi T, Lusida MI, Hayashi Y. Hepatitis B virus
infection in Indonesia. World J Gastroenterol 2015; 21(38):
10714-10720 Available from: URL: http://www.wjgnet.
com/1007-9327/full/v21/i38/10714.htm DOI: http://dx.doi.
org/10.3748/wjg.v21.i38.10714
INTRODUCTION
Hepatitis B virus (HBV) infection is associated with a
diverse range of liver damage including asymptomatic
carriers, chronic hepatitis, liver cirrhosis, and
hepatocellular carcinoma (HCC). Approximately 240
million people are chronically infected with HBV[1], 75%
of whom reside in Asia[2]. Approximately 600000 of
infected patients die each year of HBV-related diseases
or HCC[3]. The prevalence of HBV infection varies
according to the geographic region, and is categorized
as high (≥ 8%), intermediate (2%-7%), or low (<
2%) endemicity. The endemicity of HBV in Indonesia
is moderate to high[4,5], ranging from 2.5% to 10% for
hepatitis B surface antigen (HBsAg)[2,5,6]. HBV has been
classied into at least 9 genotypes (A through H and
J) and has been shown to have a distinct geographical
distribution[7,8]. The most common HBV subgenotype
is HBV B3 (HBV/B3), followed by HBV/C1[9]; however,
various novel genotypes have been detected in
Indonesia.
Indonesia is the largest archipelago in the world,
consisting of ve major islands and approximately 30
smaller groups. The archipelago is located between
two oceans, the Pacic and Indian oceans, and bridges
two continents, Asia and Australia. This strategic
position has inuenced the serological and virological
aspects of HBV infection (Figure 1). Although the
number of studies conducted on HBV in Indonesia
has increased, adequate databases on HBV infection
are still limited[10]. The epidemiology of HBV remains
obscure in Indonesia[11]. Therefore, we herein provided
an overview of HBV infection among the Indonesian
population.
PREVALENCE OF HBV INFECTION AND
RISK FACTORS IN INDONESIA
The prevalence of chronic HBV infection varies greatly

resulted in changes in predicted antigenicity[30].
Several OBI cases were detected among school
children with the variant T126I, which may be one of
the viral mechanisms helping the virus to escape from
current HB vaccines in Indonesia[31]. In Banjarmasin,
Kalimantan, OBI was identied in healthy young adults
with 13 amino acid substitutions[32]. Awareness of
the reactivation of OBI has increased in Indonesia,
especially in HBV endemic areas[33]. A total of 27.1%
and 14.7% of HIV-infected individuals and HD patients,
respectively, were considered to have OBI[12,22],
suggesting that the prevalence of HBV infection
regardless of HBsAg was high in immunosuppressive
patients.
HBV GENOTYPES/SUBGENOTYPES IN
INDONESIA
HBV is currently grouped into at least 9 genotypes (A
through H and J, with I still being controversial)[34].
The HBV sequence is characterized by more than
8% nucleotide (nt) differences for genotypes and
4%-8% for subgenotypes. The most common HBV
subgenotype in Indonesia is HBV/B3, followed by HBV/
C1[35,36] (Table 1), with various novel subgenotypes
of HBV being identified throughout Indonesia. Ten
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Sumatra
Java
Kalimantan
Sulawesi
Papua
Figure 1 Map of Indonesia. Indonesia is the largest archipelago in the world, consisting of ve major islands and approximately 30 smaller groups.
Table 1 Prevalence of hepatitis B surface antigen and risk factors in Indonesian populations
Region Prevalence (%) Subject Main genotype Ref.
Java
Bandung 4.7 Pregnant women Reniers et al[17], 1987
Jakarta 4.0 General population Akbar et al[14], 1997
Jakarta 5.8 General population Budihusodo et al[15], 1991
Jakarta 2.2 Parturient women Gunardi et al[6], 2014
Surabaya 4.0 CSW Kotaki et al[26], 2013
Solo 9.8 MSM Prasetyo et al[21], 2014
Four prisons in Central Java1 3.2 Drug abuser inmates in prisons B3, C1 Prasetyo et al[10], 2013
Yogyakarta 11.2 HD patients B3 Rinonce et al[12], 2013
5.7 Staff in HDU B3
Sumatra
Padang HBV carriers C1, B3 Siburian et al[9], 2013
Kalimantan
Banjarmasin 4.6 General population B, C Darmawan et al[32], 2015
Sulawesi
Tahuna 4.9 General population C5 Achwan et al[11], 2007
Makassar 7.1 General population Amirudin et al[13], 1991
Bali1 1.9 Pregnant women Surya et al[18], 2005
Papua
Jayapura 4.6 General population C6, D6, B3 Lusida et al[36], 2008
1Exact place is not mentioned. MSM: Men having sex with men; CSW: Commercial sex workers; HD: Hemodialysis; HDU: Hemodialysis unit.
Yano Y
et al
. Hepatitis B virus

associated with disease progression[49]. Steatosis was
identified as an independent risk factor for HCC and
the progression of hepatitis was found to be more
rapid in HCV patients with steatosis[50,51]. However,
a meta-analysis revealed that hepatic steatosis was
not related to the clinical course of HBV patients[52].
A previous study reported that hepatic steatosis was
more strongly associated with genotype C (37.9%)
than with genotype B (24.0%)[53]. Lesmana et al[54]
examined 179 CHB patients in Jakarta and found the
prevalence of hepatic steatosis to be approximately
30%. Obesity is a serious social issue in Indonesia,
as in other countries[55]. However, studies on steatosis
in Indonesia are still limited, and, as such, further
investigations are warranted.
Although the prevalence of HBV and HCV infections
in Southeast Asia including Indonesia is high, clinical
studies remain limited. Lamivudine, adefovir, and
telbivudine, therapeutic drugs for CHB, are currently
covered by health insurance in Indonesia. Although
drug resistance to lamivudine has not yet been
examined, it is common for the cheapest drug,
lamivudine, to be prescribed or antiviral therapy to be
discontinued due to economic reasons. Therefore, the
prevalence of lamivudine-resistant HBV may increase.
Telbivudine, which was recently approved in Indonesia,
was found to be effective for Indonesian HBV carriers.
Sulaiman et al[56] reported that HBeAg loss and the
seroconversion rate for HBeAg-positive patients were
28.8% and 14.1% at week 52 of telbivudine therapy,
respectively. Furthermore, undetectable HBV DNA
(PCR negativity) was 51.8% at week 24 and 62.7% at
week 52 of this therapy. However, a large-scale study
has not yet been conducted on interferon therapy for
CHB and, thus, its effectiveness currently remains
unknown.
Previous studies revealed a hepatitis virus co-
infection among HIV patients. Anggorowati et al[23]
examined 126 HIV patients in Yogyakarta city and
found that 8% had the HBsAg and were considered
to be co-infected with HBV. Utsumi et al[22] examined
118 HIV patients in Surabaya City, and reported
that 15.3% were HBsAg-positive while 27.1% were
positive for HBV-DNA regardless of being HBsAg-
negative and were considered to have OBI. These
findings suggested that HBV co-infection including
OBI was frequent among HIV patients and serological
examinations were sometimes insufcient for detecting
co-infections because of a compromised immune
system. Fibriani et al[24] recently examined 616 HIV
patients in Bandung city in West Java, found HBV co-
infection in approximately 7% of these patients, and
identied the clinical characteristics of co-infection as
being male and having a history of injection drug use.
HBV infection was examined in HD patients.
Rinonce et al[12] examined 161 HD patients in
Yogyakarta, and revealed that the prevalence of
HBsAg positivity was 11.8% and also that the viral
novel HBV subgenotypes (HBV/C7-C16) were isolated
in Indonesia between 2008 and 2012[37-41]. HBV/C6,
HBV/C11, and HBV/D6 were identified in a Papuan
population[36,40,42]. Genotype J (HBV/J) was detected in
a Japanese patient with HCC who was thought to have
been infected in Kalimantan, Indonesia, during World
War Ⅱ[28,43]. HBV isolates from subjects from Sulawesi
clustered within the HBV/C5, together with known
isolates from the Philippines and Vietnam[11]. The
distribution of genotypes/subgenotypes varies even
in different regions of a country, which may partly be
related to the ethnic origin of the infected patients.
PREVENTION
The most significant achievement in the prevention
of HB is the implementation of a universal infant
vaccination for HB. The HB universal vaccination was
introduced in Indonesia in 1997, with the Indonesian
government attempting to ensure that every newborn
was vaccinated against HBV infection during the
rst 7 d of life. The immunization project in Lombok
decreased the prevalence of HBsAg from 6.2% to 1.4%
among children less than 5 years old[44]. In Surabaya
and North Sulawesi, the prevalence of HBsAg in
preschool children was reported to be 0%[11,20], a result
that was attributed to the universal HB vaccination.
Although the prevalence of HBsAg among children
varies by region, for example, 3.1% in Lamongan in
East Java[31] and 4.2% in Papua, the HB vaccination
history is obscure. Since the HB vaccination is one
of the Expanded Program on Immunization projects
being run by the government, communication with
the local government is of great importance for better
practices.
CHARACTERISTICS OF CHRONIC HBV
INFECTION IN INDONESIA
Previous studies revealed that the clinical characteristics
of chronic HB (CHB) differed among genotypes, and
the prognosis of genotype B was better than that of
genotype C[45-47]. However, most studies in Asia were
conducted in Taiwan, China, Hong Kong, and Japan.
The main subgenotype in Indonesia is HBV/B3, which
is different from the subgenotypes HBV/B1 and
HBV/B2 mainly analyzed in other Asian countries[48].
Furthermore, HBV/C in Indonesia is mainly HBV/C1
in Java and HBV/C6 in Papua, and is different from
HBV/C, which is spreading in East Asian countries
such as China and Japan[36,42]. Since most clinical
studies conducted in Indonesia involved patients
with HBV/B, the clinical course of HBV/C in Indonesia
currently remains unclear. Although HCC is prevalent
in Indonesia, further studies are needed to determine
clinical characteristics in relation to the genotypes in
Indonesia.
Recent studies revealed that hepatic steatosis was
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genomes of several strains were identical, suggesting
nosocomial infection.
LIVER CANCER IN RELATION TO HBV IN
INDONESIA
Cancer-related death is a major public health problem
in Indonesia and accounts for the seventh largest
cause of death. According to the Jakarta Cancer
Registry, the ratio of liver cancer between 2005 and
2007 was 1.4 per 100000 (eleventh place) among
women and 4.0 per 100000 (third place) among
men[57]. On the other hand, HBV is the most common
cause of HCC. Sulaiman[58] and Marwoto et al[59] rstly
reported in 1985 that the frequency of HBV among
HCC was 67.0%, while Sulaiman showed that it was
47.6%. Wang et al[60] examined the epidemiology of
HCC in Japan, India, China, and Indonesia, and found
that the positive prevalences of the HBsAg and HCV
antibody were 21.0% and 40.0% in Indonesian patients
with liver cancer, respectively. HBV is a well-known
oncogenic virus, and previous studies revealed that
the Pre-S mutation, X mutation, and BCP-PC mutation
were associated with hepatocarcinogenesis[61,62]. The
Pre-S1 deletion, Pre-S2 deletion, T53C mutation were
found to be related to HCC at the S domain. Utama et
al[63] examined the prevalence of the Pre-S2 mutation
among 268 HBV carriers in Bantan, and showed it was
2.7%, 18.2%, 40.9%, and 28.6% in asymptomatic
carriers, chronic hepatitis, liver cirrhosis, and HCC,
respectively, indicating that the Pre-S2 mutation was
an independent factor of progressive liver disease. A
meta-analysis revealed that the X domain including
an A1762T/G1764A double mutant, T1753V, C1653T,
G1896A, and G1899A were related to HCC[64].
Heriyanto et al[35] compared 40 cirrhosis and liver
cancer patients with 109 chronic hepatitis patients in
Yogyakarta city, and a multivariate analysis identied
being older than 45 years old (OR = 2.61, P = 0.034),
having a C1638T variation (OR = 1074.57, P = 0.005),
and having a T1753V variation (OR = 6.39, P =
0.047) as independent factors participating in disease
progression.
HBV INFECTION AND HOST FACTORS
Recent technological advances revealed that various
kinds of genetic factors are associated with cancers.
The genome-wide association study showed that a
large number of single nucleotide polymorphisms
(SNPs) were related to various kinds of cancers. In
case-control and retrospective studies on liver cancers,
numerous candidate genes for SNPs were found to
be associated with HCC. In 2009, Kamatani et al[65]
examined 188 Japanese CHB patients and 934 controls
and was the first to show that SNPs in the human
leukocyte antigen (HLA)-DP region were associated
with chronic HBV carriers. The HLA gene is located
in 6p21.3 and plays an important role in antigen
presentation. Polymorphisms in this region were also
identified not only in Japanese patients, but also in
Chinese patients[66,67]. In Indonesian populations,
several SNPs including rs3135363 in HLA-DR,
rs9277535 in HLA-DP, and rs9267665 in a gene-rich
HLA class Ⅲ interval were associated with HB vaccine
responses[68]. Host factors are also important for HBV
infection and disease progression. Further analyses are
needed to conrm these ndings.
CONCLUSION
The endemicity of HBsAg in Indonesia is intermediate
to high with a geographical difference. HD patients,
MSM, and health care workers are at high risk of
HBV infection. OBI has also been detected in various
groups such as blood donors, HD patients, and HIV-
infected individuals and children. Appropriate national
immunization programs are required in HBV endemic
countries such as Indonesia in order to reduce HBV
infection. Although a number of HBV subgenotypes
have been discovered in Indonesia, genotype-
related pathogenicity has not yet been elucidated
in detail. Therefore, genotype-related differences in
the prognosis of liver disease and their effects on
treatments are eagerly awaited.
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P- Reviewer: Blum HE, Chen RF S- Editor: Yu J L- Editor: A
E- Editor: Ma S
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