Serum retinol-binding protein 4 is inversely correlated with disease severity of chronic hepatitis C.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection carries a significant risk for development of insulin resistance (IR) and/or diabetes mellitus. Recently, retinol-binding protein 4 (RBP4) has been reported as a protein contributing to IR. This study aimed to assess the correlation between RBP4 and disease severity of chronic HCV infection (CHC). METHODS: Serum RBP4 was measured in 105 treatment-nai ve CHC patients and its correlation with the homeostasis model assessment of insulin resistance index (HOMA-IR), liver histology, virology and metabolic factors was investigated. Patients were stratified into different stages of glucose tolerance by oral glucose tolerance test. RESULTS: There was a significant decreasing linear trend of RBP4 dependent on both histological grading (from 35.8+/-16.5 microg/mL of minimal to 19.2+/-12.5 microg/mL of severe, P=0.002) and staging (from 34.2+/-10.0 microg/mL of F0 to 22.2+/-11.9 microg/mL of F3-4, P=0.02) progression, whilst a significant increment of HOMA-IR was found. Multivariate regression analysis showed BMI (1.1, 95% CI 0.44 ~ 1.77, P=0.001), HDL-C (-0.40, 95% CI -0.73 ~ -0.06, P=0.02), and LDL-C (0.31, 95% CI 0.02 ~ 0.61, P=0.04) were the significant variables for prediction of RBP4. CONCLUSIONS: Disease severity may limit the role of RBP4 as a predictor of IR in CHC.

Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial.

UNLABELLED: Recommended treatment for hepatitis C virus genotype 1 (HCV-1) patients is peginterferon plus ribavirin for 48 weeks. We assessed whether treatment duration of 24 weeks is as effective as standard treatment in HCV-1 patients with a rapid virological response (RVR; seronegative for hepatitis C virus [HCV] RNA at 4 weeks). Two hundred HCV-1 patients were randomized (1:1) to either 24 or 48 weeks of peginterferon-alpha-2a (180 microg/week) and ribavirin (1000-1200 mg/day) with a 24-week follow-up. The primary endpoint was a sustained virological response (SVR; seronegative for HCV RNA at 24-week follow-up). Overall, the 48-week arm had a significantly higher SVR rate (79%) than the 24-week arm (59%, P = 0.002). For 87 (43.5%) patients with an RVR, the 24-week arm had a lower SVR rate [88.9%; 95% confidence interval (CI): 80%-98%] than the 48-week arm (100%, P = 0.056). For 52 patients with low baseline viremia (<400,000 IU/mL) and an RVR, the 24-week arm had rates (CI) of relapse and SVR of 3.6% (-3%-11%) and 96.4% (89%-103%), respectively, which were comparable to those of the 48-week arm (0% and 100%) with difference (CI) of 3.6% (-7.2%-6.6%) and -3.6% (-14.3% to -0.6%), respectively. Multivariate analysis in all patients showed that RVR was the strongest independent factor associated with an SVR, followed by treatment duration, mean weight-based exposure of ribavirin, and baseline viral load. CONCLUSION: HCV-1 patients derive a significantly better SVR from 48 weeks versus 24 weeks of peginterferon/ribavirin even if they attain an RVR. Both 24 and 48 weeks of therapy can achieve high SVR rates (>96%) in HCV-1 patients with low viral loads and an RVR.

Reappraisal of the characteristics of glucose abnormalities in patients with chronic hepatitis C infection.

OBJECTIVES: There is growing evidence suggesting the mutual link between type 2 diabetes mellitus (T2DM) and hepatitis C virus (HCV) infection. However, the impact of HCV infection on the suite of glucose abnormalities has rarely been investigated. The study aimed to determine the difference regarding the prevalence and the characteristics of glucose abnormalities between chronic hepatitis C (CHC) patients and community-based controls. It also aimed to investigate the related clinical, virological, and histological features of glucose abnormalities in HCV infection. METHODS: Six hundred eighty-three CHC patients and 515 sex-/age-matched controls were included. Oral glucose tolerance test (OGTT) was performed in 522 CHC patients and 447 controls without known T2DM. Clinical data were assessed upon the different stages of glucose abnormalities based on OGTT results. RESULTS: The prevalence of normoglycemia, IGT, and T2DM in 683 CHC patients was 27.7%, 34.6%, and 37.8%, respectively. There was a significant linear trend from normoglycemia to T2DM in terms of age, family history of T2DM, and advanced liver fibrosis in CHC patients. For those CHC patients without fibrosis, the prevalence of glucose abnormalities reached 67.9% high. All CHC patients carried a significantly higher prevalence than controls regarding those aged <65 yr. For those without known DM, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%) (OR 3.51, 95% CI 2.70-4.56, P < 0.001). CONCLUSIONS: CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested.

Changing prevalence of hepatitis C virus infection among teenagers in an endemic area in Taiwan.

Tzukuan Township in Taiwan has been reported to be an endemic area for hepatitis C virus (HCV) infection both in adults and adolescents. The maritime part of the township carries a higher prevalence than the non-maritime part and, as a consequence, several public education strategies have been introduced during the past decade. The current follow-up study aimed to clarify the changing prevalence of HCV infection among teenagers in the endemic maritime part of Tzukuan. In addition to viral hepatitis markers and biochemical profiles, we compared the epidemiological characteristics of 887 and 394 teenagers (aged 13-16 years) from the maritime part enrolled in 1995 and 2005, respectively. Compared with the results of surveillance in 1995, the prevalence of anti-HCV seropositivity (1.0% vs. 2.8%; P=0.045) and HCV RNA (0.5% vs. 2.3%; P=0.026) had decreased significantly by 2005. Transfusions and anti-HCV-positive families were the main risk factors amongst the 25 anti-HCV-positive teenagers in 1995, and became non-significant amongst the four anti-HCV-positive teenagers in 2005. In conclusion, the seroprevalence of HCV infection has significantly decreased after one decade of intervention among the teenage population in this endemic area.

Hepatitis C virus infection among children in aboriginal areas in Taiwan.

The prevalence of hepatitis C virus (HCV) infection among adults in aboriginal areas has been shown to be higher than in urban areas in Taiwan. Whether the prevalence of HCV infection is also higher among children in aboriginal areas remains unclear. In total, 1176 schoolchildren in four aboriginal areas were invited to participate in the study. All children were tested for serum antibodies to HCV (anti-HCV) and liver enzymes. The age range of children was 6-13 years. Another 606 sex- and age-matched schoolchildren from an urban area served as controls. There was no statistically significant difference in prevalence of anti-HCV between aboriginal and Han Chinese students in aboriginal areas. The prevalence of anti-HCV was 0.3% (4/1176) in aboriginal areas, which was similar to the prevalence of 0% (0/606) in the urban area. The four anti-HCV seropositive aboriginal children were all negative for HCV RNA. Our data suggest that the high prevalence of anti-HCV among aboriginal adults might be due to subsequent exposure to risk factors after school age.

Adefovir dipivoxil treatment of lamivudine-resistant chronic hepatitis B.

Adefovir dipivoxil (ADV)-resistant mutations have been identified in treating hepatitis B virus (HBV) infection. This study aimed to analyze the response, the incidence of ADV resistance and the virologic characteristics of ADV therapy. A total of 29 CHB patients with confirmed lamivudine (LAM)-resistant HBV were treated with ADV for more than 52 weeks. Serum HBV DNA, HBV genotypes and sequences of HBV polymerase reverse-transcriptase domain were determined. Rates for the biochemical response, HBeAg loss, HBeAg seroconversion and virologic response (< 200 copies/mL of HBV DNA) were 82.8, 23.5, 11.8, and 48.3%, respectively, at week 52 of treatment. Lower pre-treatment mean HBV DNA level was the only significant factor associated with negative HBV DNA after ADV therapy. Six (20.7%) patients had clearance of LAM-resistant YMDD variants with replacement by the wild type HBV at week 52. The rtN236T, rtA181V/T and rtI233V were not identified before ADV therapy and the genotypic mutation of rtN236T was detected in one (3.4%) patient. In conclusion, the 52-week ADV treatment for patients with LAM-resistant HBV variants significantly achieved normalization of ALT levels, reduced serum HBV DNA levels and induced HBeAg loss and seroconversion. The emergence of ADV-resistant mutations seemed rare at weeks 52.

Hepatic steatosis and fibrosis in chronic hepatitis C in Taiwan.

Hepatitis C virus (HCV) infection has been associated with hepatic steatosis. However, the role of hepatic steatosis in the pathogenesis of HCV infection remains controversial. In our study, 425 consecutive HCV-viremic patients with biopsy-proven chronic hepatitis C (male, 264; mean age, 49.0 years) were enrolled. Scoring of hepatic steatosis was based on the method described by Kleiner and on histopathology performed using the Knodell and Scheuer systems. HCV RNA level and genotypes were determined at the time of biopsy. Hepatic steatosis was observed in 30.8% of patients, including 113 mild, 16 moderate, and 3 with severe hepatic steatosis. Patients with a body mass index (BMI) <23 kg/m(2) had a significantly lower rate (18.9%) of hepatic steatosis (P<0.001). Hepatic steatosis did not correlate with the hepatic necroinflammatory activity, but was related to hepatic fibrosis (P=0.035). Hepatic steatosis was also not associated with HCV RNA level, and the distribution was similar between patients with HCV genotype 1 and genotype 2 infection. According to multivariate analysis, BMI is the strongest risk factor associated with hepatic steatosis, followed by hepatic fibrosis and triglyceride level with odds ratios (95% confidence intervals) of 2.51 (1.49-4.23), 2.06 (1.14-3.70), and 1.02 (1.01-1.03), respectively. Hepatic steatosis was associated with being overweight, hepatic fibrosis, and triglyceride level in chronic hepatitis C.

Qualitative application of COBAS AMPLICOR HCV test version 2.0 assays in patients with chronic hepatitis C virus infection and comparison of clinical performance with version 1.0.

The objective of this research was to investigate the clinical performance of COBAS AMPLICOR hepatitis C virus (HCV) test version 2.0 Assays (CA V2.0). Eight serial samples with standard HCV ribonucleic acid (RNA) concentration and 10 times serial dilution of the 500 IU/mL samples were tested in triplicate by CA V2.0 (the limit of detection was 50 IU/mL). HCV RNA was investigated with CA V2.0 in 220 specimens from 100 chronic hepatitis C (CHC) patients, 60 chronic hepatitis B patients, and 60 healthy blood donors. The sensitivity was 99% and the specificity was 98.3%. Sera of 84 naïve CHC patients receiving standard interferon plus ribavirin for 24 weeks were tested by CA V2.0 and CA V1.0 at weeks 2, 4 and 8. The positive detection rates of CA V2.0 were significantly higher than CA V1.0 at week 2 (60.7% vs. 51.2%; p < 0.01) and week 8 (27.4% vs. 21.4%; p < 0.05). At weeks 2, 4 and 8, the positive predictive values were 90.91%, 83.02% and 78.69% with CA V2.0, and 90.24%, 82.14% and 72.73% with CA V1.0. The negative predictive values were 58.82%, 77.42% and 86.96% with CA V2.0, and 67.44%, 82.14% and 83.33% with CA V1.0. However, there was no significant difference between CA V2.0 and CA V1.0 for predicting sustained virologic response.

Outcome of chronic hepatitis C patients who required early termination of pegylated interferon-alpha plus ribavirin combination therapy.

BACKGROUND: Pegylated interferon/ribavirin (peg-IFN/RBV) combination therapy is effective for chronic hepatitis C (CHC) but frequently causes adverse events, leading to early termination. Little is known about the outcome of CHC patients who required early termination. METHODS: Of 617 treatment-naive CHC patients prescribed a 24-week protocol of peg-IFN/RBV, 29 (4.7%) patients who terminated treatment early at <20 weeks were recruited to evaluate the rate of and the factors associated with sustained virological response (SVR), defined as seronegativity of hepatitis C virus (HCV) RNA throughout the 24-week off-treatment follow-up period. RESULTS: The reasons for early termination were flu-like symptoms/signs (n=9, 31.0%), irritability (n=1, 3.4%), severe urticaria (n=1, 3.4%), insomnia (n=2, 6.9%), pulmonary tuberculosis (n=1, 3.4%/o), suicide idea (n=2, 6.9%), poor response (n=2, 6.9%), depression (n=2, 6.9%), unwilling to continue (n=1, 3.4%), mortality (n=1, 3.4%), gastrointestinal upset (n=1, 3.4%), pancytopenia complicated with cellulitis (n=1, 3.4%), anaemia (n=3, 10.3%), overseas work (n=1, 3.4%) and an unknown cause (n=1, 3.4%). Five (17.2%) patients achieved an SVR, comprising none of 16 HCV genotype-1 and five of the 13 (38.5%) genotype-2 patients (P=0.001). All sustained responders were HCV RNA seronegative at week 4 of treatment. The SVR rate among HCV-2 patients was 0% (0/1), 0% (0/2), 25% (1/4), 33% (1/3) and 100% (3/3) in those who received peg-IFN/RBV for 1-3, 4-7, 8-11, 12-15 and 16-19 weeks, respectively (P=0.019, chi2 with linear trend). CONCLUSIONS: Based on this limited study, we observed that an SVR might be achieved in patients who required early termination of a 24-week regimen of peg-IFN/RBV, especially for HCV-2 patients with HCV RNA seronegativity at week 4.

Early mortality in Taiwanese lamivudine-treated patients with chronic hepatitis B-related decompensation: evaluation of the model for end-stage liver disease and index scoring systems as prognostic predictors.

BACKGROUND: Both Model for End-stage Liver Disease (MELD) and Index scores have been used to predict mortality in patients with end-stage liver disease and cirrhosis in Western countries. OBJECTIVES: This study aimed to determine mortality rates, identify prognostic indicators, and determine the usefulness of these 2 scoring systems in predicting short-term (6-month) survival in Taiwanese patients with chronic hepatitis B (CHB)-related decompensation who were treated with lamivudine. METHODS: This study was conducted at the Kaohsiung Medical University Hospital and the Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. Eligible patients were aged 18 to 85 years with CHB with related decompensation (with either serum total bilirubin level, >or=3 mg/dL or prolonged prothrombin time, >or=3 seconds) and were treatment naive. All patients were treated with lamivudine 100 mg PO (tablet) once daily; surviving patients were treated for at least 6 months. The clinical data, including hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B virus (HBV) DNA, were measured before treatment. Pre-treatment MELD and Index scores were calculated for all patients. RESULTS: Ninety-six patients were enrolled (79 men, 17 women; mean [SD] age, 44.5 [15.2] years). Thirteen (13.5%) patients died within 6 months. Higher international normalized ratio (INR) for prothrombin time, lower albumin level, and higher HBV DNA level (>or=10(5) copies/mL) were factors significantly associated with death. The areas under the receiver operating characteristic curve for predicting survival by the MELD and Index scores were 0.822 and 0.788, respectively. Albumin level, which was not included in the scoring systems, also was found to be a significant predictor. CONCLUSIONS: : We found that with a 13.5% mortality rate, albumin, INR, and HBV DNA levels were good prognostic indicators in Taiwanese patients with CHB-related decompensation treated with lamivudine therapy. The MELD and Index scoring systems were good predictors of 6-month survival in the patients in this study.

Viral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy.

BACKGROUND/AIMS: We conducted a case-control study to investigate the efficacy of interferon-alpha (IFN-alpha) and ribavirin combination therapy for patients with chronic hepatitis C and B virus (HCV/HBV) coinfection and to elucidate the interaction of these two viruses. METHODS: Forty-two chronic HCV/HBV-coinfected patients (29 IFN-naive, 13 IFN-relapsed) and 84 HCV-monoinfected controls, matched for age, sex and previous history of IFN-alpha therapy, were enrolled. All patients were treated with IFN-alpha-2b 6 MU three-times weekly plus ribavirin 1000-1200 mg daily for 24 weeks. Serum HCV RNA and HBV DNA were determined every 24 weeks for 72 weeks. RESULTS: The rate of HCV sustained virological response (SVR) was comparable among IFN-naive and IFN-relapsed HCV/HBV-coinfected patients and IFN-naive and IFN-relapsed HCV-monoinfected patients (69.0%, 69.2%, 67.2% and 57.7%, respectively; intention-to-treat analysis). HCV genotype 1b, high pretreatment HCV RNA levels and liver fibrosis were significantly associated with a lower HCV SVR. Of 16 baseline HBV viraemic patients, five (31.3%) achieved HBV SVR, which correlated negatively to HCV genotype non-1b and HCV SVR. Only one (6.3%) had simultaneous seroclearance of HCV and HBV. Antibodies to HBV surface antigen seroconversion developed in five (11.9%) patients during long-term follow-up. HCV responders had significantly higher rates of HBV DNA resurgence than HCV non-responders during and after treatment. Reciprocal viral interference was noted between HCV and HBV after IFN-alpha/ribavirin therapy. CONCLUSIONS: IFN-alpha/ribavirin combination therapy is effective for HCV/HBV-coinfected patients in eradicating HCV infection and might promote HBV seroclearance, and there is a mutual viral response and reciprocal viral interaction between HBV and HCV.

Polymorphisms in the interferon-gamma gene at position +874 in patients with chronic hepatitis C treated with high-dose interferon-alpha and ribavirin.

To investigate the influence of the T-to-A polymorphic sequence at position +874 in the interferon (IFN)-gamma gene (+874 IFN-gamma) on the response to combination therapy with high-dose interferon and ribavirin, the single nucleotide polymorphisms were determined by using a polymerase chain reaction sequence-specific primers approach in 150 histologically proved chronic hepatitis C (CHC) patients. The distribution of genotypes for +874 IFN-gamma were T/T: 6 (4.0%), T/A: 31 (20.7%) and A/A: 113 (75.3%) and 24.7% (37/150) of patients were inherited T allele. After undergoing combination therapy with high-dose IFN-alpha and ribavirin, 70.7% (106/150) of patients achieved sustained viral response (SVR). Based on multivariate regression analyses, the independent factors predicting HCV SVR after combination therapy were HCV genotype non-1b (P<0.001) and low pretreatment HCV RNA levels (P=0.041) (odds ratios/95% C.I.: 10.150/4.023-25.609 and 0.581/0.345-0.979, respectively). No association between genotypes, A or T alleles of +874 IFN-gamma and response to combination therapy with high-dose IFN-alpha and ribavirin. In conclusion, we found that with high SVR rates after combination therapy with high-dose IFN-alpha and ribavirin, HCV genotypes and pretreatment serum HCV RNA levels, but not inheritance of the IFN-gamma polymorphism at the position +847, were predictors for SVR.

High versus standard doses interferon-alpha in the treatment of naïve chronic hepatitis C patients in Taiwan: a 10-year cohort study.

BACKGROUND: Interferon-alpha monotherapy is effective in less than one-third patients with chronic hepatitis C. The dose-effect, tolerability and durability of interferon-alpha treatment and its long-term effect on the prevention of cirrhosis and hepatocellular carcinoma in naive Taiwanese patients with chronic hepatitis C have not been well investigated. We conducted the present cohort study treated with high and standard interferon-alpha to illustrate the issues. METHODS: We performed a long-term virologic and histological follow-up of 214 chronic hepatitis C patients treated with interferon-alpha, 3 million units (3-MU, n = 80) or 6-MU (n = 134) thrice weekly for 24 weeks, in Taiwan between 1992 and 2001. RESULTS: There was no difference in the incidence of discontinuation between 3-MU and 6-MU groups (4/80, 5.0% versus 10/134. 7.5%). The 6-MU group had similar incidence of adverse events with the 3-MU group, except that 6-MU group had significantly higher incidence of psychological manifestations, mainly presented as irritability. The rates of sustained virological response (SVR) were significantly higher in 6-MU regimen (37.1%) than in 3-MU regimen (23.7%, p < 0.05) in per protocol analysis. Based on multivariate analysis, baseline viral load was strongly associated with SVR, followed by hepatitis C virus genotype, interferon-alpha regimen, and liver fibrosis. A histological improvement in necroinflammatory activity, but not in fibrosis was observed in the follow-up biopsy performed 0.5-5.5 years (mean: 1.9 years, n = 51) after end-of-treatment. Among patients without SVR, there was more activity improvement in 6-MU group. The durability of SVR was 100% (18/18) and 97.8% (45/46) for 3-MU and 6-MU group, respectively, in a mean follow-up period of 6.81 years (5.25-9.18 years). For 163 baseline non-cirrhotic patients, 9 of 84 (10.7%) non-responders and 3 of 79 (3.8%) sustained responders progressed to cirrhosis during a mean follow-up period of 5.52 and 5.74 years, respectively (p = 0.067, Kaplan-Meier survival analysis, log-rank test). For all 200 patients, hepatocellular carcinoma was detected in 12 of 113 (10.6%) non-responders and one of 87 (1.1%) sustained responders during a mean follow-up period of 5.67 and 5.73 years, respectively (p < 0.01, Kaplan-Meier survival analysis, log-rank test). CONCLUSION: We confirm the dose effect of interferon-alpha in chronic hepatitis C. Six-MU regimen had better efficacy than 3-MU regimen in virologic and histological responses. Both regimens had good tolerability and durability in Taiwan. Sustained response could reduce the incidence of cirrhotic change and hepatocarcinogenesis.

Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin.

AIM: The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C (CHC) and response of both viruses to combination therapy with high-dose interferon-alfa (IFN) plus ribavirin remain uncertain and are being investigated. METHODS: Total 164 (97 males and 67 females, the mean age 48.1+/-11.4 years, range: 20-73 years, 128 histologically proved) naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method. Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay (COBAS AMPLICOR HCV Test, version 2.0). HCV genotypes 1a, 1b, 2a, 2b, and 3a were determined by using genotype-specific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay (Quantiplex HCV RNA 3.0). There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined. RESULTS: Sixty-one (37.2%) patients were positive for SENV-D DNA and had higher mean age than those who were negative (50.7+/-10.6 years vs 46.6+/-11.6 years, P = 0.026). The rate of sustained viral response (SVR) for HCV and SENV-D were 67.3% (105/156) and 56.3% (27/48), respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b (P<0.001), younger ages (P = 0.014), lower pretreatment levels of HCV RNA (P = 0.019) and higher histological activity index (HAI) score for intralobular regeneration and focal necrosis (P = 0.037). By multivariate analyses, HCV genotype non-1b, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR (odds ratio (OR)/95% confidence interval (CI): 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively). The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy (P = 0.04). CONCLUSION: Coexistent SENV-D infection, apparently associated with higher ages, is found in more than one-third Taiwanese CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.

A prospective study on treatment of chronic hepatitis C with tailored and extended interferon-alpha regimens according to pretreatment virological factors.

Hepatitis C virus genotype and viral loads are important predictors for sustained virologic response (SVR) to interferon-alpha therapy for chronic hepatitis C (CHC). We have conducted a prospective study on treatment of 90 patients with a tailored-dose and extended interferon-alpha regimen according to pretreatment virologic factors (low-risk, genotype non-1b/viral < or =0.65 Meq./ml, 6 million units thrice weekly for 12 weeks (6 MU x 12 weeks) followed by 3 MU weeks; high-risk, genotype 1b/viral >0.65 Meq./ml, 6 MU X 24 weeks followed by 3 MU X 24 weeks; medium-risk, the others, 6 MU X 12 weeks followed by 3 MU X 36 weeks), and compared to 123 patients with fixed-dose regimen (6 MU X 24 weeks). Patients with tailored-dose regimen had a significantly higher rate of SVR than those receiving fixed-dose interferon-alpha (46.7% versus 29.3%, P <0.01, intention-to-treat analysis). Improved efficacy was mainly seen in the medium-risk (48.9% versus 26.6%, P=0.02) and the high-risk groups (26.1% versus 8.3%, P=0.06), but not in the low-risk group. By using multivariate logistic regression, low pretreatment viral loads and tailored-dose IFN regimens were significantly associated with higher SVR in both the high- and medium-risk groups. There were no differences in the tolerability and in the incidence of adverse effects between fixed-dose and tailored-dose groups. In conclusion, our results demonstrate the efficacy of tailored-dose interferon-alpha therapy for CHC; these could provide decision-making information for standard/pegylated interferon-alpha combining ribavirin therapy according to baseline predictors.

Tumor necrosis factor alpha promoter polymorphisms at position -308 in Taiwanese chronic hepatitis C patients treated with interferon-alpha.

A G-to-A polymorphic sequence at position -308 in the tumor necrosis factor alpha promoter (TNF308.2) might be associated with disease susceptibilities. To investigate the association between -308 TNF-alpha variants and pathogenesis of hepatitis C virus (HCV) infection and response to interferon-alpha (IFN-alpha) treatment for chronic hepatitis C (CHC), -308 TNF-alpha genotypes were determined in 100 unrelated Taiwanese CHC patients treated with IFN-alpha and in 100 unrelated healthy subjects. The distribution of -308 TNF-alpha genotypes did not differ between CHC patients and controls. Age, sex, HCV genotype, and the necroinflammatory activity of liver histopathology did not differ among CHC patients with different -308 TNF-alpha genotypes. Although pretreatment HCV RNA serum levels, aminotransferase and the rate of severe fibrosis decreased with the copy number of TNF308.2, the difference did not reach significance. We failed to demonstrate any association between -308 TNF-alpha promoter polymorphisms and response to IFN therapy, which was inversely correlated to liver cirrhosis, pretreatment serum HCV RNA levels and genotype 1b by using multivariate analysis. In conclusion, our findings suggest that -308 TNF-alpha promoter polymorphisms do not play a direct role in the susceptibility and pathogenesis of HCV infection, and in the response to interferon-alpha therapy for CHC.

The prevalence and clinical characteristics of coinfection of SENV-H among Taiwanese chronic hepatitis C patients with combination therapy of high-dose interferon-alfa and ribavirin.

The clinical significance of coinfection of SENV-H among patients with chronic hepatitis C (CHC) and the response to combination therapy with high-dose interferon-alpha (IFN) plus ribavirin in Taiwan are uncertain. A total of 151 (120 histologically proved) naïve CHC patients who received 6 MU IFN thrice a week plus ribavirin for 24 weeks therapy were enrolled in this study. SENV-H DNA was tested by PCR method. Of 151 patients, 29 (19.2%) were positive for SENV-H DNA. The positive SENV-H DNA was significantly associated with HCV genotype 1b than non-1b infection (69.0% versus 43.4%; P = 0.011). No other clinical, histopathological and virological factor was related to positive SENV-H DNA. After combination therapy, the rate of sustained viral response (SVR) of HCV and SENV-H were 66.9 and 78.3%, respectively. By multivariate analyses, the significant factors associated with HCV SVR after combination therapy were HCV genotype non-1b, pretreatment HCV RNA levels less than 200,000 IU/mL, and younger age. We conclude that coexistent SENV-H infection, apparently associated with HCV genotype 1b, is found among 19.2% of Taiwanese CHC patients. Both HCV and SENV-H are highly susceptible to combination therapy with high dose IFN and ribavirin and SENV-H coinfection does not affect the HCV response.

Clinical significance of TT virus (TTV) infection in chronic hepatitis C patients with high dose interferon-alpha therapy in Taiwan: re-evaluated by using new set of TTV primers.

BACKGROUND: The clinical significance of TT virus (TTV) coinfection in chronic hepatitis C (CHC) patients and influence of TTV viremia on hepatitis C virus (HCV) response to high dose interferon-alpha therapy in Taiwan were investigated. MATERIALS AND METHODS: Total 102 HCV RNA-positive CHC patients were enrolled. TTV DNA (using polymerase chain reaction primers derived from 5' non-coding region and open reading frame 2), alanine aminotransferase (ALT), GB virus-C/hepatitis G virus (GBV-C/HGV) RNA, anti-E2 antibody, genotype and RNA levels of HCV were tested. RESULTS: The prevalence of TTV DNA was 51.0%. The mean age of TTV viremic CHC patients was significant higher than non-viremic ones (P<0.05). HCV sustained viral response (SVR) was achieved in 42 (41.2%) patients. Based on multivariate regression analyses, SVR were significantly associated with low pretreatment HCV RNA levels, HCV genotype non-1b and high pretreatment levels of ALT but not TTV viremia. CONCLUSIONS: TTV viremia is highly prevalent among Taiwanese CHC patients and related to increased ages. Neither severity of liver disease nor replication and genotype distribution of HCV was affected by concurrent TTV infection. With high HCV SVR rate associated with pretreatment HCV RNA and ALT levels and HCV genotype, TTV viremia did not influence the HCV response.

Antinuclear antibody titer and treatment response to peginterferon plus ribavirin for chronic hepatitis C patients.

Positive serum antinuclear antibody (ANA) is not infrequent in chronic hepatitis C virus (HCV)-infected patients. This prospective study evaluated the impact of ANA on the response to and safety of peginterferon/ribavirin combination therapy for chronic hepatitis C patients in clinical practice. We enrolled 243 consecutive patients who were treated with a 24-week regimen of peginterferon-α plus ribavirin, with a 24-week follow-up period. ANA titer was determined before antiviral treatment. The primary end-point was sustained virological response (SVR), defined as HCV RNA <50 IU/mL throughout the follow-up period. Overall, 187 (77.0%) patients experienced a SVR. In the 105-patient HCV genotype non-1 group, patients with ANA titer ≥1:80 had a significantly lower SVR rate than those with ANA titer <1:80 (67.7% vs. 95.8%, respectively, p = 0.013). In contrast, in the 138-patient HCV genotype 1 group, the SVR rate did not differ between patients with and without ANA titer ≥1:80. Multivariate regressive analyses showed that ANA ≥1:80, age and HCV RNA levels were independent factors associated with SVR in HCV genotype non-1 patients; whereas HCV RNA levels and hepatic fibrosis were prognostic predictors of SVR in HCV genotype 1 patients. The frequencies of adverse events were similar between patients with and without ANA seropositivity. Peginterferon/ribavirin combination therapy is effective and safe in ANA-positive chronic hepatitis C patients. A high ANA titer was a negative prognostic factor for treatment response in HCV genotype non-1 patients.

Viral hepatitis infections in southern Taiwan: a multicenter community-based study.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of liver disease in Taiwan and have a great impact on the health of this country. This study investigated the seroprevalence of HBV and HCV in southern Taiwan. Screening programs were performed from September 1999 to August 2005 for community-based surveillance of liver disease. A total of 28,797 adults from southern Taiwan, including Kaohsiung City (n = 14,036), Kaohsiung County (n = 7,713), and Pingtung County (n = 7,048) were participated. The mean age was 50.3 ± 14.6 years (range, 20-97 years), with 41.0% were men. Hepatitis B surface antigen (HBsAg), antibody to HCV (anti-HCV), and liver function tests were performed. Among the 28,797 adults, the prevalence of HBsAg(+) was 15.1% and that for anti-HCV(+) was 8.6%. The seroprevalence of HBsAg in Kaohsiung County was 18.2%, which was higher than in Kaohsiung City (14.7%, p < 0.001) or Pingtung County (12.5%, p < 0.001). The seroprevalence of anti-HCV in Kaohsiung County was 17.2%, which was higher than in the other regions (Kaohsiung City = 5.8%, p < 0.001; Pingtung County = 4.6%, p < 0.001). The prevalence of dual HBsAg and anti-HCV was 1.1% (323 patients). Tzukuan Township in Kaohsiung County was endemic for HBsAg (19.1%, 1,026/5,375 patients), anti-HCV (22.4%, 1,203/5,375 patients), and dual HBsAg/anti-HCV (3.6%, 191/5,375 patients). Subjects with anti-HCV(+) were older and had higher alanine transaminase levels than their HBsAg(+) counterparts (p < 0.001 and p < 0.001, respectively). The current study shows the epidemiological characteristics of HBV and HCV infections among adults in southern Taiwan. Viral hepatitis infections remain widely endemic in this region.