Background/Aims
The therapeutic strategies of applying adefovir for treating lamivudine resistant HBV mutants are controversial. Thus, we observed the clinical outcomes after discontinuation of lamivudine to establish the timing to initiate adefovir therapy. Methods: Fifty chronic hepatitis B (CHB) patients with lamivudine resistant HBV mutants who had received lamivudine for more than 12 months were included in the study. We investigated the clinical outcomes at 6 months after the end of treatment (EOT). We compared the serial clinical outcomes among respective groups based on serum ALT at the EOT and the clinical characteristics of patients with or without acute exacerbation (AE) and the HBeAg loss. We also investigated the predictive parameters of AE and HBeAg loss. Results: Fifteen patients (30%) had experienced AE at 6 months after the EOT. Four patients received antiviral agents because of their hepatic decompensation. Patients with AE had higher serum ALT values and lower HBV DNA titers at EOT compared with those patients without AE. Serum ALT at the EOT was the predictive parameter of AE. Eight patients (21.6%) had newly developed HBeAg loss at 6 months after EOT. The total bilirubin at EOT was the predictive parameter of HBeAg loss. Conclusions: CHB patients with lamivudine resistant HBV mutants had favorable clinical outcomes at 6 months after EOT. Therefore, we can consider observing the clinical courses after discontinuation of lamivudine and it is not always required to overlap the adefovir for treating lamivudine resistant HBV mutants except for the treatment of patients with a high risk of developing decompensation. (Korean J Hepatol 2005;11:227-242)

Background and Aims
Zinc is an essential, mostly intracellular, trace element which participates in many oxidative or deoxidative reactions and in a protective action on liver cell activity. Plasma zinc levels are known to decrease in patients with liver disease including chronic viral hepatitis. The aim of this study was to reveal whether hepatic zinc concentrations have a correlation with grades of necroinflammation or stages of fibrosis in the patients with chronic viral hepatitis.Methods:This study consisted of 50 subjects (43 chronic hepatitis B, 4 chronic hapatitis C, and 3 cirrhosis). Each specimen of liver tissue was classified with the grade of lobular inflammation, portal/periportal inflammation, and stage of fibrosis according to Scheuer’s method. Hepatic zinc concentration was determined by ICP-Atomic Emission Spectrometry. Results:The mean hepatic zinc concentration in the 50 chronic viral hepatitis patients was 233.66 ?g/g dry weight of liver tissue. The hepatic zinc levels were significantly correlated with the grades of portal/periportal inflammation (r_s=-0.385, p=0.006), and grades of lobular inflammation(r_s=-0.342, p=0.015). The stages of fibrosis were also negatively related (r_s=-0.423, p=0.002). The zinc concentrations differed significantly among grades of lobular inflammation (p=0.013) and among stages of fibrosis (p=0.044). Conclusions:Hepatic zinc concentrations showed negative correlation with grades of portal/periportal inflammation, lobular inflammation, and stage of fibrosis in the patients of chronic viral hepatitis. These results suggest that decreased hepatic zinc concentration might be associated with severe hepatic injury and reflect decreased protective activity on liver cell injury. (Korean J Hepatol 2001;7:147-152)

Background/Aims
Lamivudine is highly effective in suppressing hepatitis B virus replication and hepatitis B induced necroinflammatory activity. The objective of this study was to evaluate the virological and biochemical responses to lamivudine by patients with HBV associated chronic liver disease. In particular we stressed the importance of lamivudine therapy by patients with decompensated liver cirrhosis.Methods:We conducted a one-year trial of lamivudine in 80 patients with HBV associated chronic liver disease (chronic hepatitis 44, cirrhosis 36). We classified these patients according to the severity of hepatic dysfunction as chronic B hepatitis (Group A) or liver cirrhosis (Group B). These patients were treated for 12 months with 100 mg daily doses of lamivudine.Results:The seroconversion rate of HBeAg was 23.5% in group A patients and 26.7% in group B patients. The negative conversion of HBV-DNA was sustained for one year in 79.5% of patients in group A and 86.1% in group B. The normalization rates of serum ALT were 90.9% in group A and 88.9% in group B patients. No serious side effect after discontinuance of the treatment was found. There were 12 ALT breakthrough cases and all of them showed mutation of YMDD motif. However, they did not deteriorate clinically in spite of ALT elevation and HBV-DNA reappearance. The Child-Pugh scores improved even in patients with decompensated liver cirrhosis.Conclusion:One-year lamivudine treatment resulted in excellent virological and biochemical improvements and was well tolerated in the patients with HBV associated chronic liver disease, even in decompensated cirrhosis. We conclude that lamivudine is relatively safe in chronic hepatitis B and liver cirrhosis treatment.(Korean J Hepatol 2001;7:171-180)

Epstein-Barr virus (EBV) infection is associated with diverse clinical manifestations. Hepatic involvement by EBV can cause a broad spectrum of histologic and clinical features ranging from acute hepatitis through lymphoproliferative disorders to lymphoma. However, severe chronic active EBV infection with hepatic involvement in adults is quite rare. EBV infection can be demonstrated by serologic test or molecular biologic techniques. In situ hybridization can demonstrate the EBV infection. It has the advantage of precise localization of the virus in infected tissues or tumors. Here we will describe a 46-year-old female who was admitted to our hospital because of general weakness, ready fatiguing, and jaundice. A bone marrow biopsy revealed reactive histiocytosis with hemophagocytosis. A liver biopsy revealed lymphocyte infiltration to portal areas and sinusoids, periportal and pericellular fibrosis, mild cholestasis, and micro-and macro-vesicular fatty change. Although the results of the serologic tests were inconclusive, in situ hybridization studies which were performed on liver biopsy tissue revealed the expression of Epstein-Barr virus-encoded RNA 1 transcripts in lymphocytes infiltrating to hepatic sinusids.(Korean J Hepatol 2001;7:195-200)

Background/Aims
The aims of our study are to assess the frequency of peripheral blood mononuclear cell (PBMC) proliferation and cytokine profiles to hepatitis C virus(HCV) core protein and NS3 protein to search the potential immunosuppressive effect of HCV core in chronically HCV-infected patients.Subjects and Methods:Thirty two anti-HCV-positive patients with chronic liver diseases, eight HBsAg-positive patients with chronic liver diseases, and six healthy adults were the subjects of our study. Using recombinant HCV core and NS3, proliferative response of PBMC and cytokine production were determined.Results:Fifty nine percent and thirteen percent of patients with HCV-related chronic liver diseases showed positive PBMC proliferation to HCV core and NS3, respectively. Thirty four percent and fifty nine percent of patients with HCV-related chronic liver diseases showed significant production of interferon-gamma to HCV core and NS3, respectively. IL-4 production was negligible. When the PBMC were treated with HCV core and NS3 concurrently, or HCV core and phytohemagglutinin concurrently, the stimulation indices were significantly decreased compared to those treated either with NS3 or PHA without core.Conclusions:Although about two thirds of chronically HCV-infected patients with liver diseases showed the PBMC proliferation and Th 1 type cytokine profile, they could not eradicate the viral infection. This ineffective immune response seems to play a role in the pathogenesis of chronic inflammatory liver disease resulting in liver cirrhosis and hepatocellular carcinoma. HCV core showed a potential immunosuppressive effect, which has important meaning for the mechanism of HCV persistence.(Korean J Hepatol 2001;7:292-298)

Background/Aims
The HBsAg positivity in the normal Korean population has been reported as 2-10%. It has been decreasing since hepatitis B vaccine was introduced to routine vaccination regimens in 1992. Reports on the changes of anti-HBs over the years are hard to find since the discrepancies in sensitivities of test methods used by different researchers did not allow equivalent comparisons. The purpose of this study was to evaluate the changes of HBsAg and anti-HBs posivities for a recent 15 year period.Methods:From 1998 to 2000, 4771 subjects in Chonnam province were included in this study. Serum HBsAg and anti-HBs were detected by reversed passive hemagglutination(RPHA) and passive hemagglutination(PHA) respectively. The changes in the HBsAg and anti-HBs positivity by the same test methods for the period were analyzed by comparing our results with those of 12 other previous reports.Results:The positivities of HBsAg and anti-HBs were 5.3% and 47.5%. The positivity of HBsAg was significantly higher in males, while that of anti-HBs was significantly lower in males(p<0.01). There was a significant difference of HBsAg and anti-HBs positivities among age groups which were arbitrarily divided by decade(p<0.01). But there was no correlation between age and the positivities. In the HBsAg positive group and the anti-HBs negative group, abnormality in ALT level(ALT>40) was significantly higher statistically(p<0.01). The positivity of HBsAg decreased with years(r=-0.845, p<0.01), while that of anti-HBs increased with years(r=0.616, p<0.05).Conclusion:The positivity of HBsAg has significantly decreased and that of anti-HBs has increased with years for the period under study.(Korean J Hepatol 2001;7:299-307)

Background
/ Aims : Choronic HBV infection is associated with a wide spectrum of clinical manifestations, including asymptomatic carrier state, choronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Genotypically, HBV genomes have been calssified into seven groups, designated A to G. Several studies have suggested recently that HBV genotypic difference influence the severity of liver disease and clinical outcomes. The distribution of HBV genotypes in Korea and its clinical relevance are poorly understood. We investigated the prevalence of HBV genotypes in Korea and the association between the distinct genotypes and the severity of liver disease. Methods : A total of 214 HBV-DNA positive serum samples, were used for the genotyping. All patients were HBV-bDNA positive chronic HBsAg carries. 199 patients were histologically verified with liver cirrhosis(6), chronic hepatitis(192) and fatty liver(1). The other patients were clinically diagnosed with liver cirrhosis(13) or hepatocelluar carcinoma(2). HBV genotype was determined by PCR using type-specific primers. Results : Genotyping was possible in all patients. Out of 214 patients, 213(99.5%) were HBV genotype C. Only one(0.5%) was genotype A, The patient with genotype A had minimal hepatitis as diagnosed by liver biopsy. Conclusions : These results indicate that almost all chronic HBV infections are genotype C in Korea. HBV grnoytpic difference therefore dose not influence the clinical outcome of HBV infection in Korea. Because genotype C may be associated with more severe liver disease, the predominance of genotype C in Korea may result in more severe outcomes than in other countries where other genotypes are predominant. (Korean J Hepatol 2001;7 :373 - 380)

Background
/ Aims : This study aimed to estimate the seroepidemiology of hepatitis B virus(HBV) infection with emphasis on the transmission of HBV infection between mother`s and their children. Methods : For 452 patients with HBV associated chronic liver disease, and 1,098 of their offspring, who visited Korea University Kuro Hospital from February, 2000 to February,2001, HBsAg was tested by radioimmunoassay. Results : Among siblings whose mothers were HBsAg - positive, the overall prevalence rate of HBV infection was 44.9%(140/312) and decreased with decreasing age(54.7% in ≥ 20 years old age group, 33.3% in 10-19 years old age group, 7.6% in < 10 years old age group). The estimated proportion of perinatal infection out of modes of HBV transmissions in the general population was 38% in < 10 years and 63.4% in 10-19 years. Conclusion : The present hepatitis B vaccination strategies-especially against perinatal infection of Korea have performed to their utmost. More effective methods for prevention of HBV transmission are now needed. (Korean J Hepatol 2001;7 :387- 391)

Background
/ Aims : Increasing the susceptibility of young populations to HAV infection could result in an outbreak in a high-risk group. The author investigated the characteristics of hepatitis A outbreaks among Korean military personnel to obtain the fundamental data for determining the necessity for selective HAV vaccination. Methods : A case was defined as a person who had an onset of an illness compatible with acute viral hepatitis A between 4 February and 6 April 1998. Results : A widespread outbreak of hepatitis A affected 102 military personnel. The epidemic curve indicated a common-source exposure in the initial stage. At the end of the first month of the initial onset, the occurrence was specific to the location of the military post. Investigation suggested that contamination most likely occurred prior to the local distribution of food. The mean age was 23 years. The overall attack rate was 91 cases per 10000 persons at risk. All cases were jaundiced. The most frequently reported symptoms included icteric sclerae, daek urine,anorexia, malaise and fatigue, nausea, fever,abdominal pain, headache, upper respiratory symptoms, vomiting, itching, diarrhea, light-colores stools, myalgia, arthralgia, and skinrash. The laboratory test showed the serum total bilirubin of 5.5 mg./dL, AST of 344 IU/L, and ALT of 868 IU/L(mean value). Conclusion : All patients were clinically apparently diseased with jaundice and were completely recovered. The outbreak was food borne common-source exposure. The changing epidemiology hepatitis A in Korea calls for the economic evaluation of costs and benefits for selective HAV vaccination in high risk adult groups including military personnel. (Korean J Hepatol 2001;7 :392- 400)

Background
/ Aims : Hepatitis B virus(HBV) genotype have distinct geographic distributions. The possibility of pathogenic difference among HBV genotypes has been suggested. We investigated the prevalence of HBV genotypes in Korea and the association between distinct genotypes and clinical outcomes. Methods : Using a PCR-RFLP and sequencing, HBV genotypes were determined in 136 patients with chronic type B hepatitis. Results : The genotype C was detected in 131 patients(96.3%), and other 5 patients(3.7%) had genotype B. There were no significant differences in sex, age, disease duration, ALT level, HBeAg/anti-HBe status, or HBeAg loss between genotype B and C patients. Conclusion : These results suggest that almost all patients with chronic hepatitis B are infected with genotype C. Genotypes do not influence the outcome of chronic hepatitis B patients in Korea. (Korean J Hepatol 200 1;7 :38 1- 386 )

Background
/ Aims : It has been reported in patients with chronic hepatitis B, that the response rate of lamivudine therapy increases in proportion to the duration of the therapty. What was not well known was the durability of the therapeutic response after the cessation of lamivudine therapy in patients with chronic hepatitis B. Patients and Methods : We retrospectively analyzes 73 patients with chronic hepatitis B who were treated with lamivudine 100 mg orally once daily and followed up for more than 12 months between April 1997 and March 1999. Sixty-three patients were initially hepatitis B e antigen (HBeAg) positive and Hepatitis B virus (HBV) DNA positive(group Ⅰ). Ten patients were HBeAg negative and HBV DNA positive (group Ⅱ). Results : The response rates of group Ⅰ and group Ⅱwere 68.3% and 70.0% at 12 months, respectively(p=NS). In group I, cumulative HBeAg seroconversion rates art 1 year, 2years, and 3 years were 30.2%, 38.8%, and 42.4%, respectively. The cumulative durability of response was higher in group I than in group II (64.6% vs 33.3% at 1 year ; 35.4% vs 22.2% at 22.2% at 2 years p=.079); lamivudine therapy for more than 6 months after HBeAg seroconversion than for less than 6 months (90.0% vs 40.0% at 1 year ; 90.0% vs 20.0% at 2 years ; p=.013). Conclusions : The long-term response to lamivudine therapy showed no difference between HBeAg - negative/HBV DNA-positive and HBeAg - positive patients. The HBeAg serocinversion rate increased in proportion to the duration of lamivudine therapy. The durability of response. (Korean J Hepatol 200 1;7 :423 - 431)

Background/Aims
About 15% of Korean hepatocellular carcinoma(HCC) are negative both of Hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (anti-HCV)in their sera. They can be classified as a non-B, non-C hepatocellular carcinoma group(NBNC group). The aims of our study were, firstly, to describe the clinical characteristics of Korean NBNC HCC and compare them with those of HBsAg-positive HCC(HBV group) and anti-HCV-positive HVV(HCV group). Secondly we wanted to assess the frequency of viremia of HBV, HCV and transfusion-transmitted virus(TTV)in NBNC HCC patients. Methods : we prospectively collected clinical data and sera from 113 NBNC HCC patients and performed PCR for HBV DNA, HCV RNA and TTV DNA. We also collected clinical data from 125 HBsAg-positive HCC patients during a similar period. Results : The mean age of the NBNC HCC group was 59 years, in-between that of the HBV and the HCV groups. A History of heavy alcohol drinking was found in 48% of the NBNC HCC group. This was significantly higher than that of the HBV group, but similar to that of the HCV group. Serum α FP level in the NBNC HCC group was more frequently in the normal range compared to that in the HBV and HCV groups. The detection rates of HBV DNA, HCV RNA and TTV DNA in the NBNC HCC group were 17%, 13% and 67% respectively. Conclusions : The NBNC HCC patients seemed to comprise a heterogeneous group of various etiologies and clinical presentations. About one third of these patients displayed evidence of viremia of HBV or HCV. (Korean J Hepatol 2001;7 :439- 448)

Background
/Aim: A significant correlation between HBV DNA and liver damage was found in precore mutant strains but there was no significant association between viral replication and liver damage in HBeAg positive patients. Laboratory tests are often requested to predict hepatitis activity (grade) and fibrosis (stage) in HBeAg positive chronic hepatitis B. We assessed ALT, AST, and HBV-branched DNA to find which is the best for predicting hepatitis activity and fibrosis. Methods: Routine biochemical liver function tests and HBV DNA in sera were assessed in 119 young patients positive with HBsAg and HBeAg. The mean age of patients was 21±2 years. All patients were male. By logistic regression analysis the relationships between laboratory data, hepatitis activity, fibrosis, or risk of chronic active hepatitis were analyzed. Results: There was a significant correlation between aminotransferase (AST, ALT) and hepatitis activity/ fibrosis. A significant inverse relationship between the HBV bDNA and hepatitis activity was demonstrated (Pearson's correlation coefficient: lobular activity,-0.305; porto-periportal activity, -0.410). But HBV bDNA was not correlated with severity of fibrosis. AST and HBV bDNA was the important test for predicting the more severe hepatitis activity (lobular activity and porto-periportal activity: score≥3, respectively) Conclusion: The higher AST, but the lower HBV bDNA, in sera shows the more severe hepatitis activity. AST and HBV bDNA could be helpful for assessing the hepatitis activity in young male patients with HBeAg positive chronic hepatitis B if proper reference values are used.(Korean J Hepatol 2002;8:44-51)

Background/Aims
The protective role of HBV-specific CD8⁺ cells is dependent on their ability to efficiently migrate to the infected liver, where they may exert an effector function. The migratory behavior of CD8⁺ cells is influenced by their expression of different chemokine receptors. This study was intended to analyse the pattern of chemokine receptor expression of HBV specific CD 8+ cells in chronic B viral infection. Methods: We analysed the CCR5 and CCR3 profile of HBV-specific CD8⁺ cells isolated from the blood and liver of patients with different patterns of HBV infection. Purified T cells were stained directly ex vivo, or after antigen-specific stimulation, using HBV peptide-specific HLA tetramers and monoclonal antibodies to CD8, CCR5 and CCR3, with analysis by flow cytometry. Results: In patients with chronic hepatitis B characterised by low levels of virus (serum HBV DNA <0.5pg/mL) and minimal liver inflammation, analysis of circulating and intrahepatic CD8⁺ cells demonstrated that liver infiltrating Tc18-27-specific cells were preferentially CCR5+ (up to 80% of HBV-specific CD8⁺ cells), in contrast to cells of the same specificity within the circulating compartment (up to 35% of HBV-specific CD8⁺ cells). Furthermore, CCR3 was expressed by about 10% of Tc18-27+ cells infiltrating the liver, but was absent from circulating cells. Following HBV-specific stimulation in vitro the CCR5 expression of circulating Tc18-27-specific cells was up-regulated, to levels found in liver infiltrating cells, whereas CCR3 expression was unchanged. Conclusions: The chemokine receptor profile of HBV-specific CD8⁺ cells is influenced by the anatomical site of these cells, and the clinical pattern of disease. The ability of circulating HBV-specific CD8⁺ cells of patients with low replicating virus to upregulate CCR5 suggests that these cells may respond to increases in virus replication by efficiently migrating into the infected liver. (Korean J Hepatol 2002;8:363-370)

Background/Aims
Treatment of chronic hepatitis B with interferon results in a sustained loss of hepatitis B virus DNA and hepatitis B e antigen (HBeAg) and remission of liver disease only in a proportion of cases. Recently, mutations of hepatitis B virus (HBV) core gene have been reported as being related to the failure of interferon treatment in chronic hepatitis B. This study investigated whether core gene mutations of HBV are related to non-response to interferon therapy and whether the recurrence of HbeAg and HBV DNA in initial responders to interferon therapy is associated with the emergence of HBV core gene mutants. Methods: The precore/core gene sequence was determined by polymerase chain reaction (PCR) and direct sequencing of PCR product in serum samples obtained before interferon treatment from 10 responders and 10 non-responders to interferon therapy. In addition, precore/core gene sequence was determined in serum samples obtained before interferon treatment and after recurrence from 10 patients who showed recurrence of HBeAg and HBV DNA after initial response to interferon therapy. Results: In samples from 10 responders, there were 7 missense mutations and 71 silent mutations. However, there were 43 missense mutations and 109 silent mutations in samples from 10 non-responders. In samples obtained before interferon treatment from the 10 patients who showed recurrence after initial response, 8 missense mutations and 74 silents mutations were found. The nucleotide sequences from the samples obtained after the recurrence showed 6 silent nucleotide substitutions compared with the sequences from the samples obtained before interferon treatment. Conclusions: Mutations in the core protein of HBV occur more frequently in non-responders than responders to interferon therapy of chronic hepatitis B and may be a factor responsible for the failure of interferon treatment. The recurrence of HBeAg and HBV-DNA in initial responders to interferon therapy is not associated with the emergence of the HBV core gene mutants. (Korean J Hepatol 2002;8:381-388)

Background/Aims
Long-term lamivudine therapy can induce the emergence of lamivudine resistant hepatitis B virus (HBV) mutants. Clinically emergence of the mutant is expressed by the reappearance of disappeared HBV DNA in serum. Continued lamivudine treatment has been usually recommended in cases of viral breakthrough. However, the clinical outcome in patients with viral breakthrough is not clear. The aim of this study was to investigate the clinical course of chronic hepatitis B patients after viral breakthrough during lamivudine therapy. Methods: A total of 74 patients with chronic hepatitis B who showed viral breakthrough after at least 6 months of lamivudine treatment were included in this study. They had positive HBeAg and HBV DNA before treatment. The median follow-up duration after breakthrough was 13 months. Results: After viral breakthrough, only 8 patients (11%) maintained normal ALT levels and 66 patients (89%) showed elevation of ALT. 30 patients (41%) showed acute exacerbation of hepatitis (ALT increase over five-times upper normal limit). These acute exacerbations occurred within three months after breakthrough in 19 patients (63%). In the cases of acute exacerbation, 6 patients showed decompensated progression such as elevation of serum total bilirubin. One of them died of hepatic failure. A predictive factor for acute exacerbation was not found. HBeAg seroconversion occurred in 8 patients after viral breakthrough but their clinical course was highly variable. Conclusions: Chronic hepatitis B patients who had viral breakthrough during lamivudine therapy should be followed carefully and regularly in mind of potential clinical deterioration. New strategies are needed to manage the cases of acute exacerbation after viral breakthrough. Korean J Hepatol 2002;8:389-396)

Background/Aims
Long-term efficacy and the rate of viral breakthrough in patients with HBeAg-negative chronic hepatitis B receiving lamivudine therapy is uncertain. This study was conducted to determine the rate of viral breakthrough according to the HBeAg status and the relation of viral breakthrough with YMDD mutants. Methods: Two hundred and five patients with HBeAg-positive and 49 patients with HBeAg-negative chronic hepatitis B, who had received lamivudine for at least 9 months, were included. The mean durations of the lamivudine treatment were 176 months and 155 months in HBeAg-positive and negative patients, respectively. Analysis of HBV genome for YMDD mutations was performed by restriction-fragment-length polymorphism assay and direct sequencing. Results: While the cumulative rates of viral breakthrough at 12th and 24th months of the lamivudine therapy were 0% and 7% in the HBeAg-negative group, they were 12% and 39% in the HBeAg-positive group. The cumulative rate of viral breakthrough in the HBeAg-negative group was significantly lower than in the HBeAg-positive group (p<0.01). In multivariate analysis, the only significant factor related to viral breakthrough was the HBeAg status (p<0.05). The YMDD mutants were detected in all patients with viral breakthrough irrespective of HBeAg status. However, in patients without viral breakthrough, the rate of YMDD mutants was significantly higher in the HBeAg-negative group than in the HBeAg-positive group (13.3% vs 5.1%; p<0.01). Conclusions: Lamivudine is expected to be more persistently effective in HBeAg-negative chronic hepatitis B because of a lower viral breakthrough rate than in HBeAg-positive chronic hepatitis B in spite of the emergence of YMDD mutants. Korean J Hepatol 2002;8:397-404)

Background/Aims
Lamivudine therapy in chronic hepatitis B has been shown to be effective in inhibiting HBV replication. However, lamivudine resistance has been developed with prolonged use. We studied to etermine the prevalence, predictive factors, and clinical outcomes of lamivudine resistance. Mutations in YMDD motif of HBV polymerase, which have been associated with lamivudine resistance, were also assessed. Methods: 170 patients with HBV-associated chronic liver disease who have received lamivudine for at least one year, were studied. The clinical, biochemical, and virologic characteristics were analyzed and compared according to presence (resistance group) or absence (non-resistance group) of DNA breakthrough. Their clinical outcomes were regularly followed. Stored sera before treatment and after DNA breakthrough were examined for detection of HBV polymerase mutation by direct sequencing and/or RFLP. Results: Cumulative rates of lamivudine resistance after one and two years of treatment were 11% and 34%, respectively. In the resistance group, as compared to the non-resistance group, age, the presence of HBeAg before treatment, and disappearance of HBeAg during treatment, were significantly different. The predictive factors associated with lamivudine resistance were not found. ALT and HBV-DNA level after lamivudine resistance was variable, but jaundice or hepatic failure was absent. Mutation in YMDD motif was detected in 73% and other variable mutations were detected before treatment and after DNA breakthrough. Conclusions: Lamivudine resistance increases the longer the duration of treatment and clinical outcomes are variable. The mutation in YMDD motif was found in about 2/3 of cases. Other causes for lamivudine resistance may be considered. (Korean J Hepatol 2002;8:405-417)

Background/Aims
Lamivudine, a nucleoside analogue has been widely used as an effective antiviral agent for the treatment of patients with chronic hepatitis B infection. However, the YMDD motif mutation of HBV polymerase resistant to lamivudine very frequently occurs after long-term use of lamivudine. It is well known that the mutation is selected by the lamivudine. We hypothesized that a few mutant strains of YMDD motif are present as quasispacies before the lamivudine treatment, are selected by the treatment, and breakthrough during treatment. We investigated the prevalence of the YMDD motif mutants in patients with chronic hepatitis B infection who had not been treated by antiviral agents before. Methods: The study included the serums of 40 patients with chronic heptitis B infection, which stored at -70℃. Thirty-four patients had chronic hepatitis and 6 patients had cirrhosis. Thirty-one patients were diagnosed by liver biopsy. The average age and range were 29 years and 13-57 years respectively. None had taken any antiviral agents before. To detect YMDD mutants, YVDD (M552V), and YIDD (M552I), we used direct sequencing and the restriction fragment length polymorphism (RFLP) method. Results: The YMDD mutant was detected by RFLP method in 7.5% (3/40) of the patients with chronic hepatitis B infection, in two patients with chronic hepatitis and one with cirrhosis. All were YMDD+ YIDD mutants. Conclusions: The YMDD motif mutation occurs spontaneously without antiviral therapy in patients with chronic hepatitis B infection.(Korean J Hepatol 2003;9:1-9)

Background/Aims
Lamivudine therapy is effective in inhibiting HBV replications in patients with HBeAg-negative chronic liver disease. However, the sustained response rate appears to be particularly poor, because the vast majority of patients relapse soon after cessation of therapy. The aim of this study was to evaluate the efficacy of lamivudine, the breakthrough rate, and the relapse rate of discontinuing therapy after response in patients with HBeAg-negative chronic liver disease. Methods: Fifty-nine patients with HBeAg-negative chronic liver disease who have received lamivudine for at least 6 months, were studied. The mean duration of treatment was 14 months. Complete response was defined as undetectable serum HBV DNA by bDNA and normalization of ALT levels. Once HBV DNA disappearance and ALT normalization were observed, lamivudine therapy was continued for at least two additional months. The mean follow-up after cessation of treatment was 6 (1-22) months. Results: Fifty-six patients were undetectable HBV DNA. The cumulative HBV DNA loss rates at 3 months and 5 months were 90% and 95%, respectively. The ALT normalization was observed in 52 patients. The cumulative ALT normalization rates at 6 months and 10 months were 78% and 86%, respectively. The complete response was observed in 52 patients. The cumulative rates of complete response at 10 months and 18 months were 80% and 88%, respectively. A predictive factor for complete response was only the duration of lamivudine treatment. Virological breakthrough was observed in 5 (8.5%). Thirty-four patients stopped taking lamivudine after 7.7 (2-15) months of the additional therapy. Seventeen of those patients (50%) experienced relapse. The cumulative relapse rates at 3 months, 6 months and 10 months were 24%, 47%, and 66%, respectively. The only predictive factor for relapse was the duration of additional lamivudine treatment after response. Conclusions: Lamivudine was an effective treatment of HBeAg negative chronic liver disease. Relapse, however, was usually observed after cessation of lamivudine. Our results showed that long-term lamivudine therapy is required in order to decrease the high relapse rates in patients with HBeAg-negative chronic liver disease.(Korean J Hepatol 2003;9:69-78)

Background/Aims
End-stage liver disease caused by viral hepatitis C has been increasing recently in Korea. In this study, we investigated the clinical progress, recurrence, and management of hepatitis C patients who underwent liver transplantation, Methods: We retrospectively reviewed the clinical progress and management of 16 patients (2.7%) with hepatitis C among 587 liver transplant patients from August 1992 to August 2002. Results: Eleven cases among 16 patients were males. The median age was 56±6(42-62) years and the median follow-up period was 6±13 (1-41) months. Thirteen cases underwent living donor liver transplantation and three had cadaveric whole liver transplantation. Clinical recurrence occurred in nine cases (56.3%) and mean time of recurrence was 5.2 months, Histological recurrence cases were eight (50%). A positive result of HCV RNA PCR was found in 90.9%, and all cases of clinical and histological recurrence in groups in the same periods were PCR-positive. Among eight cases showing histological recurrence five patients were managed by ribavirin monotherapy, two patients received interferon and ribavirin combination therapy, and one patient was not treated at all, The serum serum aminotransferase level was normalized in six cases (75%) of them. Conclusions: We observed that the HCV reinfection rate of a transplanted liver was high in this study, as in other reports in the literature, The prevention of HCV recurrence and the management of post-recurrent cirrhotic change are crucial for graft and patient survival. We think customized protocols are needed for every situation of recurrent hepatitis C.(Korean J Hepatol 2003;9:180-187)

Background/Aims
The post-treatment relapse patterns and efficacy of lamivudine re-treatment for relapsed patients have not been clarified. The aims of this study were to evaluate the relapse patterns after discontinuing therapy and the effects of lamivudine re-treatment for relapsed patients after HBeAg seroconversion. Methods: Therapy was discontinued after HBeAg seroconversion in 121 patients. Sixty-six patients were relapsed and included in this study. The duration of lamivudine re-treatment therapy was from 6-35 (mean: 16) months. Post-retreatment monitoring continued for 1-40 (mean: 8,9) months. Results: Among the relapsed 66 patients, 50 (75.8%) had HBeAg reappearance while 16 (24.2%) remained HBeAg negative and anti-HBe positive, The cumulative relapse rates at 3, 6, 12 and 24 months were 27%, 47%, 60% and 66%, respectively, Forty-two relapsers received lamivudine re-treatment, Among them, 33 were HBeAg positive and 9 were HBeAg negative and anti-HBe positive, Response was achieved in 31 of the 42 patients (73.8%). The cumulative response rates at 6, 9 and 12 months were 62%, 69% and 72%, respectively. Six patients (14.3%) developed viral breakthrough, All patients were HBeAg positive chronic hepatitis B. The duration of lamivudine re-treatment was the only predictable factor for response of lamivudine re-treatment. Therapy was discontinued after response in 21 patients, Eleven patients were relapsed, including 6 who were HBeAg positive and 5 who were HBeAg negative. Predictive factors for post-retreatment relapse were age and the duration of additional lamivudine therapy after response, Conclusions: The response rate of lamivudine re-treatment was significantly higher than in initial lamivudine treatments. The response rate of lamivudine re-treatment was significantly higher than in initial lamivudine treatments. The breakthrough and relapse rates, however, were similar in both initial and retreated lamivudine therapy.(Korean J Hepatol 2003;9:188-197)

Background/Aims
The aim of this study was to measure health related quality of life (HRQOL) in patients with chronic viral hepatitis or cirrhosis and to determine factors associated with more severe impairment. Methods: We conducted a cross-sectional study in which we documented patients` demographic and clinical characteristics and measured their HRQOL using the Korean version of Short form-36. A total of 375 patients were enrolled in the study. We compared patients` HRQOL with that of 750 participants in a control group and assessed the association of HRQOL impairment with clinical parameters. Results: In all except two domains (physical functioning, bodily pain) of SF-36, HRQOL scores were significantly lower in the patient group than in the control group (p<0.001). The difference was more prominent in those domains reflective of mental, rather than physical, health. When patient group was classified as noncirrhosis, child A, B, or C according to modified Child-Pugh classification, severe liver disease was associated with a lower HRQOL score. Interestingly, scores of domains reflective of mental health were decreased from the early stage of disease (noncirrhosis or Child-Pugh A). Those of domains reflective of physical health, however, were decreased only in advanced stages of disease (Child-Pugh B or C). There are weak but significant correlations between SF-36 scores and age, serum albumin, serum bilirubin, and prothrombin time, but no correlation with histologic activity, transaminase level, disease duration, virus type (HBV or HCV) and HBV DNA level. Conclusions: Compared with the control group, patients with chronic viral hepatitis or cirrhosis showed substantial impairment of HRQOL, which is further affected by worsening disease severity. More concern about HRQOL should be warranted in the evaluation of health change due to disease progression or therapeutic trial.(Korean J Hepatol 2003;9:212-221)

Background/Aims
Long-term treatment with lamivudine causes breakthrough, but the clinical course after lamivudine breakthrough is not well known. The aims of this study were to evaluate the clinical course in lamivudine after breakthrough, and to identify predictive factors of breakthrough. Methods: 124 patients with chronic hepatitis B infection, who represented viral breakthrough during lamivudine therapy, were included. The mean duration of lamivudine therapy and additional lamivudine therapy after breakthrough was 30.5 months and 12.5 months, respectively. Results: The cumulative breakthrough rates at 12, 18, 24 and 36 months were 8, 24, 36 and 52%, respectively. After viral breakthrough, only 4 patients maintained normal ALT levels. 120 patients showed ALT elevation. The number of patients with ALT levels greater than 5 times, and greater than 10 times, the upper normal limit were 67 (56%) and 29 (24%), respectively. While still on lamivudine therapy after breakthrough, 98 patients presented ALT elevation. Only 22 had normalized ALT levels. Hepatic decompensation developed in 2 patients. HBeAg seroconversion after breakthrough occurred in 10 patients. The changing pattern of quantitative HBeAg levels during lamivudine therapy was the only predictive factor associated with viral breakthrough. The mean time of turning points in decrescendo-crescendo patterns of HBeAg levels during lamivudine therapy was earlier than viral breakthrough (9 months vs. 17 months). Conclusions: These results suggested that deterioration of hepatic function can usually be observed after breakthrough. The serial monitoring of serum quantitative HBeAg levels may allow an early recognition of viral breakthrough.(Korean J Hepatol 2003;9:293-303)

Background/Aims
HBeAg-negative chronic hepatitis B (CHB) has a poor long-term prognosis. Since no precise clinically relevant HBV thresholds are known in HBeAg-negative CHB, the decision to treat is difficult. The aim of this study was to evaluate the levels of serum HBV DNA and transaminase and to investigate the correlation of these values in patients with HBeAg-negative CHB. Methods: The study analyzed the sera from 82 patients with HBeAg-negative CHB, 61 men and 21 women. The mean age was 45 years. The patients were divided into two groups according to serum ALT levels: the patients with lower ALT level (n=52, UNL<ALT<2×UNL) and higher level (n=30, ALT≥ 2×UNL). The level of serum HBV DNA was determined by the Cobas Amplicor HBV Monitor™ (Roche). Results: The median serum HBV DNA level was 2.7×10⁵ copies/mL in patients with HBeAg-negative CHB. The median serum HBV DNA level of patients with a higher ALT level (1.0×10⁶ copies/mL) was significantly higher than that of patients with a lower ALT level (5.6×10⁴ copies/mL)(p<0.001). The serum ALT level was correlated with serum HBV DNA levels in patients with HBeAg-negative CHB (r=0.416, p<0.001). The serum level of HBV DNA in patients with cirrhosis (median 2.0×10⁵ copies/mL) did not differ from patients without cirrhosis (median 4.7×10⁵ copies/mL). Conclusions: The level of serum HBV DNA was higher in patients with higher serum ALT level than it was in patients with lower serum ALT, and it was closely correlated with serum ALT levels in HBeAg-negative CHB.(Korean J Hepatol 2003;9:284-292)

Background/Aims
: Transforming growth factor alpha (TGFα) is an important autocrine growth factor of hepatocytes. We were to evaluate the roles of TGF α in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). Me thods : We measured the amounts of TGFα mRNA in liver tissues from 18 patients with HCC, 31 with CVH and 7 normal controls. ‘Hot start’ reverse transcription polymerase chain reaction (RT - PCR) us ing oligo- dT and specific primers detected TGFα mRNA in total cellular RNA extracted from liver tissues. T he levels of TGFα mRNA were determined by the end point titers of serial two- fold dilutions of cDNA. T he amounts of HBV- RNA in livers of patients with chronic hepatitis B were also measured by Northern blot hybridization. Re s ults : TGFα mRNA levels were significantly higher in HCC than CVH and normal controls ; those of CVH were also elevated compared to normal controls . They were overexpressed in the nontumorous livers surrounding HCC compared to CVH, although lower than HCC tissues. T hey were higher in chronic hepatitis B than in chronic hepatitis C. T hey were not correlated with serum alanine aminotransferase (ALT ) or HBV- RNA levels in liver tissues (in cases of chronic hepatitis B). However, the expression of TGFα mRNA tended to be higher in the livers of patients with serum AFP levels raised. Conclus ion: Overexpress ion of TGFα mRNA in liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be closely related to the development or growth of HCC, especially in the livers of chronic hepatitis B.

Background
/Aim : Lamivudine, a reverse-transcriptase inhibitor interferes with viral replication and can reduce the level of infection, thus diminishing an attack by the immune system. The study was conducted to determine whether lamivudine therapy would result in improved clinical course and serological tests in HBV-positive patients with aggravating liver tests. Methods : Among the 116 patients with chronic replicative progressive hepatitis B and aggravating clinical course, 63 patients were in the lamivudine (100mg daily) group, 23 in the interferon alpha group and 30 were in the non-treated group were enrolled in this study. The effect of lamivudine therapy given for one year was evaluated by serologic tests on a bimonthly basis. The duration of lamivudine treatment was 6-12 months. Results : The results show that ALT normalization occurred in 56.1% of lamivudine group in the sixth month, while 39.1% of interferon alpha group and 10.0% occurred in the non-treated control group. Negative conversions in both the HBV DNA and HBeAg were achieved in 100% and 26.0% of lamivudine group, while 56.5% and 17.4% were achieved in the interferon alpha group and only 13.3% and 3.3% were achieved in the non-treated group. After 8 to 12 months of therapy six cases revealed HBV DNA breakthrough but AST, ALT flare up occurred concomitantly among 3 of them. The proportions of patients with ALT normalization and seroconversion at 1 year of lamivudine therapy were 82.5% and 16.1% respectively. Conclusion: Lamivudine treatment is associated with suppression in HBV replication and ALT levels in patients with chronic progressive hepatitis impending or ongoing liver cirrhosis by HBV without any side reaction or complication. However, it is necessary to consider the elevation of AST, ALT levels and/or reappearance of high serum level of HBV DNA under the lamivudine therapy and the influence of long-term viral suppression on the long-term outcome.(Korean J Hepatol 2000;6:73-81)

Backgrounds/Aims
: To investigate the prevalence and clinical implications of hepatitis G virus (HGV) infection in patients with chronic renal failure, a cross-sectional study of 131 hemodialysis patients and 33 kidney transplantation recipients was conducted. Methods : HGV RNA was amplified by reverse-transcription (RT) polymerase chain reaction (PCR) assay with primers from the 5'-untranslated region of the viral genome. Results : The prevalence of HGV infection in patients with chronic renal failure was 25%(41/164). The following factors were taken into consideration: the mean age(43.15±11.97 years vs 46.46±13.08 years), the male to female ratio(2.15:1 vs 1.86:1), the mean of the dialysis duration(4.58±3.18 years vs 3.90±3.31 years), transfusion history (75.6% vs 62.6%), the mean of the ALT level during the prior 6 months(25.78±21.50 IU/L vs 23.00±59.49 IU/L), and the amount of transfusion(6.22±8.03 units vs 5.74±9.44 units). The anti-HCV(4.88% vs 8.94%) showed no difference between HGV RNA positive and negative group. The HBsAg positive ratio was 19.5% and 5.81% in HGV RNA positive group and negative group, respectively. Conclusion : The prevalence of HGV infection in patients with chronic renal failure was 25%. There was a higher rate of HBsAg positivity in the HGV RNA positive group rather than in the negative group. HGV infection did not seem to be associated with clinically significant hepatitis.(Korean J Hepatol 2000;6:82-90)

Background/Aims
: According to the recent research, mutations in the HBV pre-S region may have an impact on the progression of hepatitis B virus(HBV)-related liver disease. The aim of this study was to clarify the frequency and location of naturally occurring mutations in the pre-S region of HBV, and their possible effects on the clinical course of HBV-associated chronic liver diseases. Methods : HBV DNA was extracted from the sera of 15 patients (8 with liver cirrhosis and 7 with hepatocellular carcinoma). The pre-S sequence was amplified via polymerase chain reaction, subcloning and sequenced. Results : All patients had point mutations in the pre-S region. Nine of 10 mutation sites (90%) in the pre-S1 region, and 4 of 5 mutation sites (80%) in the pre-S2 region were identical in both liver cirrhosis and hepatocellular carcinoma. Deletions were detected in seven patients (4 with liver cirrhosis and 3 with hepatocellular carcinoma). Among the 4 patients with liver cirrhosis, three had deletion in 5'-end of the pre-S2 region and one spanning the 3'-end of the pre-S1 to 5'-end of the pre-S2 region. All 3 patients with hepatocellular carcinoma had deletions in 5'-end of the pre-S1 region, and two patients had simultaneous deletion spanning the 3'-end of the pre-S1 to the 5'-end of the pre-S2. Conclusion : The pre-S mutants were frequently detected in HBV-associated liver cirrhosis or hepatocellular carcinoma and the point mutations or deletions in the pre-S gene were clustered in specific regions. (Korean J Hepatol 2000;6:91-101)

Background/Aims
Quantitation of Hepatitis C Virus (HCV) RNA in serum is important for monitoring the response to interferon-α therapy in patients with chronic hepatitis C. Several commercial assays are recently available, but they are expensive and cannot be used as a gold standard. Methods: An in-house competitive reverse transcription-polymerase chain reaction (cRT-PCR) was developed and validated. The procedure involves the construction of a mutant and wild type HCV RNA internal standard (IS), cRT-PCR, and colorimetric detection with DNA-ELISA. A standard curve was obtained and used for final HCV RNA quantitation. Results: The standard curve was linear over the range of 1×10⁴ to 5×10⁷ copies/mL of the HCV RNA standard (r=0.976). This in-house cRT-PCR was comparable with the branched DNA (bDNA) assay (Quantiplex HCV 2.0, Chiron, USA) with positive correlation between the two tests (r=0.735). Conclusion: The quantitation of HCV RNA by in-house cRT-PCR and DNA ELISA was more sensitive and had wider range of detection compared to bDNA assay. This assay is useful for follow-up of HCV RNA concentration after interferon-α therapy.(Korean J Hepatol 2000;6:156-171)

Background/Aims
Lamivudine has demonstrated a potent suppression of viral replication and a substantial histologic improvement in many patients with chronic hepatitis B. This study is intended to evaluate the effects of lamivudine and the breakthrough rate in patients with HBV associated chronic liver diseases including decompensated liver cirrhosis, and to investigate the clinical factors closely related with these events. Methods: A total of 58 patients(chronic hepatitis 21, cirrhosis 37) showing abnormal serum levels of aminotransferase and detectable serum HBV DNA for at least 6 month received 150 mg of lamivudine once a day for 3-27 months (median 13). The Kaplan-Meier methods and the Cox regression model were used for statistic analysis. Results: The one-year cumulative incidences of the negative conversion of serum HBV DNA, normalization of aminotransferase, and seroconversion of HBeAg were 98.3%, 86.2% and 20.6%, respectively. Eighteen-month and 2-year cumulative breakthrough rates were 24% and 47%, respectively. The Child-Pugh scores were improved (p<0.001) in patients with decompensated liver cirrhoses(n=21). The negative conversion of HBV DNA, breakthrough rates and seroconversion were not significantly associated with the progression of disease, mutation in pre-core region and previous treatment with interferon. The pre-treatment aspartate aminotransferase (AST) level was associated with a higher rate of seroconversion(p<0.03). Conclusion: Despite a higher breakthrough rate, 2-year lamivudine treatment has induced the seroconversion of HBeAg in 26% of patients, and improved the clinical manifestations in decompensated cirrhotic patients.(Korean J Hepatol 2000;6:172-186)

Background/Aims
This study was conducted to determine the effect of novel long-term maintenance treatment with lamivudine by gradual lengthening of the medication interval in patients with chronic active viral hepatitis B. Method: All patients were non-responder, relapsed or intolerable patients to previous interferon therapy. Patients were divided into a drug-interval changing study and a daily continual medication control group. Drug-interval changing protocol with gradual lengthening of the medication interval after conversion to undetectable HBV-DNA in serum and reduction of serum aminotransferase to normal level was monitored monthly. Results: Before treatment, 15 patients of the drug-interval change group and 11 patients of the daily medication group were similar in laboratory and pathologic findings. Mean follow-up periods were 12.8 moths and 11.4 months respectively. HBeAg seroconversion rate was higher in patients in the daily medication group (86.7% vs. 40.0%, p<0.05). The odds of loss of HBeAg, development of anti-HBe, and suppression of HBV-DNA are about 11 times, 7 times, and 8 times higher in the drug-interval change group compared with the daily medication group, respectively (p<0.05). Conclusion: Drug-interval lengthening method was effective in long-term suppression of viral replication with low cost.