Hepatitis: Lee CM

Lee CM, Hung CH, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niaosong Township, Kaohsiung, Taiwan, ROC. · Chang Gung Med J. · Pubmed #18419050 links to  free full text

Abstract: The incidence of hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) has been increasing in several countries including Taiwan. There are six main genotypes, each of which contains closely related subtypes. Molecular epidemiological studies have shown marked differences in the genotype distribution by geographical region and between patient groups. HCV genotype 1 may play a role in the development of HCC, although some studies have argued against this. A sustained virological response secondary to interferon monotherapy or interferon/ribavirin combination therapy may reduce the risk of HCC and improve survival in chronic hepatitis C patients. The HCV genotypes are associated with therapeutic response. Rapid virological response is also a predictor of therapeutic response. Although viral characteristics have consistently been shown to be important predictors of treatment response, identification of additional host immune and genetic factors involved in determining the outcome of antiviral therapy is necessary. Newly developed bio-techniques (microarray, proteomes, bioinformatics), drugs, and treatment strategies may elucidate the pathogenesis and improve the therapeutic response in HCV infection.

Lee CM, Hung CH, Lu SN, Wang JH, Tung HD, Huang WS, Chen CL, Chen WJ, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan (ROC). · Intervirology. · Pubmed #16166793 No free full text.

Abstract: Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.

Kee KM, Wang JH, Lee CM, Changchien CS, Eng HL. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung. · Chang Gung Med J. · Pubmed #15796260 links to  free full text

Abstract: Dermatomyositis is a rare and idiopathic inflammatory myopathy with characteristic cutaneous manifestations. In recent years, some researchers have showed the cause of dermatomyositis might be due to an autoimmune response induced by viral infections. However, chronic hepatitis C virus (HCV) infection associated with dermatomyositis is very rare. In this report, we present a patient with dematomyositis with abnormal liver function test results and elevated alfa-fetoprotein level. After excluding multiple viral infections known to cause myositis, the case was proven to be chronic hepatitis C by positive HCV-RNA in the serum. Abdominal computed tomography showed a liver tumor on the right lobe and needle biopsy proved it to be hepatocellular carcinoma. Chronic hepatitis C or hepatocellular carcinoma might cause dermatomyositis by inducing the formation of autoantibodies. Chronic hepatitis C or hepatocellular carcinoma should be considered in patients of dermatomyositis if no other cause is found.

Yen YH, Lu SN, Chen CH, Wang JH, Wu CM, Hung CH, Tseng PL, Hu TH, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. · Liver Int. · Pubmed #18036099 No free full text.

Abstract: BACKGROUND: To elucidate the associations between the changing patterns of hepatitis B e antigen (HBeAg) levels and the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants in HBeAg non-seroconverted patients undergoing lamivudine therapy. METHODS: This study analysed 76 HBeAg-positive naïve chronic hepatitis B patients treated with lamivudine. The median duration of therapy was 52 weeks. The YMDD mutants were detected in 35 patients. The changing patterns of HBeAg levels were categorized into three groups: Descending, Descending-Ascending and Fluctuation. HBeAg breakthrough was defined as progressive HBeAg decreasing to <10% of pretreatment levels, followed by increases exceeding 50 S/Co [the ratio of the sample (S) to the cut-off (Co)] above nadir levels. RESULTS: Of 76 patients, the sensitivity and specificity for predicting YMDD mutants by the Descending-Ascending pattern were 66 and 100% respectively. Of 17 patients with YMDD mutants in the Descending-Ascending group, hepatitis B virus (HBV) DNA first increased, followed by increased HBeAg levels and finally by biochemical breakthrough. The median intervals between virological breakthrough and HBeAg breakthrough, between HBeAg breakthrough and biochemical breakthrough and between virological breakthrough and biochemical breakthrough were 4, 24 and 33 weeks respectively. CONCLUSIONS: Serial HBeAg levels are useful in predicting YMDD mutant emergence in HBeAg non-seroconverted patients during lamivudine therapy.

Chen CH, Wang JH, Lee CM, Hung CH, Hu TH, Wang JC, Lu SN, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung Univeristy College of Medicine, Kaohsiung, Taiwan. · Antivir Ther. · Pubmed #17310821 No free full text.

Abstract: BACKGROUND AND AIMS: The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients. PATIENTS AND METHODS: Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance. RESULTS: IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86-0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12-25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance. CONCLUSION: Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.

Yu ML, Lin SM, Lee CM, Dai CY, Chang WY, Chen SC, Lee LP, Lin ZY, Hsieh MY, Wang LY, Chuang WL, Liaw YF. · Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. · Hepatology. · Pubmed #17058238 No free full text.

Abstract: Changes in hepatic fibrosis after interferon-based therapy may be important in determining the long-term outcome of chronic hepatitis C (CHC). The use of liver biopsy for posttreatment assessment is not a viable option as a routine follow-up procedure. This study evaluated the predictive value of a simple noninvasive index, the aspartate aminotransferase (AST)-to-platelet ratio index assessed 6 months after end of treatment (APRI-M6). We evaluated APRI-M6, platelet-M6, AST-M6, and alpha-fetoprotein-M6 of 776 CHC patients with interferon-based therapy as well as the parameters at baseline of 562 untreated patients who were evaluated to predict the risk of hepatocellular carcinoma (HCC) and mortality, during a mean follow-up period of 4.75 (1.0-12.2) and 5.15 (1.0-16) years, respectively. Based on analysis of receiver operating characteristics (ROC) and using optimized cutoff point, the APRI-M6 and platelet-M6 had superior prediction models for long-term outcome with area under the curve of 0.870-0.875 and 0.824-0.847, respectively, and accuracy of 78%-81% and 76%-78%, respectively, for interferon-based-treated patients. The predictive values of all 4 parameters were poor in untreated patients. In subgroup analysis, the APRI-M6 provided a more consistent prediction ratio than platelet-M6 for sustained responders and cirrhosis-free subgroups; both parameters had similar prediction power for nonresponders and were unsatisfactory in patients with cirrhosis. According to Cox proportional hazards analysis, cirrhosis and APRI-M6 were the 2 most important factors for predicting HCC. In conclusion, APRI-M6 can accurately predict the long-term outcome of patients subjected to interferon-based treatment. Nevertheless, the data needs further validation, particularly since the predictive accuracy for patients with cirrhosis is low.

Hung CH, Kuo FY, Wang JH, Lu SN, Hu TH, Chen CH, Lee CM, Eng HL. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Antivir Ther. · Pubmed #16856622 No free full text.

Abstract: BACKGROUND/AIMS: Steatosis is recognized as a cofactor influencing the presence and progression of fibrosis in chronic hepatitis C. It has been reported that antiviral therapy may reduce the progression of fibrosis and leads to regression in chronic hepatitis C patients achieving a sustained virological response (SVR). Whether steatosis might affect the long-term histological outcome of antiviral therapy remains unclear. METHODS: One-hundred and sixty-one consecutive patients (genotype 1, n=76; genotype 2, n=73) receiving interferon-alpha2b and ribavirin were analysed. Ninety patients had paired biopsies with a mean interval of 29.1 +/- 7.1 months. RESULTS: Variables associated with baseline steatosis were higher body mass index (> or = 25, P=0.002) and higher fibrosis stage (> or = 2, P=0.019). Neither the presence nor the severity of steatosis was associated with SVR. Evaluation of paired biopsies showed no different distribution of steatosis evolution between patients with and without SVR (P=0.374). Among patients achieving a SVR, there was a significant difference in fibrosis changes between those with grade 0 or 1 steatosis and with grade 2 or 3 steatosis at post-treatment biopsy (-0.6 +/- 1.2 vs 0.3 +/- 1.3, P=0.041), whereas changes in histological activity index did not differ (-3.7 +/- 2.6 vs -4.0 +/- 2.9, P=0.740). Stepwise logistic regression analysis showed that SVR (odds ratio [OR]: 16.33, P=0.004) and grade 0 or 1 post-treatment steatosis (OR: 12.82, P=0.018) were independently associated with fibrosis regression. CONCLUSIONS: In patients with chronic hepatitis C, steatosis not only correlates with advanced fibrosis at baseline but also affects fibrosis regression after antiviral therapy.

Hung CH, Lee CM, Lu SN, Wang JH, Hu TH, Tung HD, Chen CH, Chen WJ, Changchien CS. · Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Viral Hepat. · Pubmed #16842444 No free full text.

Abstract: We assessed the efficacy of interferon (IFN) alpha-2b plus ribavirin therapy in patients with hepatitis C virus (HCV)-related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty-two HCV-cirrhotic patients receiving IFN alpha-2b (3 or 5 MU thrice weekly) and oral ribavirin (1,000-1,200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan-Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log-rank test and by multivariate Cox's regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow-up period of 37 (12-63) months, HCC developed in 11 patients with non-SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan-Meier method also showed that old age (>or=60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Cox's regression analysis, non-SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha-2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV-related cirrhosis.

Tseng PL, Lu SN, Tung HD, Wang JH, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Viral Hepat. · Pubmed #15985009 No free full text.

Abstract: Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.

Hung CH, Lee CM, Lu SN, Wang JH, Tung HD, Chen CH, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15853986 No free full text.

Abstract: BACKGROUND: Patients with dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection have responded poorly to interferon (IFN) monotherapy. The purpose of the present paper was to assess the effect of combined IFN-alpha and ribavirin therapy in patients infected with both hepatitis B and C. METHODS: Thirty-six patients received 3 or 5 MU IFN-alpha-2b thrice weekly and oral ribavirin (800-1200 mg/day) for 24 weeks. All patients had positive hepatitis B surface antigen, antibody to HCV, and HCV-RNA. Before treatment, one patient had positive hepatitis B e antigen. Eighteen patients had positive HBV-DNA tested by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA), with a mean HBV-DNA level of 3.1 +/- 0.9 log copies/mL. Another 72 patients with HCV infection alone served as controls. RESULTS: Adverse events led to withdrawal in three patients receiving 5 MU IFN. Based on an intent-to-treat analysis, the biochemical response and serum HCV clearance rate at the end of 48 weeks follow up was similar in patients with dual infection and HCV infection alone (56% vs 72%; and 69% vs 71%, respectively). There was no significant difference in sustained HCV clearance rate between the 3-MU group (n = 13) and the 5-MU group (n = 23; 85% vs 61%). At the end of 48 weeks follow up, two (11%) of 18 pretreatment viremic patients had negative serum HBV-DNA (<200 copies/mL), while eight of those without pretreatment viremia had re-occurrence of HBV-DNA. CONCLUSIONS: Combination therapy with IFN-alpha and ribavirin was effective in achieving sustained HCV clearance in patients with dual HBV and HCV infection, comparable to those with hepatitis C infection alone. Combination therapy using 3 MU IFN-alpha seemed as effective as 5 MU, and was well tolerated in the study population. However, large-scale control trials are necessary to clarify these findings.

Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, Ng KY, Nicholls GJ, Dent JC, Leung NW. · Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15482535 No free full text.

Abstract: 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.

Chen CH, Lee CM, Lu SN, Wang JH, Tung HD, Hung CH, Chen WJ, Changchien CS. · Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan. · J Hepatol. · Pubmed #15336449 No free full text.

Abstract: BACKGROUND/AIMS: The aim of this study was to compare the clinical outcome between patients continuing and discontinuing lamivudine therapy after the biochemical breakthrough of hepatitis B virus tyrosine-methionine-aspartate-aspartate (YMDD) mutant. METHODS: YMDD mutants were detected in 51 chronic hepatitis B patients who experienced a flare-up of alanine aminotransferase (ALT) during lamivudine treatment. Twenty-seven of them discontinued lamivudine therapy (group A), and 24 continued therapy (group B) after biochemical breakthrough. The follow-up period was 12 months in both the groups. RESULTS: There was no significant difference between groups A and B in the incidence and severity of ALT peaks and hepatic decompensation within the first 3 months after biochemical breakthrough. After the fourth month of biochemical breakthrough, however, group A experienced acute exacerbation more frequently [20/26 (77%) vs. 7/23 (30%); P=0.002] and higher ALT peaks than group B. The same result was found when the patients were divided into naïve and retreated or cirrhotic and non-cirrhotic groups. Hepatic decompensation at the onset of biochemical breakthrough was associated with higher mortality (OR=70, 95% CI=6.06-807.75). CONCLUSIONS: Patients who discontinued lamivudine therapy increased the frequency of flare-ups and higher ALT peaks than those who continued therapy after 4 months post-breakthrough.

Lee CM, Ong GY, Lu SN, Wang JH, Liao CA, Tung HD, Chen TM, Changchien CS. · Liver Unit, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. · J Hepatol. · Pubmed #12399235 No free full text.

Abstract: BACKGROUND/AIMS: Lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B was reported to be durable by several studies but controversy still exists. The aim of this study was to evaluate the durability of the responses of lamivudine treatment. METHODS: Among 53 chronic hepatitis B patients who had acute exacerbation and had finished lamivudine therapy after at least 6 months of treatment, 31 patients achieved full HBeAg seroconversion twice at least 1 month apart, and subsequently stopped lamivudine therapy. Post-treatment monitoring was continued for up to 87 weeks. Alanine transaminase (ALT), HBeAg and hepatitis B virus (HBV) DNA were used as indicators for relapse. RESULTS: The cumulative relapse rates at 48 and 72 weeks post-treatment were 45.4% and 56.3%, respectively. During follow up, normal ALT levels precluded relapse while ALT levels over two times the upper limit of normal indicated relapse, which correlated well with HBeAg or HBV DNA reappearance. Patients older than 25 years were more likely to experience post-treatment relapse. CONCLUSIONS: Lamivudine-induced full HBeAg seroconversion was not durable in the Taiwanese population. ALT levels were useful for relapse detection. Age was the only independent predictive factor for relapse.

Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S, Condreay LD, Chien RN, Anonymous00252. · Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong. · Hepatology. · Pubmed #11391543 No free full text.

Abstract: 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.

Chen CH, Changchien CS, Lee CM, Tung WC, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. · Department of Internal Medicine, Division of Hepatogastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. · Int J Cancer. · Pubmed #19431214 No free full text.

Abstract: This study was to investigate the clinical significance and virologic factors of occult hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients without hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (non-B, non-C) in Taiwan. Serum HBV DNA (occult HBV) was detected in 90 of 222 non-B, non-C HCC patients and 24 of 300 non-B, non-C controls without HCC. Of 90 occult HBV-infected HCC patients, the sequences of HBV pre-S/surface, X and enhancer II/core promoter/precore genes were analyzed from 40 patients. Direct sequencing of such genes was also performed in 24 non-B, non-C controls without HCC and 40 HBsAg-positive HCC controls. Compared with non-B, non-C controls without HCC, non-B, non-C subjects with HCC had significantly higher prevalence of occult HBV (p < 0.0001). Moreover, M1I and Q2K in pre-S2 gene and G1721A were more common in occult HBV-infected patients with HCC than in those without HCC. Compared with the HBsAg-positive HCC controls, occult HBV-infected HCC patients had higher frequencies of M1I and Q2K in pre-S2 gene, G185R and S210N in surface gene, A36T and A44L in X gene, and G1721A in enhancer II gene, and had lower rates of pre-S deletions and A1762T/G1764A, A1846T, G1896A and G1899A in core promoter/precore genes. Multivariate analysis showed Q2K in pre-S2 gene, G1721A and A1846T were independent factors for occult HBV-infected HCC. Our study suggested that the virological factors of HBV related to HCC were different between occult HBV-infected and HBsAg-positive patients. The G1721A, M1I and Q2K in pre-S2 gene may be useful viral markers for HCC in occult HBV carriers.

Wang JH, Changchien CS, Hung CH, Eng HL, Tung WC, Kee KM, Chen CH, Hu TH, Lee CM, Lu SN. · Department of Internal Medicine, Division of Hepato-Gastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao Sung, Kaohsiung, Taiwan. · J Gastroenterol. · Pubmed #19308312 No free full text.

Abstract: BACKGROUND: The aim of this study was to assess the diagnostic performances of liver stiffness measurement (LSM), ultrasonography (US) and their combined use in predicting the extent of hepatic fibrosis. METHODS: Consecutive patients with chronic hepatitis B (HBV) or hepatitis C virus (HCV) infections, with indications for liver biopsy, were prospectively enrolled. LSM was performed on the same day as biopsy. US scores, including assessment of liver surface, liver parenchyma, intrahepatic vessels and spleen index, were used to assess the degree of hepatic fibrosis. The pathological findings were used as a reference standard and diagnostic accuracy was assessed and compared. RESULTS: Three-hundred and twenty patients, including 199 men and 121 women, with a mean age of 50.8 years, were analyzed. There were 214 (66.9%) HCV patients, 88 (27.5%) HBV patients and 18 (5.6%) patients with both HCV and HBV. LSM correlated significantly with the hepatic fibrosis (F) scores, necro-inflammatory activity and US scores in multivariate analysis. The diagnostic accuracy of LSM is significantly superior to US, and equal to combined LSM with US, in the prediction of all HCV-related fibrosis scores. The cut-off value of LSM is 6 kPa for diagnosing F > =1, with a positive predictive value of 91%. Also, the cut-off value is 12 kPa for the prediction of cirrhosis, with a negative predictive value of 94%. CONCLUSIONS: LSM is useful for predicting hepatic fibrosis and excluding cirrhosis. A combination of LSM and US does not improve the accuracy in assessing hepatic fibrosis.

Hung CH, Lee CM, Chen CH, Hu TH, Jiang SR, Wang JH, Lu SN, Wang PW. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Liver Int. · Pubmed #19302182 No free full text.

Abstract: BACKGROUND: The pathogenetic basis for the association between hepatitis C virus (HCV) infection and type-2 diabetes remains uncertain. It has been reported that insulin resistance (IR) plays an essential role. We investigated the association of inflammatory [tumour necrosis factor (TNF)-alpha, interleukin (IL)-6] and anti-inflammatory cytokines (adiponectin and IL-10) with IR in chronic HCV infection. METHODS: Eighty-one consecutive non-diabetic chronic hepatitis C patients (37 men and 44 women, mean age of 51.9+/-12.2 years) and 40 age, sex and body mass index (BMI)-matched healthy individuals were collected. IR was evaluated by the homoeostasis model assessment (HOMA). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with chronic hepatitis C have a higher HOMA-IR, TNF-alpha, IL-6, adiponectin and IL-10, as compared with controls. By multiple linear regression analysis, moderate/severe steatosis grade, total cholesterol level and adiponectin was significantly associated with HOMA-IR, whereas, TNF-alpha, IL-6 and IL-10 was not. Male gender, BMI and HOMA-IR was inversely correlated with the serum adiponectin level. Serum adiponectin was positively correlated with TNF-alpha level, which was significantly associated with higher degree of hepatic necroinflammation. CONCLUSION: Our data suggest that chronic HCV infection is associated with increased IR, which is correlated inversely with the serum adiponectin level. The complex role of adiponectin in the pathogenesis of IR and hepatic necroinflammation in chronic HCV infection merit further investigation.

Tai WC, Hu TH, Wang JH, Hung CH, Lu SN, Changchien CS, Lee CM. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · J Formos Med Assoc. · Pubmed #19293036 links to  free full text

Abstract: BACKGROUND/PURPOSE: Chronic hepatitis C (CHC) shows a significant association with cirrhosis and hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is important in the diagnosis of HCC, but elevated AFP levels have also been observed in CHC without HCC. We evaluated the clinical correlation between elevated AFP levels and CHC. METHODS: From April 1999 to November 2004, 654 CHC patients with no evidence of HCC from imaging studies were collected by chart review. RESULTS: The prevalence of elevated AFP levels (>or= 15 ng/mL) was 23.9%. Univariate analysis revealed that age, histological activity index (HAI) fibrosis score of 3/4, HAI inflammation score >or= 7, aspartate aminotransferase (AST) and alanine transaminase (ALT) levels, AST/ALT ratio, and total bilirubin level were associated with elevated AFP levels. Multivariate analysis revealed that age (>or= 55 vs. < 55 years), HAI inflammation score (>or= 7 vs. < 7), ALT (> 150 vs. <or= 150 U/L), and platelet count (<or= 150 x 109 vs. > 150 x 109 cells/L) were associated with elevated AFP levels. Multivariate analysis also revealed that hepatitis C virus (HCV) genotype 1b, platelet count <or= 150 x 109 cells/L, AST > 80 U/L and AFP >or= 6 ng/mL were associated with advanced fibrosis. Using a cut-off AFP level of >or= 6.0 ng/mL, the sensitivity and specificity of diagnosing fibrosis score 3/4 was 74.3% and 68.4%, respectively. Using a cut-off AFP level of >or= 15.0 ng/mL, the sensitivity and specificity of diagnosing fibrosis score 3/4 was 35.7% and 91.1%, respectively. Conclusion: Elevated AFP levels were observed in 23.9% of patients with CHC. Elevated AFP levels correlated positively with age, HAI inflammation score, ALT elevation, and thrombocytopenia. In addition, HCV genotype 1b, thrombocytopenia, AST elevation, and AFP level >or= 6 ng/mL were associated with advanced fibrosis.

Kao JT, Wang JH, Hung CH, Yen YH, Hung SF, Hu TH, Lee CM, Lu SN. · Department of Internal Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Vaccine. · Pubmed #19186203 No free full text.

Abstract: AIMS: To assess the differences of long-term efficacy between plasma-derived and recombinant hepatitis B virus (HBV) vaccines and the effectiveness of catch-up vaccination in adolescents with undetectable anti-HBs. METHODS: Before 1992, infants born in Taiwan were immunized using plasma-derived HB vaccine, and thereafter, by using recombinant HB vaccine. From the only junior middle school of a rural township in central-southern Taiwan, 1788 (93.7%) students from five cross-sectional screenings, grouping into three birth cohorts (Group I: born during 1984-1986, II: 1986-1992 and III: 1992-1995), were enrolled for checking HBsAg, anti-HBs and anti-HBc. Students with undetectable HBsAg and anti-HBs underwent a booster dose (2.5ug) of recombinant HB vaccine (Engerix-B; GlaxoSmithKline, Rixensart, Belgium) and had anti-HBs re-checked 3 weeks later. Individuals who had remained undetectable for anti-HBs completed the other two doses of HB vaccines at 1 and 6 months later. RESULTS: The prevalence of HBsAg (11.4, 5.4 and 1.2%), anti-HBs (64.5, 44.1 and 36.0%) and anti-HBc (29.5, 12.5 and 4.4%) decreased from Group I to III (P<0.001 for trends). After a booster dose, the positive rates of anti-HBs increased up to 80.5% (16% increase) in Group I, 81.0% (36.9% increase) in Group II, and 94.4% (58.4% increase) in Group III. The percentages of anamnestic response increased with a trend (P<0.001). A total of 110 non-responders completed 3 doses of catch-up HB vaccination, but 3 cases (2.7%) of Group II, evoked primary vaccination response. CONCLUSION: Recombinant vaccine showed predominant disappearance rate (62.7%) of anti-HBs 12-15 years after vaccination, but provided better anamnestic response after a booster dose. It also showed high success rate (97.3%) in catch-up vaccination in adolescents.

Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, Liao LY, Chen CL, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Liu CH, Su WW, Lin CL, Jeng YM, Chen PJ, Chen DS. · National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan. · Gastroenterology. · Pubmed #19084016 No free full text.

Abstract: BACKGROUND & AIMS: Dual chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is common in areas endemic for either virus. Combination therapy with ribavirin and pegylated interferon (peginterferon) is the standard of care for patients with HCV monoinfection. We investigated the effects of combination therapy in patients infected with both HBV and HCV (genotypes 1, 2, or 3). METHODS: The study included 321 Taiwanese patients with active HCV infection; 161 also tested positive for hepatitis B surface antigen (HBsAg) and 160 were HBsAg-negative (controls). Patients with HCV genotype 1 infection received peginterferon alfa-2a (180 mug) weekly for 48 weeks and ribavirin (1000-1200 mg) daily. Patients with HCV genotypes 2 or 3 received peginterferon alfa-2a weekly for 24 weeks and ribavirin (800 mg) daily. At 24 weeks posttreatment, patient samples were examined for a sustained virologic response (SVR) against HCV (serum HCV levels decreased to <25 IU/mL). RESULTS: In patients with HCV genotype 1 infection, the SVR was 72.2% in dually infected patients vs 77.3% in monoinfected patients after treatment. For patients with HCV genotype 2/3 infections, the SVR values were 82.8% and 84.0%, respectively, after treatment. Serum HBV DNA eventually appeared in 36.3% of 77 dual-infected patients with undetectable pretreatment levels of HBV DNA; this was not accompanied by significant hepatitis. Posttreatment HBsAg clearance was observed in 11.2% of 161 dual-infected patients. CONCLUSIONS: Combination therapy with peginterferon alfa-2a and ribavirin is equally effective in patients with HCV monoinfection and in those with dual chronic HCV/HBV infection.

Tsai MC, Chen CH, Lee CM, Chen YT, Chien YS, Hung CH, Wang JH, Lu SN, Yen YH, Changchien CS, Hu TH. · Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan. · J Hepatol. · Pubmed #19070392 No free full text.

Abstract: BACKGROUND/AIMS: In renal transplant recipients (RTRs), chronic hepatitis B virus (HBV) infection may lead to poor outcomes. This study aimed to investigate the role of the HBV genotype, core promoter and precore mutations in advanced liver disease in RTRs. METHODS: We retrospectively reviewed 51 RTRs positive for hepatitis B surface antigen (HBsAg). HBV genotype determination and direct sequencing of core promoter and precore regions were performed using the baseline and end-of-follow-up sera post-renal transplantation. RESULTS: Alanine Transaminase (ALT) and HBV DNA levels were elevated after transplantation (66%). HBV genotypes B and C were found in 45 (88%) and 6 (12%) patients, respectively. There was no significant association of cirrhosis development with ALT, and hepatitis B-e antigen (HBeAg) levels, type of immunosuppressant, HBV genotype, T1762/A1764 and A1896 mutations, and duration of follow-up, except endpoint HBV DNA levels (> or =10(5)copies/ml). High T1762/A1764 mutation rates were associated with high HBV DNA levels (P=0.036) at the endpoint. CONCLUSIONS: HBV DNA replication was enhanced in RTRs with T1762/A1764 mutation. Increased serum HBV DNA levels were associated with cirrhosis development. T1762/A1764 mutation and cirrhosis development did not show significant correlation because of small sample size and/or interventional anti-viral therapies during follow-up.

Chen CH, Changchien CS, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. · Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan. · J Infect Dis. · Pubmed #18939932 No free full text.

Abstract: BACKGROUND: We sought to investigate the role of sequence variations in pre-S/surface and basal core promoter (BCP)/precore regions of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC). METHODS: The direct sequencing in pre-S/surface and BCP/precore regions of HBV was determined for 80 patients with HCC and 160 control patients with HBV infection. RESULTS: Compared with control patients, patients with HCC had higher frequencies of pre-S deletions and amino acid substitutions at codon 4, 7, and 81 in pre-S1 genes; at the start codon in pre-S2 genes; and at codon 68 in surface genes. Patients also had a lower frequency of amino acid substitution at codon 2 in pre-S2 genes, compared with control patients. In BCP/precore regions, patients with HCC had higher frequencies of C or G1753, A1762/T1764, T1846, and A1899. Multivariate analysis showed that pre-S deletions, I68T surface gene, T1762/A1764, and A1899 were independent factors associated with the development of HCC. The HBV strain with a complex mutation pattern rather than a single mutation was associated with HCC, and the HCC risks increased for patients having these factors in combination. CONCLUSIONS: Pre-S deletions, I68T in surface gene, T1762/A1764, and A1899 were independent risk factors for HCC. Combination of these viral mutations appeared to increase the risk of HCC.

Kao JT, Wang JH, Hung CH, Hu TH, Lee CM, Hung SF, Lu SN. · Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · Liver Int. · Pubmed #18662273 No free full text.

Abstract: BACKGROUND/AIM: Geographical variation in viral hepatitis infection complicates various levels of liver diseases. This study elucidates the changing aetiology of alanine transaminase elevation (ALT levels >40 IU/L) in a previously hepatitis-endemic township. DESIGN/METHODS: Five cross-sectional screenings were performed on teenagers born from 1984 to 1993. We examined hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV), ALT and body mass index, and additionally checked hepatitis B envelope antigen (HBeAg) for positive HBsAg and HCV RNA for positive anti-HCV. Teenagers with ALT elevation underwent an ultrasonography examination. RESULTS: This study enrolled 1788 (93.7%) of 1909 students, discovering individual prevalence of HBsAg (6.3%), anti-hepatitis B core (anti-HBc) (15.5%), anti-HCV (2.2%), overweight (22.4%), obesity (12.8%) and ALT >40 IU/L (3.7%). HBsAg and anti-HBc prevalence declined with trends, while obesity increased with trends (P<0.001). Among 66 ALT-elevated teenagers, prevalence percentages of risk factors were HBsAg (22.7%), anti-HCV (1.5%), obesity (45.5%), HBsAg with obesity (7.6%) and anti-HCV with obesity (3.0%). Additionally, obesity showed predominance (85.7%) among aetiologies of teenagers with fatty livers (60.9%). The independently associated factors of ALT elevation included being male (odds ratio, 2.18; 95% confidence interval, 1.21-3.93), HBsAg (4.25; 1.06-17.13), HBeAg (7.24; 1.64-31.9), HCV RNA (29.03; 5.8-145.29) and obesity (16.5; 8.79-30.98). CONCLUSION: In place of viral hepatitis, obesity is becoming the major aetiology of abnormal liver function among the young generation in a previously hepatitis-endemic area.

Tseng PL, Tai MH, Huang CC, Wang CC, Lin JW, Hung CH, Chen CH, Wang JH, Lu SN, Lee CM, Changchien CS, Hu TH. · Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. · J Surg Oncol. · Pubmed #18646041 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: To elucidate the clinicopathological correlations among vascular endothelial growth factor (VEGF), microvessel density (MVD) and tumor suppressor gene p53 in hepatocellular carcinomas (HCCs), we adopted a new definition of "VEGF overexpression." METHODS: The expressions of VEGF, MVD, and p53 in 113 HCC specimens were analyzed by immunohistochemistry. RESULTS: VEGF expression in surrounding liver tended to be stronger (VEGF overexpression, 31%) than, or similar to (57%) that in HCCs (P = 0.001). P53 positivity was noted in 42 cases (37.1%). MVD ranged from 22 to 201 microvessels/field determined for 5 high-power fields. VEGF expression in HCCs was positively correlated with MVD (P = 0.001). VEGF overexpression is positively correlated with young age (P = 0.008), male gender (P = 0.01), hepatitis B viremia (P = 0.013), high alpha-fetoprotein levels (P < 0.001), p53 (+) (P = 0.036), advanced-stage HCC (P = 0.015), and HCC dedifferentiation (P = 0.004). Survival analyses indicated that VEGF overexpression, high MVD, and advanced-stage HCC were independent poor prognostic factors for disease-free and overall survival. CONCLUSION: This study provides evidence of a positive association between parameters reflective of angiogenesis, and p53 expression in HCCs. VEGF overexpression exhibited a significant correlation with viremia and survival.

Veenstra DL, Sullivan SD, Lai MY, Lee CM, Tsai CM, Patel KK. · University of Washington, Seattle, WA, USA. · Value Health. · Pubmed #18380625 No free full text.

Abstract: OBJECTIVE: In Taiwan, the carrier rate of hepatitis B surface antigen is 15% to 20%, one of the highest in the world. Among chronic hepatitis B (CHB) patients, hepatitis B e antigen (HBeAg)-negative accounts for approximately 40% to 50% of these patients. A recent study found that peginterferon alfa-2a (40 KD) is more effective than lamivudine in treating HBeAg-negative CHB, but its cost-effectiveness has not been evaluated. Our objective is to evaluate the incremental cost-effectiveness of 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine, from the perspective of the Taiwan Bureau of National Health Insurance. METHODS: A Markov model was used to simulate the natural history of HBeAg-negative CHB in a cohort of 40-year-old patients. Efficacy, disease progression, economic, and quality-of-life data were derived from published literature and a survey of clinical experts in Taiwan. Life expectancy, quality-adjusted life expectancy, lifetime costs in New Taiwan Dollars (NTD) (1 USD = 31.96 NTD), and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: The gain in quality-adjusted life-years (QALYs) for 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine was 0.45 at an additional cost of 157,000 NTD (4900 USD), resulting in an ICER of 347,000 NTD (10,900 USD) per QALY gained. The 95% central range for the ICER from a probabilistic sensitivity analysis was 228,000-566,000 NTD (7100-17,700 USD). CONCLUSIONS: In HBeAg-negative CHB, 48 weeks of treatment with peginterferon alfa-2a compared to 48 weeks of lamivudine appears to offer life expectancy and quality-of-life improvements at an acceptable cost-effectiveness ratio.