Amelioration of glucose intolerance through directly acting antiviral agents in chronic hepatitis C cirrhotic patients without overt diabetes.

Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2-h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty-three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end-of-treatment) by DAAs were consecutively enrolled. Pre- and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p < 0.001). High baseline 2HPG was independently associated with improved 2HPG in multivariate analysis (odds ratio [OR]/CI: 1.05/1.03-1.06, p < 0.001). When baseline 2HPG was not taken into account, cirrhosis was the only factor independently associated with improved 2HPG status (OR/CI: 2.58/1.29-5.15, p = 0.007). Linear regression analysis revealed that factors independently correlated to changes in 2HPG levels were female sex (ß: 8.78; 95% CI:2.34, 15.22; p = 0.01), diabetes (ß: -27.72; 95% CI: -50.16, -5.28; p = 0.02), liver cirrhosis (ß: -8.91; 95% CI: -16.75, -2.20; p = 0.01), and genotype 1 of HCV (ß: -0.12; 95% CI: -15.19, -2.43; p = 0.01). 2HPG improved after HCV eradication by DAAs, particularly in cirrhotic patients.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in nonalcoholic steatohepatitis patients.

The role of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) in the prediction of disease severity in nonalcoholic fatty liver disease (NAFLD) remains elusive. This study evaluated the performance of WFA+ -M2BP in predicting fibrosis in patients with NAFLD. A total of 80 patients with biopsy-proven nonalcoholic steatohepatitis (NASH) were enrolled. Serum WFA+ -M2BP levels were measured using standard methods. The fibrosis-4 (FIB-4) index was also measured. The mean values of WFA+ -M2BP were 1.0, 1.0, 0.8, and 2.2 in Metavir fibrosis stage F0, F1, F2, and F3-4, respectively (linear trend p = 0.005). The optimal cut-off value of WFA+ -M2BP in predicting advanced fibrosis (F3-4) was 1.37 cut-off index (COI), yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of 75.0, 79.4, 39.1, 94.7, and 78.7%, respectively (p < 0.001). Combining WFA+ -M2BP with FIB-4 significantly increased the diagnostic performance for advanced fibrosis, yielding specificity, PPV, and accuracy of 100, 100, and 93%, respectively. The significant factors predicting advanced liver fibrosis in the multivariate regression analysis were WFA+ -M2BP ≥ 1.37 COI (OR/confidence interval [CI]: 9.49/1.63-55.21, p = 0.01) and FIB-4 ≥ 2.80 (OR/CI: 38.18/4.89-297.93, p = 0.001). Monitoring WFA+ -M2BP is suitable for noninvasive assessment of liver fibrosis in NASH patients, particularly in combination with FIB-4.

Regorafenib for Taiwanese patients with unresectable hepatocellular carcinoma after sorafenib failure: Impact of alpha-fetoprotein levels.

BACKGROUND AND AIMS: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. METHODS: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. RESULTS: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml. CONCLUSIONS: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response.

Artificial intelligence based on serum biomarkers predicts the efficacy of lenvatinib for unresectable hepatocellular carcinoma.

Lenvatinib has been effective not only as a first-line but also as a later-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) in real-world clinical practice. How to predict the efficacy of lenvatinib and guide appropriate therapy selection in patients with uHCC have become important issues. This study aimed to investigate the impact of serum biomarkers on the treatment outcomes of patients with uHCC treated with lenvatinib in a real-world setting using an artificial intelligence algorithm. We measured serum biomarkers, including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, and circulating angiogenic factors (CAFs [i.e., vascular endothelial growth factor, angiopoietin-2, fibroblast growth factor-19 [FGF19], and FGF21]) and analyzed treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with uHCC treated with lenvatinib. The results of this study demonstrated that an AFP reduction ≥ 40% from baseline within 8 weeks after lenvatinib induction was associated with a higher ORR. With baseline biomarkers using a decision tree-based model, we identified patients with high, intermediate, and low ORRs (84.6%, 21.7% and 0%, respectively; odds ratio, 53.04, P < 0.001, high versus intermediate/low groups). Based on the decision tree-based survival predictive model, baseline AFP was the most important factor for OS, followed by ALBI grade and FGF21.

First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients.

BACKGROUND: The efficacy and safety of insulin sensitizer in Asians with non-alcoholic steatohepatitis (NASH) remain elusive. AIMS: The double-blind, randomized, placebo-controlled trial was conducted aiming to investigate the efficacy and safety of pioglitazone in NASH patients. METHODS: A total of 90 NASH patients (66 males, age = 44.1 ± 12.7 years) were prospectively randomized into oral pioglitazone 30 mg/day (Arm A) or placebo (Arm B) for 24 weeks. The primary endpoint was the efficacy of pioglitazone in reducing inflammation and liver fat at end-of-treatment (EOT). NASH resolution/improvement without fibrosis worsening was also evaluated. RESULTS: At EOT, there was a significantly decline of alanine aminotransferase (86.9 ± 34.3 to 45.7 ± 35.8 IU/L, p = 0.003) level in Arm A patients. In intention-to-treat analysis among 66 patients who completed paired biopsies, The NAFLD activity score (NAS) of 30 Arm A patients significantly decreased from 4.27 ± 1.14 at baseline to 2.53 ± 1.63 at EOT (p < 0.0001), whereas there was no significant change in patients of Arm B (3.94 ± 1.41 vs 3.94 ± 1.51, p = 1.0). NASH improvement without worsening of fibrosis was achieved in 46.7% (14/30) patients in Arm A, compared to 11.1% (4/36) patients in Arm B (p = 0.002). Liver fat content reduced (20.2 ± 9.0 to 14.3 ± 6.9%, p < 0.0001) on MRI-PDFF in Arm A compared to their counterparts. No significant difference of adverse events occurred between groups. CONCLUSIONS: A 24-week pioglitazone treatment was well-tolerated and effective in improving liver histology and reducing liver steatosis in Asian NASH patients. (ClinicalTrials.gov number: NCT01068444).

Concordance of SVR12, SVR24 and SVR durability in Taiwanese chronic hepatitis C patients with direct-acting antivirals.

BACKGROUND/AIMS: Undetectable HCV RNA 12 weeks after the end of treatment (SVR12) has been the valid efficacy endpoint in the era of direct-acting antivirals (DAAs). Its concordance with SVR4 and SVR24 and long-term durability is unknown in Taiwanese chronic hepatitis C (CHC) patients. METHODS: A total of 1080 CHC patients who received all-oral DAAs and an achieved end-of-treatment virological response (EOTVR), defined as undetectable HCV RNA at the end of therapy, were consecutively enrolled. HCV RNA was monitored 4, 12, and 24 weeks after EOT. Patients who achieved SVR24, defined as undetectable HCV RNA 24 weeks after EOT, were followed annually for assessing SVR durability. RESULTS: Eleven (1.02%) patients experienced HCV RNA reappearance after EOT. The most frequent timing of RNA reappearance was observed at SVR4 (n = 7), followed by SVR12 (n = 3) and SVR 24 (n = 1). The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 in predicting SVR12 were 99.7% and 100%, respectively, whereas the PPV and NPV of SVR12 in predicting SVR24 were 99.9% and 100%, respectively. Pyrosequencing confirmed delayed relapse rather than reinfection for the patient who had detectable HCV RNA at SVR24. Among 978 patients who achieved SVR24, after a median follow-up period of 17.3±8.2 months, the SVR durability is 100% up to a 4-year follow-up. CONCLUSION: Achievement of SVR12 provides excellent durability of HCV seroclearance after DAA therapy. On-demand HCV RNA beyond SVR12 should be recommended for patients with unexplainable abnormal liver function or high-risk behaviors.

Cure or curd: Modification of lipid profiles and cardio-cerebrovascular events after hepatitis C virus eradication.

Hepatitis C virus (HCV) eradication deteriorates lipid profiles. Although HCV eradication may reduce the risk of vascular events as a whole, whether deteriorated lipid profiles increases the risk of cardio-cerebral disease in certain patients is elusive. Serial lipid profiles were measured before, during, at and 3 months after the end of direct-acting antivirals (DAAs) therapy, and annually thereafter in chronic hepatitis C patients who achieved a sustained virological response (SVR, undetectable HCV RNA at posttreatment week 12). The primary end-point was the occurrence of the events. A total of 617 patients were included, with a mean follow-up period of 26.8 months (range: 1-65 months). The total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from treatment week 4 to 2 years after treatment. Logistic regression analysis revealed that the factors independently associated with a significant cholesterol increase included age (odds ratio [OR]/95% confidence intervals [CIs]:1.02/1.006-1.039, P = .007) and smoking (OR/CI:3.21/1.14-9.02, P = .027). Five patients developed cardio-cerebral diseases during 1376 person-years follow-up period. Compared to patients without vascular events, a significantly higher proportion of those with vascular events experienced an LDL-C surge >40% (80% vs 19.9%, P = .001). Cox-regression analysis revealed that an LDL-C surge >40% was the only factor predictive of vascular events (HR/CI: 15.44/1.73-138.20, P = .014). Dyslipidemia occurred after HCV eradication, and it was associated with the risk of cardio-cerebrovascular diseases. Attention should also be paid to the extrahepatic consequence beyond liver-related complications in the post-SVR era.

Improvement of hyperuricemia in chronic hepatitis C patients receiving directly acting antiviral agents.

BACKGROUND AND AIM: Hepatitis C virus eradication via the use of antivirals ameliorates metabolic profiles. The changes in serum uric acid (SUA) levels in chronic hepatitis C patients who receive antivirals are not well understood. We aimed to address this issue by comparing the SUA changes before and after the achievement of a sustained virological response (which is defined as hepatitis C virus RNA seronegativity at 12 weeks after the end of treatment). METHODS: Two hundred and thirteen sustained virological response patients who were treated by directly acting antivirals were consecutively enrolled. Pretreatment and post-treatment SUA levels were compared. Hyperuricemia was defined as a uric acid level > 7.0 mg/dL in men and > 6.0 mg/dL in women. RESULTS: The SUA levels significantly decreased after treatment, as compared to the pretreatment levels (5.6 ± 1.5 vs 6.0 ± 1.7 mg/dL, respectively; P < 0.001). The proportion of hyperuricemia incidences significantly decreased after treatment (25.8% vs 35.7%, respectively; P = 0.001). The improvement was only observed in patients with a fibrosis-4 index (FIB-4) < 6.5 (25.7% vs 37.1%, P = 0.001) but not in those patients with a FIB-4 â‰§ 6.5 (26.3% vs 28.9%, P = 1.00). A multivariate analysis revealed that the factor that was associated with significantly decreased SUA levels was FIB-4 < 6.5 (odds ratio [OR]/95% confidence interval [CI]: 3.22/1.04-9.95, P = 0.04) and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (OR/CI: 4.34/1.94-9.73, P < 0.001). There existed a trend of a higher proportion of patients with significant SUA improvement along with the decrement of FIB-4 (29.7%, 25%, and 10.5% in patients with FIB-4 < 3.25, 3.25-6.5, and > 6.5, respectively; trend P = 0.03). CONCLUSIONS: SUA levels were significantly decreased in chronic hepatitis C patients after viral eradication. The improvement was particularly enhanced in patients with mild liver disease.

Identification of treatment-experienced hepatitis C patients with poor cost-effectiveness of pegylated interferon plus ribavirin from a real-world cohort.

BACKGROUND/PURPOSE: Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients. METHODS: A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated. RESULTS: We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved. CONCLUSION: In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients.

Identification of groups with poor cost-effectiveness of peginterferon plus ribavirin for naïve hepatitis C patients with a real-world cohort and database.

BACKGROUND: For decades, peginterferon and ribavirin (PegIFN/RBV) have been the standard-of-care for chronic hepatitis C virus (CHC) infection. However, the actual cost-effectiveness of this therapy remains unclear. We purposed to explore the real-world cost effectiveness for subgroups of treatment-naïve CHC patients with PegIFN/RBV therapy in a large real-world cohort using a whole population database. METHODS: A total of 1809 treatment-naïve chronic hepatitis C virus (HCV) patients (829 HCV genotype 1 [G1] and 980 HCV G2) treated with PegIFN/RBV therapies were linked to the National Health Insurance Research Database, covering the entire population of Taiwan from 1998 to 2013 to collect the total medical-care expenses of outpatient (antiviral agents, nonantiviral agents, laboratory, and consultation costs) and inpatient (medication, logistic, laboratory, and intervention costs) visits. The costs per treatment and the cost per sustained virological response (SVR) achieved were calculated. RESULTS: The average medical-care cost was USD $4823 (±$2984) per treatment and $6105 (±$3778) per SVR achieved. With SVR rates of 68.6% and 87.8%, the cost/SVR was significantly higher in G1 than those in G2 patients, respectively ($8285 vs $4663, P < .001). Treatment-naïve G1 patients of old ages, those with advanced fibrosis, high viral loads, or interleukin-28B unfavorable genotypes, or those without a rapid virological response (RVR: undetectable HCV RNA at week 4), or those with complete early virological response (cEVR: undetectable HCV RNA at week 12). Treatment-naïve G2 patients with high viral loads or without RVR or cEVR incurred significantly higher costs per SVR than their counterparts. The cost/SVR was extremely high among patients without RVR and in patients without cEVR. CONCLUSION: We investigated the real-world cost effectiveness data for different subgroups of treatment-naïve HCV patients with PegIFN/RBV therapies, which could provide useful, informative evidence for making decisions regarding future therapeutic strategies comprising costly direct-acting antivirals.

A real-world impact of cost-effectiveness of pegylated interferon/ribavarin regimens on treatment-naïve chronic hepatitis C patients in Taiwan.

Treatments with pegylated interferon/ribavirin (PEG-IFN/RBV) has been standard-of-care in patients with chronic hepatitis C virus (HCV) (CHC) infection and reimbursed in Taiwan. However, the actual cost-effectiveness remains unclear. We aimed to evaluate a real-world cost-effectiveness for CHC patients treated with PEG-IFN/RBV by using a clinical cohort with linkage to the National Health Insurance Research Database of Taiwan. The total and itemized medical-care expenses of outpatient visits of 117 treatment-naïve CHC patients with linkage to the two million sampling of the National Health Insurance Research Database were collected. Four components of costs were assessed, including antiviral agents, nonantiviral agents, laboratory testing and consultation costs. The cost per sustained virological response (SVR) achieved was calculated to evaluate the cost-effectiveness. The average cost per treatment in 117 naïve Taiwanese CHC patients was $4620. With an overall SVR rate of 78.6%, the average cost per SVR was $5878. The average medical-care cost per treatment for 52 Genotype 1 (G1) patients was $5133, including $4420 for antivirals, $380 for nonantivirals, $302 for laboratory, and $78 for consultation, compared to $4209, $3635, $317, $233, and $56 for 65 Genotype 2 (G2) patients. With an SVR rate at 67.3% for G1 and 87.7% for G2 patients, the cost per SVR achieved was significantly higher in G1 patients than those in G2 patients ($7627 vs. $4799, p = 0.001). In the current study, we provided the real-world cost-effectiveness of PEG-IFN/RBV for treatment-naïve CHC patients. The genotype-specific cost-effectiveness could enhance decision-making for policy-makers in the coming era of directly acting antiviral therapy.

Disease severity and erythropoiesis in chronic hepatitis C.

BACKGROUND/AIMS: The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients. METHODS: The red blood cell (RBC) components, serum erythropoietin (EPO) levels, and their relationship to clinical characteristics were evaluated between 124 age-matched and sex-matched healthy controls and 248 histology-proven CHC patients. RESULTS: Chronic hepatitis C patients had significantly higher serum levels of EPO (1.44 ± 0.36 log mIU/mL versus 1.03 ± 0.31 log mIU/mL, P < 0.0001) and lower hemoglobin (Hb) concentrations (14.6 ± 1.4 g/dL versus 15.3 ± 1.2 g/dL, P < 0.001) as compared with healthy controls. Among the CHC patients, the serum EPO level was negatively associated with the Hb concentration (ß = -0.227; 95% confidence intervals [CI]: -0.09-0.027; P < 0.001) and RBC counts (ß = -0.204; 95% CI: -0.245-0.061; P = 0.001) and was positively correlated with necroinflammatory activity (ß = 0.201; 95% CI: 0.009-0.046; P = 0.003) and fibrosis (ß = 0.143; 95% CI: 0.003-0.076; P = 0.04) of liver histopathology. For non-cirrhotic CHC patients, the severity of liver necroinflammatory activity was positively correlated with the reticulocyte and serum EPO levels (P = 0.001 and 0.008, respectively), and negatively related to the RBC counts (P = 0.03). Using stepwise multivariate linear regression analysis, the grade of necroinflammatory activity was positive (ß = 0.214; 95% CI: 0.046-0.209, P = 0.002), whereas the Hb concentration was inversely (ß = -0.205; 95% CI: -0.09-0.018, P = 0.004) associated with the serum EPO levels in CHC patients. CONCLUSIONS: The disease activity in CHC patients had a negative impact on erythropoiesis with compensatory higher but blunted EPO responses.

Dynamics of PBMC gene expression in hepatitis C virus genotype 1-infected patients during combined peginterferon/ribavirin therapy.

Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype.

Elevated on-treatment levels of serum IFN-gamma is associated with treatment failure of peginterferon plus ribavirin therapy for chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1ß, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.

Personalized Therapy of Chronic Hepatitis C and B Dually Infected Patients With Pegylated Interferon Plus Ribavirin: A Randomized Study.

We aimed to investigate whether response-guided therapy (RGT) with peginterferon-alpha plus ribavirin by using hepatitis C virus (HCV) genotype, pretreatment HCV RNA levels, and rapid virological response (RVR, undetectable HCV RNA at treatment week 4) could be applied for active HCV/hepatitis B virus (HBV) dually infected patients, without compromised the treatment efficacy.A total of 203 patients, seropositive of HCV antibody, HCV RNA and HBV surface antigen (HBsAg), and seronegative for HBV e antigen for >6 months, were randomized to receive peginterferon-alpha/ribavirin by either genotype-guided therapy (GGT, n = 102: HCV genotype 1 [HCV-1], 48 weeks; HCV-2/3, 24 weeks) or RGT (n = 101: HCV-1, 48 or 24 weeks if patients with baseline VL <400,000 IU/mL and RVR; HCV-2/3, 24 or 16 weeks if patients with RVR). The primary endpoint was HCV-sustained virological response (SVR).The HCV SVR rate was comparable between the GGT (77.5%, 79/102) and RGT groups (70.3%, 71/101, P = 0.267), either among HCV-1/HBV (69.4% [43/62] vs 63.5% [40/63], P = 0.571) or among HCV-2/3/HBV (90.0% [36/40] vs 81.6% [31/38], P = 0.342) dually infected patients based on intention-to-treat analysis. In HCV-1/HBV dually infected patients, RVR (odds ratio [OR]: 6.05; 95% confidence intervals [CI]: 2.148-17.025, P = 0.001) and lower pretreatment blood glucose levels (OR: 0.97; CI: 0.944-0.989, P = 0.003) were independent predictors of HCV SVR. Although RVR (OR: 10.68; CI: 1.948-58.514, P = 0.006) was the only significant factor associated with HCV SVR in HCV-2/3/HBV dually infected patients. HBsAg loss at 1 year posttreatment was observed in 17 of 185 (9.2%) patients. The rates of discontinuation and adverse events were similar between the 2 groups.RGT with peginterferon-alpha/RBV may be considered for HBeAg-negative HBV/HCV dually infected patients.

The tertiary prevention of hepatocellular carcinoma in chronic hepatitis C patients.

BACKGROUND AND AIM: Pegylated interferon-alpha plus ribavirin combination (PegIFN/RBV) therapy possesses positive effect in the secondary prevention of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients. The current study aimed to assess its efficacy in the tertiary prevention and to validate the performance of the MHC class I polypeptide-related chain A (MICA) level in the prediction of hepatocellular carcinoma (HCC) recurrence. METHODS: A multi-center study enrolling 105 consecutive HCC patients post curative therapies were prospectively recruited. The primary outcome measurement was recurrence of HCC. RESULTS: The mean observational period was 52.7 months (range = 3.9-121.5 months). Fifty-six (53.3%) patients achieved sustained virological response (SVR). After completion of treatment, 43 (41.0%) patients developed HCC recurrence, and 24 (55.8%) of them had their recurrence within 6 months after completion of therapy. Thirty-three (76.7%) of the patients with HCC recurrence were of de novo pattern. Those responders tended to have a lower cumulative incidence of recurrence than those non-responders (43.2 vs 84.8/100 person-month, log-rank P = 0.13). Those non-responders with a high MICA level (>100 pg/mL) carried the lowest cancer-free survival than those non-responders with a low MICA level and those responders (P = 0.002). Cox regression hazard analysis showed high baseline MICA level (Odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.1-20.8, P = 0.04) and a low platelet count (<100 000/mm(3) ) (OR = 5.4, 95% CI = 1.1-27.0, P = 0.04) predicted HCC recurrence. CONCLUSIONS: PegIFN/RBV therapy carried a limited effect in the tertiary prevention of HCC. A high MICA level predicted HCC recurrence, particularly among those non-responders.

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

Peginterferon/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.

Association between gallbladder stones and chronic hepatitis C: ultrasonographic survey in a hepatitis C and B hyperendemic township in Taiwan.

Gallbladder (GB) stones have been associated with several metabolic factors and liver diseases. This community-based study aimed at investigating the prevalence rate of GB stones and its associated factors in a hepatitis B virus (HBV)/hepatitis C virus (HCV)-endemic township in southern Taiwan. A total of 1701 residents (689 males and 1012 females; mean age: 51.2 ± 16.0 years) were enrolled in this prospectively designed screening project. Serum biochemistry tests, including testing for levels of serum aspartate aminotransferase, alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and antibody to HCV (anti-HCV) were conducted. In addition, a hepatobiliary ultrasonographic (US) examination was also conducted. Of the 1701 residents, 243 (14.3%) and 475 (27.9%) were found to be positive for HBsAg and anti-HCV, respectively. Results of the US examination revealed the prevalence rate of GB stone and fatty liver to be 6.8% and 55.6%, respectively. Using univariate analyses we found that significantly higher proportions of the participants with GB stone were male, over 50 years of age, positive for anti-HCV (p = 0.001, p < 0.001, and p = 0.001, respectively), with significantly higher mean age and ALT level (p ≤ 0.001 and p = 0.048, respectively) than did those without GB stone. By applying multivariate analyses, male gender, positive anti-HCV, and older age (>50 year) were identified as independent factors associated with the formation of GB stones. Anti-HCV was associated with GB stones in males but not in females in both univariate and multivariate analyses. GB stones were found to have a prevalence rate of 6.8% in this HCV/HBV hyperendemic township and are associated with higher mean age. A correlation between chronic hepatitis C and GB stones is observed only among males.

Interferon-associated hepatic steatosis is related to discrepancies in biochemical and virological responses of chronic hepatitis C to IFN-based therapy.

BACKGROUND AND AIMS: A discrepancy in virological and biochemical responses may occur throughout interferon-based therapy for hepatitis C virus (HCV). We aimed to explore the risk, associated factors, potential mechanisms, and impact on the treatment outcome of the discrepancy. SUBJECTS AND METHODS: Consecutive 496, chronic HCV-infected patients receiving interferon/ribavirin or peginterferon/ribavirin for 24 weeks with a 24-week follow-up period were enrolled. Of 433 patients with pretreatment liver biopsy, 46 received serial liver biopsies at the end of treatment and end of follow-up to explore the corresponding change in liver histopathology. A virological/biochemical discrepancy was defined as persistently elevated alanine aminotransferase levels throughout the treatment period, despite the seronegativity for HCV RNA at least at the end of treatment. The sustained virological response (SVR) was defined as seronegativity for HCV RNA 6 months after the end of treatment. RESULTS: Virological/biochemical discrepancy was observed in 28.7 % (137/478) patients. The SVR rate was comparable between patients with (75.2 %, 103/137) and without discrepancy (81.2 %, 277/341, p = 0.14). For patients with discrepancy and SVR, 78 (75.7 %) had a subsequent normalization of alanine aminotransferase. Hepatic steatosis, advanced fibrosis, obesity, older age, peginterferon preparation, and low viral load were independently predictive of a virological/biochemical discrepancy. Serial liver histology showed that significant transient aggravation of hepatic steatosis during interferon-based therapy was observed among patients with a virological/biochemical discrepancy (difference 0.64 ± 0.93, p = 0.022), but not among those without it (difference 0.09 ± 0.69, p = 0.447). CONCLUSIONS: A virological/biochemical discrepancy no longer exists after treatment cessation in most patients, and had little impact on the HCV treatment outcome. Treatment-related hepatic steatosis might play an important role in the pathogenesis of the discrepancy.

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.