Ming-Lun Yeh

Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication

BACKGROUND & AIMS Hepatitis C virus (HCV)-infected patients with cirrhosis remain at risk of hepatocellular carcinoma (HCC) even after achieving sustained virological response (SVR). The aim of the study was to explore the incidence and risk for HCC among non-cirrhotic patients with an SVR. METHODS A total of 642 patients with an SVR after peginterferon/ribavirin therapy were enrolled with a median follow-up period of 53.0 months (range: 6-133 months). RESULTS Thirty-three of the 642 (5.1%) patients developed HCC over 2324.8 person-years of follow-up. Cox regression analysis revealed that the strongest predictive factor of HCC occurrence was liver cirrhosis (HR 4.98, 95% CI 2.32-10.71, p<0.001), followed by age (HR 1.06, 95% CI 1.02-1.11, p=0.005) and γGT levels (HR 1.008, 95% CI 1.004-1.013, p<0.001). The incidence of HCC did not differ between patients with high and low baseline γGT levels among patients with cirrhosis (p=0.53), but the incidence of HCC was significantly higher in non-cirrhotic patients with high γGT levels compared with those with low γGT levels (p=0.001). Cox regression analysis revealed that the strongest factors associated with HCC development in non-cirrhotic sustained responders were baseline γGT levels (HR 6.44, 95% CI 2.20-18.89, p=0.001) and age (HR 3.68, 95% CI 1.33-10.17, p=0.012). The incidence of HCC was not different between older non-cirrhotic patients with high γGT levels and cirrhotic patients (p=0.34). CONCLUSIONS HCC remains a threat in non-cirrhotic patients with an SVR. Serum γGT levels helped to identify potential patients at high risk.

Host interleukin-28B genetic variants versus viral kinetics in determining responses to standard-of-care for Asians with hepatitis C genotype 1.

BACKGROUND Both interleukin-28B genetic variants and on-treatment virological responses are factors predictive of treatment outcome in hepatitis C virus genotype 1 (HCV-1) patients. We aimed to compare the clinical significance of the two factors. METHODS Rs8099917 genotype and on-treatment responses were determined in 182 HCV-1 patients with 48-week peginterferon/ribavirin. RESULTS Comparing to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, 46.2% vs. 19.2%, P=0.01) and sustained virological response (SVR, 85.3% vs. 42.3%, P<0.001) rates. Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/95% confidence intervals [OR/CI]: 4.25/1.39-13.01). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 57.22/6.23-525.37), followed by the carriage of rs8099917 TT genotype (OR/CI: 10.06/3.12-32.44). However, while on-treatment factors were taken into account, the cEVR was the most important determinant to an SVR (OR/CI:54.98/9.07-333.38), whereas the influence of rs8099917 genotype became non-significant in non-RVR patients. CONCLUSIONS Rs8099917 TT genotype is significantly independently predictive of on-treatment virological responses, which were the major determinants of an SVR, in Asian HCV-1 patients.

Huge gap between clinical efficacy and community effectiveness in the treatment of chronic hepatitis C: a nationwide survey in Taiwan.

AbstractPeginterferon/ribavirin provides a substantially high treatment efficacy for chronic hepatitis C virus (HCV) infections in Asians. Whether the clinical efficacy can be translated to community effectiveness remains unclear.The disease awareness, treatment accessibility, recommendations, acceptance, and barriers to anti-HCV treatment were explored to clarify the issue with a 3-step nationwide investigation in Taiwan. A crude HCV-infected population was estimated using databases from 3 large-scale surveillance studies and age-/geographic-specific population database. HCV awareness and accessibility were investigated at the patient level in 58,129 residents. The recommendations/acceptances and barriers to treatment at the provider level were evaluated using a prospective, nationwide approach to 89 gastroenterologists/hepatologists.The estimated 10-year interval age-adjusted anti-HCV-seropositive population is 745,109 (3.28%), with an anticipated HCV-viremic population of 554,361. Of anti-HCV-seropositive subjects, 36.2% had disease awareness. Among those with awareness, 39.6% had accessibility. The recommendation/acceptance rate of antiviral therapy was 70.6%. The treatment rate was 10.1% and 13.7% for the anti-HCV-seropositive and HCV-viremic population, respectively. With an anticipated treatment success rate of 80% in Taiwan, 8.1% of the anti-HCV-seropositive and 10.9% of the HCV-viremic population achieved successful treatment. The major treatment barriers were fear of adverse effects (37%), major disorders (17.6%), ineligibility for insurance reimbursement (17.6%), and lack of therapy awareness (11.3%).Despite the high rates of treatment response and nationwide coverage of insurance reimbursement, there remains a large gap between clinical efficacy and community effectiveness in anti-HCV treatment in Taiwan. Increasing disease awareness/treatment accessibility and introducing new therapeutic strategies with high tolerability are warranted.

Hepatitis C virus infection and metabolic syndrome - a community-based study in an endemic area of Taiwan.

Metabolic syndrome (MS) is a complicated disorder associated with a high risk of future development of micro‐ and macrovascular complications. The extrahepatic manifestations of hepatitis C virus (HCV) infection can include multiple metabolic abnormalities. However, the extent, severity, and characteristics of MS in HCV‐infected patients have rarely been investigated in community‐based settings. This study aimed to determine the difference in prevalence and distribution of the components of MS between HCV‐infected patients and healthy controls. Multipurpose mass screening of adults was conducted in an HCV‐endemic area of Southern Taiwan. Clinical profiles in terms of anthropometric data and MS components, as well as viral hepatitis markers, were assessed. Two hundred and thirty‐seven adults (94 males; mean age, 55.5 ± 10.8 years) were recruited. The prevalence of anti‐HCV seropositivity was 39.2% (93/237). The prevalence of MS was higher in the HCV‐infected individuals (24.7%, 23/93) than in the control, uninfected subjects (13.2%, 19/144, p = 0.02). In terms of MS components, HCV‐infected subjects had a higher prevalence of high waist circumference (51.6% vs. 25.7%, p < 0.001) and hypertension (58.1% vs. 36.8%, p = 0.001) than controls. Multivariate logistic regression analysis demonstrated that anti‐HCV positivity was significantly associated with MS (odds ratio, 6.4; 95% confidence interval, 1.82–22.84; p = 0.004). HCV infection was associated with a higher prevalence of MS. Determination of MS in patients with HCV infection could therefore be indicated.

Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis B virus infection treated with direct acting antivirals

Hepatitis B virus (HBV) may reactivate when treating chronic hepatitis C (CHC) with direct acting antivirals (DAA). We aim to investigate the risk of HBV reactivation during DAA therapy.

Chronic hepatitis C infection is associated with insulin resistance and lipid profiles.

Chronic hepatitis C virus (HCV) infection has been suggested to be associated with non‐insulin‐dependent diabetes mellitus and lipid profiles. This study aimed to investigate the possible relationships of insulin resistance (IR) and lipid profiles with chronic hepatitis C (CHC) patients in Taiwan.

High hepatitis B virus surface antigen levels and favorable interleukin 28B genotype predict spontaneous hepatitis C virus clearance in uremic patients

BACKGROUND & AIMS Host and viral factors interplay in the spontaneous clearance of hepatitis C virus (HCV) infection. We aimed to explore the roles of IL28B genotypes and hepatitis B virus (HBV) infections in spontaneous HCV seroclearance. METHODS IL28B rs8099917 genotypes, HCV and HBV markers were determined in 290 patients who were seropositive for HCV antibodies from 1681 total uremic patients on maintenance hemodialysis. RESULTS Persistent HCV viremia was observed in 74.6% (214/287) of patients. Logistic regression revealed that the strongest factors associated with spontaneous HCV seroclearance were carriage of rs8099917 TT-type (odds ratio/95% confidence intervals [OR/CI]: 6.22/1.41-27.35, p=0.016), followed by concurrent hepatitis B surface antigen (HBsAg) seropositivity (OR/CI: 2.37/1.06-5.26, p=0.035). The clearance rate was highest among patients with both positive HBsAg/rs8099917 TT-type (44.8%, OR/CI: 20.88/3.5-402.5), followed by positive HBsAg/rs8099917 non-TT-type (28.6%, OR/CI: 8.86/1.8-160.8), and negative HBsAg/rs8099917 TT-type (26.7%, OR/CI: 12.75/1.0-319.4), compared to 4% of negative HBsAg/rs8099917 non-TT-type (trend p=0.0002). HBsAg levels, but not HBV DNA levels, were significantly associated with spontaneous HCV seroclearance. Spontaneous HCV seroclearance rate was 58.3% in patients with HBsAg>200IU/ml/rs8099917 TT-type (OR/CI: 42.54/5.7-908.4), 28.0% in patients with HBsAg<200IU/ml/rs8099917 TT-type or HBsAg>200IU/ml/rs8099917 non-TT-type (OR/CI: 11.12/2.3-201.0), compared to only 3.3% in those with HBsAg<200IU/ml/rs8099917 non-TT-type (trend p=0.0004). Five of 214 (2.3%) HCV viremic patients at enrollment had spontaneous HCV seroclearance during one-year follow-up, which was associated with baseline HCV RNA and HBsAg levels. CONCLUSIONS High HBsAg levels and favorable IL28B genotype were additively associated with spontaneous HCV seroclearance in uremic patients.

Comparison of the Abbott RealTime HBV assay with the Roche Cobas AmpliPrep/Cobas TaqMan HBV assay for HBV DNA detection and quantification.

BACKGROUND Measurement of hepatitis B virus (HBV) DNA levels is essential in the clinical management of patients with chronic HBV infection. Performance and accuracy of quantitation for HBV DNA are therefore critical in clinical practice. OBJECTIVES We aimed to compare and evaluate the performance characteristics of two HBV DNA quantitative assays: Abbott RealTime HBV (RealTime assay) and Cobas AmpliPrep/Cobas TaqMan HBV assays 2.0 (TaqMan assay). STUDY DESIGN Serum samples from 220 HBV-infected patients were collected. Performance characteristics of the HBV DNA quantitative assays, including sensitivity, linearity, and reproducibility were measured. The assays were compared based on the viral status, including HBeAg, genotype, core promoter and pre-core region mutations. RESULTS The RealTime assay had a sensitivity and specificity of 98.2% and 100%, respectively. The intra-assay coefficients of variation of serum samples ranged from 0.00% to 11.25% for the RealTime assay and 1.22% to 8.22% for TaqMan assay. Paired quantitative results showed excellent correlation by linear regression analysis (R(2)=0.961), good level of agreement with a mean difference of 0.31log10IU/mL, and limits of agreement of -0.62 to 1.24log10IU/mL, irrespective of HBeAg, genotype, core promoter and pre-core region mutation-specific differences. In this study, a difference of ≥1log10IU/mL between the two assays was observed in 8.6% of the samples. Genotype B and average HBV DNA levels of <3log10IU/mL were significant associated factors of this discordance. CONCLUSIONS The Abbott assay delivered high performance for HBV DNA quantification and correlated extremely well with the TaqMan assay, irrespective of viral status.

The efficacy and safety of pegylated interferon plus ribavirin combination therapy in chronic hepatitis c patients with hepatocellular carcinoma post curative therapies – A multicenter prospective trial

BACKGROUND & AIMS Evidence on the efficacy of antiviral treatment in chronic hepatitis C (CHC) patients with hepatocellular carcinoma (HCC) after curative treatment is scarce. We aimed to evaluate the efficacy and safety of pegylated interferon-alpha plus ribavirin (pegIFN/RBV) combination therapy in these patients, compared to cirrhotic patients. METHODS This prospective, multicenter, case-control study recruited 82 consecutive CHC patients with HCC after curative management and 87 sex/age-matched cirrhotic patients. All patients received pegIFN-alpha-2a and weight-based RBV according to current treatment recommendations. The primary outcome measurement was sustained virological response (SVR, seronegative of hepatitis C virus RNA throughout the 6-month post-treatment follow-up period). RESULTS The SVR rate was significantly lower in the HCC group compared to the cirrhosis group (48.8% vs 64.4%, p=0.04). However, the significantly lower rate of SVR in the HCC group was observed among genotype-1 patients (33.3% vs 60.7%, p=0.005) but not among genotype-2/3 patients (70.6% vs 71.0%, p=0.88). In patients who achieved 80/80/80 adherence, there was no significant difference of SVR rate between groups (50.7% vs 64.2%, p=0.12) Multivariate logistic regression analysis demonstrated that rapid virological response (viral clearance during the first 4 weeks of treatment, odds ratio=22.1, p<0.001) and adherence (odds ratio=3.1, p=0.05) were predictive factors associated with SVR, whilst previous occurrence of HCC was not associated with SVR (Odds ratio=0.4, p=0.09). The incidence of severe adverse events did not differ between the two groups. CONCLUSIONS The study proved the feasibility of pegIFN/RBV therapy with current treatment guidelines in CHC patients after successful eradication of HCC, with careful monitoring.

Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.

BACKGROUND & AIMS Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. METHODS The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. RESULTS Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). CONCLUSIONS The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.