Chuan Mo Lee

Peginterferon Alfa-2a Plus Ribavirin for the Treatment of Dual Chronic Infection With Hepatitis B and C Viruses

BACKGROUND & AIMSnDual 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).nnnMETHODSnThe 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).nnnRESULTSnIn 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.nnnCONCLUSIONSnCombination therapy with peginterferon alfa-2a and ribavirin is equally effective in patients with HCV monoinfection and in those with dual chronic HCV/HBV infection.

Prevalence and clinical implications of hepatitis B virus genotypes in southern Taiwan

Background: Hepatitis B virus (HBV) infection is a major health problem. HBV genotypes may be associated with progression of liver disease. The distribution and clinical implications of HBV genotypes in southern Taiwan are evaluated. Methods: We used a polymerase chain reaction-restriction fragment length polymorphism genotyping method to determine HBV genotypes. Results: The genotype distribution for 265 patients with chronic HBV infection was as follows: A, 3 (1%); B, 158 (60%); C, 90 (34%); D, 7 (2.5%); E, 0; F, 0; and unclassified, 7 (2.5%). Compared with genotype B patients, genotype C patients had a higher hepatitis B e antigen positive rate and higher fibrosis score. There was no significant difference in the mean age between genotype B and genotype C patients with hepatocellular carcinoma (HCC). However, when patients were stratified by age, the prevalence of genotype C was significantly higher in young HCC patients (around 50 years of age) than in age-matched asymptomatic carriers (40% versus 10%, P ≺ 0.001). Using multivariate analysis, the significant risk factors for advanced liver disease (cirrhosis or HCC) for patients with chronic HBV infection were old age, male gender and genotype C. Conclusions: These results suggest that genotype C is associated with more severe liver diseases than the B variant.

Fatal Hepatic Failure After Emergence of the Hepatitis B Virus Mutant During Lamivudine Therapy in a Patient with Liver Cirrhosis

Lamivudine therapy for chronic hepatitis and decompensated liver cirrhosis related to the hepatitis B virus (HBV) resulted in improvement of liver function and inhibition of viral replication. Despite emergence of the HBV mutant, e-antigen seroconversion and improvement of liver function may be achieved with continuation of lamivudine therapy. Although hepatic decompensation has been reported in a few cases after the emergence of lamivudine-resistant mutants, fatal cases of non-transplant patients have only rarely been reported in the literature. Here, we describe a patient with HBV-related liver cirrhosis who died after a breakthrough infection with a lamivudine-resistant mutant. Hepatic failure and mortality developed after flare-up of severe hepatitis after 13 months of lamivudine treatment. Emergence of the HBV mutant with substitution of isoleucine for leucine at residue 426 (L426I) in combination with isoleucine for methionine at residue 550 (M550I) was observed at 10 and 13 months of treatment.

A novel predictive score for hepatocellular carcinoma development in patients with chronic hepatitis C after sustained response to pegylated interferon and ribavirin combination therapy

OBJECTIVESnAntiviral therapy can prevent the development of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients. However, HCC still develops in patients achieving sustained virological response (SVR). We proposed to evaluate the risk factors and derive a novel risk score for HCC (score(HCC)) by summation of products of clinical weights based on the regression coefficients in the final proportional hazards model.nnnMETHODSnFrom March 2002 to October 2009, we enrolled 871 patients with biopsy-proven CHC, who received combined pegylated interferon and ribavirin therapy and achieved SVR.nnnRESULTSnCox regression analysis showed that old age [hazard ratio (HR) 3.82, 95% CI 1.74-8.37, Pu200a=u200a0.001], high α-fetoprotein levels (HR 3.15, 95% CI 1.60-6.19, Pu200a=u200a0.001), low platelet counts (HR 2.81, 95% CI 1.22-6.44, Pu200a=u200a0.015) and high fibrotic stage (HR 3.95, 95% CI 1.46-10.70, Pu200a=u200a0.007) were independent risk factors. The cut-off level of risk scores was a derived value of 10 and was able to predict the HCC risk with 89.2% sensitivity and 69.5% specificity. The AUC value for the prediction was 0.848. The score(HCC) values were further categorized into three risk groups: low risk (score(HCC) ≤10), intermediate risk (score(HCC) 11-15) and high risk (score(HCC) ≥16). The proportion of HCC development increased from 1.37% (9/657) in the low-risk group to 9.14% (16/175) in the intermediate-risk group and 30.77% (12/39) in the high-risk group (Pu200a<u200a0.001).nnnCONCLUSIONSnWith the novel risk scores, we can estimate the chance of HCC development more exactly and practically. This approach can be used for HCC screening in CHC patients achieving SVR.

Sustained virological response to interferon reduces cirrhosis in chronic hepatitis C: a 1386‐patient study from Taiwan

Background The long‐term benefits of interferon‐based therapy on preventing cirrhosis at non‐cirrhotic stage in chronic hepatitis C patients are not fully clarified.

Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirin.

summary. Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)‐induced RNA‐dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV‐1b patients who had received IFN‐α2b (3 or 5 MU three times weekly) and ribavirin (800–1200u2003mg per day) for 24u2003weeks. The amino acid sequences of the NS5A and PKR‐eIF2α phosphorylation homology domain (E2‐PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A–PKR binding domain (2209–2274), interferon sensitivity‐determining region (ISDR) (2209–2248), and E2‐PePHD sequence (659–670) in patients with and without SVR were 4.53u2003±u20033.31 vs 2.83u2003±u20031.78 (Pu2003=u20030.094), 2.45u2003±u20032.74 vs 1.03u2003±u20031.32 (Pu2003=u20030.042) and 0.25u2003±u20030.70 vs 0.03u2003±u20030.17 (Pu2003=u20030.109), respectively. Patients with a mutant‐type (≥u20034) NS5A–ISDR had a higher rate of SVR (six of nine, 67%) than those with wild‐type (five of 22, 23%) (Pu2003=u20030.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A–ISDR (≥u20034 vs <u20034) was the only independent variable of treatment outcome. Our study showed that NS5A–ISDR mutations were correlated with the SVR to combination therapy in chronic HCV‐1b patients in Taiwan.

Switching to adefovir monotherapy after emergence of lamivudine-resistant mutations in patients with liver cirrhosis

Summary.u2002 Switching to adefovir (ADV) monotherapy is effective in patients with lamivudine (LAM)‐resistant hepatitis B virus (HBV) mutations (rtM204 I/V). However, it was recommended to continue LAM therapy for months after starting ADV therapy for safety concern. The safety and efficacy of switching to ADV monotherapy was examined in compensated and decompensated patients with liver cirrhosis. The clinical, biochemical and virological responses were compared between ADV monotherapy in 18 cirrhotic patients and ADV add‐on LAM therapy in 10 comparable cirrhotic patients with LAM‐resistant rtM204 I/V. After switching to ADV monotherapy, Child‐Pughs score, serum alanine aminotransferase (ALT), bilirubin, albumin and HBV DNA levels improved significantly (Pu2003<u20030.01). Serum HBV DNA response, defined as HBV DNA decreased to below 105 copies/mL or ≥2u2003log10 reduction form baseline, was achieved in all patients. A transient ALT flare without concurrent changes in serum bilirubin or prothrombin time was observed in only two patients (11%). The efficacy and safety profile was similar to those with ADV add‐on LAM therapy. In conclusion, switching to ADV monotherapy after emergence of LAM‐resistant rtM204 I/V is effective and safe in cirrhotic patients, even in those with hepatic decompensation. To stop LAM and switch to ADV in patients with breakthrough is a reasonably safe and cost‐effective approach.

Long‐term trends and geographic variations in the survival of patients with hepatocellular carcinoma: Analysis of 11 312 patients in Taiwan

Background/Aims:u2002 The survival rates of patients with hepatocellular carcinoma (HCC) were investigated over the past 20u2003years to clarify the long‐term survival trend.

Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin

Backgroundu2002 Most reports suggest that mutations in the interferon sensitivity‐determining region (ISDR) correlate with response to conventional interferon‐based therapies in hepatitis C virus‐1b (HCV‐1b) patients. However, the correlation between ISDR region mutations and response to pegylated interferon plus ribavirin therapy in HCV‐1b patients remains unclear.

Long-term efficacy of plasma-derived and recombinant hepatitis B vaccines in a rural township of Central Taiwan

AIMSnTo 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.nnnMETHODSnBefore 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.nnnRESULTSnThe 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.nnnCONCLUSIONnRecombinant 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.