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To prospectively develop and evaluate the accuracy of a duplex Doppler ultrasonographic (US) index for predicting the presence or absence of esophageal varices in patients with compensated cirrhosis (Child-Pugh class A) by using endoscopy as the reference standard.The study had institutional review board approval; all participants gave informed consent. Data in a total of 383 prospectively enrolled patients who underwent duplex Doppler US and screening endoscopy were divided into training (n = 240) and validation (n = 143) sets. Duplex Doppler US indexes, including mean portal vein velocity (PVV), hepatic impedance indexes, splenic impedance indexes, and the splenic index were evaluated with univariate and multivariate logistic regression analyses to find the independent factors predictive of the presence of esophageal varices. Receiver operating characteristic (ROC) curves were constructed for these factors to evaluate diagnostic accuracy in the training set and reproducibility in the validation set.Multivariate logistic regression analysis showed that splenic index and mean PVV were predictive of the presence of esophageal varices in the training set. A splenoportal index (SPI) was calculated as the splenic index divided by mean PVV to amplify the opposite effects on esophageal varices. Areas under ROC curves for SPI were significantly higher than those for the splenic index (0.93 vs 0.90, P = .02) and mean PVV (0.93 vs 0.67, P.001) in the training set and in the validation set (0.96 vs 0.91 for splenic index, P = .01; 0.93 vs 0.80 for mean PVV, P.001). An SPI threshold of 3.0 had 92% sensitivity, 93% specificity, 91% positive predictive value, and 94% negative predictive value for esophageal varices. Applying this cutoff value correctly predicted the presence or absence of esophageal varices in 92% of the patients without screening endoscopy.SPI can serve as a useful noninvasive index to predict the presence or absence of esophageal varices.

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg-positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non-responders at the end of treatment and 6 months post-treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine-naive patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non-seroconverters. Conclusions: For lamivudine-treated HBeAg-positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.

Background. Whether hepatitis B (HB) vaccine– conferred immunity persists into adulthood is unknown. We aimed to investigate long-term HB immunity in adolescents. Methods. In 2004 –2005, 6156 high school students (15–21 years old) who had been vaccinated with plasmaderived HB vaccine as infants were recruited for HB seromarker screening. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. HB surface antibody (anti-HBs) titers and levels of HB surface antigen (HBsAg)–specific interferon (IFN)–– or interleukin (IL)–5–secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. Results. Although the vaccine remained highly efficacious in reducing the HBsAg positivity rate, 63.0% of the vaccinees had no protective anti-HBs. After the booster, anti-HBs remained undetectable in 28.7% (158/551) of the subjects who had received complete HB vaccination (4 doses) during infancy. We estimated that 10.1% of the total population had lost their HB vaccine– conferred booster response. HBsAg-specific IFN-– or IL-5–secreting PBMCs remained negative in 27.2% (25/92) of subjects after the booster. Conclusions. A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15–18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run.

Background and Aim: Chronic viral infections such as human immunodeficiency virus and hepatitis C virus (HCV) may decrease tissue response to insulin, thereby causing insulin resistance. In addition, insulin resistance is associated with hepatic steatosis. However, whether these phenomena hold true for chronic hepatitis B virus (HBV) infection remains largely unknown. The present study therefore aimed to investigate the association of chronic HBV infection with insulin resistance and hepatic steatosis. Methods: A total of 507 subjects (243 men and 264 women; mean age 46.56 years) less than 60 years-old attending a health examination center were enrolled in the study. All the subjects were negative for antibodies against HCV and consumed less than 140 g alcohol/week. Demographic, anthropometric, clinical, and laboratory data were obtained from each subject. Insulin resistance index was determined using homeostasis model assessment (HOMA-IR). Hepatic steatosis was identified by ultrasound examination. Results: Of the 507 subjects, 50 (9.9%) were positive for hepatitis B surface antigen (HBsAg) and designated HBV carriers. All variables were comparable between HBV carriers and non-HBV carriers, except that HBV carriers had significantly higher serum alanine aminotransferase and aspartate aminotransferase levels (P

The clinical implications of metabolic profiles in patients with chronic hepatitis C remain controversial. To study the association of metabolic abnormalities with chronic hepatitis C, we conducted a case-control study with special emphasis on serum lipid pattern, fasting blood glucose, and adiponectin.We enrolled 500 patients with chronic hepatitis C and 536 sex and age-matched controls. Unadjusted and adjusted associations of demographic and metabolic variables were estimated.Chronic hepatitis C patients had higher alanine aminotransferase (ALT) and high-density lipoprotein-cholesterol levels, but lower total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol levels than controls. Stratifying ALT level according to its upper limit of normal, HCV infection was associated with younger age, female gender, and higher TC levels in chronic hepatitis C patients with normal ALT levels, but with lower TC and lower TG levels in those with abnormal ALT levels. By using multiple linear regression analyses for subjects with available adiponectin data, presence of HCV infection was independently associated with higher serum adiponectin levels.Metabolic profiles of chronic hepatitis C patients are affected by age, gender, serum adiponectin, and ALT levels. Further longitudinal studies are needed to clarify the complex interplay between HCV infection and metabolic profiles.

Hepatitis B virus (HBV) infection is the major cause of cirrhosis and hepatocellular carcinoma worldwide. Based on virus-host interactions, the natural history of HBV carriers can be divided into four phases. In the prolonged immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication but minimal liver disease. Early termination of immune tolerance and subsequent HBeAg seroconversion usually confer a favorable outcome, whereas delayed HBeAg seroconversion may accelerate the progression of liver disease. In recent years, viral and host factors such as the rapid decline of serum HBV DNA level, HBV genotype, possible naturally occurring mutants, and specific HLA haplotypes have been shown to affect the loss of immune tolerance in chronic hepatitis B. HBV carriers with an immune tolerant phenotype may be defined as having HBeAg positivity, persistently low-normal serum alanine aminotransferase, and serum HBV DNA greater than 2 × 107 IU/mL. These patients should be monitored; many have a rapid transition to an inactive carrier state with favorable outcomes.

Taiwan began a universal hepatitis B virus (HBV) vaccination program for infants in July 1984. The seroprevalence of hepatitis B surface antigen (HBsAg) decreased from 9.8% before the vaccination program to less than 1% by 25 years afterward. We continued to monitor HBV infections in this population.We conducted a series of serologic and epidemiologic surveys in the Taipei metropolitan area every 5 years from 1984 through 2014. From January 1 through December 31 of 2014, we collected serum samples from 4605 apparently healthy individuals (ages: 287 were3 y, 405 were 3-6 y, 675 were 7-12 y, 686 were 13-18 y, 468 were 18-22 y, and 2084 were 22-50 y). All subjects were tested for HBsAg, its antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). We performed genotype and viral load analyses for patients who tested positive for anti-HBc.Of vaccinated participants (age,30 y; n = 3299), 0.5% tested positive for HBsAg, 47.4% tested positive for anti-HBs, and 4.5% tested positive for anti-HBc. Of unvaccinated participants (age, 30-50 y, n = 1306), 6.7% tested positive for HBsAg (P.0001), 69.4% tested positive for anti-HBs, and 44.1% tested positive for anti-HBc. One occult HBV infection was found in each age group. Among subjects positive for HBsAg younger than age 30, 77% were born to mothers positive for HBsAg.Based on a series of serologic and epidemiologic surveys performed in the Taipei metropolitan area, 6.7% of persons born before the universal HBV vaccination program were positive for HBsAg, compared with 0.5% of those born afterward. Most subjects positive for HBsAg younger than age 30 were born to mothers positive for HBsAg.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Background and Aims: Although insulin resistance affects liver fibrosis progression and treatment response in chronic hepatitis C (CHC), the relationship between chronic hepatitis C virus (HCV) infection and insulin resistance (IR) remains to be firmly established. We thus studied the impact of host, metabolic and viral factors on IR in CHC patients. Methods: A total of 162 CHC patients with complete clinical data were enrolled. Among them, 94 received histological examinations. Quantitative HCV RNA was assayed by a real-time polymerase chain reaction (PCR) assay. Genotyping was performed by reverse transcription PCR with type-specific primers. The pretreatment IR index was determined using homeostasis model assessment (HOMA), and an index value of more than 2.4 was designated IR. Unadjusted and adjusted association of the HCV RNA level and IR was further analysed. Results: In multivariate linear regression analysis, a dose‐ response relationship was observed between the log10HCV RNA level and the presence of IR. IR was positively correlated with body mass index, triglyceride, HCV RNA and alanine aminotransferase levels, but negatively correlated with adiponectin level. Subgroup analysis stratified by HCV genotype showed that there was a trend towards a higher HOMR-IR index value and lower adiponectin levels in genotype 1 patients. Histological analysis showed that IR was positively associated with the severity of hepatic steatosis. Conclusions: Our data indicate that higher HCV RNA levels are associated with the presence of IR in CHC patients. Further studies are needed to clarify the interplays between HCV infection, IR and adiponectin in an attempt to develop new adjuvant therapy for CHC.

Background: Hepatitis B virus (HBV) genotype C (HBV/C) has two subgenotypes: HBV/Cs and Ce. The prevalence and clinical implications of subgenotype Cs and Ce in Taiwanese HBV carriers remain unknown. Methods: Subgenotypes of HBV/C were determined in 242 Taiwanese HBV carriers with various stages of liver disease. The clinical as well as virologic features between patients with HBV/Cs and HBV/Ce infection were further compared. Results: HBV/Ce was the predominant subgenotype in Taiwan. The prevalence of HBV/Ce was 93.6% in the inactive carriers group, 84.2% in chronic hepatitis patients, 81.2% in cirrhosis patients, 92.5% in hepatocellular carcinoma (HCC) patients without cirrhosis and 91.9% in HCC patients with cirrhosis. There was no significant difference in the distribution of the HBV/C subgenotypes among patients with different stages of liver disease. Conclusions: Subgenotypes of HBV/C may not have a clinical impact on the disease progression of chronic hepatitis B in Taiwan.

Hepatocellular carcinoma (HCC) is common in Taiwan. The age-adjusted incidence rates have been increasing, from approxiimately 15/100 000 in the 1980s to approximately 30/100 000 recently. The main causes are chronic hepatitis B and C infections, with >90% of patients positive for hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV). Before 1990, approximately 80% of patients with HCC were positive for HBsAg. The infection is mainly from perinatal mother-to-infant transmission. HCV is the second important cause, accounting for approximately 70% of HBsAg negative patients. Overall, 5-10% patients have infections of both viruses. In HBsAg negative-anti-HCV negative patients, polymerase chain reaction assay still reveals the key role of HBV. Epidemiologic studies also reveal the important role of HBV. In a nested case-control study, cumulative incidence of HCC was 10% after nine years of follow-up in hepatitis B e-antigen (HBeAg) positive carriers, with a relative risk of 60.2 compared to 9.6 in HBeAg negative carriers. The role of high viral load was confirmed when another community-based prospective study of 3644 HBsAg carriers stratified by serum hepatitis B virus (HBV) DNA levels correlated well with the occurrence of HCC, especially in carriers with levels >10(5) copies/mL. Genotype C infection contributed more to hepatocarcinogenesis than genotype B. Although HBV is dominant in causing HCC, in the last two decades the relative importance of HCV has changed. The proportion of anti-HCV positive cases has increased. In some areas of southern Taiwan where HCV infection is rampant, HCV-associated HCC have surpassed HBV-associated cases. To control hepatitis B, a mass neonatal vaccination program against hepatitis B was launched in 1984. The HBsAg carrier rate decreased from the historical 15-20% to < 1% after vaccination. Most importantly, annual incidence of childhood HCC has decreased from 0.67 to 0.19/100 000 children. To control hepatitis C, besides interrupting the transmission routes and screening blood donors with anti-HCV, treatment with interferon and ribavirin was implemented on a national basis in 2003. Through these efforts, virally-induced HCC will be controlled in 20-30 years, and a decrease of approximately 85% is anticipated by 2040. Then, HCC will not be commonly seen in Taiwanese people, and the major cause of HCC will be non-viral factors that lead to cirrhosis, such as non-alcoholic steatohepatitis.

BACKGROUND Ribavirin's mechanism of action in the treatment of chronic hepatitis C remains to be clarified. Double-stranded RNA-activated protein kinase (PKR) plays a role in cell defense against virus infection. This study investigated whether PKR is a mediator of the effectiveness of ribavirin, used either alone or in combination with interferon (IFN)- alpha , against hepatitis C virus (HCV) infection. METHODS Primary human hepatocytes and HCV-replicon cells were treated with ribavirin and/or IFN- alpha . PKR activity was assayed by immunoblotting. A pulse-chase assay of the half-life of PKR protein was performed to study whether ribavirin decreases PKR degradation. We used small-interference RNA (siRNA) to knock down PKR to assess its importance in the suppression of HCV-RNA replication in the replicon system. RESULTS Ribavirin was able to up-regulate the levels of phosphorylated PKR and phosphorylated eIF2 alpha , leading to suppression of HCV-RNA replication. The effects that treatment with ribavirin plus IFN- alpha had on PKR activity were greater than those observed for treatment with either ribavirin alone or IFN- alpha alone. Knockdown of PKR increased HCV-RNA replication, supporting the importance of PKR in the control of HCV-RNA replication. The pulse-chase experiment showed that ribavirin can reduce the degradation rate of PKR protein. CONCLUSION These results suggest that the anti-HCV action of ribavirin is partly attributable to its ability to up-regulate PKR activity.

Partial hepatectomy or carbon tetrachloride (CCl4) injury, following treatment of rats with 2-acetylaminofluorene (2-AAF) to inhibit proliferation of hepatocytes, induces proliferation of oval cells and possibly their differentiation into nodular foci of hepatocytes when higher doses of 2-AAF are used. Unfortunately, immunohistochemistry in previous studies failed to show oval cell markers in these foci, and thereby to demonstrate the precursor-product relationship between oval cells and hepatocytes. Immunohistochemistry on livers of rats treated with high dose 2-AAF/CCl4 was used. We found 7.6% of the hepatocyte foci were positive for an oval cell marker cytokeratin 19 (CK-19). These foci were positive for alpha-fetoprotein, less positive for carbamoylphosphate synthetase 1, and more positive for laminin in the basement membrane lining. Rarely present transitional foci had weaker expression of CK-19 and discontinuous laminin. Focal hepatocyte differentiation of oval cells was characterized by cell hypertrophy, membranous CK-19, and positive hepatocyte nuclear factor 4 (HNF-4). HNF-4+ small oval cells surrounding CK-19+ foci were frequently seen, suggesting that a paracrine mechanism(s) may be responsible for the enlargement of CK-19+ foci. In conclusions, oval cells appear to differentiate to CK-19+ foci and then to CK-19- foci in the high dose 2-AAF/CCl4 model.

This article shortly illustrates about Taiwan as a clinical trial center of excellence in the Asia Pacific.

Background & Aims: Following the world’s first successful implementation of a universal hepatitis B virus (HBV) vaccination program for infants in Taiwan 20 years ago, we performed this study to evaluate the long-term protection afforded by HBV vaccination and to rationalize further prevention strategies. Methods: HBV seromarkers, including hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc), were studied in 18,779 subjects from neonates to adults below 30 years of age in 2004. The birth cohort effect was evaluated by comparing the results of the same birth cohorts at different ages among this survey and the previous 1984, 1989, 1994, and 1999 surveys. Results: The seropositive rates for HBsAg, anti-HBs, and antiHBc were 1.2%, 50.5%, and 3.7%, respectively, in those born after the vaccination program (

Advanced age and high hepatitis B virus (HBV) DNA level are risk factors associated with the development of HBV-related hepatocellular carcinoma (HCC). However, little is known about the role of viral load in the carcinogenesis of HCC in young people. A total of 183 HBV-related HCC patients and 202 HBV carriers were therefore enrolled to compare serum viral loads in young (/=40 years of age) and old (40 years of age) age groups. Other factors associated with the development of HCC were also analysed. The results showed that serum alanine aminotransferase (38.7 +/- 24.1 vs 58.4 +/- 65.4 IU/L, P = 0.006) and HBV DNA levels (log(10) titre: 4.20 +/- 1.33 vs 4.80 +/- 1.39, P = 0.053) were lower in young HCC patients than in old HCC patients. There was a positive correlation between age and serum HBV DNA level in HCC patients but a negative correlation in HBV carriers. Young HCC patients with HBV genotype B infection had higher viral loads than those with genotype C infection (log(10) titre: 4.79 +/- 1.34 vs 3.27 +/- 0.60, P = 0.001). By multivariate logistic regression analyses, high serum HBV DNA level was associated with the development of HCC in old patients [odds ratio (OR) 1.584, 95% confidence interval (CI) 1.075-2.333] rather than in young patients (OR 0.848, 95% CI 0.645-1.116). In conclusion, viral factors in association with the development of HBV-related HCC in young patients may be different from their old counterparts. The complicated interplay between host and virus could be responsible for the emergence and aggressive outcome of early-onset HCC.

Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBV-related HCC is the male predominance, with a male to female ratio of 5–7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.

Clinical and pathogenic differences exist between hepatitis B viral (HBV) genotypes B and C, and genotype C has a higher risk of hepatocellular carcinoma (HCC) development than genotype B. The aim of this study was to investigate whether HBV genotypes B and C influence the clinicopathological features of patients with resectable HCC. Stored serum samples from 193 patients with resectable HBV-related HCC were tested for HBV genotypes by a molecular method. Of 193 patients undergoing resection of HCC, 107 (55%) and 86 (45%) were infected with genotypes B and C, respectively. Compared with genotype C patients, genotype B patients were less likely to be associated with liver cirrhosis (33%vs 51%, P = 0.01). Pathologically, genotype B patients had a higher rate of solitary tumour (94%vs 86%, P = 0.048) and more satellite nodules (22%vs 12%, P = 0.05) than genotype C patients. Our results indicate that genotype B-related HCC is less associated with liver cirrhosis and has a higher frequency of solitary tumour as well as more satellite nodules than genotype C-related HCC. These characteristics may contribute to the recurrence patterns and prognosis of HBV-related HCC in patients with genotype B or C infection.

The epidemiology and impact of occult HBV infection in intravenous drug users remain largely unknown. The aim of the study was to investigate the prevalence of occult HBV infection among intravenous drug users in Taiwan. Molecular assays were used to determine the level of serum HBV DNA and the genotype in 304 intravenous drug users negative for both HBsAg and anti-HCV. Of 304 intravenous drug users, 125 (41.1%) were positive for serum HBV DNA. The genotype distribution of HBV was as follows: B, 55 (44%); C, 29 (23%); and mixed B and C infections, 41 (33%). The mean and median serum HBV DNA levels in 125 intravenous drug users with occult HBV infection were 4.0 +/- 0.6 and 4.0 log(10) copies/ml, respectively. The mean serum HBV DNA level in carriers with mixed genotype B and C infections was significantly higher than those infected with HBV genotype B or genotype C alone (mean, 4.2 +/- 0.6 log(10) vs. 3.9 +/- 0.5 log(10), and 3.9 +/- 0.7 log(10) copies/ml, P = 0.01 and 0.05, respectively). The amino acid sequence determination of HBV surface gene in 20 intravenous drug users with occult HBV infection selected at random showed no mutation of amino acid at codon 145. In conclusion, the prevalence of occult HBV infection and mixed HBV genotype infections are not uncommon in intravenous drug users residing in an HBV endemic areas. In addition, intravenous drug users with occult mixed genotype B and C infections have significantly higher viral loads than those with occult infection of single HBV genotype.

Objectives: Early hepatitis C viral (HCV) kinetics following pegylated interferon-α (PEG-IFN) and ribavirin help to assess treatment in the Western world. Whether this functions in Taiwanese patients remains unknown. Studying the early HCV kinetics in Taiwanese patients may clarify this issue. Methods: Six chronic hepatitis C patients were enrolled. A PEG-IFN-α dose was administered at week 1, then it was administered weekly with daily ribavirin for 24 weeks. Serum HCV RNA levels were determined frequently during the trial and qualitatively at week 49. Kinetic parameters Ε (effectiveness at inhibiting viral production)and δ (loss rate of infected cells) were estimated from viral loads and alanine aminotransferase (ALT) kinetics, respectively. Results: All serum HCV RNA levels became undetectable at week 12. The Ε ranged from 0.4128 to 0.9904 and δ from 0.0019 to 0.1245. The log values of viral load differences between day 7 and 14 ranged from 0.15 to 1.21. Only 1 patient had an abnormal ALT level at week 49. Conclusions: Viral kinetic parameters in Taiwanese patients were similar to those in Western studies. However, the early viral decline pattern and viral negativity rate in Taiwanese patients might be different from Caucasian patients. Further large-scale studies to clarify this issue are ongoing.

Data are limited on the effectiveness and safety of peginterferon plus ribavirin in HIV-infected Asian patients with acute or chronic HCV infection. HIV-infected Taiwanese patients with acute HCV infection received peginterferon plus weight-based ribavirin for 24 weeks (n = 24) and those with chronic HCV genotype 1 or 6 (HCV-1/6) and HCV genotype 2 or 3 (HCV-2/3) infection received response-guided therapy for 12–72 and 24–48 weeks, respectively (n = 92). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks off-therapy. The SVR rates were 83% and 72% in patients with acute and chronic HCV infection (p = 0.30) and 68% and 72% in patients with chronic HCV-1/6 and HCV-2/3 infection (p = 0.48), respectively. While no factors predicted SVR in acute HCV and chronic HCV-2/3 infection, age (odds ratio [OR] per 1-year increase: 0.88, 95% confidence interval [CI]: 0.78–0.99, p = 0.04), HCV RNA (OR per 1-log10 increase: 0.18, 95% CI: 0.03–0.98, p = 0.03), IL28B genotype (OR: 5.52, 95% CI: 1.55–12.2, p = 0.02) and RVR (OR: 9.62, 95% CI: 3.89–15.3, p = 0.007) predicted SVR in chronic HCV-1/6 infection. In conclusion, the SVR rates of peginterferon plus ribavirin for 24 weeks and for response-guided 12–72 weeks are satisfactory in HIV-infected Taiwanese patients with acute and chronic HCV infection.

The impact of ribavirin (RBV) dosage on sustained virologic response (SVR) rates remains elusive in hepatitis C virus genotype 2 (HCV-2) rapid responders receiving 16 weeks of peginterferon (Peg-IFN) plus RBV. Treatment-naïve HCV-2 patients with rapid virologic response (RVR) received Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000 or 1,200 mg/day; cut-off body weight: 75 kg) for 6 weeks and then randomly received Peg-IFN alfa-2a 180 μg/week plus weight-based (1,000 or 1,200 mg/day; n = 247) or flat-dose (800 mg/day; n = 246) RBV for additional 10 weeks. The primary endpoint was SVR24. Patients receiving weight-based and flat-dose RBV therapies had comparable SVR24 rates (93.5% versus 91.9%, P = 0.49). The risk differences (RDs) of SVR24 receiving weight-based and flat-dose RBV arms were 7.1% [95% CI: 0.7% to 13.6%] in males and −5.8% [95% CI: −12.1% to 0.5%] in females (interaction P = 0.01). The SVR24 rate was higher in males receiving ≥13 mg/kg/day than those receiving P = 0.001). In conclusion, Peg-IFN alfa-2a plus weight-based or flat-dose RBV for 16 weeks provides comparable SVR24 rates in treatment-naïve HCV-2 rapid responders. However, males should receive weight-based RBV to achieve a high SVR24 rate.

Hepatitis C virus genotype 2 (HCV-2) slow responders poorly respond to 24 weeks of peginterferon (Peg-IFN) plus ribavirin (RBV). We evaluated the efficacy of extended 48-week regimen and the role of interleukin-28B (IL-28B) genotype in this clinical setting. Treatment-naïve HCV-2 patients not achieving rapid virologic response (RVR) by Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000–1,200 mg/day, cutoff body weight of 75 kg) were randomly assigned to receive a total duration of 48 (n = 94) or 24 (n = 93) weeks of therapy. The primary endpoint was sustained virologic response (SVR). Baseline patient characteristics to predict SVR were analyzed. Patients receiving 48 weeks of treatment had a greater SVR rate than those receiving 24 weeks of treatment (70.2% versus 46.2%, P = 0.001). Compared to patients treated for 24 weeks, the SVR rate in those treated for 48 weeks increased by 10.9% [95% CI: −5.9% to 27.7%] and 65.6% [95% CI: 44.5% to 86.7%] if they had IL-28B rs8099917 TT genotype and GT/GG genotype, respectively (interaction P = 0.002). In conclusion, 48-week treatment with Peg-IFN plus weight-based RBV provides a greater SVR rate than 24-week treatment in treatment-naïve HCV-2 patients with unfavorable IL-28B genotypes who fail to achieve RVR.

Summary Background The impact of diabetes for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients remains controversial. Aim To investigate the risk of HCC in CHC patients who develop new onset diabetes. Methods We conducted a nation-wide cohort study by using Taiwanese National Health Insurance Research Database, which comprised of data from >99% of entire population. Among randomly sampled one million enrollees, 6251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in the patient who was given the diagnosis in the years 1999–2009 but not in 1997–1998. The cohorts of CHC with new onset diabetes (n = 1100) and 1:1 ratio age-, gender-, and inception point (onset date of diabetes) matched nondiabetes (n = 1087) were followed up from the inception point until the development of HCC, withdrawal from insurance, or December 2009. Results After adjustment for competing mortality, patients with new onset diabetes had a significantly higher cumulative incidence of HCC (Relative Risk = 1.544, 95% CI = 1.000–2.387, modified log-rank test, P = 0.047) as compared to those without. After adjustment for age, gender, cirrhosis, hyperlipidaemia, CHC treatment, diabetes treatment, comorbidity index, obesity and statins therapy by Cox proportional hazard model, diabetes was still an independent predictor for HCC (hazard ratio (HR) = 1.906, 95% CI = 1.102–3.295, P = 0.021). The risk for HCC was increased in those who were 40–59 years old, independent of other variables (HR = 3.086, 95% CI = 1.045–9.112, P = 0.041), and after adjustment for competing mortality (modified log-rank test, P = 0.009). Conclusion Chronic hepatitis C patients who develop diabetes are at an increased risk of hepatocellular carcinoma over time.

Over 500 million people are estimated to be infected with chronic viral hepatitis with an increasing burden resulting from the infections. In 2010, the World Health Organization recommended national governments develop effective strategies to reduce the global impact of viral hepatitis. Taiwan, to support the implementation of the world’s first national vaccination program, developed the first of a series of 5-year national strategies in 1982. Our study sought to identify the essential constituents of the strategic response to chronic viral hepatitis in Taiwan, which could then be used by other governments to inform best practice in strategy development. Semistructured qualitative interviews were conducted with key participants involved in the national response to viral hepatitis in Taiwan (n = 26) and a review of the literature. The development of a national strategic response is one of several factors in reducing the burden of viral hepatitis in Taiwan. Other critical factors are effective health services, a prioritization of disease prevention, government funding of science and technology, and sustained advocacy informed by a rigorous evidence base. While there has been significant policy, structural and financial commitment to reduce the burden of related to viral hepatitis, essential challenges remain. Taiwan’s viral hepatitis policy response focuses on clinical interventions and would be strengthened by a broader involvement of interdisciplinary stakeholders, including people with viral hepatitis, and stronger coordination between the policy and government agencies responsible for their implementation.

Hepatitis C virus (HCV) is the leading cause of hepatocellular carcinoma (HCC) and several antiviral agents are available for the treatment of chronic HCV infection. However, the impact of antiviral therapy on the long-term outcomes of HCV-related HCC patients remains inconclusive. We aimed to examine the impact of antiviral therapy on the long-term outcomes of HCV-related HCC patients. We conducted a systematic review using PRISMA guidelines to identify trials and English-language literature from PubMed, Ovid MEDLINE, Scopus and the Cochrane Library database till August 2014. Randomized trials of antiviral treatments examining the effects of antiviral therapy on CHC patients and HCV-related HCC patients were screened and selected. We identified 6 trials evaluated the effectiveness of interferon (IFN)-alfa treatment, 3 studies examined pegylated interferon-alfa treatment and 2 studies examined IFN-beta treatment. IFN-based therapy may decrease HCC incidence in HCV cirrhotic patients after a >5-year follow-up, improve liver reserve, decrease HCC recurrence rate and increase survival rate in HCV-related HCC patients after curative HCC therapy. In conclusion, IFN-based therapy is beneficial and may be recommended in the management of HCV-related HCC patients who are IFN eligible.

Background: The diagnostic value of Doppler and various noninvasive indices in predicting significant hepatic fibrosis in hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferases (PNALT) is unknown. Methods: Seventy-nine treatment-naive HCV carriers with PNALT, who received Doppler ultrasonography and percutaneous liver biopsies, were enrolled in the study. Doppler indices, including portal vein velocity (PVV), hepatic arterial resistive index (HARI), hepatic arterial pulsatility index (HAPI), splenic arterial resistive index (SARI), and splenic arterial pulsatility index (SAPI), were compared with known biochemical indices used in HCV carriers with elevated ALT levels, including aspartate aminotransferase (AST) to platelet ratio index (APRI), age-platelet index (API), and AST to ALT ratio (AAR), for the diagnostic accuracy of significant hepatic fibrosis. Results: SAPI was the most discriminatory index among the Doppler indices (P

Background/Aims: The survival rates of patients with hepatocellular carcinoma (HCC) were investigated over the past 20 years to clarify the long-term survival trend. Methods: A total of 11 312 patients with HCC from seven medical centers from 1986 to 2002 were included. Survival was analyzed by correlating data with the national mortality databank. Results: Multivariate analysis showed that the following factors were associated with shorter survival: male sex, younger age, hepatitis B virus, earlier year of diagnosis, alpha fetoprotein higher than 400 ng/mL, alanine aminotransferase (ALT) higher than two times the upper normal limit, higher aspartate aminotransferase (AST)/ALT ratio, central or southern Taiwan residence, and rural areas residence. Patients diagnosed during 1998–2002 showed the highest survival rate, followed by patients diagnosed during 1994–1997, 1990–1993, and 1986–1989, respectively. Conclusions: There are geographic variations in the survival rates of patients with HCC. Survival has been improving gradually over the past 20 years, probably due to earlier detection of HCC or to improved patient care.

Liu C-J, Chen P-J, Lai M-Y, Lin F-Y, Wang T, Kao J-H, Chen D-S. Viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B. Liver International 2006: 26: 949-955. r2006 The Authors. Journal compilation r 2006 Blackwell Munksgaard Abstract: Background/Aims: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg. Methods: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/ A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay. Results: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients. Conclusion: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.

Background Apart from the presence of liver cirrhosis, hepatitis B virus (HBV) factors have also been shown to play a role in the development of hepatocellular carcinoma (HCC). Studying HBV-related noncirrhotic HCC may help clarify the effect of viral factors. Methods In a hospital-based, age- and genotype-matched study, we aimed to determine the role played by basal core promoter (BCP) T1762/A1764 mutation, precore A1896 mutation, and serum viral load in noncirrhotic hepatocarcinogenesis by comparing 44 patients with HBV-related noncirrhotic HCC, 45 patients with chronic hepatitis B, and 42 patients with HBV-related cirrhotic HCC. HBV genotype, precore and BCP mutations, and viral load were determined by molecular assays. Results In univariate analysis, statistically significant odds ratios were obtained for male sex (P=.005) and BCP T1762/A1764 mutation (P=.0003) in patients with noncirrhotic HCC, compared with patients with chronic hepatitis B. By multiple logistic regression analysis, male sex, BCP T1762/A1764 mutation, and viral load >or=10(5) copies/mL were independently associated with the risk of noncirrhotic HCC. The virologic characteristics were similar between patients with cirrhotic HCC and those with noncirrhotic HCC. Conclusions Our results suggest that BCP T1762/A1764 mutation and higher viral load may be involved in the carcinogenesis of cirrhotic and noncirrhotic HCC.

Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNA-directed RNA polymerase alpha subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n = 95) compared with 30.9% for gastritis (n = 94) and 35.5% for DU (n = 124). GroES seropositivity was more commonly associated with antral GC than with non-antral GC (odds ratio = 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and prostaglandin E(2). Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27(Kip1). We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.

Background: A combination of interferon-α (IFN-α) and ribavirin has been the choice for treating chronic hepatitis C (CHC) patients. It achieves an overall sustained response rate of approximately 50%; however, the treatment takes 6–12 months and often brings significant adverse reactions to some patients. It would therefore be beneficial to include a pretreatment evaluation in order to maximize the efficacy. In addition to viral genotypes, we hypothesize that patient genotypes might also be useful for the prediction of treatment response. Methods: We retrospectively analyzed the genetic differences of CHC patients that are associated with IFN/ribavirin responses. The DNA polymorphisms among 195 sustained responders and 122 nonresponders of CHC patients of Taiwanese origin were compared. Statistical and algorithmic methods were used to select the genes associated with drug response and single nucleotide polymorphisms (SNPs) that permitted the construction of a predictive model. Results: Association studies and haplotype reconstruction revealed selection of seven genes: adenosine deaminase, RNA-specific (ADAR), caspase 5, apoptosis-related cysteine peptidase (CASP5), fibroblast growth factor 1 (FGF1), interferon consensus sequence binding protein 1 (ICSBP1), interferon-induced protein 44 (IFI44), transporter 2, ATP-binding cassette, subfamily B (TAP2) and transforming growth factor, β receptor associated protein 1 (TGFBRAP1) for the responsiveness trait. Based on confirmed linkage disequilibrium block in the population, a minimal set of 26 SNPs in the seven selected genes was inferred. To predict treatment outcome, a multiple logistic regression model was constructed using susceptible genotypes of SNPs. The performance of the resultant model had a sensitivity of 68.2% and specificity of 60.7% on 317 CHC patients treated with IFN-combined therapy. In addition, a prediction model with both the host genetic and viral genotype information was also constructed which enhanced the performance with a sensitivity of 80.7% and specificity of 67.2%. Conclusions: A genetic model was constructed to predict outcomes of the combination therapy in CHC patients with high sensitivity and specificity. Results also provide a possible process of selecting targets for predicting treatment outcomes and the basis for developing pharmacogenetic tests.

Although the significant risk factors for hepatocellular carcinoma (HCC) are well known from epidemiological studies, diagnosis of this disease at an early stage is difficult, and HCC remains one of the leading causes of cancer death worldwide. Thus, to identify any useful HCC-related biomarkers is still a need. We performed SELDI-TOF MS to identify differentially expressed proteins in HCC serum using weak cation exchange protein chips. Protein characterization was performed by 2-DE separation and nano flow LC-MS/MS. A total of 55 sera were collected from HCC patients and compared with those from 48 patients with chronic hepatitis and 9 healthy individuals. A candidate marker of about 8900 Da was detected as differentially expressed in patients with chronic hepatitis C and hepatitis C virus (HCV)-related HCC. We identified this differentially expressed protein as complement C3a. The expression of C3a in HCC sera was further validated by PS20 chip immunoassay and Western blotting. Complement C3a was found to be elevated in patients with chronic hepatitis C and HCV-related HCC. The combination of SELDI-TOF MS and 2-DE provides a solution to identify disease-associated serum biomarkers.

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.

PURPOSE: Allelic loss at chromosome 4q21-23 occurs frequently in human hepatocellular carcinoma, and the putative tumor suppressor gene (TSG) has not yet been identified. We studied the Fas-associated phosphatase-1 (FAP-1) gene as a potential candidate TSG in this region. EXPERIMENTAL DESIGN: The expression level of FAP-1 RNA in hepatocellular carcinomas was evaluated by RNase protection and quantitative PCR. Sodium bisulfite modification and subsequent single-strand conformational polymorphism and sequence analyses were used to assay the methylation of CpGs at FAP-1 promoter. Direct sequencing of the FAP-1 coding region was conducted for detecting the genetic mutations. Two common single nucleotide polymorphisms of FAP-1 were selected for evaluating their association with the hepatocellular carcinoma trait in sporadic and familial hepatocellular carcinomas. Moreover, the functional effect of FAP-1 on cellular proliferation has been evaluated by small interfering RNA approach. RESULTS: Around 50% of hepatocellular carcinomas showed significantly decreased expression of FAP-1 compared with the corresponding nontumorous liver tissues. In most cases, the RNA level was well correlated with the methylation status of promoter CpGs, suggesting that the promoter methylation may contribute to the down-regulation. Several genetic mutations of FAP-1 have been identified in hepatocellular carcinomas. The G/G genotype of FAP-1 cSNP6304 was significantly associated with the increased risk of multiplex familial hepatocellular carcinomas (odds ratio, 2.44; 95% confidence interval, 1.19-5.01). Finally, knockdown expression of FAP-1 was shown to enhance the cellular proliferation in PLC5 cells. CONCLUSIONS: FAP-1 could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation. The genetic mutations and polymorphisms may also confront with the higher hepatocellular carcinoma risk. These results first suggested FAP-1 as a putative TSG in hepatocarcinogenesis.

Polymorphisms in cytokine genes can influence immune responses, inflammation and tissue injury, and may affect the outcome of hepatitis B virus (HBV) infection. We analyzed single nucleotide polymorphisms (SNP) in the interleukin (IL)-10 gene among 344 HBV carriers and 208 patients with hepatocellular carcinoma (HCC). Genotypes and haplotypes were tested for association with HCC. IL-10/-592 C/C genotype was associated with a higher risk for HCC compared with IL-10/-592 A/C and A/A genotypes [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.2-3.6]. IL-10/1927 A/A genotype was also associated with a higher risk for HCC compared with IL-10/1927 A/C and C/C genotypes (OR: 1.5, 95% CI: 1.0-2.2). Haplotype analysis revealed that the homozygosity of the C-A haplotype (defined by SNPs at positions -592 and 1927) of IL-10 gene conveys the highest risk for HCC among HBV carriers compared with the homozygosity for the A-C haplotype (OR: 2.6, 95% CI: 1.3-4.9). The results demonstrate that IL-10 gene polymorphism can affect the outcome of chronic HBV infection. Further studies are necessary to clarify how variation in the IL-10 gene affects IL-10 function and risk of HCC.

Hepatitis B virus (HBV) infection is a global health problem and eight different genotypes (A to H) have been identified. The epidemiology of HBV genotypes and their implications for the natural history of HBV infection have become increasingly recognized. Genotypes A and D are common in Europe, whereas genotypes B and C are prevalent in Asia. In Asian countries, genotype B is shown to be associated with spontaneous hepatitis B e antigen (HBeAg) seroconversion at a younger age, less active liver disease, slower progression to cirrhosis, and less frequent development of hepatocellular carcinoma than genotype C. In Western countries, genotype D is shown to have a lower positivity of HBeAg, less chance of sustained remission after seroconversion, and a less favorable prognosis than genotype A. Thus, clinical differences do exist among HBV genotypes, and further research is needed on the molecular mechanisms underlying the clinical phenotypes of different HBV genotypes.

Background/Aims The infectivity of occult hepatitis B virus (HBV), defined as HBsAg-negative but HBV DNA-positive, after transfusion has been low but not negligible. To address this, we investigated the incidence of post-transfusion HBV infection after receiving screened blood units in Taiwan. Methods Consecutive HBV-naive (anti-HBc-negative) recipients with normal ALT were followed for HBV DNA and serologic markers before and after transfusion. Among 4448 blood recipients, 467 (10.5%) were anti-HBc-negative. Post-transfusion 6-month follow-up was completed for 327. We identified 5 (1.5%) who developed hepatitis B viremia 1 week after transfusion. Three were children who later seroconverted to anti-HBc but with normal ALT indicating subclinical acute infection, despite all had anti-HBs from previous vaccination. One had transient transfusion-transmitted HBV without seroconversion to anti-HBc and one possibly had occult HBV infection. Our findings suggested the possibility that occult HBV infection was transmissible by transfusion. The incidence of post-transfusion acute HBV infection was 0.9% (100 per million units) in naive recipients in Taiwan, a figure 7∼40-fold higher than in developed countries. Moreover, some vaccinated children with anti-HBs were still susceptible. Conclusions Therefore, despite active immunization, sensitive screening assays for occult HBV infection such as nucleic acid amplification test could be considered in endemic areas.

Background/Aims: Hepatitis B virus (HBV) is a global health problem. In addition to the implementation of universal hepatitis B vaccination, effective and individualized treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma is still needed. HBV has been designated eight genotypes (A–H) based on genome sequence divergence. The epidemiology of HBV genotypes and their implications on the responses to antiviral therapy have become increasingly recognized in both Asian and Western countries. Methods: Published data are thus reviewed. Results: Each genotype has its distinct geographical and ethnic distribution. Genotypes A and D occur frequently in Africa, Europe, and India, while genotypes B and C are prevalent in Asia. Genotype E is restricted to West Africa, and genotype F is found in Central and South America. The distribution of genotypes G and H is less clear. Accumulating evidence indicates a better sustained response to conventional interferon in patients with genotype B than those with C, and in patients with genotype A than those with D. In contrast, conflicting results exist regarding the response to pegylated interferon. On the other hand, the therapeutic responses to nucleoside/nucleotide analogues are comparable among patients with different HBV genotypes. The impact of HBV subgenotypes, mixed genotype infections, and recombinants of different genotypes on the response to antiviral treatments awaits further examinations. Conclusion: Remarkable clinical and pathogenic differences do exist among HBV genotypes; however, researches on molecular and virologic mechanisms underlying the clinical phenotypes of different HBV genotypes are urgently needed.

Background. Infection with hepatitis B virus (HBV) in early life frequently results in persistent infection, and clustering of the chronic infection within a family is common. However, the relative contribution of perinatal mother-to-infant transmission or early horizontal transmission to the intrafamilial clustering of HBV infection remains unclear. Therefore, we used HBV genotyping and phylogenetic analysis to elucidate the modes of intrafamilial HBV transmission in Taiwan. Methods. HBV genotypes and serological markers were determined for 103 individuals from 20 families with evidence of clustering HBV infection. Results. Three patterns of intrafamilial clustering of HBV infection were identified. Among the 20 families, 8 included a hepatitis B surface antigen (HBsAg)-positive mother (pattern I), 7 included an HBsAg-positive father (pattern II), and in the remaining 5, both parents were positive for HBsAg (pattern III). The rates of HBsAg positivity for children of the 3 representative groups of families were 85.7%, 65.4%, and 87.5%, respectively (P = .16). The identical genotyping results between index parent and carrier children indicated that pattern I clustering was caused by maternal transmission, whereas pattern II clustering was caused by paternal transmission. In pattern III clustering, a concordant HBV genotype between carrier children and mother or father was found in 3 and 2 families, respectively. The modes of transmission were confirmed by phylogenetic analysis in 1 family of each pattern. Conclusions. In Taiwan, maternal and paternal transmissions are both important in the intrafamilial spread of HBV infection.

Purpose: In spite of the success of hepatitis B immunization, still a significant proportion of childhood hepatocellular carcinoma (HCC) failed to be prevented by the hepatitis B immunization program. This study is aimed to investigate the problems in the HCC prevention in children. Experimental Design: All HCC children ages 6 to 14 diagnosed between 1981 and 2000 in Taiwan were collected from two national childhood HCC registry systems. We analyzed the causes of HCC prevention failure and the risk ratio of HCC among hepatitis B carriers born before versus after the vaccination program. Results: The incidence of HCC per 100,000 children declined from 0.54 to 0.20 in those born before versus after the vaccination program (risk ratio, 0.36). Vaccine failure (33.3-51.4%) and failure to receive hepatitis B immunoglobulin at birth (42.4-57.5%) were the main causes of HCC prevention failure. Mother-to-child transmission of hepatitis B virus infection is an important risk factor of HCC development. This is evidenced by the very high hepatitis B surface antigen seropositive rate in our HCC children (97%) and their mothers (96%). Hepatitis B carrier children born after the vaccination program had a higher risk of developing HCC than those born before the program (risk ratio, 2.3-4.5). Conclusions: Vaccine failure and failure to receive hepatitis B immunoglobulin are the main problems preventing eradication of HCC. Hepatitis B carrier children born after the immunization program have a higher risk of developing HCC than those born before.

The epigenetic modulation by histone deacetylase (HDAC) inhibitors including trichostatin A (TSA) has been known to block cell proliferation, induce apoptosis and inhibit cell migration in human cancer cells that represents the potential therapeutic agents for cancers and fibrosis. However, more than 55% of Hep3B cells remained alive after our initial study of 100 nM TSA treatment. To further study the epigenetic modulation and the biological function of newly activated genes by HDAC inhibitor involved in HCC progression and metastasis, we profiled 23 integrin genes including 15alpha and 8beta in TSA-treated Hep3B cells. Six integrins including three down-regulated alpha6, alpha10, beta8 and three significant up-regulated alpha4, beta2, beta6 integrins were revealed after semi-quantitative RT-PCR. To confirm the epigenetic modulation and explore their biological functions, we selected the three significantly up-regulated integrins for confirmation of protein up-regulation, hyperacetylated-histones by ChIP assays, and functional inhibition by specific neutralizing antibodies of integrins. Our results indicated that epigenetic modulation in TSA-treated Hep3B cells up-regulated new integrins including alpha4, beta2 and beta6 and reduced migration activities by specific neutralizing antibodies to 61.3%, 42.4% and 34.5%, respectively. Our novel findings provided a better understanding of the epigenetic modulation of integrins and suggested that targeting the epigenetic up-regulated integrins to abrogate the migration activity might be a promising strategy to prevent HCC progression.

Background/Aims: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. Methods: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. Results: HBV carriers with older age (>50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22–25, P

Background/aims The prevalence and clinical implications of non-alcoholic fatty liver disease in patients with chronic hepatitis C remain unknown in Taiwan. Methods We addressed the relevant issues by analysing 95 naive Taiwanese patients infected with either hepatitis C virus (HCV) genotype 1 ( n=57) or 2 ( n=38), receiving interferon alone ( n=41) or in combination with ribavirin ( n=54) therapy. A single pathologist scored steatosis and steatohepatitis at baseline and 24 weeks after antiviral treatment. Results At baseline, steatosis and steatohepatitis were present in 44 (46%) and four (4%) patients, respectively. Variables associated with steatosis in logistical regression were hyperglycaemia ( P=0.01), hypertriglyceridaemia ( P=004) and body mass index ≥27 ( P=0.009), but not HCV genotype or viral load. The grade of steatosis correlated well with the number of metabolic syndrome parameters ( P=0.018). Interferon monotherapy, advanced age and HCV genotype 1, but not steatosis, correlated with lower sustained response rate. After treatment, steatosis improved in 19 and worsened in nine, which also did not correlate with HCV genotype ( P=0.850) or sustained response to antiviral therapy ( P=0.246). Conclusions Hepatic steatosis in Taiwanese patients with chronic hepatitis C was associated with features of the metabolic syndrome, but did not correlate with HCV genotype, advanced fibrosis or the response to antiviral therapy.

Background: Although chronic infection with hepatitis B virus (HBV) has been established as a cause of hepatocellular carcinoma (HCC), the roles of viral load and HBV genotype remain unclear. Methods: From 1988 through 1992, baseline blood samples were collected from 4841 Taiwanese men who were HBV carriers but had not been diagnosed with HCC. We used real-time polymerase chain reaction assays of plasma DNA samples to quantify HBV DNA levels (a measure of viral load) and determine HBV genotypes for 154 case patients who were diagnosed with HCC during 14 years of follow-up and 316 control subjects. Unconditional logistic regression was used to assess odds ratios (ORs) of HCC for HBV-related factors. All statistical tests were two-sided. Results: The risk of HCC increased with increasing HBV viral load (adjusted OR for the highest versus the lowest quintile of HBV DNA copies/mL = 7.26, 95% confidence interval [CI] = 3.54 to 14.89; P trend

Objective. Kawasaki disease (KD) is the most common acquired heart disease in children worldwide. The incidence of KD varies among different countries, with Asian countries supposedly having higher incidences than Western countries. However, the incidence of KD in Taiwan has not been well investigated.Methods. Since the implementation of Taiwan's National Health Insurance (NHI) in 1995, NHI has covered health care for >96% its population. Using the NHI database from 1996 to 2002, we investigated epidemiologic features of KD (International Classification of Diseases, Ninth Revision, code 446.1), the rate of coronary artery aneurysm formation (International Classification of Diseases, Ninth Revision, code 414.11), and the change in incidence during the recent 7 years. We also compared the annual incidences in Taiwan with those reported by other countries.Results. During the 7-year study period, KD occurred most frequently in the summer and least frequently in winter. It is interesting that the highest peak occurred in the summer of 1998 at the same time that Taiwan's enterovirus 71 epidemic was occurring. Ninety-one percent of KD cases occurred in children who were Conclusions. KD in Taiwan occurs more frequently in boys and in the summer months. During the 7-year study period, the annual KD incidence in Taiwan of 66/100000 in children

The aim of this study was to investigate the influence of hepatitis B virus (HBV) genotypes on the clinical outcome of chronic childhood HBV infection and hepatocellular carcinoma (HCC).A total of 460 HBV carrier children were followed-up for 15 years and 26 children with HBV-related HCC were recruited. HBV genotyping was examined at enrollment and the latest follow-up of these carrier children and at diagnosis in HCC children. Viral load was checked at enrollment for the carrier children. These carriers were grouped based on their initial hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) status. The HBeAg positive (+) group was divided further into an HBeAg(+/+) group and HBeAg(+/-) group, depending on whether spontaneous HBeAg seroconversion occurred during the follow-up period.Genotype B constituted 73%, 86%, and 76% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) groups, respectively. Genotype C was found in 27%, 8%, and 6% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) group, respectively. Genotype C carriers were more prevalent in the HBeAg(+/+) group than the other 2 groups (P = .01), and had a delayed HBeAg seroconversion compared with the genotype B carriers (P.001). Changes of genotype during the follow-up period were rare (2.8%). In those with HCC, genotype B was also the major type (74%). There was no difference in the baseline viral load between genotypes B and C.Although HBV genotype B dominates in children with chronic HBV infection and HCC in Taiwan, genotype C delays HBeAg seroconversion in pediatric chronic HBV infection.