Hepatitis: Taiwan

Chen CJ, Iloeje UH, Yang HI. · Genomics Research Center, Academia Sinica, 128 Academia Road Section 2, Nankang, Taipei 115, Taiwan. · Clin Liver Dis. · Pubmed #17981229 No free full text.

Abstract: This article reviews results from the REVEAL-HBV study, which found that hepatitis B virus DNA across a biologic gradient is very strongly predictive of the risk of disease progression and remains a strong predictor of risk after accounting for other important factors.

Chen CJ, Jeng LB, Huang SF. · Department of Pathology, Taipei Municipal Wang-Fang Hospital, Taipei. · Chang Gung Med J. · Pubmed #17596007 links to  free full text

Abstract: Lymphoepithelioma-like carcinomas (LELC) of the liver are rare. Only nine cases have been reported. All of them were considered to be cholangiocarcinoma and the majority were positive for Epstein-Barr virus (EBV) on EBER in situ hybridization. Here we report a case of hepatocellular carcinoma (HCC) mainly composed of LELC. The patient was a 56-year-old man with chronic hepatitis C virus (HCV) infection and cirrhosis. A right-side hepatectomy was performed to remove a 3-cm diameter tumor. Microscopically, the tumor was mainly composed of undifferentiated carcinoma with heavy lymphocytic infiltration, consistent with LELC. The tumor cells of the LELC component were focally positive for HePar 1, CK19 and CK7 and more diffusely positive (50% of tumor cells) for AE1/AE3 on immuno-histochemical study. EBER in situ hybridization was negative. This is the first confirmed case of HCC with an LELC component. In the available literature, all three cases of LELC of the liver that were negative for EBV were associated with chronic viral hepatitis and cirrhosis, suggesting a different carcinogenesis of EBV-positive LELC of the liver.

Liu CJ, Kao JH. · Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, R.O.C. · J Chin Med Assoc. · Pubmed #17475593 links to  free full text

Abstract: Chronic hepatitis B virus (HBV) infection is the primary risk factor for the development of hepatocellular carcinoma worldwide. After decades of chronic hepatitis, about 30-40% of patients progress into liver cirrhosis, and of them, around 1-5% subsequently develop hepatocellular carcinoma (HCC) annually. Since the carcinogenic process involves the interplay between the hepatitis virus and the host hepatocytes, both genomes contribute to the final pathogenic outcome, either individually or synergistically. Studying the genetic factors predisposing hepatocarcinogenesis in both host and viral genomes will help illuminate the critical carcinogenic mechanisms, and create molecular targets for future therapy. In this article, we thus review the epidemiology of HBV-related HCC and viral factors involved in hepatocarcinogenesis.

Chang MH. · Department of Pediatrics, National Taiwan University Hospital, 7F, No 7 Chung-Shan South Road, Taipei 100, Taiwan. · Semin Fetal Neonatal Med. · Pubmed #17336170 No free full text.

Abstract: Hepatitis B virus (HBV) infection is a worldwide health problem and may cause acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC). Infection with HBV in infancy or early childhood may lead to a high rate of persistent infection (25-90%), while the rates are lower if infection occurs during adulthood (5-10%). In most endemic areas, infection occurs mainly during early childhood and mother-to-infant transmission accounts for approximately 50% of the chronic infection cases. Hepatitis B during pregnancy does not increase maternal mortality or morbidity or the risk of fetal complications. Approximately 90% of the infants of HBsAg carrier mothers with positive hepatitis B e-antigen (HBeAg) will become carriers if no immunoprophylaxis is given. Transplacental HBeAg may induce a specific non-responsiveness of helper T cells and HBcAg. Spontaneous HBeAg seroconversion to anti-HBe may develop with time but liver damage may occur during the process of the immune clearance of HBV and HBeAg. Mother-to-infant transmission of HBV from HBeAg negative but HBsAg positive mothers is the most important cause of acute or fulminant hepatitis B in infancy. Although antiviral agents are available to treat and avoid the complications of chronic hepatitis B, prevention of HBV infection is the best way for control. Screening for maternal HBsAg with/without HBeAg, followed by three to four doses of HBV vaccine in infancy and hepatitis B immunoglobulin (HBIG) within 24h of birth is the most effective way to prevent HBV infection. In areas with a low prevalence of HBV infection or with limited resources, omitting maternal screening but giving three doses of HBV vaccine universally in infancy can also produce good protective efficacy. The first universal HBV immunisation programme in the world was launched in Taiwan 22 years ago. HBV infection rates, chronicity rates, incidence of HCC and incidence of fulminant hepatitis in children have been effectively reduced.

Liaw YF. · Liver Research Unit, Chang Gung University, Taipei, Taiwan. · Antivir Ther. · Pubmed #17310811 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is a serious health issue worldwide. The presence of HBV replication markers--hepatitis B e antigen (HBeAg) or HBV DNA--is associated with continuing hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation and development of liver cirrhosis or hepatocellular carcinoma (HCC). Long-term (>10 years) prospective studies in patients >30 years of age have shown that HBeAg seropositivity is associated with increased risk of disease progression, and the risk of cirrhosis and HCC begins to increase at an HBV DNA level of 10(4) copies/ml. Therefore, elimination of HBV, or at least sustained or maintained suppression of HBV, is the key to reducing hepatitis and thereby halting or preventing disease progression. Therapy with interferon-alpha or a direct antiviral agent has been shown to reduce the risk of cirrhosis and prevent further disease worsening. In both the woodchuck hepatitis model and in HBV patients, maintained suppression of HBV replication by a direct antiviral agent may reduce the progression to HCC. However, the efficacy of current antiviral therapy is still far from satisfactory. The ability to achieve a high rate of sustained or maintained HBV suppression with a low risk of drug resistance would be the ultimate goal in the treatment of chronic HBV infection.

Chu CM, Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · J Viral Hepat. · Pubmed #17305879 No free full text.

Abstract: In high endemic areas of hepatitis B virus (HBV) infection, the vast majority of infection is acquired perinatally or during early childhood. The age of the patient is, therefore, almost equivalent to the duration of HBV infection. The natural history of chronic HBV infection consists of three chronological phases: immune tolerance, immune clearance and low replicative phases. The prevalence of hepatitis B e antigen (HBeAg) in asymptomatic HBV carriers is around 90% before 15 years of age, and decreases remarkably to less than 10% after 40 years of age. The immune clearance phase is characterized by a series of hepatitis flares and remissions. These will be followed eventually by HBeAg seroconversion, which is usually accompanied by remission of liver disease and confers favourable outcome. However, patients with persistent HBeAg seropositivity over 40 years of age are associated with a significantly higher risk for progression to cirrhosis than those with HBeAg seroconversion before 40 years of age, and thus should be considered as patients with 'delayed' HBeAg seroconversion. Antiviral or immunomodulatory therapy should be considered seriously for these patients.

Chao M. · Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Tao-yang 333, Taiwan. · Virus Res. · Pubmed #17296240 No free full text.

Abstract: Hepatitis delta virus (HDV) requires the surface antigens of hepatitis B virus (HBV) for packaging and transmission, but replicates its RNA in an HBV-independent fashion. HDV contains a 1.7-kb circular RNA genome that is folded into an unbranched rod-like structure via intramolecular base-pairing, and possesses ribozyme activity. The HDV genome does not encode an RNA-dependent RNA polymerase (RdRp), but is instead replicated by host RNA polymerase(s) via a rolling-circle mechanism. As such, HDV is similar to the viroid plant pathogens. Recent findings suggest that HDV can also undergo template-switching recombination, a well-documented process that has been found in a large number of RdRp-encoding RNA viruses and is thought to affect viral evolution and pathogenesis. This mini-review examines HDV RNA recombination and how it may improve our understanding of the capacities of host RNA polymerases beyond typical DNA-directed transcription, and speculates on the role of host RNA polymerase-directed RNA template-switching in the origin of HDV.

Wang SN, Tsai KB, Lee KT. · Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, USA. · J Clin Pathol. · Pubmed #17071805 No free full text.

Abstract: Hepatic angiomyolipoma (AML), a rare benign mesenchymal tumour, is characterised by the presence of mature adipose tissue, smooth-muscle cells and thick-walled blood vessels. Increasing attention to hepatic AMLs has led to the discovery that sufficient proportions of fat often allow for definite diagnoses preoperatively. However, the proportion of fatty tissue in these tumours is highly variable. One case of hepatic AML is reported, where the amount of fat was <1%. In this case, the viral hepatitis markers, including hepatitis B antigen and anti-hepatitis C virus antibody, were negative. The serum alpha-fetoprotein level was 3.4 ng/ml and in the normal range. Abdominal ultrasonography showed a hypoechoic mass measuring 5 cm in diameter and without an obvious capsule in the left lobe of the liver. A dynamic computed tomography scan showed a well-defined and slightly enhanced mass in the medial segment of the left lobe of the liver. Angiography showed that the mass was hypervascular in character. As hepatocellular carcinoma was highly suspected from these preoperative image studies, a left lobectomy was carried out. Microscopically, the amount of fat was too low to establish a diagnosis of hepatic AML. However, positive homatropine methylbromide 45 immunoreactivity of the smooth-muscle cells seemed to assist in arriving at the diagnosis.

Chang MH. · Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. · Indian J Pediatr. · Pubmed #17006039 No free full text.

Abstract: Due to the lack of proof reading activity of hepatitis B virus (HBV) polymerase, mutation/variation of the viral sequence is frequently found during long term follow-ups. In the majority of children with chronic HBV infection, wild type HBV is the dominant viral strain during the natural course of chronic HBV infection. During long-term follow-up, HBV precore mutants developed spontaneously in approximately 10 to 24% of children before HBeAg seroconversion and in around 50% of children after HBeAg seroconversion mutants. Occasionally, children may be infected primarily by mutant strains of HBV. Approximately 36% of children with fulminant hepatitis and 30% of children with acute hepatitis B were infected by precore mutants of HBV transmitted by their mothers or blood donors. In addition, after universal HBV vaccination, HBV surface gene variants emerge or are selected under the immune pressure generated by the host or by administration of hepatitis B immune globulin and hepatitis B vaccination. In HBV DNA positive children from four sequential surveys in Taiwan, the prevalence of hepatitis B surface gene a determinant mutants increased from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the program. Nucleoside analogue may also induce mutant strains, which reduces the antiviral effects. The most common example is the YMDD mutation of the HBV polymerase gene after antiviral therapy with lamivudine. It developed in 19% of the treated children. In conclusion, children may be infected primarily by mutant strains of HBV either naturally during acute HBV infection. Those infected with wild type HBV initially may develop mutant strains gradually during the course of chronic infection under the host immune pressure. Vaccine escape mutants may develop after immunoprophylaxis. In addition, antiviral therapy with nucleoside analogues may also induce drug resistant mutant strains. Understanding the viral mutation status will help to design accurate strategies of immmunoprophylaxis and antiviral therapy against HBV infection.

Wu JC. · Department of Medical Research and Education, Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taiwan. · Curr Top Microbiol Immunol. · Pubmed #16903226 No free full text.

Abstract: Hepatitis D virus (HDV) infection is one of the important etiologies of fulminant hepatitis and may aggravate the clinical course of chronic HBV infection to cirrhosis and liver failure. HDV was classified into three genotypes. Recent molecular phylogenetic analysis of HDV suggests at least seven major clades. The genotype I HDV is widely spread, genotype II is found in East Asia and genotype III HDV is prevalent in South America. The genomic size is 1682-1685 nucleotides (nt) for genotype II, and 1676 nt for genotype IV (IIb). The divergence in HDV nucleic acid sequences between genotype II and other genotypes varies from 13.8% to 35.3%. The divergences in the HDAg-coding region may range from 17.8% to 29.8% between genotype II and other genotypes. There is no genotypic or size restriction on the interactions of either the small or the large hepatitis delta antigens (HDAgs) between genotypes I and II, and there is also no genotypic incompatibility during co-package of HDAgs of different genotypes into virus like particles. There appears no apparent universal genotypic restriction of the transactivation of genotype I HDV RNA replication by small HDAg of genotype II. In contrast, there appears more genotypic restriction for genotype I small HDAgs to transactivate genotype II HDV RNA replication. Of the functional domains of HDAg, the 19 amino acids at the carboxyl-end of the large HDAg show the greatest divergences (70%-80%) between genotypes I and II. The viral packaging efficiencies of genotype I HDV isolates are usually higher than those of genotype II. The 19 amino acids at the carboxyl-end seem to be the most important determinant for viral packaging efficiencies. The editing efficiencies of the genotype I HDV are also higher than those of the genotype II. Genotype II HDV infection is relatively less frequently associated with fulminant hepatitis at the acute stage and less unfavorable outcomes [cirrhosis or hepatocellular carcinoma (HCC)] at the chronic stage as compared to genotype I. It appears that the clinical manifestations and outcomes of patients with genotype IV (IIb) HDV infection are more like those of patients with genotype II HDV infection. Persistent replication of HBV or HDV was associated with higher adverse outcomes (cirrhosis, HCC or mortality) compared to those who cleared both viruses from the sera. HBV of the genotype C is also a significant factor associated with adverse outcomes (cirrhosis, HCC or mortality) in patients with chronic hepatitis D in addition to genotype I HDV and age. However, most patients with chronic HDV infection have low or undetectable hepatitis B virus DNA levels. During longitudinal follow-up, genotype I HDV is the most important determinant associated with survival.

Huang WH, Chen CW, Wu HL, Chen PJ. · Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, and Hepatitis Research Center, National Taiwan University Hospital, Taipei. · Curr Top Microbiol Immunol. · Pubmed #16903222 No free full text.

Abstract: The hepatitis delta virus (HDV) genome has only one open reading frame, which encodes the viral small delta antigen. After RNA editing, the same open reading frame is extended 19 amino acids at the carboxyl terminus and encodes the large delta antigen. These two viral proteins escort the HDV genome through different cellular compartments for the complicated phases of replication, transcription and, eventually, the formation of progeny virions. To orchestrate these events, the delta antigens have to take distinct cues to traffic to the right compartments and make correct molecular contacts. In eukaryotes, post-translational modification (PTM) is a major mechanism of dictating the multiple functions of a single protein. Multiple PTMs, including phosphorylation, isoprenylation, acetylation, and methylation, have been identified on hepatitis delta antigens. In this chapter we review these PTMs and discuss their functions in regulating and coordinating the life cycle of HDV.

Wang HC, Huang W, Lai MD, Su IJ. · Division of Clinical Research, National Health Research Institutes, National Cheng Kung University College of Medicine, Tainan 704, Taiwan. · Cancer Sci. · Pubmed #16863502 No free full text.

Abstract: Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (DeltaS1-LHBs) and pre-S2 (DeltaS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly DeltaS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.

Chang MH. · Department of Pediatrics, National Taiwan University Hospital, Taipei. · J Clin Virol. · Pubmed #16831693 No free full text.

Abstract: Hepatitis B virus (HBV) infection is highly prevalent in Asia, Africa, southern Europe and Latin America, HBV vaccination has effectively reduced the acute and chronic infection rates as well as related complications in the vaccinated children. The incidence of hepatocellular carcinoma in children has been reduced to approximately 25% of the incidence before the vaccination program, and fulminant hepatitis in children has also been reduced after universal hepatitis B vaccination. HBV DNA sero-positive rate was 98-100% in HBsAg positive vaccinated children, while the positive rate was only 11-20% in those vaccinees with a negative HBsAg but positive anti-HBc reaction. Hepatitis B surface gene mutants in HBV DNA positive children increased gradually from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the vaccination program. Long-term follow-up of vaccinated children has confirmed that universal HBV vaccination in infancy has produced adequate protection up to 14 years of age. The annual decay rate of hepatitis B surface antibody (anti-HBs) was 10.2% in children who did not receive a booster dose. The new HBV infection rate was not different between those who did and those who did not receive a booster dose of HBV vaccine. During a follow-up period of seven years for 1200 vaccinated 7-year-old children in Taiwan, the mean annual hepatitis B core antibody sero-conversion rate was 0.2%. All were negative for HBV DNA. No new chronic HBV infections developed. A booster dose of HBV vaccine is not recommended in children under 15 years of age. Systematic HBV DNA screening of a large population such as blood donors may be instrumental in following the long-term effect of the universal vaccination program on the incidence of silent HBV infection and vaccine escape mutants.

Liu CJ, Chen DS, Chen PJ. · Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei. · J Clin Virol. · Pubmed #16831692 No free full text.

Abstract: Hepatitis B virus (HBV) infection is endemic in many Asian countries. Among many transmission routes, transfusion is the one that should be prevented. The first major success in enhancing transfusion safety came with the implementation of hepatitis B surface antigen (HBsAg) in the early 1970s. However, the studies quoted in this review demonstrate that transmission by blood components negative for HBsAg can still occur in the acute phase of infection during the seronegative window period, or during chronic stages of infection (i.c. "occult" HBV infection, OHB). OHB is defined as the presence of HBV DNA in blood or liver tissues in patients negative for HBsAg, with or without any HBV antibodies. Because of limitations in current blood screening practices, OHB is an overlooked source of HBV transmission. For policy development on screening for HBV infection in blood donors, it would be useful to assess the relative contribution of the above two sources of transfusion-transmitted HBV infection from HBsAg-negative donations. New screening policy should be evaluated on the basis of available data or newly designed studies. While anti-HBc screening can climinate residual risk of occult HBV transmission by transfusion in low-endemic areas, it would not be practical in most parts of the world where the prevalence of anti-HBc is >10% as too many otherwise healthy donors will be ineligible. On the contrary, studies mentioned in this paper indicate that nucleic acid amplification test (NAT) or new HBsAg tests of enhanced sensitivity would be effective in the screening of blood donors for OHB in highly endemic countries. However, the cost-effectiveness of blood screening tests is a major concern in Asia. We therefore have systemically reviewed the literature on prevalence and infectivity of OHB in Asian countries and the possible role of NAT for identifying blood donors in the pre-HBsAg window phase or in later stages of OHB.

Lin CF, Wan SW, Cheng HJ, Lei HY, Lin YS. · Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan. · Viral Immunol. · Pubmed #16817755 No free full text.

Abstract: The pathogenic mechanisms of dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) caused by dengue virus (DV) infection remain unresolved. Patients with DHF/DSS are characterized by several manifestations, including severe thrombocytopenia, vascular leakage, and hepatomegaly. In addition to the effect of virus load and virus variation, abnormal immune responses of the host after DV infection may also account for the progression of DHF/DSS. Actually, viral autoimmunity is involved in the pathogenesis of numerous viral infections, such as human immunodeficiency virus, human hepatitis C virus, human cytomegalovirus, herpes simplex virus, Epstein- Barr virus, and DV. In this review, we discuss the implications of autoimmunity in dengue pathogenesis. Antibodies directed against DV nonstructural protein 1 (NS1) showed cross-reactivity with human platelets and endothelial cells, which lead to platelet and endothelial cell damage and inflammatory activation. Based on these findings, we hypothesize that anti-DV NS1 is involved in the pathogenesis of DF and DHF/DSS, and this may provide important information in dengue vaccine development.

Chien YC, Jan CF, Kuo HS, Chen CJ. · Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan. · Epidemiol Rev. · Pubmed #16782778 No free full text.

Abstract: The national hepatitis B vaccination program in Taiwan is considered one of the most successful and effective public health programs to control chronic hepatitis B infection in the past 20 years. This review illustrates how to implement a successful hepatitis B vaccination program based on Taiwan's experience. Several important controlled randomized clinical trials on hepatitis B immunoglobulin and vaccine in Taiwan demonstrated an 80-90% protective effect among infants of mothers who were positive for either hepatitis B envelope antigen or hepatitis B surface antigen. A series of prevalence surveys on children born before and after the national vaccination program began disclosed a steady decrease in seroprevalence of hepatitis B surface antigen in Taiwan, with 78-87% effectiveness after the national vaccination program was launched. Studies on the secular trend of liver disease risk also documented a 68% decline in mortality from fulminant hepatitis in infants and a 75% decrease in the incidence of hepatocellular carcinoma in children 6-9 years of age after the national vaccination program began. In conclusion, since 1984, the national hepatitis B vaccination program has been successful in preventing acute and chronic liver diseases in Taiwan.

Lo SJ, Lee CC, Lai HJ. · Department of Life Science, Graduate Institute of Basic Medical Science, 259, Wen-Hwa 1st Road, Chang Gung University, TaoYuan 333. · Cell Res. · Pubmed #16775624 links to  free full text

Abstract: The nucleolus is the most prominent compartment in the nucleus and known as the site for ribosome biogenesis in eucaryotes. In contrast, there is no such equivalent structure for ribosome synthesis in procaryotes. This raises two concerns that how does the nucleolus evolve and that whether the nucleolus remains playing a single role in ribosome biogenesis along the evolution. Increasing data support new nucleolus functions, including signal recognition particle assembly, small RNA modification, telomerase maturation, cell-cycle and aging control, and cell stress sensor. Multiple functions of the nucleolus possibly result from the plurifunctionality of nucleolar proteins, such as nucleolin and Nopp140. Proteomic analyses of human and Arabidopsis nucleolus lead a remarkable progress in understanding the evolution and new functions of nucleoli. In this review, we present a brief history of nucleolus research and new concepts and unresolved questions. Also, we introduce hepatitis D virus for studying the communication between the nucleolus and other subnuclear compartments, and Caenorhabditis elegans for the role of nucleolus in the development and the epistatic control of nucleologenesis.

Shen LJ, Shen WC. · School of Pharmacy, College of Medicine, National Taiwan University, 12F 1 Ren-Ai Road, Sec 1, Taipei 100, Taiwan. · Curr Opin Mol Ther. · Pubmed #16774044 No free full text.

Abstract: Pheonix is developing ADI-PEG-20, a PEGylated arginine deiminase for the potential treatment of hepatocellular carcinoma, for which the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products have granted the drug Orphan Drug status, and melanoma, for which the FDA has also awarded ADI-PEG-20 Orphan Drug status. ADI-PEG-20 is also being investigated for the potential treatment of influenza virus infection and hepatitis C virus infection.

Huang CF, Lin SS, Ho YC, Chen FL, Yang CC. · Department of Biological Science and Technology, I-Shou University, Kaoshiung, Taiwan. · Cell Mol Immunol. · Pubmed #16696896 links to  free full text

Abstract: Hepatitis B virus (HBV) infection occurs primarily in hepatocytes in the liver with release of infectious virions and non-infectious empty surface antigen particles into the bloodstream. HBV replication is non-cytopathic. Transient infections run a course of several months, and chronic infections are often life-long. Chronic infections can lead to liver failure with cirrhosis and hepatocellular carcinoma. It is generally accepted that neutralizing anti-HBs antibodies plays a key role in recovery from HBV infection by containing the spread of infection in the infected host and facilitating the removal and destruction of viral particles. However, the immune response initiated by the T-cell response to viral antigens is also important for viral clearance and disease pathogenesis in HBV infection. The three structural forms of the viral proteins, the HBsAg, the particulate HBcAg, and the nonparticulate HBeAg, may preferentially elicit different Th cell subsets. The different IgG subclass profiles of anti-HBs, anti-HBc, and anti-HBe in different HBV infection status were revealed. Moreover, the different IgG subclass profiles in chronic carriers did not change with different ALT and AST levels and may reflect the difference between stimulating antigens, immune response, and the stages of viral disease and provide the basis for the use of vaccines and prophylactic treatments for individuals at high risk of human HBV infection. This review elucidates the detailed understanding of the immune responses induced during transient and persistent infection, and the development of immunotherapy and immunodiagnosis in patients with HBV infection, and possible means of reducing the liver damage.

Chu CM, Liaw YF. · Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan. · Semin Liver Dis. · Pubmed #16673292 No free full text.

Abstract: In patients with compensated hepatitis B virus (HBV) cirrhosis, active viral replication correlates significantly with the risk of hepatic flare, decompensation, and the development of hepatocellular carcinoma (HCC). The 5-year survival of patients with compensated cirrhosis was reported to be 80 to 85%, and is significantly lower in patients with replicative HBV. Both interferon and maintenance lamivudine therapy have been shown to reduce the risk of decompensation or HCC and prolong survival in responders. A finite course of interferon is recommended as the first-line agent. For patients who had a contraindication for or who have failed interferon therapy, direct antiviral(s) can be considered for long-term treatment. Once decompensation occurs, mortality increases remarkably. Early treatment with nucleoside analogues should be instituted. Lamivudine therapy is associated with rapid viral suppression, improvement in Child-Pugh scores, and improved survival, but drug resistance is a major problem and is associated directly with a poor clinical outcome. Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance.

Hwang LH. · Hepatitis Research Center, National Taiwan University Hospital and Graduate Institute of Microbiology, National Taiwan University College of Medicine, 7 Chung-Shan S. Road, Taipei 10016, Taiwan, R.O.C. · J Biomed Sci. · Pubmed #16633742 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. Effective therapy to this cancer is currently lacking, creating an urgent need for new therapeutic strategies for HCC. Gene therapy approach that relies on the transduction of cells with genetic materials, such as apoptotic genes, suicide genes, genes coding for antiangiogenic factors or immunomodulatory molecules, small interfering RNA (siRNA), or oncolytic viral vectors, may provide a promising strategy. The aforementioned strategies have been largely evaluated in the animal models with HCC or liver metastasis. Due to the diversity of vectors and therapeutic genes, being used alone or in combination, gene therapy approach may generate great beneficial effects to control the growth of tumors within the liver.

Tsai CH, Lee PY, Stollar V, Li ML. · Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan. · Curr Pharm Des. · Pubmed #16611119 No free full text.

Abstract: Viral DNA and RNA polymerases are enzymes, which are responsible for copying the genetic materials of viruses and are therefore central components in the life cycles of viruses. The polymerases are essentially required for the replication of viruses. The reverse transcriptase (RT) of the retroviruses and the hepadnaviruses is the sole viral enzyme required for the synthesis of DNA from viral RNA. Viral polymerases are therefore an extremely favorable target for the development of antiviral therapy. The success of anti-HIV-1 therapy using inhibitors specifically targeting HIV RT suggests that other viral polymerases can be the valid molecular targets for the design of antiviral drugs. Intensive structural and functional studies of viral polymerases have been conducted and have opened new avenues for the development of more effective antiviral therapy. This review summarizes the insights gained from recent structural and functional studies of antiviral agents, which target viral polymerases. The primary focus will be on hepatitis C virus (HCV), herpesviruses, HIV, hepatitis B virus (HBV) and influenza virus.

Liu CJ, Liou JM, Chen DS, Chen PJ. · Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. · J Formos Med Assoc. · Pubmed #16496056 No free full text.

Abstract: In areas where hepatitis B virus (HBV) infection is endemic such as Southeast Asia, the Far East and southern Europe, a substantial number of patients are infected with both hepatitis C and B. Moreover, patients who are dually infected with hepatitis C virus (HCV) and HBV have been reported to carry a significantly higher risk of developing fulminant hepatic failure, liver cirrhosis and hepatocellular carcinoma than those with HCV or HBV infection alone. Such dually infected patients need careful medical attention and effective treatment. Dually infected hepatitis patients can be classified into 2 groups according to the dominant viral activity: the first in which hepatitis C dominates over hepatitis B (hepatitis C/B) and the second in which hepatitis B dominates over hepatitis C (hepatitis B/C). Their natural histories may differ and require distinct treatments. For hepatitis C/B, conventional interferon (IFN) alone has not been shown to be effective in the clearance of HCV RNA. IFN in combination with ribavirin for 6 months has been used to treat hepatitis C/B patients in a few pilot studies and a sustained HCV clearance rate could be achieved to an extent comparable to that in simple hepatitis C. Nevertheless, the treatment outcomes in those infected with HCV genotype 1 remain unsatisfactory. Systematic trials of treatment for hepatitis B/C patients have not yet been reported. In this article, we review recent updates in the natural history and treatment of dual HBV and HCV infections, and draw attention to several unresolved issues requiring further study. These efforts may culminate in better treatment for patients co-infected with HCV and HBV.

Liaw YF. · Liner Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · J Clin Virol. · Pubmed #16461216 No free full text.

Abstract: Lamivudine and adefovir have potent inhibitory effects on hepatitis B virus (HBV) replication. Although short-term therapy is feasible in a selected subgroup of patients, prolonged therapy is required for sustained suppression in the majority of patients. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rtM204 I/V) conferring resistance to lamivudine may emerge after 9-10 months therapy. The incidence increases with duration of therapy up to 70% after 5 years lamivudine therapy. Serum alanine aminotransferase (ALT) elevation and HBV DNA rebound ( I log) occur in >90% of the patients with rtM204 I/V during continued lamivudine therapy. Marked flare of serum ALT may occur, sometimes severe, and may be complicated with decompensation or even fatality. The initial clinical and histologic improvement may also reverse after emergence of rtM204 IN Studies do suggest that stopping seems better than continuing lamivudine therapy. Limited data show that interferon therapy seems ineffective. Add-on adefovir therapy is effective in suppressing rtM204 I/V in both compensated and decompensated patients. Switching to adefovir monotherapy is effective and safe even in cirrhotic patients with decompensation. The overall incidence of adefovirresistant rtN236T and A181V is low, being 0 after one year and 5.9% after 3 years' therapy. The impact of adefovir resistance is less clear but is responsive to lamivudine therapy. In conclusion, monitoring of viral breakthrough to start effective intervention is mandatory during direct antiviral therapy.

Hsieh YC, Wu TZ, Liu DP, Shao PL, Chang LY, Lu CY, Lee CY, Huang FY, Huang LM. · Section of Infection, Department of Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C. · J Formos Med Assoc. · Pubmed #16440064 links to  free full text

Abstract: Influenza A virus is well known for its capability for genetic changes either through antigen drift or antigen shift. Antigen shift is derived from reassortment of gene segments between viruses, and may result in an antigenically novel virus that is capable of causing a worldwide pandemic. As we trace backwards through the history of influenza pandemics, a repeating pattern can be observed, namely, a limited wave in the first year followed by global spread in the following year. In the 20th century alone, there were three overwhelming pandemics, in 1918, 1957 and 1968, caused by H1N1 (Spanish flu), H2N2 (Asian flu) and H3N2 (Hong Kong flu), respectively. In 1957 and 1968, excess mortality was noted in infants, the elderly and persons with chronic diseases, similar to what occurred during interpandemic periods. In 1918, there was one distinct peak of excess death in young adults aged between 20 and 40 years old; leukopenia and hemorrhage were prominent features. Acute pulmonary edema and hemorrhagic pneumonia contributed to rapidly lethal outcome in young adults. Autopsies disclosed multiple-organ involvement, including pericarditis, myocarditis, hepatitis and splenomegaly. These findings are, in part, consistent with clinical manifestations of human infection with avian influenza A H5N1 virus, in which reactive hemophagocytic syndrome was a characteristic pathologic finding that accounted for pancytopenia, abnormal liver function and multiple organ failure. All the elements of an impending pandemic are in place. Unless effective measures are implemented, we will likely observe a pandemic in the coming seasons. Host immune response plays a crucial role in disease caused by newly emerged influenza virus, such as the 1918 pandemic strain and the recent avian H5N1 strain. Sustained activation of lymphocytes and macrophages after infection results in massive cytokine response, thus leading to severe systemic inflammation. Further investigations into how the virus interacts with the host's immune system will be helpful in guiding future therapeutic strategies in facing influenza pandemics.