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Archives of Virology | 2001

Molecular epidemiology of TT virus (TTV) and characterization of two novel TTV genotypes in Indonesia

David H. Muljono; Tsutomu Nishizawa; Fumio Tsuda; Masaharu Takahashi; Hiroaki Okamoto

Summary. The prevalence of TT virus (TTV) DNA among 244 healthy individuals in 23 cities on 12 islands in Indonesia was determined by polymerase chain reaction (PCR) with primers derived from the coding region (N22), which can detect TTV DNA of genotypes 1–6. By N22 PCR, TTV DNA was detected in 102 (42%) individuals. The amplified PCR products were molecularly cloned and three clones each were subjected to sequence analysis. Three hundred one (98%) of the 306 TTV clones were classified into genotype 1, 2 or 3, and none into genotypes 4–6. The remaining five clones from two individuals (Kt-08 and Kt-10) on Kutai, Kalimantan Island, differed by >30% from known TTV isolates of all 21 genotypes and were tentatively classified into genotypes 22 and 23, respectively. Using primers specific for the new TTV genotype 22 or 23, TTV genotype 22 was detected significantly more frequently in Kutai than in the other 22 cities (41% vs. 5%, P < 0.001). TTV genotype 23 was restricted to Kutai (17% vs. 0%, P < 0.001), suggesting the indigenous nature of this genotype. Analysis of two TTV isolates (Kt-08F and Kt-10F) demonstrated the extreme diversity of TTV and the preservation of the genomic organization and transcription profile.


Archives of Virology | 2011

Ethnogeographical structure of hepatitis B virus genotype distribution in Indonesia and discovery of a new subgenotype, B9

Meta Dewi Thedja; David H. Muljono; Neni Nurainy; Caecilia H. C. Sukowati; Jan Verhoef; Sangkot Marzuki

The distribution of hepatitis B virus (HBV) in the populations of island Southeast Asia is of medical and anthropological interest and is associated with an unusually high genetic diversity. This study examined the association of this HBV genetic diversity with the ethnogeography of the populations of the Indonesian archipelago. Whole genome analysis of 21 HBV isolates from East Nusa Tenggara and Papua revealed two recently reported HBV/B subgenotypes unique to the former, B7 (7 isolates) and B8 (5 isolates), and uncovered a further novel subgenotype designated B9 (4 isolates). Further isolates were collected from 419 individuals with defined ethnic backgrounds representing 40 populations. HBV/B was predominant in Austronesian-language-speaking populations, whereas HBV/C was the major genotype in Papua and Papua-influenced populations of Moluccas; HBV/B3 was the predominant subgenotype in the western half of the archipelago (speakers of the Western Malayo-Polynesian [WMP] branch of Austronesian languages), whereas B7, B8 and B9 were specific to Nusa Tenggara (Central Malayo-Polynesian (CMP)). The result provides the first direct evidence that the distribution of HBV genotypes/subgenotypes in the Indonesian archipelago is related to the ethnic origin of its populations and suggests that the HBV distribution is associated with the ancient migratory events in the peopling of the archipelago.


Archives of Virology | 2008

Genetic study of hepatitis B virus in Indonesia reveals a new subgenotype of genotype B in east Nusa Tenggara

Neni Nurainy; David H. Muljono; Herawati Sudoyo; Sangkot Marzuki

The hepatitis B virus (HBV) genotype is associated with viral anthropological history, clinical outcome of disease and response to treatment. This study examines the HBV genotypes in Indonesia. HBV genotypes were determined by whole-genome sequencing and from the sequence of the Pre-S2 and S regions in a larger series. Two HBV genotypes, B (HBV/B) and C (HBV/C), were predominant. Three previously reported HBV/B subgenotypes were identified, with certain population association: HBV/B2 (HBV/Ba) was found mostly in Indonesians of Chinese ethnic origin, HBV/B3 was dominant among the Javanese, and HBV/B5, reported earlier from the Philippines, was also discovered, albeit at low frequency. Two other subgenotypes, HBV/B4 from Vietnam and HBV/B6, recently reported from the Arctic region, were not found. A novel subgenotype, HBV/B7, was recognized, associated with populations of the Nusa Tenggara islands in eastern Indonesia. Characteristic differences in HBsAg serotype and single nucleotide polymorphisms (SNPs) in the Pre-S2 region distinguish HBV/B7 from other HBV/B subgenotypes and further establish the new HBV subgenotype.


Hepatology International | 2010

Occult hepatitis B in blood donors in Indonesia: altered antigenicity of the hepatitis B virus surface protein

Meta Dewi Thedja; Martono Roni; Alida Harahap; Nurjati C. Siregar; Susan I. Ie; David H. Muljono

Background and aimsOccult hepatitis B virus infection (OBI) poses a challenge to the safety of blood donation. The prevalence of OBI is not well documented in Indonesia, although this information in such an endemic country is needed. This study was aimed to evaluate the prevalence of occult hepatitis B in blood donors from two cities of Indonesia, and to study the genetic variation and its effect on the predicted antigenicity of HBsAg.MethodsSerum samples of 309 regular blood donors negative for HBsAg were tested for anti-HBs and anti-HBc. Hepatitis B virus (HBV) DNA isolated from anti-HBc-positive samples were analyzed by polymerase chain reaction, cloned and sequenced. Antigenic properties of identified HBsAg mutants were predicted by calculation of the antigenic index.ResultsOf the 309 HBsAg-negative samples, anti-HBc was positive in 134 (43.4%) and HBV DNA was detected in 25 (8.1%). Seven of the viremic samples had nucleotide substitutions (A521G, A551T, C582T, and A562G) in the S gene, causing amino acid mutations (T123A, M133L, and T143M) in the ‘a’ determinant of HBsAg that resulted in changes in the predicted antigenicity.ConclusionsOBI was detected in blood donors’ samples in Indonesia. Anti-HBc was shown to be a better screening parameter than HBsAg, however, it might result in the loss of donors particularly in endemic countries. HBsAg detection failure in this study might be due to mutations altering the protein antigenicity and/or the low-level carriage of HBV.


World Journal of Gastroenterology | 2016

Significance of hepatitis virus infection in the oncogenic initiation of hepatocellular carcinoma

Caecilia H.C. Sukowati; Korri E. El-Khobar; Susan I. Ie; Beatrice Anfuso; David H. Muljono; Claudio Tiribelli

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, and DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.


Current Pharmacogenomics and Personalized Medicine | 2011

Asia-Pacific Health 2020 and Genomics without Borders: Co-Production of Knowledge by Science and Society Partnership for Global Personalized Medicine

Vural Ozdemir; David H. Muljono; Tikki Pang; Lynnette R. Ferguson; Aresha Manamperi; Sofia Samper; Toshiyuki Someya; Anne Marie Tassé; Shih-Jen Tsai; Hong-Hao Zhou; Edmund J.D. Lee

Is Asia-Pacific emerging as a leader in genome-based personalized medicine in 21st century? With news of senior “star” scientists from North America and Europe relocating to, or establishing satellite outpost laboratories in the Asia-Pacific region, this question has become topical among sci-entists, research funding agencies as well as investors in global health and knowledge-based innovations. In addition to attracting established scientists, the Asia-Pacific is ac-tively investing in a young generation of skilled profession-als. Based on the annual


Journal of Medical Virology | 2015

Seroepidemiology and occult hepatitis B virus infection in young adults in Banjarmasin, Indonesia

Erica Darmawan; Turyadi; Korri E. El-Khobar; Ni Ketut Dias Nursanty; Meta Dewi Thedja; David H. Muljono

Hepatitis B virus (HBV) infection remains a public health problem in Indonesia. There has been limited data regarding HBV infection in young adult population. This study aimed to evaluate the seroepidemiology of HBV infection and characterize occult HBV variants in healthy young adults in Banjarmasin, Indonesia, who were born before the implementation of the universal infant hepatitis B vaccination. Serum samples of 195 healthy young adults were tested for HBsAg, anti‐HBc, and anti‐HBs. The prevalence of HBsAg, anti‐HBc, and anti‐HBs was 9 (4.6%), 62 (31.8%), and 96 (49.2%), respectively. Seventy four (37.9%) samples were seronegative for all three parameters, indicating the susceptibility to HBV infection. Among 66 samples positive for HBsAg and/or anti‐HBc, 13 (19.7%) were HBV DNA positive; of these, four were HBsAg positive and nine were HBsAg negative, and categorized as occult HBV infection. Most occult HBV cases had high‐level anti‐HBs (>100 IU/l), suggesting that blood with positive anti‐HBs and anti‐HBc could not be regarded as noninfectious. Thirteen amino acid substitutions were identified: T126S, P127S, Q129R, T131N, M133T, and Y161S in the HBsAg‐positive group; P120T, T126I, G145S, Y161F, E164V, and V168F in the occult‐HBV group; and T143S in both groups. More studies are required to provide data on the prevalence and characteristics of mutants to ensure reliable diagnosis. The occult HBV infection, combined with the HBsAg prevalence, could indicate the high HBV carriage among young adults in this area. The high percentage of individuals susceptible to HBV infection reiterates the need for catch‐up immunization strategies targeted at young adults. J. Med. Virol. 87:199–207, 2015.


PLOS ONE | 2015

Genogeography and Immune Epitope Characteristics of Hepatitis B Virus Genotype C Reveals Two Distinct Types: Asian and Papua-Pacific.

Meta Dewi Thedja; David H. Muljono; Susan I. Ie; Erick Sidarta; Turyadi; Jan Verhoef; Sangkot Marzuki

Distribution of hepatitis B virus (HBV) genotypes/subgenotypes is geographically and ethnologically specific. In the Indonesian archipelago, HBV genotype C (HBV/C) is prevalent with high genome variability, reflected by the presence of 13 of currently existing 16 subgenotypes. We investigated the association between HBV/C molecular characteristics with host ethnicity and geographical distribution by examining various subgenotypes of HBV/C isolates from the Asia and Pacific region, with further analysis on the immune epitope characteristics of the core and surface proteins. Phylogenetic tree was constructed based on complete HBV/C genome sequences from Asia and Pacific region, and genetic distance between isolates was also examined. HBV/C surface and core immune epitopes were analyzed and grouped by comparing the amino acid residue characteristics and geographical origins. Based on phylogenetic tree and geographical origins of isolates, two major groups of HBV/C isolates—East-Southeast Asia and Papua-Pacific—were identified. Analysis of core and surface immune epitopes supported these findings with several amino acid substitutions distinguishing the East-Southeast Asia isolates from the Papua-Pacific isolates. A west-to-east gradient of HBsAg subtype distribution was observed with adrq+ prominent in the East and Southeast Asia and adrq- in the Pacific, with several adrq-indeterminate subtypes observed in Papua and Papua New Guinea (PNG). This study indicates that HBV/C isolates can be classified into two types, the Asian and the Papua-Pacific, based on the virus genome diversity, immune epitope characteristics, and geographical distribution, with Papua and PNG as the molecular evolutionary admixture region in the switching from adrq+ to adrq-.


The Lancet Gastroenterology & Hepatology | 2016

Hepatitis B and hepatitis C in southeast and southern Asia: challenges for governments

Suzanne Wait; Emily Kell; Saeed Hamid; David H. Muljono; Jose D. Sollano; Rosmawati Mohamed; Samir Shah; Mamun-Al-Mahtab; Z. Abbas; Jennifer Johnston; Tawesak Tanwandee; Jack Wallace

In 2015, the Coalition to Eradicate Viral Hepatitis in Asia Pacific gathered leading hepatitis experts from Bangladesh, India, Indonesia, Malaysia, Pakistan, the Philippines, and Thailand to discuss common challenges to the burden posed by hepatitis B virus (HBV) and hepatitis C virus (HCV), to learn from each others experience, and identify sustainable approaches. In this report, we summarise these discussions. Countries differ in their policy responses to HBV and HCV; however, substantial systemic, cultural, and financial barriers to achievement of elimination of these infections persist in all countries. Common challenges to elimination include limited availability of reliable epidemiological data; insufficient public awareness of risk factors and modes of transmission, leading to underdiagnosis; high rates of transmission through infected blood products, including in medical settings; limited access to care for people who inject drugs; prevailing stigma and discrimination against people infected with viral hepatitis; and financial barriers to treatment and care. Despite these challenges, promising examples of effective programmes, public-private initiatives, and other innovative approaches are evident in all countries we studied in Asia Pacific. The draft WHO Global Health Sector Strategy on Viral Hepatitis 2016-21 provides a solid framework upon which governments can build their local strategies towards viral hepatitis. However, greater recognition by national governments and the international community of the urgency to comprehensively tackle both HBV and HCV are still needed. In all countries, strategic plans and policy goals need to be translated into resources and concrete actions, with national governments at the helm, to enable a sustainable response to the rising burden of hepatitis B and C in all countries.


Hepatology International | 2013

HBsAg, HBeAg and HBV DNA level changes and precore/basal core promoter mutations in the natural history of chronic hepatitis B in Indonesian patients

Turyadi; Meta Dewi Thedja; Susan I. Ie; Alida Harahap; Korri E. El-Khobar; Martono Roni; David H. Muljono

IntroductionChronic hepatitis B (CHB) is a state of complex interactions between the hepatitis B virus (HBV) and host. We studied the changes in hepatitis B surface antigen (HBsAg), hepatitis B ‘e’ antigen (HBeAg) and HBV DNA levels, considering the implications of HBV genotype, basal core promoter (BCP) A1762T/G1764A and precore G1896A mutations in CHB.MethodsOne hundred fifty-two treatment-naïve CHB patients were classified into immune-tolerant (IT), immune-clearance (IC), low/non-replicative (LR) and ‘e’-negative hepatitis B (ENH) phases, based on HBeAg status, HBV DNA and ALT levels. HBV DNA was detected and quantified by polymerase chain reaction, then analyzed by sequencing. HBsAg and HBeAg levels were measured serologically.ResultsHBsAg and HBV DNA levels varied between CHB phases, with HBsAg highest in IT and lowest in LR, and HBV DNA high in IT and IC, and lowest in LR. Both markers increased in ENH. Correlation between HBsAg and HBV DNA was significant in IT and IC, modest in ENH, but missing in LR. HBeAg and HBV DNA levels were dissociated in HBeAg-positive patients. Genotypes B and C were similarly distributed, with precore mutations higher in HBeAg-negative patients and BCP mutations comparable in all phases. Temporal association between HBeAg seroconversion and an increase of BCP/precore mutations was observed.ConclusionHBsAg and HBV DNA levels were high and correlated in early CHB phases and dissociated after HBeAg seroconversion, indicating different controls affecting HBV replication and HBsAg production. Selection of BCP/precore mutants may affect disease course and explain the HBeAg–HBV DNA dissociation, a precaution for clinical application of quantitative HBeAg.

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Susan I. Ie

Eijkman Institute for Molecular Biology

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Meta Dewi Thedja

Eijkman Institute for Molecular Biology

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Turyadi

Eijkman Institute for Molecular Biology

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Martono Roni

Eijkman Institute for Molecular Biology

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Sangkot Marzuki

Eijkman Institute for Molecular Biology

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Korri E. El-Khobar

Eijkman Institute for Molecular Biology

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Neni Nurainy

Eijkman Institute for Molecular Biology

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Herawati Sudoyo

Eijkman Institute for Molecular Biology

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