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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 (β: 8.78; 95% CI:2.34, 15.22; p = 0.01), diabetes (β: -27.72; 95% CI: -50.16, -5.28; p = 0.02), liver cirrhosis (β: -8.91; 95% CI: -16.75, -2.20; p = 0.01), and genotype 1 of HCV (β: -0.12; 95% CI: -15.19, -2.43; p = 0.01). 2HPG improved after HCV eradication by DAAs, particularly in cirrhotic patients.

The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10–0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13–0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04–40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.

Whether patients with advanced hepatocellular carcinoma (aHCC) benefit from hepatitis C virus (HCV) eradication is uncertain. We aimed to investigate whether a survival benefit was conferred by HCV eradication in aHCC patients. This retrospective cohort study enrolled 168 HCV‐infected aHCC patients from April 2013 to January 2019. All patients were treated with sorafenib. Endpoints included overall survival (OS), progression free survival (PFS), and time to liver decompensation. Patients with undetectable HCV RNA exhibited reduced aspartate aminotransferase and alpha fetoprotein levels, as well as an attenuated proportion of aHCC at initial diagnosis but increased albumin and mean sorafenib daily dosing. Patients with undetectable HCV RNA exhibited significantly longer OS compared to patients with detectable or unknown HCV RNA, which was an independent factor of OS (HR: 0.56, 95% CI: 0.350‐0.903, P = .017). Patients with undetectable HCV RNA also presented a trend for longer PFS (HR 0.68, 95% CI: 0.46‐1.00, P = .053). The survival benefit was considered with respect to the significantly prolonged time to Child‐Pugh B scores in patients with undetectable HCV RNA (HR 0.59, 95% CI: 0.38‐0.92, P = .020). Patients with detectable HCV RNA at sorafenib initiation who further received direct acting antiviral therapy also had significantly longer OS (HR 0.11, 95% CI: 0.02‐0.81, P = .030) and PFS (HR 0.23, 95% CI: 0.06‐0.99, P = .048). In conclusion, abolishing HCV viremia preserves liver function and confers a survival benefit in advanced HCC patients on sorafenib treatment.

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.

Background During autophagy defense against invading microbes, certain lipid types are indispensable for generating specialized membrane-bound organelles. The lipid composition of autophagosomes remains obscure, as does the issue of how specific lipids and lipid-associated enzymes participate in autophagosome formation and maturation. Helicobacter pylori is auxotrophic for cholesterol and converts cholesterol to cholesteryl glucoside derivatives, including cholesteryl 6ʹ-O-acyl-α-d-glucoside (CAG). We investigated how CAG and its biosynthetic acyltransferase assist H. pylori to escape host-cell autophagy. Methods We applied a metabolite-tagging method to obtain fluorophore-containing cholesteryl glucosides that were utilized to understand their intracellular locations. H. pylori 26695 and a cholesteryl glucosyltransferase (CGT)-deletion mutant (ΔCGT) were used as the standard strain and the negative control that contains no cholesterol-derived metabolites, respectively. Bacterial internalization and several autophagy-related assays were conducted to unravel the possible mechanism that H. pylori develops to hijack the host-cell autophagy response. Subcellular fractions of H. pylori-infected AGS cells were obtained and measured for the acyltransferase activity. Results The imaging studies of fluorophore-labeled cholesteryl glucosides pinpointed their intracellular localization in AGS cells. The result indicated that CAG enhances the internalization of H. pylori in AGS cells. Particularly, CAG, instead of CG and CPG, is able to augment the autophagy response induced by H. pylori. How CAG participates in the autophagy process is multifaceted. CAG was found to intervene in the degradation of autophagosomes and reduce lysosomal biogenesis, supporting the idea that intracellular H. pylori is harbored by autophago-lysosomes in favor of the bacterial survival. Furthermore, we performed the enzyme activity assay of subcellular fractions of H. pylori-infected AGS cells. The analysis showed that the acyltransferase is mainly distributed in autophago-lysosomal compartments. Conclusions Our results support the idea that the acyltransferase is mainly distributed in the subcellular compartment consisting of autophagosomes, late endosomes, and lysosomes, in which the acidic environment is beneficial for the maximal acyltransferase activity. The resulting elevated level of CAG can facilitate bacterial internalization, interfere with the autophagy flux, and causes reduced lysosomal biogenesis.

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

The features of non-viral, nonalcohol hepatocellular carcinoma (NBNC-HCC) remain elusive. The aim of this study was to investigate this clinical characteristics and overall survival of NBNC-HCC compared to hepatitis B- (HBV-HCC) and hepatitis C-related (HCV-HCC) HCC. We analyzed the etiologies, fibrosis stages, clinical data, and outcomes of newly diagnosed patients with HCC. A total of 1777 HCC patients were recruited, including 332 patients with NBNC-HCC, 682 patients with HBV-HCC, 680 patients with HCV-HCC, and 83 patients with HBV/HCV HCC. Patients with NBNC-HCC were older (69.9 ± 11.9 years). Patients with NBNC-HCC exhibited a higher prevalence of diabetes (43.9%) compared to the HBV-HCC (27.1%, p

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).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.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 ≧ 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 mSUA levels were significantly decreased in chronic hepatitis C patients after viral eradication. The improvement was particularly enhanced in patients with mild liver disease.

Sorafenib is currently the first‐line therapy for advanced hepatocellular carcinoma (aHCC) patients. However, the outcomes and prognostic factors of sorafenib therapy have not been well investigated. We aimed to investigate the pretreatment factors and outcomes among Taiwanese aHCC patients receiving sorafenib treatment. A total of 347 patients with aHCC and well‐compensated liver cirrhosis (Child‐Pugh A) status receiving sorafenib were consecutively enrolled from March 2013 through December 2016. Pre‐treatment clinical data and viral hepatitis markers were collected and analyzed with their outcomes. The primary endpoint of the study was overall survival. The factors associated with overall survival were also investigated. The median overall survival of all the patients was 238 days (range, 9‐1504 days) with a 1‐year overall survival of 43.2%. Positive hepatitis B surface antigen and absence of portal vein thrombosis (PVT) were independent factors associated with better overall survival. The median duration of sorafenib therapy was 93.0 days (range, 4‐1504 days). After stopping sorafenib, the median survival was 93.0 days (range, 1‐1254 days). The 1‐year survival after stopping sorafenib was 21.2%. In chronic hepatitis B patients, total bilirubin level was the only factor associated with overall survival. Hepatitis C antibody RNA negativity, tumor size, PVT, and white blood cell count were the independent factors associated with survival among those chronic hepatitis C patients. There were different prognostic factors stratified by viral etiologies in aHCC patients receiving sorafenib. Viral eradication increased survival in chronic hepatitis C patients.

Background and aims The itemization difference of patient-reported outcome (PRO) in hepatitis patients with different etiologies remains elusive in Asia. We aimed to assess the characteristics and the difference of health-related quality of life (HRQoL) in chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) patients. Methods We conducted the study in an outpatient setting. The 36-Item Short Form Health Survey (SF-36) was completed by the patients upon the initial diagnosis and recruitment for a long-term follow-up purpose. The PRO results were also assessed by disease severity. Results There were 244 patients (198 males) of CHB, 54 patients (29 males) of CHC, and 129 patients (85 males) of NAFLD, respectively. CHC patient had the mean score of 67.1 ± 23.3 in physical component summary (PCS) of the SF-36 health survey, which was significantly lower than CHB patients (76.4 ± 19.5), and NAFLD patients (77.5 ± 13.7), respectively (p = 0.001). The significantly lower performance of PCS in CHC patients was mainly attributed to the lower performance in physical functioning and bodily pain components. Higher fibrosis 4 index scores were significantly associated with lower PCS scores in all patient groups. There was no significant difference of mean mental component summary (MCS) between groups. However, NAFLD patients had significantly lower mental health scores than other groups (p = 0.02). Conclusions The significant difference of HRQoL exists in hepatitis patients with different etiologies. Disease severity leads to a lower PCS performance.

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 were 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%, PConclusions: A 24-weeks pioglitazone treatment was well-tolerated and effective in improving liver histology and reducing liver steatosis in Asian NASH patients. (ClinicalTrials.gov number: NCT01068444)

BACKGROUND AND AIM Hemodialysis patients are at increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Both HBV and HCV infections lead to risks of end-stage liver diseases and extrahepatic manifestations. This study aimed to investigate hepatic and extrahepatic comorbidities in hemodialysis patients with HBV or HCV infections compared with those without viral hepatitis. METHODS A total of 1910 hemodialysis patients, including 159 HCV viremic patients (HCV group), 217 seropositive for HBV surface antigen (HBsAg, HBV group) and 1534 seronegative for both anti-HCV and HBsAg (non-B and non-C [NBNC] group), from 23 hemodialysis centers were enrolled. Comorbidities were classified into 10 categories by the International Classification of Diseases-10th Revision. RESULTS Among the 1910 patients, the mean age was 64.6 years, and 52.7% were male patients. A total of 1834 (96%) patients had at least one comorbidity, and the mean number of comorbidities was 2.9 ± 1.5 per person. The three most common comorbidities were hypertension, diabetes, and ischemic heart diseases. The mean number of comorbidities per person was significantly higher in the HCV group (3.3 ± 1.7) than in the HBV (2.7 ± 1.5, P

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.

BACKGROUND/PURPOSE Switching to a tenofovir alafenamide (TAF)-containing regimen has been reported to be associated with body weight gain in human immunodeficiency virus-infected subjects. We aimed to investigate the body weight change and virological, hepatic, and renal outcomes of TAF switching among chronic hepatitis B (CHB) patients. METHODS This retrospective study included 121 CHB patients who were switched to TAF after >12 months of treatment with another nucleot(s)ide analog (NUC). All patients were monitored for 12 months. RESULTS The cohort was mostly Asian (96.7%) with a mean age of 55 years, 72% male, 14% cirrhosis, 21% HBeAg positive, and 75% with prior use of tenofovir disoproxil fumarate. At 12 months after TAF switching, their body weight significantly increased from 66.4 ± 11.8 to 67.8 ± 12.3 kg (p

Background The accurate assessment of liver fibrosis among hemodialysis patients with chronic hepatitis C (CHC) is important for both treatment and for follow up strategies. Applying the non-invasive methods in general population with viral hepatitis have been successful but the applicability of the aminotransferase/platelet ratio index (APRI) or the fibrosis-4 index (FIB-4) in hemodialysis patients need further evaluation. Materials and methods We conducted a prospective, multi-center, uremic cohort to verify the applicability of APRI and FIB-4 in identifying liver fibrosis by reference with the standard transient elastography (TE) measures. Results There were 116 CHC cases with valid TE were enrolled in our analysis. 46 cases (39.6%) were classified as F1, 35 cases (30.2%) as F2, 11 cases (9.5%) as F3, and 24 cases (20.7%) as F4, respectively. The traditional APRI and FIB-4 criteria did not correctly identify liver fibrosis. The optimal cut-off value of APRI was 0.28 and of FIB-4 was 1.91 to best excluding liver cirrhosis with AUC of 76% and 77%, respectively. The subgroup analysis showed that female CHC hemodialysis patients had better diagnostic accuracy with 74.1% by APRI. And CHC hemodialysis patients without hypertension had better diagnostic accuracy with 78.6% by FIB-4. Conclusions This study confirmed the traditional category level of APRI and FIB-4 were unable to identify liver fibrosis of CHC hemodialysis patients. With the adjusted cut-off value, APRI and FIB-4 still showed suboptimal diagnostic accuracy. Our results suggest the necessary of TE measures for liver fibrosis in the CHC uremic population.

Background We aimed to investigate the long-term outcomes in hepatitis B (HBV)/hepatitis C virus (HCV) dual-infected patients after anti-HCV therapy. Methods A total of 192 HBV/HCV dual-infected patients who had received pegylated interferon treatment were recruited. The investigation outcomes included HBV DNA ≥2000 IU/mL, with or without alanine aminotransferase (ALT) ≥2-fold the upper limit of normal, and hepatitis B surface antigen (HBsAg) seroclearance. Results Four (2.1%) patients developed early HBV reactivation before the end of treatment. Fifty (26.6%) of the remaining patients had an episode of HBV DNA ≥2000 IU/mL in a mean follow-up of 68.8 months. The risk was 4.6 per 100 person years. Only 19 (10.1%) patients developed concomitant ALT flare with oral HBV antiviral therapy; the risk was 1.7 per 100 person years. Despite HBV flare, 67 (34.9%) patients had a favorable outcome of HBsAg seroclearance. The probability was 5.7 per 100 person years. A pretreatment HBV DNA level of 300 IU/mL served as an independent predictor for all the outcomes. The combined pretreatment HBV DNA level and HCV response further enhanced the prediction of HBV flare and HBsAg seroclearance. Conclusions A pretreatment HBV DNA level of 300 IU/mL predicts HBV flare and HBsAg seroclearance after anti-HCV therapy.

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.

Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has recently been developed as a promising liver fibrosis glyco biomarker. We assessed its efficacy in evaluating liver disease severity in chronic hepatitis C (CHC) in Taiwan. The association between WFA+-M2BP and histological features was evaluated among those CHC patients underwent liver biopsy. We also aimed to clarify the factors determining the performance of WFA+-M2BP in CHC. A total of 229 CHC patients were consecutively recruited. The mean value of WFA+-M2BP in patients from F0 to F4 was 1.68, 2.23, 3.45, 3.48, 3.77 respectively (linear trend P = 0.008). Linear regression analysis revealed that alanine aminotransferase (odds ratio [OR]: 0.03, 95% confidence intervals [CI]: 0.02–0.05, P

Background & Aims The outcome of HBV infection, including the dynamics of HBsAg and HBV virological reactivation, among patients coinfected with HCV receiving direct-acting antivirals (DAAs) remains unclear. Thus, we aimed to analyze HBV-related outcomes in these patients. Methods Serial HBsAg and HBV DNA levels were measured in 79 HBV/HCV-coinfected patients receiving DAAs (13 receiving anti-HBV nucleot(s)ide analog [NUC] therapy simultaneously). The endpoints included HBsAg dynamics and seroclearance, HBV reactivation (HBV DNA >1 log increase or >100 IU/ml if undetectable at baseline) and HBV-related clinical reactivation. Results HBsAg levels declined from a median of 73.3 IU/ml at baseline to 16.2 IU/ml at the end-of-DAA treatment and increased to 94.1 IU/ml at 12 months post-treatment. During a mean 11.1-months of follow-up, 8 (10.1%) patients experienced HBsAg seroclearance and 30 (38.0%) HBV reactivation (12-month cumulative incidence, 10.3% and 40.4%, respectively). Patients with pre-treatment HBsAg ≤10 IU/ml had a significantly higher rate of HBsAg seroclearance (hazard ratio [HR] 8.52; 95% CI 1.048–69.312) and lower risk of HBV reactivation than those with pre-treatment HBsAg >10 IU/ml (HR 2.88; 95% CI 1.057–7.844) in multivariate analyses. Six patients (4 cirrhotics) not receiving NUC therapy experienced HBV-related clinical reactivation; 3 of the 4 cirrhotics developed liver failure and 2 died despite immediate NUC therapy. Compared to untreated HBV-monoinfected patients, HBV/HCV-coinfected patients without NUC prophylaxis had a similar rate of HBsAg seroclearance, but a significantly higher risk of HBV reactivation following DAA therapy (HR 6.59; 95% CI 2.488–17.432). Conclusions DAA-treated HBV/HCV-coinfected patients had significantly higher rates of HBV seroclearance, particularly among those with low pre-treatment HBsAg titer, but were at higher risk of HBV reactivation, particularly among those with higher pre-treatment HBsAg titer. Prophylactic anti-HBV therapy is essential for cirrhotic patients, irrespective of baseline HBV DNA levels. Lay summary We studied outcomes relating to hepatitis B virus (HBV) in patients coinfected with both hepatitis B and C. Patients receiving direct-acting antiviral treatment for hepatitis C were more likely to experience seroclearance (or functional cure of HBV), but were also more likely to experience HBV reactivation, which can lead to hepatitis, liver failure and death. In coinfected cirrhotic patients being treated for HCV, prophylactic treatment for HBV is mandatory.

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.

In Taiwan, injecting drug use has been the main route of human immunodeficiency virus (HIV) transmission since 2005, with hepatitis B virus (HBV) and hepatitis D virus (HDV) also having similar transmission routes. This has now become an important public health issue. The aim of this study is to explore the conditions of HDV infections between injecting drug users (IDUs) with and without HIV infection in Southern Taiwan. In this study, 87 IDUs were enrolled, including 27 anti-HDV seronegative IDUs and 60 anti-HDV seropositive IDUs, and the results of their liver function tests, CD4 cell counts, and anti-HIV and HIV RNA levels were analyzed. The prevalence of anti-HDV seropositivity among hepatitis B surface antigen (HBsAg) seropositive IDUs in this study was 68.9% (60/87). The prevalence rate of anti-HDV seropositive IDUs among anti-HIV seronegative and anti-HIV seropositive cases was 40.0% (12/30) and 84.2% (48/57), respectively. Anti-HIV seropositivity was related to anti-HDV seropositivity (odds ratio = 9.34, 95% confidence interval = 2.67–31.59, p

In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26–4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005–4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02–2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely.

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as β-thalassemia and SCD.

The prevalence of mixed cryoglobulinemia is 15-50% in chronic hepatitis C (CHC) patients, and these patients are in an increased risk of liver fibrosis and cirrhosis, but it is controversial. This study aimed to reveal the prevalence of mixed cryoglobulinemia in Asian population and to determine the relationship between presence of serum cryoglobulinemia and liver fibrosis in CHC patients with or without liver biopsy.In total, 2255 treatment-naïve patients retrospectively enrolled in our study. Serum cryoglobulinemia precipitation, liver biopsy, and four indexes of fibrosis (FIB4) were assessed to detect the associated factors.Three hundred sixty-four (32%) out of 1135 liver biopsy patients and 341 (30.4%) out of 1120 non-biopsy patients were positive for serum cryoglobulinemia. Multivariate analysis revealed that male gender, hepatitis C virus RNA, platelet and advanced fibrosis (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.05-1.87, P = 0.021) were significantly associated with the presence of cryoglobulinemia in the liver biopsy proven patients. The presence of serum cryoglobulinemia (OR 1.43, 95% CI 1.04-1.96, P = 0.026) was associated with advanced liver fibrosis (F3 and F4) by multivariate logistic regression analysis. In patients without liver biopsy, FIB4 (OR 1.72, 95% CI 1.30-2.27, P = 0.0001) was associated with the presence of serum cryoglobulinemia, and also cryoglobulinemia (OR 1.74, 95% CI 1.32-2.30, P = 0.0001) was associated with high FIB4 (≥ 3.25) patients.The prevalence of the presence of serum cryoglobulinemia is 30.4-32% in CHC patients and associated with advanced fibrosis in liver biopsy proven patients and high-FIB4 (≥ 3.25) patients without liver biopsy.

The prevalence and characteristics of patients with hepatitis C virus mixed genotype 1 and 2 infection (HCV-1/2) remains unclear. For each HCV-1/2 patient with histological data available, two age- and sex-matched HCV-1 and HCV-2 infected patients were selected for comparison, respectively. Of the 2776 patients, 261 (9.4%) patients were identified as having mixed HCV-1/2 infection. The histological severity did not differ among HCV-1/2 patients and controls. The proportion of patients with the interleukin-28B (IL-28B) rs8099917 TT genotype did not differ between patients with mixed-1/2 and HCV-1 infection (82.6% vs. 86.5%, p = 0.38). However, HCV-2 infected patients had a significantly higher proportion of the rs8099917 TT genotype compared to patients with mixed HCV-1/2 infections (91.6% vs. 82.6%, p = 0.03). The HCV RNA levels were similar in patients with HCV-1/2 and HCV-1 infections (5.5 ± 0.8 log IU/mL vs. 5.5 ± 0.9 log IU/L, p = 0.73), which were both significantly higher than that of HCV-2 infection (5.1 ± 0.9 log IU/mL, both p

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.

The role of transcatheter arterial chemoembolization (TACE) prior to curative therapy is still unclear. The aim of our study was to elucidate the survival of single hepatocellular carcinoma (HCC) and also to clarify whether TACE plus sequential curative therapy provides benefits in single HCC. A total of 470 patients with a diagnosis of single HCC between 2005 and 2010 were studied. The factors associated with clinical outcomes were analyzed. The outcomes between patients who underwent neoadjuvant TACE and those who did not were also compared. The 1-, 3-, and 5-year overall survival (OS) rates of all patients were 92.6%, 73.3%, and 59.6%, respectively. Child-Pugh class A [HR: 2.04, 95% confidence interval (CI): 1.277–3.254, p = 0.003], very early stage Barcelona Clinic Liver Cancer (BCLC) (HR: 2.03, 95% CI: 1.021–4.025, p = 0.043), tumor size

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

ObjectiveThe treatment outcome of direct-acting antivirals (DAAs) in chronic hepatitis C patients with hepatocellular carcinoma (HCC) is controversial. The current study aimed to address the treatment efficacy and safety of DAAs in patients with curative or active HCC, compared with those of patients without HCC.DesignA prospective cohort studySettingA medical centre and two regional hospitals in TaiwanParticipantsA total of 713 Taiwanese patients (601 non-HCC, 74 curative HCC and 38 active HCC patients) who received standard-of-care DAAs were consecutively enrolled in the study.Main outcome measurementThe primary objective was to determine treatment efficacy, defined as undetectable hepatitis C virus RNA throughout 12 weeks of the post-treatment follow-up period (sustained virological response 12 [SVR12]).ResultsThe overall SVR12 rate was 96.9%. The SVR12 rate was similar between the patients with HCC and those without HCC (95.5% vs 97.2%, p=0.37). The HCC patients were divided into two groups, those with curative HCC and those with viable HCC; a substantially but not significantly lower SVR rate, 92.1% (35/38), was observed in the patients with viable HCC compared with the SVR rate, 97.3% (72/74), in those with curative HCC (p=0.33). Compared with the patients with curative HCC, the patients with viable HCC had a significantly higher proportion of serious adverse events (10.5% vs 1.0%, p=0.002), early treatment discontinuation (10.5% vs 2.8%, p=0.03) and mortality (5.3% vs 0.1%, p=0.008).ConclusionsAn equivalently high SVR rate was observed in patients with either past or active HCC compared with those without HCC. The safety concerns in the HCC patients did not compromise treatment efficacy.

Background/Aims Hepatitis C virus (HCV) prevails in patients with thalassemia. We aimed to investigate the efficacy, safety, and impact on red blood cells (RBC) transfusion demand of pegylated interferon (Peg-IFN)/ribavirin therapy in thalassemic patients with HCV. Methods This retrospective study included 18 thalassemic patients (16 with HCV-1b, one HCV-1b/2b, and one HCV-2b) and 54 consecutive sex- and genotype-matched controls. Patients with HCV-2, or HCV-1 or mixed HCV-1/2 with lower viral loads plus rapid virological response (RVR) received 24-week Peg-IFN/ribavirin; whereas HCV-1 or mixed HCV-1/2 with higher viral loads or without RVR received 48-week regimens. Results The rates of RVR, complete early virological response, and sustained virological response (SVR) in thalassemic patients were 72.2% (13/18), 94.1% (16/17), and 77.8% (14/18), which resembled those of controls (63.0%, 94.4%, and 81.5%, respectively). RVR was the only significant factor associated with SVR in thalassemic group, and was the strongest predictor for SVR among both groups (OR/95% CI = 14.7/2.20–98.6), followed by male gender and lower viral loads. More proportion of interleukin-28B-TT carriage were observed among thalassemic patients with SVR versus non-SVR (78.6% vs. 50.0%). Thalassemic patients experienced significantly less 80/80/80 adherence, more ribavirin reduction and serious adverse events than controls. Notably, there was a decreased post-treatment RBC transfusion demand versus baseline in thalassemic patients with SVR (5.21 vs. 5.64 units/month, p = 0.05), but not in those without SVR (6.33 vs. 6.56 units/month, p = 0.54). Conclusion Peg-IFN/ribavirin was effective and tolerable for thalassemic HCV patients. Successful antiviral therapy might have extra benefit of reducing the post-treatment transfusion demand.

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 patients receiving pan-oral DAA therapy from December 2013 to August 2016 were evaluated. Fifty-seven patients that had a past HBV infection (negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody) and seven patients that had a current HBV infection (positive HBsAg) were enrolled. Serum HBV and hepatitis C virus (HCV) markers were regularly measured. The endpoints were the HCV sustained virological response (SVR) and the HBV virological/clinical reactivation.The overall SVRThere was a minimal impact of hepatitis B core antibody seropositivity on HCV efficacy and safety. For CHC patients with current HBV infection, the risk of HBV reactivation was present, and monitoring the HBV DNA level during therapy is warranted.

The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients.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.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 (β = -0.227; 95% confidence intervals [CI]: -0.09-0.027; P 0.001) and RBC counts (β = -0.204; 95% CI: -0.245-0.061; P = 0.001) and was positively correlated with necroinflammatory activity (β = 0.201; 95% CI: 0.009-0.046; P = 0.003) and fibrosis (β = 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 (β = 0.214; 95% CI: 0.046-0.209, P = 0.002), whereas the Hb concentration was inversely (β = -0.205; 95% CI: -0.09-0.018, P = 0.004) associated with the serum EPO levels in CHC patients.The disease activity in CHC patients had a negative impact on erythropoiesis with compensatory higher but blunted EPO responses.

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.

Purpose: Age and hepatic fibrosis are the factors that increase the risk of hepatocellular carcinoma over time. We aimed to explore their impact at the initiation of antiviral therapy on hepatocellular carcinoma among chronic hepatitis C (CHC) patients. Experimental Design: A total of 1,281 biopsy-proven CHC patients receiving IFN-based therapy were followed for a mean period of 5.5 years. Results: The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non–sustained virological response (SVR) and SVR patients who were 55 years old (15.1% vs. 7.9%, P = 0.03). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients 40 to 55 years old [HR/95% confidence intervals (CI), 10.92/3.78–31.56; P < 0.001] and >55 years old (HR/CI, 1.96/1.06–3.63; P = 0.03) but not in patients Conclusions: Delayed hepatitis C virus clearance for patients with CHC >40 years old or with a fibrosis stage >2 increases the risk of hepatocellular carcinoma over time. Clin Cancer Res; 23(7); 1690–7. ©2016 AACR.

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-1β, 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.

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

A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen.Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24 weeks peginterferon/ribavirin.Compared to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, p0.001) and SVR (64.7% vs. 25.6%, p0.001) rates, and lower relapse rate (28.0% vs. 54.5%, p=0.01). 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]: 6.24/2.34-16.63), followed by lower viral loads (OR/CI: 5.29/2.81-9.93) and age (OR/CI:0.94/0.91-9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22-53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18-9.65), lower viral loads (OR/CI: 2.23/1.00-4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06-1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%.Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment.

The purpose of this study was to investigate the potential risk factors for the reactivation of the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma. Forty-four hepatocellular carcinoma patients treated by TACE using epirubicin plus mitomycin C were studied. Serum HBV DNA ( n =17) and HCV RNA ( n =27) levels were measured 1 day before and 3 months after TACE. Plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE. A total of 29 patients ( n =13 for chronic hepatitis Band n =16 for chronic hepatitis C) showed significant changes of the viral loads after TACE. Patients with increased viral loads after TACE were older ( p =0.041), had higher incidence of pre-TACE white blood cell counts being less than normal limit ( p =0.023), and had higher plasma mitomycin C concentrations ( p =0.039) than those in patients with decreased viral loads. Analysis by multiple logistic regressions using age, decreased or normal pre-TACE white blood cell counts, mitomycin C concentrations >3.95ng/mL adopted by receiver operating characteristic curve ( p =0.037), and epirubicin concentrations have shown that decreased pre-TACE white blood cell counts was the only significant factor associated with increased viral loads after TACE ( p =0.048). In conclusion, patients with decreased pre-TACE white blood cell counts have a potential risk for the reactivation of the replication of HBV or HCV after TACE.

Vascular endothelial growth factor (VEGF), angiopoietin-2, and endostatin have been reported to be related with angiogenesis of hepatocellular carcinoma (HCC). The potential feasibility of serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with HCC treated by transcatheter arterial chemoembolization (TACE) was investigated. VEGF-A, angiopoietin-2, and endostatin serum level were determined by enzyme-linked immunosorbent assay 1 day before and 7 days after TACE in 40 patients. Then they were followed up for 3 months. The results showed that TACE could cause significant increase of VEGF-A (p 0.1). Twenty-five patients with rapid growth of HCC within 3 months after TACE had higher proportion of American Joint Committee on Cancer HCC staging >II and higher increase of VEGF-A after TACE than 15 patients without rapid growth (all p 16.7 pg/mL 7 days after TACE selected by receiver operating characteristic curve analysis (p

This prospective study was to investigate the possible risk factors for the leakage of chemotherapeutic agent into the systemic circulation after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Peripheral plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE by high-performance liquid chromatography in 53 patients. HCC were divided into three types namely single nodule (

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 4weeks of treatment, odds ratio=22.1, p 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.

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.

Hepatitis C virus (HCV) infection has been shown to be associated with a low platelet count. This study aimed to elucidate the association between virologic status and platelet count in individuals with HCV infection.A large-scale survey, enrolling 11,239 residents, was conducted in the Kaohsiung area of Taiwan. Serum HCV RNA and non-invasive markers of fibrosis (FibroTest) were tested for antibody to HCV (anti-HCV)-positive subjects. The platelet counts of age- and sex-matched, biopsy-proven, hospital-based patients and community-based patients with minimal fibrosis were compared.Anti-HCV was positive in 703 (6.2%) subjects and was significantly associated with older age, female sex, abnormal alanine aminotransferase (ALT) value and low platelet count (150,000/microl). The independent factors significantly associated with low platelet count were abnormal ALT value (odds ratio [OR]: 3.70, 95% confidence intervals [CI]: 2.18-6.28) and positive HCV RNA (OR: 2.00, 95% CI: 1.01-3.97). After adjustment for the fibrosis, HCV RNA remained significantly associated with platelet counts.Our results evaluating the association between platelet count and HCV viremia and taking the influences of fibrosis into consideration implicate that platelets may be affected directly by HCV.

Aim: Thedevelopment of Type2 diabetes mellitus (T2DM) has been recognized to beassociated with a combination of pancreatic β-cell dysfunction and insulin resistance. Nuclear factor-κB (NF-κB) has been recognized as one central mediator in the reaction of inflammation and proapoptotic event in β-cells. A functional polymorphism at the codon 55 (methionine to valine; A163G) of the small ubiquitin-like modifier-4 (SUMO4) gene may result in higher NF-κB activity. This study investigates whether this SUMO4 Met55Val polymorphism also contributes to the development of T2DM. Materials and methods: The study was peformed using genomic DNA samples from 574 Type 2 diabetic patients and 323 healthy controls. The SUMO4 Met55Val polymorphism was genotyped using allele-specific real-time PCR. Results: The frequency of the G allele (encoding Val55) was-significantly higher in Type 2 diabetic patients and Type 2 diabetic patients with the GG genotype had higherhemoglobin A1c level. Multivariate logistic regression analysis revealed the genotype of GG and GA was an independent risk factor contributing to the development of T2DM. Conclusion: This study suggests that in Taiwan the SUMO4 Met 55Val polymorphism is associated with susceptibility to T2DM and Type 2 diabetic patients with GG genotype have worse glycemic control

Diagnosis of abdominal splenosis is often undiagnosed until treatment for splenic rupture or splenectomy. This report describes a patient with splenosis mimicking hepatic tumor. The patient had a history of splenic trauma with splenectomy and chronic hepatitis C. After routine abdominal ultrasound revealed a liver nodule, further imaging studies, including magnetic resonance imaging, computed tomography and angiography, were performed. After the patient eventually underwent surgery, pathology revealed splenic tissue. Despite its distinguishable clinical features, splenosis is difficult to identify by modern imaging modalities. Therefore, accurate and timely diagnosis of this disease requires constant vigilance.

The production of transforming growth factor beta 1 (TGF-beta1) has been reported as being significantly associated with the gene polymorphism in the leader sequence at positions +29. The current study aimed to evaluate the associations between the polymorphism and the clinical characteristics of chronic hepatitis C (CHC). A total of 422 (252 men; mean age: 49.7 +/- 11.2 years) Taiwanese CHC patients with liver biopsies were enrolled. The TGF-beta1 gene polymorphism at position +29 (T or C), hepatitis C virus (HCV) RNA genotypes, and serum HCV RNA levels of these patients were determined. Of the 422 patients, the frequency of the T allele was 45.4%. Based on univariate analyses, a significantly lesser proportion of patients with allele T had high viral loads than those who were without allele T (P = 0.026). The lesser HCV RNA levels and HCV genotype 1b infection were significantly associated with the inheritance of the T allele in female patients based on univariate (P = 0.012 and 0.007, respectively) and multivariate regression (odds ratio/95% confidence interval: 0.434/0.219-0.859 and 0.468/0.237-0.927, respectively) analyses. In male patients with or without inheritance of the T allele, the clinical characteristics were similar. In conclusion, the association between TGF-beta1 polymorphism and virologic characteristics of chronic HCV infection implicated a significant role of host genetic factors on the clinical features of CHC. Female patients who carry T allele at position +29 were predisposed to be associated with HCV genotype non-1b infection and lesser HCV viral load, which revealed the gender effect.

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.

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.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.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 aged65 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, P0.001).CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested.

Background/Aims To evaluate the association of virologic status with serum cholesterol and triglyceride levels in individuals with hepatitis C virus (HCV) infection. Methods We conducted a large scale community-based study enrolling 11,239 residents in an area endemic for hepatitis B virus (HBV) and HCV infection in southern Taiwan. Overall, 703 (6.3%), 1,536 (13.7%), 84 (0.7%) and 9,084 (80.8%) subjects were sero-positive for anti-HCV antibody (anti-HCV), hepatitis B surface antigen (HBsAg), and both anti-HCV and HBsAg, and negative for anti-HCV and HBsAg, respectively. Results By multivariate logistic analyses, the independent factors significantly associated with elevated serum cholesterol level were older age, female, negative for diabetes, anti-HCV or HBsAg and elevated triglyceride levels. The independent factors significantly associated with elevated serum triglyceride level were male, positive for diabetes, negative for anti-HCV or HBsAg, higher body mass index (BMI) and elevated cholesterol levels. Of 642 anti-HCV-positive subjects that have HCV RNA tested by standardized automated qualitative PCR assay, 478 (74.5%) were positive for HCV RNA. By multivariate logistic analyses, the independent factors associated with elevated serum cholesterol level were female, elevated serum triglyceride levels, negative for diabetes or HCV RNA. The independent factors associated with elevated serum triglyceride levels were elevated serum cholesterol levels, positive for diabetes, higher BMI and negative for HCV RNA. Diabetes, lower cholesterol and triglyceride levels were independent factors associated with positive HCV RNA. Conclusions Based on the result of this large scale community study, HCV viremia appears to be associated with lower serum cholesterol and triglyceride levels which implies that HCV itself might play a significant role on serum lipid profile of patients with chronic HCV infection.

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.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.