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Following development of liver cirrhosis in patients with chronic hepatitis B, liver disease may continue to progress and decompensation or hepatocellular carcinoma (HCC) may occur, especially in those with active viral replication. Decompensation may manifest with jaundice, ascites, variceal bleeding or hepatic encephalopathy. Earlier studies have shown that the prognosis of decompensated cirrhosis is usually poor with a 5-year survival rate at 14-35% under conventional standard of care. The approval of oral antiviral agents has greatly improved the prognosis, as demonstrated in several cohort studies and randomized clinical trials involving therapy with lamivudine, adefovir dipivoxil, entecavir, telbivudine, or tenofovir disoproxil fumarate. Oral antiviral agents are effective in restoring liver function and improving survival in patients with decompensated cirrhosis especially if therapy is initiated early enough. These agents are generally well tolerated without significant side effects. However, their preventive effect in HCC development has yet to be convincingly demonstrated. Given their known resistance profiles, entecavir and tenofovir should be considered as the first-line therapy for patients with HBV-related decompensated cirrhosis., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.

Objectives: The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants., Methods: Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations., Results: Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired., Conclusions: The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.

Background: Combination therapy with pegylated interferon (pegIFN)-α and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection is associated with reduction in hemoglobin (Hb) concentrations and anemia. The aim of this study was to evaluate the magnitude and frequency of change in Hb and determine the predictive risk factors for Hb decrease during this therapy., Methods: We enrolled 308 patients with chronic HCV infection who were receiving weekly subcutaneous pegIFN injection in combination with body weight-based oral RBV for 24 weeks. Clinical and virological characteristics were used for studying the predictors of decrease in Hb., Results: The majority (95%) of patients showed reduction in Hb concentration of at least 1 g/dL during pegIFN and RBV combination therapy. The mean and median maximal decrease in Hb level of the study patients was 3.9 g/dL (range -0.3 to 8.2 g/dL; interquartile range 2.8-5.0 g/dL). Of all patients, 49.4% showed a reduction in Hb level of more than 4 g/dL; a higher number of male patients than female patients showed an Hb decrease of >4 g/dL. Multivariate analysis of our data showed that older age, high baseline Hb concentration, high HCV RNA viral load, low estimated glomerular filtration rate (eGFR), and low platelet count were independent predictors of significant decline in Hb levels., Conclusions: Patients with low eGFR before antiviral therapy may have an increased risk of RBV-related anemia and should be closely monitored. Clinician should consider the potential risk of significant reduction in Hb level according to eGFR while deciding the RBV dose.

Background/aims: Simple compound of Helicobacter pylori eradication therapy may improve drug compliance of patients. The aims of this study were to compare the efficacy and tolerability of a simple combination containing levofloxacin 7-day once-daily with standard twice-daily triple therapy., Patients and Methods: This was a prospective, randomised, open-label trial. A total of 189 consecutive patients diagnosed with peptic ulcer and H. pylori infection were enrolled. Patients were randomly divided into two groups: LEC group--levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily for 7 days; AEC group--amoxicillin 1 g, esomeprazole 40 mg and clarithromycin 500 mg twice daily for 7 days., Results: There were 90 patients in the LEC group and 99 patients in the AEC group. By intention-to-treat and per-protocol analysis, the H. pylori eradication rate was 78.9% [71/90; 95% confidence interval (CI), 70.3-87.5%] and 83.5% (71/85; 95% CI, 75.5-91.6%) respectively, in the LEC group; and 74.8% (74/99; 95% CI, 66.0-83.5%) and 86.0% (74/86; 95% CI, 78.6-93.5%) respectively, in the AEC group. The incidence and tolerability of side effects were similar between these two groups., Conclusion: The efficacy and tolerability of once-daily levofloxacin-containing triple therapy are equal to those of the standard twice-daily triple therapy in this study. However, none of the treatment regimens evaluated achieved enough eradication efficacies to be considered as a recommendable first-line treatment., (© 2010 Blackwell Publishing Ltd.)

Chronic infection with hepatitis B virus (HBV) is a major global health problem and an important cause of morbidity and mortality from sequelae of liver cirrhosis and hepatocellular carcinoma. In the past decades, better understanding of the natural history and immunopathogenesis of chronic HBV infection and of the development of many powerful antiviral agents has allowed us to improve therapeutic efficacy. Among these agents, nucleos(t)ide analogs are important and potent viral suppressors. However, when administered alone, they are not able to permanently eradicate HBV, and long-term maintenance therapy is required for therapeutic efficacy. Additionally, prolonged treatment is frequently associated with the emergence of drug-resistant HBV mutants. Before an 'ideal' drug(s), or drug combination, with optimal antiviral efficacy and negligible rates of drug resistance becomes available, the on-treatment monitoring approach using serum HBV DNA level as a predictor for therapeutic efficacy and drug resistance is useful. However, most countries in the Asia-Pacific region have low income economies, insufficient medical care systems, and low awareness of the disease among the general population and government officers. The easy approach of the road-map concept using an affordable drug to treat chronic HBV infection is more important in this region. There is already evidence that the long-term outcomes of chronic HBV infection can be improved under well-managed antiviral therapy. Profound and long-lasting suppression of HBV replication, either maintained on-therapy or sustained after stopping therapy, has been identified as the key determinant for achieving the goals of therapy, for reducing liver damage, and for preventing development of cirrhosis and/ or hepatocellular carcinoma.

Background/aims: The survival duration for patients diagnosed with hepatocellular carcinoma (HCC) with main portal vein thrombosis (MPVT) was usually less than 3 months. The aim of this study is to elucidate whether treatment can prolong the survival for such patients., Methodology: Retrospectively we analyzed the clinical features and outcomes of 63 patients with HCC and MPVT over a 7-year period. Three therapeutic modalities--transcatheter arterial chemotherapy (TAC) with or without radiotherapy (RT), and systemic chemotherapy--were applied., Results: The patients were divided into two groups: 34 (54%) patients were treated, while the remaining 29 (46%) were not. Multivariate analysis revealed that Child-Pugh class, Okuda stage for HCC and the presence of treatment were the principal factors to predict survival. The survival was significantly longer in treated patients than those untreated both in the Child-Pugh class A or B patients. Significantly longer survival is evident in patients treated by TAC combing RT compared to those underwent TAC alone, systemic chemotherapy or no treatment., Conclusions: The survival of Child-Pugh class A or B patients can be extended by the use of an appropriate therapeutic modality. TAC combined with RT did the best benefit to prolong survival in such patients.

Background and Aim: Occult hepatitis B virus (HBV) infection is defined by the detectable serum HBV-DNA in HBV surface antigen-negative patients. This retrospective study aims to evaluate the therapeutic effects of combined pegylated interferon (PEG-IFN) plus ribavirin (RBV) in patients with concurrent occult HBV/hepatitis C virus (HCV) dual infection., Methods: In total, 126 consecutive chronic hepatitis C (CHC) patients who received combined PEG-IFN and RBV therapy were included. Patients were divided into the occult HBV/HCV dual infection group or the HCV-monoinfected group according to whether or not they had the detectable serum HBV-DNA. The biochemical and virological responses to combined therapy were compared between these two groups. Serum HCV-RNA and HBV-DNA were checked before treatment, at the end of treatment as well as at 6- and 12-months' follow up in the occult HBV/HCV group., Result: Six patients were seropositive for HBV-DNA and were included in the occult HBV/HCV dual infection group. There were no statistical differences in the biochemical and virological responses to combined therapy between these two groups. Undetectable serum HBV-DNA was noted at the end of the treatment and the 6- and 12-months' follow up in patients with occult HBV/HCV dual infection., Conclusion: Occult HBV infection in CHC patients is rare. The biochemical and virological responses to combined PEG-IFN and RBV therapy might be similar in CHC patients with or without occult HBV infection. The serum HBV-DNA level was low in patients with occult HBV/HCV dual infection who responded to combined therapy.

Background: Endoscopic ultrasonography (EUS) has often been used to evaluate gastric subepithelial masses (SEM) and their malignant potential. Information on the use of EUS to survey small gastric SEM is limited., Methods: A total of 125 consecutive patients referred for evaluation of a suspected gastric SEM were evaluated by EUS from February 2002 to February 2008. Periodic surveillance using EUS or upper gastrointestinal endoscopy was routinely advised. Surgical treatment was considered if a malignant tumor was suspected or symptomatic., Results: In the 125 patients, EUS found 23 (18.4%) cases of extraluminal compression, 70 (56%) gastrointestinal stromal tumors (GISTs), 9 (7.2%) cases of ectopic pancreas, 5 (4.0%) mucosal tumors, 3 (2.4%) cases of varices, 2 (1.6%) cysts, 2 (1.6%) lipomas, 1 (0.8%) mucosal polyp, 1 (0.8%) submucosal tumor, 6 (4.8%) patients with no abnormality, and 3 (2.4%) unidentified lesions. Surgery was performed in 15 patients, revealing GISTs in 10 patients, and gastrointestinal autonomic nervous tumors (GANTs) in 2 patients as well as other malignant lesions in 3 patients. The pathological findings confirmed that 11 (73.3%) of 15 larger tumors (> 30 mm) were accurately diagnosed. Only 1 of 9 suspected GIST (mean initial tumor size 13.4 +/- 8.3 mm, mean follow-up period 23 months), in the EUS surveillance group significantly increased in size, and surgical pathology disclosed a GIST with intermediate malignant potential., Conclusions: For evaluating gastric SEM, EUS is able to accurately differentiate intramural from extramural lesions and aid in narrowing the differential diagnosis. In this limited case study, most small gastric SEM (< 30 mm) did not exhibit size changes during follow-up. If the tumor size increases or the ultrasonographic features of a tumor suggest malignant possibility during EUS surveillance, surgical resection should be considered.

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/mul or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.

Background and Aims: Chronic hepatitis B (CHB) and its sequelae are major health problems in Taiwan. The purpose of the present study was the economic evaluation of short-duration treatments of CHB and longer duration antiviral treatment for up to 5 years., Methods: Ten-health state CHB disease progression Markov models were used for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients, respectively, that included the emergence of antiviral resistance. The perspective of this economic evaluation was the Taiwan health-care system. Costs and benefits were discounted at 3% per annum., Results: Short-course therapies of up to 1-year treatment had limited impact on improving patient survival. Long-term viral suppression with lamivudine and adefovir sequential rescue therapies (including add-on therapies) for up to 5 years were found to be highly cost-effective by international standards (estimated to be NT$580,000 per quality adjusted life year [QALY] for Taiwan). When Taiwan-specific model inputs were used for HBeAg-positive CHB, the cost per QALY for lamivudine plus adefovir sequential antiviral therapy increased by approximately 100% over the base-case estimate, but was still well within the estimated NT$580,000 per QALY threshold., Conclusions: In Taiwan, treatment of CHB patients with lamivudine and adefovir sequential antiviral therapies for up to 5 years results in survival benefits and is highly cost-effective.

We herein report a case of primary adenocarcinoma of the appendix, a very rare disease that is seldom diagnosed before surgical intervention. This case was first suspected for its unique colonoscopic presentation as a cecal submucosal tumor with an overlying mucin-coat at the appendiceal orifice. The diagnosis was later confirmed after the operation. The imaging features of this exceptional disease are presented in detail.

Studies in the past decades have shown that active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression, and thus sustained viral suppression is of paramount importance in the management of chronic HBV infection. The nucleos(t)ide analogues lamivudine, adefovir, entecavir, telbivudine and tenofovir are potent inhibitors of HBV polymerase/reverse transcriptase activity and are highly effective in the suppression of HBV replication, but rarely eliminate the virus. Long-term therapy is usually required to achieve sustained hepatitis B e antigen seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. Maintained long-term therapy has been demonstrated to significantly lower the rate of hepatic decompensation and development of cirrhosis or hepatocellular carcinoma. However, drug resistance is a serious risk on prolonged nucleos(t)ide analogue therapy, and this poses a critical challenge. Prevention and proper management of drug resistance are crucial to ensure long-term success.

Background/aims: Although H. pyloric eradication therapy is indicated for peptic ulcer patients, the prevalence of H. pylori infection may be different between patients with active or chronic (scarred) peptic ulcers. This study aimed to compare the prevalence of H. pylori infection in active and chronic peptic ulcer patients with or without previous H. pyloric eradication therapy., Methodology: Both non-invasive (13C or 14C urea breath test) and invasive methods (rapid urease test and histology) were used to detect H. pylori. From Dec. 2002 to Jan. 2003, 153 patients with 63% male were enrolled in this study. Fifty-six patients who previously received H. pyloric eradication therapy were enrolled as treated patients, and 97 patients who did not receive therapy were enrolled as untreated patients., Results: H. pylori infection rate was still high in untreated patients even when duodenal ulcer had been scarred (96% in active duodenal ulcer and 63% in scarred duodenal ulcer). In treated patients, H. pyloric infected rates were very low when peptic ulcers were scarred (0% in scarred gastric ulcer, 4% in scarred duodenal ulcer and 0% in both scarred ulcers)., Conclusions: H. pyloric eradication therapy is indicated for untreated patients even when endoscopic examination revealed chronic scarred duodenal ulcer.

Spontaneous rupture of the liver is a rare condition with serious consequences, if not recognized and treated in time. It has been reported as a complication of several disorders, including benign or malignant liver tumors, connective tissue disease, infiltrating liver disease, preeclampsia, and post anticoagulant therapy. We report a case of spontaneous rupture of liver in a non-cirrhotic, chronic hepatitis B and D patient presenting with acute hemoperitoneum and shock. The subcapsular hematoma and rupture of liver were documented by image studies. The patients' condition gradually stabilized after fluid resuscitation. The reported case and literature review suggest that spontaneous rupture of liver must be considered in a differential diagnosis of acute hemoperitoneum. A high index of suspicion and early diagnosis with imaging are critically important.

Chronic hepatitis B virus (HBV) infection is associated with impairment of HBV-specific immune responses. Recently, it has been shown that regulatory T (Treg) cells downregulate HBV-specific immune responses but their role in chronic hepatitis B is still controversial. We hypothesized that liver injury enhances the influence of Treg cells on HBV-specific immune responses. The frequency of Treg cell and the in vitro expansion of HBV-specific CD8+ T cell detected by the tetramer method were investigated in 79 patients with chronic hepatitis B. Thirty-three healthy volunteers were enrolled to measure the frequency of Treg cell as controls. The results showed that in chronic hepatitis B cases, the frequency of Treg cells in peripheral blood was significantly higher than that in normal volunteers. The higher level of serum transaminase was associated with higher frequency of Treg cells, which both had a linear correlation relationship. HBV-DNA level, HBe status, age and sex had no statistical association with Treg cell frequency. Furthermore, in patients with higher serum transaminase levels, the expansion of HBV-specific CD8+ T cells was higher after removal of Treg cells when compared with patients with lower serum transaminase levels. In conclusion, our data indicate a significant association between serum transaminase level and frequency/activity of Treg cells. Based on this observation, we propose that liver-injury enhances Treg cell frequency/activity in chronic hepatitis B patients.

Hepatitis C virus (HCV) and hepatitis B virus (HBV) share similar transmission routes, but concurrent acute HCV and HBV infection was rarely reported. Little is known about viral interaction and hepatic biochemical features of acute HBV and HCV coinfection. We report an intravenous drug abuser with simultaneous acute HBV and HCV infections presenting as biphasic elevation of both alanine aminotransferase (ALT) and total bilirubin levels. HCV infection is the major cause of continuing hepatitis after termination of HBsAg antigenemia.

Background/aims: The long-term outcomes of interferon-alpha (IFN-alpha) therapy in hepatitis B e antigen (HBeAg) seropositive patients remain controversial. This study was conducted to address this issue., Methods: The long-term outcomes were compared in 233 IFN-treated patients and 233 well-matched untreated controls., Results: The cumulative incidence at the end of 15 years of follow-up (median 6.8 years, range 1.1-16.5 years) in the IFN-treated patients and controls was: HBeAg seroconversion 74.6% vs. 51.7% (P=0.031); hepatitis B surface antigen (HBsAg) seroclearance 3% vs. 0.4% (P=0.03); cirrhosis 17.8% vs. 33.7% (P=0.041); and hepatocellular carcinoma (HCC) 2.7% vs. 12.5% (P=0.011). Significant reduction of HCC was only observed in patients with pre-existing cirrhosis (P<0.01). Compared with untreated controls with persistent HBeAg, HBeAg seroconverters in untreated and IFN-treated group showed significantly lower incidence of cirrhosis and HCC (P=0.003-0.031), while non-seroconverters of IFN-treated group had marginally significant lower incidence of cirrhosis (P=0.065). Multivariate analysis showed that IFN therapy, HBeAg seroconversion and genotype B HBV infection are independent factors for better long-term outcomes., Conclusions: IFN therapy reduces cirrhosis and HCC development.

Hepatitis B virus (HBV) genotype has been reported to correlate with response to interferon treatment in several studies. The relationship between HBV genotype and thymosin alpha1 (T-alpha1) treatment is unknown. We retrospectively examine HBV genotypes, precore and core promoter mutations in patients treated with Talpha1 and analyse the correlation between complete response [alanine aminotransferase (ALT) normalization plus seroclearance of HBeAg and HBV-DNA] and HBV genotype. It consisted 98 patients with chronic hepatitis B randomly allocating to three groups: (i) T6 group (n = 32) received a 26-week course of Talpha1 1.6 mg two times a week; (ii) T12 group (n = 34) received the same regimen as T6 group, but Talpha1 therapy extended for 52 weeks; (iii) T0 group (n = 32) served as a control and was followed up for 18 months without specific treatment. Stepwise logistic regression analysis showed that genotype (OR, 3.747; 95% CI, 1.066-13.170; P = 0.039), precore mutation (OR, 6.285; 95% CI, 1.874-21.086; P = 0.003) and Talpha-1 treatment (OR, 12.045; 95% CI, 2.220-65.354; P = 0.004) as independent factors associated with complete response. The complete response of Talpha-1 therapy was higher in patients with genotype B compared to patients with genotype C (52%vs 24%; P = 0.036) and in patients with precore mutation (64%vs 19%; P = 0.002). In conclusion, genotype, presence of precore mutation and Talpha-1 therapy were independent predictors to complete response. Genotype B, compared to genotype C, is associated with a higher response rate to T-alpha1 therapy.

Switching to adefovir (ADV) monotherapy is effective in patients with lamivudine (LAM)-resistant hepatitis B virus (HBV) mutations (rtM204 I/V). However, it was recommended to continue LAM therapy for months after starting ADV therapy for safety concern. The safety and efficacy of switching to ADV monotherapy was examined in compensated and decompensated patients with liver cirrhosis. The clinical, biochemical and virological responses were compared between ADV monotherapy in 18 cirrhotic patients and ADV add-on LAM therapy in 10 comparable cirrhotic patients with LAM-resistant rtM204 I/V. After switching to ADV monotherapy, Child-Pugh's score, serum alanine aminotransferase (ALT), bilirubin, albumin and HBV DNA levels improved significantly (P < 0.01). Serum HBV DNA response, defined as HBV DNA decreased to below 10(5) copies/mL or > or =2 log(10) reduction form baseline, was achieved in all patients. A transient ALT flare without concurrent changes in serum bilirubin or prothrombin time was observed in only two patients (11%). The efficacy and safety profile was similar to those with ADV add-on LAM therapy. In conclusion, switching to ADV monotherapy after emergence of LAM-resistant rtM204 I/V is effective and safe in cirrhotic patients, even in those with hepatic decompensation. To stop LAM and switch to ADV in patients with breakthrough is a reasonably safe and cost-effective approach.

Lamivudine treatment in hepatitis B e antigen (HBeAg)-negative and hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHB) patients is associated with poor sustained response. A previous study has shown that short-term lamivudine therapy in HBeAg-positive patients with alanine aminotransferase (ALT) > 5x upper limit of normal (ULN) could achieve a high HBeAg response rate and low lamivudine resistance rate. We, therefore, prospectively treated 85 HBeAg-negative CHB patients with ALT > 5x ULN by lamivudine for 6-12 months. The mean pretreatment levels were as follows: ALT (normal < 36 U/I) 533 U/I (range: 180-2,418 U/I); total bilirubin (normal < 1.3 mg/dl) 2.0 mg/dl (range: 0.2-29.6 mg/dl), HBV DNA (normal, undetectable) 1.6 x 10(8) copies/ml (range: 1.4 x 10(5)-1.7 x 10(9) copies/ml). After a mean of 7.4 months (6-12 months) treatment, 69 (81%) patients achieved complete response. In a follow-up, 12 months after stopping lamivudine therapy, 33 (39%) patients showed sustained complete response. Patients with sustained response were younger than the relapsed patients (39.7 +/- 11.9 years versus 47.0 +/- 10.3 years; P = 0.005). The emergence of lamivudine-resistant variant HBV was documented in two patients (2%). It is concluded that in HBeAg-negative chronic hepatitis B patients with ALT levels above 5x ULN, a 6-12 month course of lamivudine therapy may achieve sustained an off-treatment response in approximately one-third of patients.

Hepatic actinomycotic abscesses are rare and secondary to other intra-abdominal infections. History of intra-abdominal surgery is a principal contributing factor for the abscess formation. Patients with hepatic actinomycotic abscess may suffer from fever, malaise, abdominal pain and bodyweight loss. The clinical progress of actinomycotic abscess is more indolent than the usual course of other pyogenic abscess. It is sometimes diagnosed as malignancy. This report consists of two cases of hepatic actinomycotic abscess mimicking tumours. Laboratory data revealed elevated alkaline phosphatase and leucocytosis. The abdominal computed tomography scan showed multiloculated lesions with peripheral contrast enhancement appearance. Diagnosis confirmation was based on the typical histologic feature of sulfur granules with inflammatory process by echo-guided fine needle biopsy or surgical specimen. These two cases were resolved with extended courses of intravenous and oral penicillin treatment.

Background and Objectives: Perforated gastric cancer is rare and generally not diagnosed preoperatively or intraoperatively, if a frozen section is unavailable. Therefore, the elucidation of its clinicopathological features and disease outcomes will help surgeons manage perforated gastric cancer., Patients and Methods: The clinicopathological features, surgical management, and disease outcomes of 13 patients with perforated gastric cancer from March 1989 to May 2003 were retrospectively analyzed. Disease outcomes were analyzed in-depth based on tumor stage, depth of tumor invasion, operative curability, and three treatment groups., Results: All 13 patients (median age of 72 years) received emergent laparotomy. Malignant gastric perforation was diagnosed intraoperatively in eight (61.5%) patients. Four patients whose frozen sections exhibited perforated gastric cancer underwent radical surgery with curative intent and were assigned to Group 1. Another four patients with overt distal metastases underwent palliative surgery and were assigned to Group 2. The remaining five patients were misdiagnosed as having benign gastric perforation and underwent local surgery; these patients were assigned to Group 3. All patients received follow-up for a median of 26 months. The survival rates for Stage I disease (P = 0.0342), T1/T2 tumors (P = 0.0342), and curative resection (P = 0.0012) significantly exceeded those of Stage III/IV, T3/T4 tumors, and non-curative resection. Additionally, the survival rates of Group 1 (P = 0.0067) and Group 3 (P = 0.0067) significantly exceeded those of Group 2. Stepwise logistic regression analysis revealed no significant predictor of prognosis., Conclusions: In resectable cases, one-stage radical gastrectomy with possible extensive lymphadenectomy should be encouraged if conditions allow. In cases of misdiagnosis, non-radical local surgery with curative resection is sufficient to treat early-stage cancer., (Copyright 2005 Wiley-Liss, Inc.)

Background/aims: The results of earlier studies on determinants for the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants (rtM204 I/V) were controversial. The aim was to evaluate the impact of viral factors, host factors, host-viral interaction and drug factor on the emergence of rtM204 I/V., Methods: 56 non-cirrhotic and 58 cirrhotic patients received lamivudine therapy for a median of 34 (12-60) months., Results: rtM204 I/V emerged in 37 noncirrhotic and 36 cirrhotic patients. Stepwise logistic regression analysis showed that baseline hepatitis B e antigen (HBeAg) status [odds ratio (OR), 7.728; 95% confidental interval (CI), 2.886-12.957; P=0.0026], HBV-DNA level (OR, 3.756; 95% CI, 1.058-5.089; P=0.0202), alanine transaminase (ALT) level (OR, 6.285; 95% CI, 1.057-11.990; P=0.00246) and treatment duration (OR, 19.88; 95% CI, 8.652-31.762; P<0.0004) were independent determinants for the emergence of rtM204 I/V. Further categorical analysis and correlation test disclosed that patients with HBeAg positivity, HBV-DNA>500 pg/ml and ALT <5x upper limit of normal had significantly higher mutation rates., Conclusions: HBeAg status, HBV-DNA, ALT levels and treatment duration are the major determinants for the YMDD mutation during lamivudine therapy, and should be considered in designing the therapeutic strategy.

Background: Many determinants for a sustained response to lamivudine therapy have been reported but the role of T cell responsiveness remains unclear. The finding that tyrosine-methionine-aspartate-aspartate (YMDD) motif of the reverse transcriptase domain of hepatitis B virus (HBV) DNA polymerase carries a HLA-A2 restricted cytotoxic T lymphocyte (CTL) epitope makes quantitative measurement of the numbers of peptide specific CTLs feasible using MHC tetramer-peptide complex staining., Aim: To investigate the correlation between anti-YMDD motif CTL activity and the efficacy of lamivudine therapy in HLA-A2 positive patients with chronic hepatitis B (CH-B)., Methods: The function and phenotype of peptide and interleukin 2 expanded peripheral blood mononuclear cells were quantified by cell lytic assay and immunocytochemical analysis by staining with HLA-A2-peptide tetramer complexes., Results: After in vitro expansion, sustained responders had more potent CTL responses against YMDD, YVDD, and YIDD, as well as other epitopes on HBV antigens than non-responders. The frequency of YMDD/YVDD/YIDD motif specific CTLs increased significantly with an effective cell lytic function during and after therapy in sustained responders but not in non-responders. YMDD specific CTLs cross reacted with YIDD and YVDD mutant epitopes, and shared T cell receptor gene usages with YIDD and YVDD specific CTLs., Conclusions: Sustained responders, at least HLA-A2 patients, elicited a more potent CTL immunity against YMDD and its mutants. YMDD specific CTLs are cross reactive with YVDD and YIDD mutant epitopes, which may further contribute to immune clearance of the mutant viruses and a successful response to lamivudine therapy in CH-B patients.

Extensive clinical data have shown that lamivudine is an effective and safe drug for patients with chronic hepatitis B virus infection. No significant serious side effect has been reported. Four hundred and forty-eight patients with chronic hepatitis B, treated with lamivudine for more than 6 months, were closely monitored. Two patients developed acute myeloid leukaemia during or after lamivudine therapy. The first case developed acute myeloid leukaemia, 1 year after stopping lamivudine therapy, when A529T mutant HBV-DNA was still detectable. The second case achieved complete virological response but suffered from acute myeloid leukaemia during the ninth month of lamivudine treatment. D553N mutant hepatitis B virus was detected in granulocytes of her peripheral blood. Based on our lamivudine therapy data, the calculated incidence of acute myeloid leukaemia in patients during or after lamivudine therapy was higher in males and females than that of the general population. Whether lamivudine-selected viral mutations have enhanced activity/production of transcriptional transactivator and thereby increased the chance of leukaemic transformation of haematopoietic progenitor cells deserves further investigation.

Background and Aims: This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV)., Methods: Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here., Results: The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2-5 x upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study., Conclusions: Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine.

Splenic tumours are occasionally found during routine physical check-ups or elective abdominal image studies. Histologically, most splenic tumours are of benign vascular origin. To avoid unnecessary surgery for asymptomatic patients with benign splenic tumours and clarify the clinicopathological features of spleen tumours, this study gathered 44 cases of primary or isolated metastatic spleen tumours confirmed by pathology from surgery specimens or biopsies. The differences in clinicopathological features and image presentations between benign and malignant spleen tumour were investigated. Thirty-two cases involved benign tumours while 12 cases were malignant. Among the benign tumours, vascular originating tumours were most common (with 14 cases of cavernous haemangiomas, 13 cases of lymphangioma, three cases of lymphangiohaemangioma and one case of Littoral cell angioma). Notably, one, case of inflammatory pseudotumour because of Schistosoma parasite infection was also noted. Among the malignant tumours, there were four cases of angiosarcomas with vascular endothelium origins, as well as lymphomas and six metastatic tumours. Image studies were non-specific. Image study alone is an inadequate basis for making differential diagnoses between benign and malignant tumours. Instead, pathological studies are required for a final diagnosis. Using previous studies and this investigation, fine needle aspiration biopsy of spleen tumours with the help of ultrasonic or computed tomography appears a safe and effective method for obtaining biopsy specimens. Splenectomy is recommended only for patients with malignancies or complications such as intractable abdominal pain, coagulopathy or tumour rupture with an unstable haemodynamic state.

To compare the long-term effect of natural lymphoblastoid interferon-alpha (IFN-alpha nl) and recombinant IFN-alpha 2a therapy in patients with chronic hepatitis B, 210 patients in two trials were followed-up for 1.1-15.5 years following the end of therapy. They included 34 patients who received placebo (control), 67 treated with IFN-alpha nl (36 after prednisolone priming) and 109 treated with IFN-alpha 2a (56 after prednisolone priming). The cumulative sustained response was higher in patients who had been treated with IFN-alpha nl after prednisolone priming than was exhibited using IFN-alpha nl alone, IFN-alpha 2a alone or the placebo (P < 0.05), or IFN-alpha 2a following prednisolone priming (P = 0.052) at the end of 11 years. Hepatocellular carcinoma (HCC) was detected in 1.5% of the IFN-alpha nl group, 3.7% of the IFN-alpha 2a group and 14.7% of the control group (control vs IFN-alpha nl or IFN-alpha 2a, P < 0.05). The cumulative HCC development was higher in the control group than in the IFN-alpha nl group (P < 0.002) and the IFN-alpha 2a group (P = 0.06). The cumulative survival rate was lower in the control group than in the IFN-alpha nl group (P < 0.01) and the IFN-alpha 2a group (P = 0.02). Multivariate analysis revealed that IFN-alpha nl therapy and female gender are significant predictors of sustained response; preexisting cirrhosis, age at entry and IFN therapy are significant factors in both HCC development and survival. In conclusion, IFN-alpha nl treatment may have a better long-term effect on hepatitis B virus (HBV) clearance than IFN-alpha 2a and placebo, and IFN therapy may provide better long-term beneficial effects than placebo in terms of HBV clearance, reduction of HCC and prolonged survival.

Background: Mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rt M 204 I/V) may develop after 6-9 months of lamivudine therapy. The current practice of continuing lamivudine therapy has been associated with hepatitis flares or even hepatic decompensation. In addition, experiments have shown that the defective replication competency of rt M 204 I/V restores upon addition of lamivudine., Aim: To evaluate whether continuing lamivudine therapy after emergence of rt M 204 I/V is appropriate., Patients and Methods: The clinical courses of 66 patients with continuing lamivudine therapy (continued group) and 68 patients who discontinued lamivudine therapy (discontinued group) were monitored monthly or more frequently if condition required. Hepatitis flare, jaundice, hepatic decompensation and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive patients were documented as events., Results: In a 12-month period, hepatitis flares and decompensations occurred in 67 and 11%, respectively, in patients who continued lamivudine therapy, as compared with 54 and 7%, respectively (P>0.05), in those who stopped therapy. HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group (P=0.08). Serum HBV DNA increased in 48 (73%) of the continued group, and the median level increased from 46 pg/ml upon first detection of mutation to 330 pg/ml (P<0.001) at the end of 12 months continuing therapy. In contrast, serum HBV DNA level in the discontinued group increased in 22 (33%) patients but decreased in 39 patients, and median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping lamivudine., Conclusion: These results suggest that there is no benefit to continued lamivudine therapy after emergence of rt M 204 I/V.

Background & Aims: Superinfection in patients with chronic hepatitis B virus (HBV) infection is not uncommon. Acute hepatitis delta virus (HDV) superinfection is associated with severe and/or progressive liver disease. The natural course following acute hepatitis C virus (HCV) superinfection has not been well studied. The aim of this study was to investigate the impact of acute HCV superinfection., Methods: The clinical features during acute phase and long-term outcomes of acute HCV superinfection were studied and compared with a cohort of acute HDV superinfection and a matched control group of active chronic hepatitis B., Results: Acute HCV superinfection typically occurs as acute icteric hepatitis. The severity is similar to acute HDV superinfection in that hepatic decompensation developed in 34% of patients, hepatitis failure occurred in 11%, and 10% died. During a follow-up period of 1-21 years, patients with acute HCV superinfection had a significantly higher cumulated incidence of cirrhosis (48% at 10 years) and hepatocellular carcinoma (14% at 10 years, 21% at 15 years, and 32% at 20 years) than acute HDV superinfection or active chronic hepatitis B. Hepatitis B surface antigen (HBsAg) seroclearance occurred earlier in HCV superinfected patients. Continuing hepatitis after HBsAg seroclearance was observed only in HCV superinfected patients., Conclusions: Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma.

The development of peptide-MHC tetrameric complexes heralds a new era in the study of antigen-specific T cells and their role in viral infections. However, the frequencies of tetramer-staining CD8+ T cells in fresh peripheral blood mononuclear cells (PBMCs) are usually below 1% in patients with chronic hepatitis B and C viruses (HBV and HCV) as well as human immunodeficiency virus (HIV) infections, which makes difficult the comparison and sequential evaluation of different individuals. Thus, the development of a method to enumerate efficiently antigen-specific CD8+ T cells will be clinically beneficial in monitoring the antiviral cellular immunity during therapy. We report here a modified CRI-p culture method (cytotoxic T lymphocyte response index of the epitope-peptide method), using a panel of peptides to stimulate PBMCs in bulk culture. The modified CRI-p cultured cells were, in turn, subjected to fluorescence-activated cell sorter (FACS) analysis, tetramer staining or T-cell functional assays to quantify the antiviral immunity of HLA-A2 (+) HBV and HCV patients receiving antiviral therapies. The results obtained showed that patients with a sustained response had a significantly higher increase in the frequencies of tetramer staining of virus-specific CD8+ T cells than did nonresponders. This method permits semi-quantitative determination of the relative strength of CTL activity against a panel of peptides and provides a large number of cells for FACS analysis from a single blood sampling. Significantly, it achieves high frequencies of tetramer staining of CD8+ T cells allowing the data of different individuals to be easily compared and sequentially evaluated. The mechanisms involved in this method are discussed.

Chronic hepatitis B virus infection is a serious problem because of its worldwide distribution and possible adverse chronic sequelae, such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is a dynamic state of interactions between the virus, hepatocyte and host immune response. Interferon-alpha and direct antiviral agents, such as lamivudine (Epivir, GlaxoSmithKline), are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory. Thymalfasin (thymosin alpha1; Talpha1, Zadaxintrade mark, SciClone Pharmaceuticals, Inc.) is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that Talpha1 can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-gamma and interleukin-2, and activate natural killer cell-mediated cytotoxicity. Seven randomized controlled studies on Talpha1 monotherapy in patients with chronic hepatitis B showed that 6 months treatment with Talpha1 (1.6 mg twice-weekly) resulted in a significantly higher sustained response rate than untreated controls. The benefits of Talpha1 therapy is usually not immediately apparent during therapy. There is a trend for complete virological response to increase or accumulate gradually after the end of thymosin therapy. The results of Talpha1 and interferon combination therapy in two open-label trials were also promising. In terms of the mechanisms of action, a combination of Talpha1 and nucleoside or nucleotide analogs is a logical approach in the control of chronic HBV infection and a randomized control study is ongoing.

Hepatic involvement in primary amyloidosis (AL type) is not rare but is often clinically silent. However, presentation with jaundice in AL-type amyloidosis is rare, with an incidence of less than 5% reported in the literature. It is considered to be a preterminal sign. We herein report on a case of primary hepatic amyloidosis presenting with severe intrahepatic cholestasis. Viral, drug, alcohol, and autoimmune etiologies were all excluded. A liver biopsy was performed because of unexplained cholestatic jaundice for 3 months. The pathology showed hepatic amyloidosis with extensive amyloid deposition in the expanded portal tracts and sinusoidal space. The patient received supportive treatment only, because of persistent jaundice, coexistent colon cancer with para-aortic lymph node metastasis, and possibly peritoneal carcinomatosis. Unfortunately, the patient died of sepsis 10 months after the onset of jaundice. We suggest that hepatic amyloidosis must be considered in the differential diagnosis of unexplained cholestatic jaundice.

We present the case of a female patient in whom acute overt hepatitis developed after 60 days of ketoconazole administration (200 mg/day). A prompt renewed hepatic injury 48 hours after an unintentional rechallenge 30 months later provided definitive evidence for a causative relationship between ketoconazole and acute liver injury. Histological examination revealed acute hepatitis with bridging hepatic necrosis. Clinicians should be aware of this cause and effect relationship between ketoconazole and acute liver injury, which can result in prompt severe acute liver injury after rechallenge.

There are inconsistent data on the durability of hepatitis B e antigen (HBeAg) seroconversion after lamivudine is discontinued. The aim of this study was to examine the determinants for sustained HBeAg response to lamivudine therapy. Both host and viral factors as well as the drug factor were compared between 43 patients with sustained HBeAg response and 39 patients whose response was not sustained. All of them received a mean period of 16 months (range, 3-55 months) lamivudine therapy and had achieved complete response (HBeAg seroconversion plus HBV DNA seroclearance by hybrid capture assay and normal alanine aminotransferase [ALT]) and were followed-up for a mean period of 44 months (range, 12-88 months). Stepwise logistic regression model was used to estimate the sustained response on the presence of the following variables: age; gender; pretherapy ALT; total bilirubin and HBV DNA levels; time to HBeAg seroconversion; additional lamivudine treatment after HBeAg seroconversion; total duration of treatment; hepatitis activity index scores; periportal, intralobular, and portal inflammation and fibrosis scores; scores excluding fibrosis; status of precore mutation; basal core promoter mutation; and genotype. The results showed that genotype (OR, 5.922; 95% CI, 1.611-21.768; P =.007), age (OR, 0.943; 95% CI, 0.891-0.997; P =.040), and additional treatment (OR, 1.097; 95% CI, 1.028-1.171; P =.005) were independent factors to sustained HBeAg response. Further categorical analysis disclosed that patients with genotype B, age < or =36 years, and additional lamivudine treatment over 8 months have higher sustained response. In conclusion, HBV genotype, age, and additional treatment are the major determinants for the sustained HBeAg response to lamivudine therapy.

Background/aims: Severe acute exacerbation (AE) of chronic hepatitis B (CHB) can lead to hepatic decompensation and death. The aim of this study was to investigate the effect of lamivudine therapy in hepatic decompensation during such AEs., Methods: In a 10-month period, a total of 60 consecutive AE patients with jaundice and prolonged prothrombin time over 3s were treated with lamivudine 150 mg daily. As a historical control, another 31 CHB patients with AE resulting in hepatic decompensation hospitalized in an immediate past 6-month period were enrolled for comparison., Results: Patients in both groups were comparable in clinical and biochemical features. After a median treatment period of 6 weeks (range 1-48 weeks), all of the 25 patients with pretherapy bilirubin level < 20 mg/dl in the treatment group survived, while five (25%) of 20 patients in the control group died (P=0.013; odds ratios, 2.667; 95% confidence interval, 1.787-3.979). However, the mortality rate was similar in patients with pretherapy bilirubin level > or =20 mg/dl in both groups., Conclusions: These results suggest that lamivudine may prevent fatality in CHB patients with hepatic decompensation if therapy starts early enough or before serum bilirubin level rise over 20 mg/dl, but helps little if serum level already risen over that level.

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) polymerase/reverse transcriptase activity. The rate of hepatitis B e antigen (HBeAg) seroconversion in a large series of Asian patients treated with lamivudine 100 mg daily for 1 year was only 16% and the incidence of YMDD mutants was 14%. Further analysis of this Asian trial has shown that patients with a pretreatment alanine aminotransferase (ALT) level higher than 5-fold the upper limit of normal (ULN) have a much higher HBeAg seroconversion rate as compared with patients with a pretreatment ALT level <2 x upper limit of normal (64 vs. 5%; p < 0.001). In order to avoid the development of YMDD mutants, we selected 186 patients with acute exacerbation for treatment with lamivudine during 9 months, if possible, and not more than 15 months. They were all seropositive for both hepatitis B surface antigen and HBeAg for more than 6 months and also had serum HBV DNA; 138 (74%) of them were male. HBV genotypes were A in 2 (1%), B in 115 (62%), C in 65 (35%), D in 2 (1%) and F in the remaining 2 (1%). Four patients (2%) had liver cirrhosis. They had mean pretreatment levels of ALT at 608 IU/l (range: 184-2,400 IU/l), total bilirubin at 1.5 mg/dl (0.3-14.8 mg/dl), and HBV DNA at 2,246 pg/ml (0.5-25,903 pg/ml). After a median of 8.2 months (3-15 months) on lamivudine, 96 patients (51%) achieved HBeAg seroconversion, while the other 90 (48%) patients did not. Genotype B was detected comparably frequently in seroconverters and nonconverters (63 vs. 61%). During 1-year follow-up after withdrawal of lamivudine, 56 (58%) of the 96 seroconverters experienced flare-ups with ALT levels elevated higher than 5 x ULN in 50 (89%). Of 90 patients who remained HBeAg-positive, in contrast, 80 (86%) experienced ALT flares (with ALT >5 x ULN in 84%) within 1 year. YMDD mutants did not develop in any of these 186 patients during the course of lamivudine therapy. In conclusion, short-term lamivudine therapy in patients with chronic active hepatitis B can reduce the incidence of YMDD mutants and achieve an acceptable HBeAg seroconversion rate. However, the relapse rate was high (60% during 1-year follow-up). Further study is needed to establish how to improve a sustained HBeAg response., (Copyright 2003 S. Karger AG, Basel)

Both chronic hepatitis B and C virus (HBV and HCV) infections respond ineffectively to current antiviral therapies. Recent studies have suggested that treatment outcomes may depend on the development of type 1 T helper (Th1) and Th2 cell responses. Specifically, activation of Th1 immunity may play a major role in successfully treating hepatitis B and C. This model was revisited herein by evaluating immune responses in 36 HBV and 40 HCV patients with or without treatment, in an attempt to find a common immune mechanism for successful treatment. The immune responses in all examined cases were studied by peripheral blood mononuclear cell (PBMC) proliferation and cytokine responses to viral antigens, cytotoxic T lymphocyte (CTL) responses, enzyme-linked immunospot (ELISPOT) assay, and tetramer staining of virus-specific CD8+ T cells. The overall results revealed that all responders among both HBV- and HCV-infected cases displayed significantly higher PBMC proliferation to viral antigens with a predominant Th1 cytokine profile. Furthermore, the Th1-dominant responses were associated with significant enhancement of CTL activities and were correlated with ELISPOT data, while non-responders responded more weakly. During therapy, the numbers of tetramer-staining, virus-specific CD8+ T cells showed greater increases in responders than in non-responders (p = 0.001). The frequencies determined by the tetramer assay were approximately 200-fold higher than data estimated by limiting-dilution analysis. In conclusion, activation of Th1 immunity accompanied by enhancement of CTL activity during therapy is a common immune mechanism for successfully treating hepatitis B and C, and therefore may have important therapeutic implications., (Copyright 2003 National Science Council, ROC and S. Karger AG, Basel)

During the course of chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) often coincides with normalization of liver biochemical test and clinical remission, but data regarding long-term outcome after spontaneous seroconversion are still scarce. Excluding patients with other virus(es) concurrent infection, 283 patients with chronic HBV infection were followed up for at least 1 year after spontaneous HBeAg seroconversion to anti-HBe. Follow-up studies included clinical, biochemical, and virologic evaluation and hepatocellular carcinoma (HCC) screening with ultrasonography and alpha-fetoprotein assay. During a median follow-up period of 8.6 years (range, 1 to 18.4 years) after HBeAg seroconversion in 283 patients, 189 (66.8%) showed sustained remission, whereas the remaining 94 (33.2%) experienced alanine aminotransferase (ALT) elevation over twice the upper limit of normal: 12 (4.2%) associated with HBeAg reversion, 68 (24%) with detectable serum HBV DNA but HBeAg negative, and 14 (4.9%) of undetermined causes. Of the 269 patients without evidence of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed cirrhosis with a cumulative incidence and relative risk significantly higher in patients developing active hepatitis than in patients with sustained remission (P <.05). HCC developed in 6 (2.2%) of the 283 patients, also with a significantly higher cumulative incidence in patients developing active hepatitis after HBeAg seroconversion (P <.005). In conclusion, the results suggest that spontaneous HBeAg seroconversion confers favorable long-term outcomes. However, active hepatitis still may develop and lead to cirrhosis and HCC.

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe-positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2 x upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.

A 63-year-old men suffered from fever, jaundice, and right upper quadrant pain for 1 week. Biliary stones with biliary tract infection were diagnosed. He was treated with parenteral antibiotics. However, abdominal ultrasonography showed multiple hyperechoic lesions in both lobes, and infiltrating hepatocellular carcinoma was suspected initially. Numerous hypervascular nodular-enhancing lesions were revealed by computed tomography. Magnetic resonance imaging further disclosed numerous tiny cystic lesions with peripheral enhancement. Exploratory laparotomy was performed for biliary calculi and probable underlying malignancy. Cholecystectomy, choledocholithotomy, and liver wedge biopsy were done. The pathology revealed bile duct hamartomas with microabscess formation. The past literature about biliary hamartomas is reviewed.

Asian lamivudine trial has shown that hepatitis B e antigen (HBeAg) seroconversion rate during 1 year of lamivudine therapy was only 16% but was 64% in the subgroup of patients with a pretherapy serum alanine transaminase (ALT) level over 5 times the upper limit of normal (ULN). To test whether ALT rebound following corticosteroid priming enhances response to lamivudine therapy, a pilot study was conducted in 30 patients with ALT levels less than 5x ULN (43-169; N < 36 U/L). They received 30 mg of prednisolone daily for 3 weeks, 15 mg daily for 1 week, no treatment for 2 weeks, and then 150 mg of lamivudine daily for 9 months. Complete response (CR) was defined as ALT normalization with HBV-DNA seroclearance and HBeAg seroconversion. Peripheral blood mononuclear cell proliferation and cytokine secretion in response to recombinant HBV core antigen were serially assayed in 7 patients during priming and after withdrawal of prednisolone. Clinical rebound with an ALT over 5x ULN was observed in 20 patients (67%). Of these 20, 12 (60%) showed CR as compared with 1 (10%) of the 10 patients without significant ALT rebound (P <.002). The HBeAg seroconversion sustained in 70% of the patients 3 to 6 months after the end of lamivudine therapy. Immunological assays revealed that the responders showed Th1 dominant response and higher stimulation index to prednisolone priming. No serious side effect was encountered. These results suggest that corticosteroid priming induced immune/ALT rebound greatly enhances response to lamivudine therapy in chronic hepatitis B. Confirmation by randomized controlled trial is needed.

Background & Aims: One-year lamivudine therapy significantly suppressed hepatitis B virus (HBV) replication, improved hepatic necroinflammatory activity, and prevented progression of fibrosis. However, the effects of prolonged therapy are unknown., Methods: A total of 334 Asian patients with chronic hepatitis B from a previously reported 1-year study were randomized to receive either lamivudine (100 or 25 mg) or placebo for another year. The effects of treatment on serum HBV-DNA suppression, alanine transaminase (ALT) normalization, and hepatitis B e antigen (HBeAg) seroconversion were measured. The presence of YMDD variant HBV and its effect were also determined., Results: A significantly greater proportion of patients achieved sustained HBV-DNA suppression and ALT normalization with 100 mg lamivudine daily for 2 years compared with lamivudine for 1 year followed by placebo for the second year (P<0.001). Daily lamivudine therapy for 2 years was safe and resulted in incremental HBeAg seroconversion from 17% at week 52 to 27% at week 104. HBeAg seroconversion during continued lamivudine therapy increased linearly with increasing pretherapy ALT levels (P< 0.001). Despite the emergence of YMDD mutant in 38% of the patients, they continued to clear serum HBeAg and maintain lower median serum HBV-DNA and ALT levels than baseline values. In contrast, ALT levels increased 8-12 weeks after switching from lamivudine to placebo, but returned to normal once lamivudine treatment was resumed., Conclusions: Treatment with lamivudine for 2 years is both well tolerated and efficacious in patients with chronic hepatitis B.