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Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients. This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups. A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups. This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.

Background and aim Tenofovir disoproxil fumarate (TDF) and entecavir are effective antiviral medications that are recommended as first-line monotherapies for the treatment of chronic hepatitis B (CHB) infection, including decompensated liver cirrhosis with ascites. Acute kidney injury (AKI) commonly occurs in patients with cirrhosis and ascites. The aim of this study was to compare the development of AKI during TDF and entecavir treatment of CHB patients with cirrhotic refractory ascites. Methods From January 2011 to April 2017, we identified patients who were diagnosed with cirrhosis with refractory ascites and received TDF or entecavir treatments at Kaohsiung Chang Gung Memorial Hospital. AKI was defined as an increase in serum creatinine of more than 0.3 mg/dL or 1.5-fold from baseline. All episodes of AKI were recorded and compared between those who received TDF and entecavir. Results A total of 111 patients were enrolled in this retrospective study, of which 22 patients were treated with TDF and 89 were treated with entecavir. Patients with AKI episodes had a higher proportion of TDF treatment (P = 0.01), male (P = 0.023), hepatocellular carcinoma (P = 0.007), admission (P = 0.045), and mortality (P = 0.018). Logistic regression analysis illustrated that TDF treatment of patients with comorbidity was an independent risk factor for the development of AKI [odds ratio (OR), 3.756; 95% confidence interval (CI), 1.293-10.912; P = 0.015] and hepatorenal syndrome (OR, 7.651; 95% CI, 1.697-34.508; P = 0.008). Conclusions TDF treatment is a risk factor for AKI and HRS development in cirrhotic patients with refractory ascites in comparison with entecavir treatment, especially in patients with comorbidity.

Renal toxicity of direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients has not been well-characterized. The aim of this study was to assess renal safety of DAAs in an Asian CHC patient cohort. Data from CHC patients (n = 1536) treated with DAAs were used in this retrospective study. Serial estimated glomerular filtration rate (eGFR) at pretreatment (1-year prior to treatment), baseline, end of treatment (EOT), and 12 weeks after treatment (SVR12 ) was evaluated. While a significant decrease in eGFR from baseline to EOT (84.8 → 81.8 mL/min/1.73 m2 , P 65 years (OR = 1.862, P = .011), baseline eGFR ≥ 60 mL/min/1.73 m2 (OR = 2.684, P = .023), and liver transplant (OR = 3.894, P = .001) were independent risk factors for deteriorating renal function. In conclusion, DAA treatment led to a significant decline in eGFR at EOT but was followed by a slight rise at 12 weeks after treatment. A similar trend was observed with PrOD, DCV/ASV and GZP/EBV, but not in SOF-based regimens. As age >65 years, baseline eGFR ≥ 60 mL/min/1.73 m2 and liver transplantation are significant risk factors for deterioration in renal function, we strongly advice close monitoring of renal function in these populations.

Background Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted. Aims We investigated whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients. Methods A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC was studied. After excluding patients with biopsy-proven or ultrasound-identified cirrhosis, there were 684 patients without cirrhosis. All 684 patients underwent hepatocellular carcinoma surveillance using ultrasound every 6 months, with a median duration of follow-up evaluation of 102.4 months. During the follow-up period, 60 patients developed cirrhosis according to ultrasound findings. Results For the subgroup of 684 patients without cirrhosis, Kaplan–Meier survival analyses showed no significantly different cumulative incidences of cirrhosis (log-rank test; P = 0.71) among the patients with diabetes as compared to those without. However, after making adjustments for age, gender, fibrosis, steatosis, sustained virological response status, and obesity using Cox’s proportional hazard model, diabetes was found to be an independent predictor for cirrhosis (HR = 1.9; 95% CI = 1.05–3.43, P = 0.03). Conclusions Diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients.

Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography.To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation.A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in5% of hepatocytes.No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91-1; P .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP 257 dB/m, none had HS, while of the 12 candidates with CAP ≥257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (β = 0.71, P .001) was found to be independently associated with CAP in those without HS.CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.

Background and importance Clinical decision support systems (CDSSs) are frequently adopted in hospitals to increase prescription accuracy in patients with renal impairment, but the alerts from CDSSs are usually overridden in clinical practice. Therefore, an intensified CDSS with more detailed information should be developed and its effectiveness with regard to prescribing errors determined. Aim and objectives To evaluate the effectiveness of an intensified CDSS with regard to prescribing errors for inappropriate drugs in cases of renal dysfunction. Material and methods We conducted a pre- and post-intervention study in an inpatient setting in the largest medical centre in Taiwan in 2019. Previously, the CDSS only reminded clinicians to adjust drugs according to the patient’s renal function. After May 2019, we initiated an intensified CDSS directly providing clinicians with the precise drug dosage or alternative drug recommendations for patients with renal impairment. The study outcome was the rate of prescribing errors, as identified by pharmacists after prescribing by clinicians. We used interrupted time series analysis to estimate the trend in prescribing error rate before (January 2019 to May 2019) and after (June 2019 to December 2019) implementing the intensified CDSS. As a control, we conducted similar analyses in another hospital with the same healthcare systems but without an intensified CDSS. We hypothesised there would be a reduction in the rate of prescribing errors for inappropriate drugs in cases of renal dysfunction after the intensification of CDSS in the study hospital, compared with the control hospital. Results The mean prescribing error rates due to inappropriate drugs in patients with renal dysfunction were 1.70 and 1.59 per 1000 inpatient beds before and after the introduction of the intensified CDSS, respectively, which did not constitute a significant change between the pre- and post- intervention (β=0.01; 95% CI −0.32 to 0.35). However, we observed a non-significantly increased prescribing error rate between the study hospital and the control hospital (β=0.04; 95% CI −0.51 to 0.59) after the introduction of the intensified CDSS. Conclusion and relevance The deployment of an intensified CDSS providing detailed information on how to prescribe drugs for patients with renal impairment may inhibit the increase in prescribing error rate due to inappropriate drugs in patients with renal dysfunction. References and/or acknowledgements Conflict of interest No conflict of interest

Background and importance Pan-genotypic direct acting antiviral agents (ie, glecaprevir/pibrentasvir (GLE/PIB)), have been proven in clinical trials to be effective and safe in the treatment of chronic hepatitis C (CHC) infection. However, CHC genotypes may vary in different populations and limited evidence is available regarding the effects of GLE/PIB in patients with different genotypes. Aim and objectives To compare the effectiveness and safety of GLE/PIB in CHC patients with different genotypes in Taiwan. Material and methods We retrospectively identified a cohort of CHC patients newly initiating GLE/PIB between August 2018 and June 2019 from the Chang Gung Research Database, a multi-institutional electronic medical records database covering approximately 1.3 million individuals (6% of the Taiwan population). We classified patients by genotype who were followed up for 12 weeks from completion of GLE/PIB therapy. Sustained virological response at 12 weeks (SVR12) was observed as the primary outcome. The safety outcome included elevation of alanine aminotransferase (ALT) or total bilirubin by three times the upper limit of normal (ULN), which was taken as an indicator of liver related adverse events. We calculated the rate of study outcomes among CHC patients with different genotypes. Results We identified 1589 CHC patients newly initiating GLE/PIB. Mean age was 61.7 (SD 12.6) years and 53% were women. The major CHC genotype was type 2 (60.2%), followed by type 1b (16.5%) and mixed type (5.7%). We found the rate of SVR12 was relatively lower among patients with genotype type 6 (91.1%), type 2 (91.4%) and type 3 (92.2%) compared with genotype type 1 (100%), type 5 (100%), mixed type (96.7%) and unknown type (93.8%). Furthermore, 14.7% of patients were found to have ALT elevation (>3 times the ULN). Most of these were genotype type 2 (8.7%), followed by type 1b (1.8%) and type 3 (1.2%). No patient had total bilirubin levels over three times the ULN. Conclusion and relevance The effectiveness and safety of GLE/PIB in Taiwan may vary in CHC patients with different genotypes. The findings could be strong grounds for future large scale prospective studies to confirm the association between CHC genotypes and treatment outcome with GLE/PIB. References and/or acknowledgements Conflict of interest No conflict of interest

Background Non-invasive techniques for liver fibrosis diagnosis are very important for clinician especially in high-risk patients for liver biopsy. We further explored the diagnostic accuracy of FibroScan, FIB-4 and aminotransferase-to-platelet ratio index (APRI) in identifying liver fibrosis and assess their predictive role for oesophageal varices in patients with hepatocellular carcinoma (HCC). Methods In total, 380 patients who underwent surgery for HCC were included based on retrospective study design. Liver fibrosis was pathologically diagnosed using the Ishak scoring system. Liver stiffness parameters were measured using FibroScan. APRI and FIB-4 were calculated. Among those, 121 patients who received oesophagogastroduodenoscopic examination underwent variceal evaluation. Results For liver cirrhosis diagnosis with FibroScan, the optimal cut-off values for the patients with HCC overall, left HCC and right HCC were 8.85, 11.75 and 8.70 kPa (the accuracy were 78.7%, 78.4% and 79.2%, respectively). They had high areas under the receiver operating characteristic curve of 0.84, 0.84 and 0.85. The combined FibroScan, APRI and FIB-4 had very high specificity (more than 92%) for cirrhosis diagnosis. The optimal cut-off liver stiffness values for the diagnosis of varices were all 11.2 kPa. For predicting varices, the optimal cut-off values of FIB-4 and APRI were 2.64 and 0.71, their accuracy were 64.3%-78.4%, 69.4% and 72.7%, respectively. Conclusions FibroScan, FIB-4 and APRI have moderate accuracy for liver fibrosis diagnosis and oesophageal varices prediction in patients with hepatoma. This is a study of these non-invasive techniques applied in specific hepatoma patients and with inevitable limitations and need future more studies for validation.

Background/Purpose: Prdevious meta-analyses assess whether or not patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C > G) was associated with increased risk of hepatocellular carcinoma (HCC) in Caucasians patients with hepatitis C virus (HCV)-related cirrhosis, these meta-analyses did not provide firm conclusions. Only one cross-sectional study involving Asian patients has previously been conducted to explore this issue. We aim to investigate this in a longitudinal cohort of Asian chronic hepatitis C (CHC) patients. Methods: We consecutively enrolled 1011 CHC patients who underwent liver biopsy before initiating interferon-based therapy. These patients were followed-up and screened for HCC up to a median of 6.9 years. The influence of rs738409 (GG) genotype on the occurrence of HCC was assessed using the Kaplan–Meier method, then according to the multivariate Cox model. Results: During follow-up, 143 (14.1%) patients developed HCC. rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.634). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.12). Among 261 patients with liver cirrhosis, rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.737). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.72). Conclusion: In this longitudinal study with liver biopsy to stage liver fibrosis, we affirm there is no influence of the rs738409 (GG) genotype on the occurrence of HCC in Asian CHC patients, including cirrhotic patients. Keywords: Patatin-like phospholipase domain containing 3, Hepatocellular carcinoma, Hepatitis C virus

Background Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease that is involved in the invasiveness and progression of cancer. There is good evidence that uPA expression is a clinically relevant biomarker in some solid tumors, but its role in hepatocellulcar carcinoma (HCC) is uncertain. We evaluated the prognostic value of serum uPA before surgery in HCC patients receiving curative resection. Methods Serum uPA levels were determined by enzyme-linked immunosorbent assay in 282 HCC patients who received complete liver resections at Kaohsiung Chang Gung Memorial Hospital. Overall survival (OS) curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional -hazards regression model was used to identify independent prognostic factors. The median follow-up time was 52 months. Results Patients with higher pretreatment serum uPA (≥1 ng/ml) had significantly shorter OS (p = 0.002). Patients with liver cirrhosis, hypoalbuminemia, and thrombocytopenia were significantly more likely to present with elevated uPA levels. Multivariate Cox regression analyses indicated that high pretreatment serum uPA [hazard ratio (HR), 1.848, p = 0.006], vascular invasion (HR, 2.940, p p Conclusions We conclude that uPA is a clinically relevant biomarker in HCC patients receiving curative resection, with higher expression of uPA being associated with higher mortality. This also highlights the potential utility of uPA as a therapeutic target for improved treatment strategies.

BACKGROUND AND AIM This study investigated whether hepatitis B surface antigen (HBsAg) could predict hepatitis B virus (HBV) relapse after cessation of entecavir or tenofovir disoproxil fumarate (TDF) prophylaxis for chronic hepatitis B cancer patients who are undergoing chemotherapy. METHODS The study enrolled 122 hepatitis B e-antigen-negative cancer patients who underwent chemotherapy with entecavir or TDF for antiviral prophylaxis and posttreatment follow-up for at least 6 months. RESULTS Of the 122 patients, 52 and 18 experienced virological and clinical relapse, which had 3-year cumulative incidences of 46.6% and 18.6%, respectively. Multivariate analysis showed that end-of-treatment HBsAg levels and baseline HBV-DNA ≥ 2000 IU/mL were independent predictors of virological relapse. The best HBsAg cutoff value was 500 IU/mL. An end-of-treatment HBsAg of 500 IU/mL was useful for predicting virological relapse in patients with baseline HBV-DNA

Background/Purpose: Metabolic risk factors are associated with liver fibrosis. Whether or not metabolic risk factors affect the severity of liver fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), or risk factors associated with non-alcoholic fatty liver disease (NAFLD) remains unclear. We aimed to investigate this by transient elastography. Methods: In this cross-sectional study, we enrolled 1513 patients who presented with chronic liver disease (CLD) at a tertiary hospital. Liver stiffness measurement (LSM) >13 kPa was used as a cutoff suggesting possible liver cirrhosis (LC). Results: Possible LC was noted in 7.8% of the CHB patients, 19.9% of the CHC patients, and 11.9% of the patients with risk factors associated with NAFLD. After adjustments for biochemical and virological factors were made, BMI (per 1 kg/m2 increase) (OR: 1.17, 95% CI: 1.06–1.29, P = 0.002) was found to be an independent factor associated with possible LC in CHB patients; BMI (per 1 kg/m2 increase) (OR: 1.15, 95% CI: 1.07–1.24, P

Background and Aim. Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after resection. The fibrosis-4 (FIB-4) index is an accurate and noninvasive marker to determine the degree of liver fibrosis. Here, we evaluated the effect of pre- and postoperative FIB-4 index in predicting the outcomes after resection of HCC in patients who have chronic hepatitis B (CHB) infection. Methods. A total of 534 CHB patients with HCC who received curative hepatectomy between 2001 and 2016 at Kaohsiung Chang Gung Memorial Hospital, Taiwan, were enrolled in this study. The impact of the FIB-4 index (preoperative and the 1st year after operation) on overall survival (OS) and recurrence-free survival (RFS) was evaluated. Results. There was a significant association between the preoperative FIB-4 index and Metavir fibrosis stage (p<0.01). The multivariate analysis showed that preoperative FIB‐4>2 is an independent risk factor for RFS and OS after HCC curative resection [hazard ratio (HR), 1.902; 95% CI, 1.491–2.460; p<0.001, and HR, 2.207; 95% CI, 1.420–3.429; p<0.001, respectively]. Notably, preoperative FIB-4 is also an independent risk factor for RFS (HR, 1.219; p=0.035) in noncirrhotic patients. Furthermore, patients had deteriorated FIB-4 1 year after operation [definition: the value the 1st year FIB‐4 after operation minus preoperative FIB‐4>1] and had an adverse outcome in RFS and OS (p<0.001, both). Conclusion. The pre and postoperative FIB-4 indexes are useful clinical markers to predict the prognosis in HBV-HCC patients after curative hepatectomy.

Hepatocellular carcinoma (HCC) development is ameliorated with nucleos(t)ide agent (NA) therapy for hepatitis B virus (HBV)‐related cirrhosis patients. This study investigates whether liver stiffness (LS) measurement at complete virological response (CVR) was useful in predicting HCC development. Between July 2006 and August 2016, HBV‐related cirrhosis patients with potent NA (entecavir/tenofovir) with the first LS measurement during CVR and with serial LS were enrolled. Patients developing HCC 6 months after potent NA or before the first LS measurement were excluded. Three hundred and seventy‐one patients were enrolled. The median follow‐up was 5.6 and 3.8 years from potent NA treatment and the first LS measurement respectively. Twenty‐seven patients developed HCC. The 1‐, 3‐, 5‐ and 7‐year cumulated incidences of HCC occurrence were 0%, 2.8%, 5.8% and 9%, respectively. In addition to age > 57 years, LS > =21.5 kPa (HR: 3.86, 95%CI: 1.67‐8.94) was an independent factor associated with HCC occurrence in multivariate analysis. However, the magnitude of change in LS was not associated with HCC development. For the first LS in HCC prediction, the performance was 0.636. There were two to thirteen LS measurements during CVR. The change in LS was classified into four patterns stratified by the first and serial LS. Compared with those with serial LS =21.5 kPa tend to have higher HCC occurrence (P = .062). In summary, LS at CVR was an independent factor associated with HCC development for HBV‐related cirrhosis patients with potent NA. However, LS was not satisfactory in the prediction performance of HCC development.

Current guidelines recommend that patients with hepatitis B virus-hepatitis C virus (HBV-HCV) coinfection be treated with direct anti-viral agents (DAAs). Compared with DAAs, pegylated interferon (PEG-IFN) and ribavirin therapy has the advantages of treating both viruses while maintaining an acceptable HCV sustained virological response (SVR) rate (70–80%) in Asian cohorts. In this study, we aimed to develop a simple scoring system to predict hepatitis B surface antigen (HBsAg) seroclearance in these patients. We enrolled 201 patients with HCV-HBV coinfection after IFN and ribavirin therapy. The study population was randomly allocated into derivation and validation sets in a 1:1 ratio. In the derivation cohort, multivariate analysis by Cox regression analysis revealed that HBsAg seroclearance was associated with age > 60 years (HR: 5.55, 95% CI: 1.68–18.37, P = .005), male gender (HR: 3.88, 95% CI: 1.18–12.80, P = .03), and qHBsAg level ≤100 IU/ml (HR: 4.87, 95% CI: 1.20–19.74, P = .03). Regression coefficients were used to build up a risk score, and the accuracy of the risk score was evaluated by using the area under the receiver operating characteristic curve (AUROC). The patients were classified into either a low-risk group or high-risk group based on the risk scores. Twenty-three (23.0%) patients in the derivation cohort and 30 (29.7%) patients in the validation cohort showed HBsAg seroclearance with an AUROC of 71.8%, sensitivity of 65.22%, and specificity of 75.32%. In the validation cohort, the 5-year HBsAg seroclearance incidence rates were 23.4% in the low-risk category and 43.8% in the high-risk category (HR = 2.21; 95% CI, 1.04–4.68, P = .04) The risk scoring system could be used to predict HBsAg seroclearance for HCV-HBV coinfected patients treated with IFN and ribavirin.

Background and Aims: This study compared the efficacy and safety of tenofovir disoproxil fumarate (TDF) up to 3 years of innucleos(t)ide analog (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients. Methods: Tenofovir disoproxil fumarate-treated NA-naive and NA-experienced CHB patients were retrospectively analyzed. Results: After 3 years of TDF therapy, 97.7%, 71%, and 45.5% NA-naive patients achieved a virological response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion, respectively. Compared with NA-naive patients, NA-experienced patients without drug resistance and infected with lamivudine/telbivudine-resistant mutants showed similar results. In contrast, patients previously infected with adefovir-resistant mutants and with a suboptimal entecavir response showed significantly lower rates of virological response and hepatitis B e antigen loss/seroconverion than NA-naive patients. Mean estimated glomerular filtration rate markedly reduced within 12 months of TDF therapy; however, it did not decrease significantly during 12–36 months of treatment. Diabetes mellitus was an independent predictor of a ≥ 0.5 mg/dL increase above baseline in serum creatinine level, and age, hypertension, diabetes mellitus, and baseline creatinine level were independent factors for > 20% decline in estimated glomerular filtration rate from baseline. Liver stiffness measurements improved significantly, but bone mineral density did not change significantly during treatment. Hepatocellular carcinoma incidence was low at 36 months. Age of > 60 years, cirrhosis, a low baseline platelet count and a high α-fetoprotein level at 12 months were significant predictors of hepatocellular carcinoma development. Conclusions: Tenofovir disoproxil fumarate is effective and safe for NA-naive and NA-experienced CHB patients and should be used cautiously in patients with comorbidities because of a renal dysfunction risk.

Background Resistance-associated variants (RAVs) to direct-antiviral agents (DAAs) may hamper treatment. There was a lack of data on the natural prevalence of RAVs in Taiwanese HCV-infected patients. Aims The aim of this study was to investigate the real-life presence of RAVs in the non-structural 5A (NS5A) region in HCV genotype 1a and 1b in chronically infected individuals in Taiwan. Methods In this single-center cohort study, nested polymerase chain reaction and direct sequencing analysis was used to determine the frequency of RAVs in the HCV NS5A region in patients with HCV genotype 1a (n = 55) and 1b (n = 525). Results In genotype 1a strains, the incidence of RAVs was 16.4% (9/55) in the NS5A region (M28V/T, n = 6, 10.9%; Q30L, n = 1, 1.8%; Y93N/H, n = 3, 5.5%). In genotype 1b, the incidence of RAVs was 17.5% (92/525) in the NS5A region (L31I/M/V, n = 7, 1.3%; Y93 H/S, n = 87, 16.5%). Patients with RAVs had significantly higher HCV RNA levels (6.1 ± 0.7 vs 5.9 ± 0.8 log IU/mL, p = 0.001) and lower rGT levels (28.9 ± 18.9 vs. 42.9 ± 57.0 U/L, p = 0.001) compared to those without RAVs. Multivariate analysis identified HCV RNA levels (odds ratio = 1.145, 95% CI: 1.060–1.237, p = 0.001) and rGT (OR = 0.989, 95% CI: 0.978–0.999, p = 0.035) as risk factors that are associated with the presence of RAVs. Importantly, there is no association between the presence of RAVs and no SVR (3.8% in patients with RAVs, 15.9% in patients without RAVs, p = 0.32). Conclusion RAVs, especially M28V and Y93H in the NS5A region, were highly prevalent in patients with genotype 1a and 1b HCV, respectively, in Taiwan, and they were linked to high HCV RNA levels and low rGT levels. Before using the NS5A inhibitors, the presence of mutated HCV variants should be taken into consideration.

Background: Hepatitis C virus (HCV)-infected patients who achieved sustained virologic response (SVR) may still develop hepatocellular carcinoma (HCC). The characteristic of HCC and the prognosis between SVR and non-SVR patients were not well known. Methods: Among 1884 HCV-infected patients who were treated with pegylated IFN plus ribavirin therapies, 122 patients developed HCC during follow-up were enrolled in this study. Laboratory data were collected before and at least 1 year after IFN-based therapy, as well as the latest follow-up. Results: Both SVR and non-SVR patients had similar risk factors to develop HCC, but with a little difference. Liver cirrhosis plays a key role in HCC occurrence in both groups. Among the patients who developed HCC, non-SVR patients had significantly higher total bilirubin, higher FIB-4, lower pre-treatment platelet count, higher pre-treatment AFP levels and higher proportion of cirrhosis than SVR patients before occurrence of HCC. After curative treatment, SVR patients had lower recurrence and longer overall survival than non-SVR patients by Kaplan–Meier analysis. Multivariate analysis revealed that APRI ≥0.7 was the independent risk factor for HCC recurrence; and AFP ≥20 ng/ml post IFN therapy, as well as HCC recurrence were the independent risk factors of mortality. Conclusion: Liver cirrhosis plays a key role in HCC occurrence after antiviral therapies. SVR patients may have lower HCC recurrence and longer survival rates than non-SVR patients. Only APRI was associated with HCC recurrence; and post-IFN AFP and HCC recurrence were predictive of subsequent mortality independently. Keywords: Hepatitis C virus, Hepatocellular carcinoma, Mortality, Recurrence, Antiviral therapy

In the community screening, those subjects with elevated serum alpha-fetoprotein (AFP) required further abdomen ultrasonography (US) to detect hepatocellular carcinoma (HCC). However, some chronic hepatitis patients might have elevated AFP. AFP-L3, has been proposed to differentiate HCC and hepatitis in elevated AFP cases in Japan for decades, but the utility is limited outside Japan. We conducted this study to elucidate the role of AFP-L3 in the community and the possibility of saving unnecessary US. A total of 56,702 subjects underwent a large-scale healthcare screening in Tainan county in 2004. Among them, 286 residents with AFP more than 20 ng/ml further received US and 169 (59%) had stored baseline sera were enrolled into this study in 2013. Their AFP and AFP-L3 levels were further detected. HCC patients were initially identified through US and personal history. Among 169 studied sera, only 148 (87.6%) samples still had AFP level more than 20 ng/ml after a 10-years frozen period. The decrease of AFP level was significant (481.3 ± 2093.8 ng/ml and 456.1 ± 2095.3 ng/ml in paired-T test, p

Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin.In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC.The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P.05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P.05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC.Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.

Background and Aim Hepatocellular carcinoma (HCC) diagnosis could be made with one typical imaging study in a cirrhotic liver by the guideline of the American Association for the Study of Liver Diseases (AASLD) in 2010. Patients with hepatitis B who may not have fully developed cirrhosis could be applied. We aim to retrospectively analyze and validate the diagnostic power of the 2010 guideline in an HCC endemic area (Taiwan). Methods From January 2006 to December 2010, a total of 648 patients with liver tumor post-surgical resection were reviewed. The fibrotic scores were verified by METAVIR score 4. Among the 648 patients, 569 (87.8%) were HCC patients. Hepatitis B accounts for 54.5%, hepatitis C 21.9%, hepatitis B + C 2.8%, and non-hepatitis B or C 20.7% of patients. Two hundred eighty-eight of 648 (44%) patients were with cirrhotic liver. Results The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of the 2010 AASLD guideline f are 99.1%, 36.7%, 91.9%, 85.3%, and 91.5%, respectively. Cirrhotic liver exhibited a higher PPV (P 0.05). Conclusions Similar sensitivity of HCC diagnosis existed between cirrhotic and non-cirrhotic liver, and across different fibrotic stages. But cirrhotic liver exhibited a higher PPV. Hepatitis B or C has no decisive effect in HCC diagnosis.

Background & Aims Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. Methods A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. Results Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age ≥ 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. Conclusions Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR.

Background/Purpose: Although antiviral therapy reduces development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), HCC often develops in patients with non-sustained virologic response (non-SVR). We aimed to evaluate risk factors for HCC in HCV patients with non-SVR. Methods: From March 2002 to December 2013, 800 patients with CHC who had received combined pegylated interferon (peg-IFN)/ribavirin (RBV) therapy without achieving SVR were enrolled. Main outcome measure was HCC development. Variables were cirrhosis, platelet count, α-fetoprotein (AFP) levels, aspartate aminotransferase (AST) to platelet ratio index (APRI), and IL28B polymorphism (CT + TT). Results: One-hundred of 800 non-SVR patients developed HCC within a median 53.5-months follow-up. Cumulative incidence of HCC for all patients was 1.4%, 5.6% and 12.3%, respectively, at 1st, 3rd and 5th years of follow-up. In univariate analysis, patients who developed HCC tended to have LC (p

Metabolic syndrome, an etiological factor in non-alcoholic fatty liver disease (NAFLD), is often present in hemodialysis patients. Little is known about the prevalence of, and factors associated with, liver fibrosis in hemodialysis populations. We used transient elastography (TE) to investigate these phenomena. 659 patients treated with chronic hemodialysis were enrolled. We excluded those with excess alcohol intake, liver stiffness measurement (LSM) failure, or unreliable LSM values. LSM ≥8.0 kPa was used as a cutoff suggesting clinically relevant fibrosis. Controlled attenuation parameter (CAP) ≥ 232.5 dB/m was used as a cutoff suggesting steatosis. 333 patients (50.5%) had steatosis, 159 (24.1%) had hepatitis B or C, and 149 (22.6%) had LSM ≥8.0 kPa. In multivariable analyses, male gender (OR: 2.16; 95% CI: 1.29–3.63; P = 0.004), overweight body habitus (OR:2.31; 95% CI: 1.35–3.94; P = 0.002), high AST level (OR:1.08; 95% CI: 1.04–1.12; P

Controlled attenuation parameter (CAP) is a method for measuring steatosis based on FibroScan. Despite observer dependency, ultrasound (US) robustly diagnoses moderate and severe steatosis. Here, we aimed to evaluate the correlation of CAP with US-identified steatosis in real-world clinical practice. Methods: CAP and US were performed for 1554 chronic liver disease (CLD) patients. CAP was performed by two technicians, and US was performed by 30 hepatologists. The performance of the CAP as compared with the US results was assessed using the area under the receiver operating characteristic curve (AUROC). Results: 532 (34.2%) of the patients had hepatitis C virus (HCV) infection, 723 (46.5%) of the patients had hepatitis B virus (HBV) infection, and the rest were patients with metabolic risk factors. CAP values were significantly correlated with the steatosis grades identified by US for all the patients (ρ = 0.497, P

Background and aims Controlled attenuation parameter (CAP) is a non-invasive method for measuring hepatic steatosis (HS). Non-alcoholic fatty liver disease (NAFLD) is closely related to cardiovascular diseases (CVDs). CVDs are the leading cause of morbidity and mortality in hemodialysis patients. The aim of this study was to investigate the prevalence of NAFLD in hemodialysis patients. Method We prospectively enrolled patients undergoing chronic hemodialysis, as well as patients with normal renal function who served as controls. The control group patients were referred by an endocrinologist to be tested for NAFLD; most of these patients had diabetes, hypertension, or dyslipidemia. We excluded those with excess alcohol intake, use of drugs known to induce HS, chronic viral hepatitis, or CAP failure. CAP ≥ 238 dB/m was used as a cutoff suggesting HS. An increased liver kidney contrast, as defined by ultrasound, was used to make the diagnosis of HS. Results Three hundred and forty-three hemodialysis patients and 252 control group patients were enrolled. Among the hemodialysis patients, 192 (56.0%) had CAP- or ultrasound-identified HS compared with 91 (26.5%) who only had ultrasound-identified HS (P

Background and aims A recent meta-analysis revealed that the genotype PNPLA3 rs738409 GG is associated with a higher risk of hepatic steatosis (HS) in Caucasian patients with chronic hepatitis C (CHC). However, controversial results were found regarding Asian populations. Furthermore, previous studies have shown a negative association between interferon lambda 3 (IFNL3) rs12979860 CC and HS in Caucasian CHC patients, but there have been no reports indicating any such association in Asian populations. In this study, then, we investigated the association of PNPLA3 and IFNL3 polymorphisms with HS in Asian CHC patients. Methods We enrolled consecutive CHC patients who underwent liver biopsy prior to antiviral therapy. We excluded those patients with decompensated liver disease, any co-existing chronic liver disease, or HIV or HBV co-infection. Results 1080 CHC patients were enrolled, and HS was found in 453 (41.9%) patients. The frequency distribution of the G allele was significantly associated with HS (P

Background and Aim There is limited data on the efficacy and outcome of telbivudine (LdT) therapy in patients with chronic hepatitis B and compensated cirrhosis. We evaluated LdT as first-line therapy in these patients and compared with those treated with entecavir (ETV). Methods We consecutively enrolled 88 chronic hepatitis B patients with compensated cirrhosis primarily treated with LdT at least for 2 years or less than 2 years but developed resistance, and evaluated the efficacy and clinical outcomes. Meanwhile, we matched a control group who treated with ETV for comparison. Results In LdT group, alanine aminotransferase normalization (65.8%), hepatitis B e antigen seroconversion (39.8%), hepatitis B virus (HBV) DNA undetectablility (71.6%), and virologic resistance (23.9%) were noted after 2 years treatment. Compared with ETV group, there were significant difference in HBV DNA undetectablility (P

Background. Recent findings suggest that patients admitted on the weekend with peptic ulcer bleeding might be at increased risk of adverse outcomes. However, other reports found that there was no “holiday effect.” The purpose of this study was to determine if these findings hold true for a real-life Taiwanese medical gastroenterology practice.Materials and Methods. We reviewed the medical files of hospital admissions for patients with peptic ulcer bleeding who received initial endoscopic hemostasis between January 2009 and March 2011. A total of 744 patients were enrolled (nonholiday group,n=615; holiday group,n=129) after applying strict exclusion criteria. Holidays were defined as weekends and national holidays in Taiwan.Results. Our results showed that there was no significant difference in baseline characteristics between the two groups. We also observed that, compared to the nonholiday group, patients in the holiday group received earlier endoscopy treatment (12.20 hours versus 16.68 hours,P=0.005), needed less transfused blood (4.8 units versus 6.6 units,P=0.02), shifted from intravenous to oral proton-pump inhibitors (PPIs) more quickly (5.3 days versus 6.9 days,P=0.05), and had shorter hospital stays (13.05 days versus 17.36 days,P=0.005). In the holiday and nonholiday groups, the rebleeding rates were 17.8% and 23.41% (P=0.167), the mortality rates were 11.63% versus 13.66% (P=0.537), and surgery was required in 2.11% versus 4.66% (P=0.093), respectively.Conclusions. Patients who presented with peptic ulcer bleeding on holidays did not experience delayed endoscopy or increased adverse outcomes. In fact, patients who received endoscopic hemostasis on the holiday had shorter waiting times, needed less transfused blood, switched to oral PPIs quicker, and experienced shorter hospital stays.

Background Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. Study Design 2 prospective observational cohort studies. Setting & Participants From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. Predictors Peginterferon alfa-2b monotherapy, 1.0 μg/kg/wk, versus peginterferon alfa-2b, 1.0 μg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. Outcomes & Measurements End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level Results Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [ P = 0.03] and 100% vs 80% in PP [ P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [ P = 0.01] and 73% vs 35% in PP [ P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. Limitations Comparison of 2 sequential cohorts rather than a randomized control study. Conclusions Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

A prominent factor in hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Diabetes mellitus (DM), metabolic syndrome (MetS), and obesity have also been implicated in HCC development, but these associations are not observed in all HBV- and HCV-endemic areas. We attempted to clarify the role of these factors in HCC development in an HBV- and HCV-endemic area in southern Taiwan. A community-based health examination was conducted in 2004 in Tainan County. After individuals with incomplete data and those with known HCC were excluded, there were 56,231 participants who were over 40 years of age. A further 262 HCC cases were identified from the National Cancer Registration Database records from 2005 to 2007. The hepatitis B surface antigen (HBsAg) seropositivity, anti-HCV seropositivity, platelet count, serum biochemical data, blood pressure, sociodemographic information, and anthropometric measurements were analyzed. Survival analyses were used to identify the associations between these factors and HCC. For the 262 HCC cases, male gender and age greater than 65 years were risk factors. Furthermore, a high alanine aminotransferase level, chronic HBV and/or HCV infection, and liver cirrhosis were also risk factors for HCC. However, DM, MetS and obesity were not associated with HCC development in the non-HBV-/non-HCV-infected, HBV, HCV, or dual B/C groups. In this HBV- and HCV- endemic area, DM, MetS and obesity were not risk factors for developing HCC.

Hepatocellular Carcinoma Surveillance at 4- vs. 12-Month Intervals for Patients With Chronic Viral Hepatitis: A Randomized Study in Community

The oxidation of an SiGe-on-Insulator (SGOI) that is caused by Ge condensation increases the fraction of Ge therein and significantly increases the hole mobility. This effect can be exploited to improve the sensitivity of SGOI nano-wires. However, previous investigations by the authors have revealed that the sensitivity of SGOI nano-wires is reduced when the Ge fraction increase over 20%, because a high Ge fraction destabilizes the surface state of SiGe. In this work, a top surface passivation PECVD SiO2 layer that was deposited on a Si0.8Ge0.2 nano-wire improved its sensitivity to approximately 1.3 times that of a nano-wire sample without a top passivation layer.

Liver stiffness measurement (LSM) is a noninvasive method for the diagnosis of hepatic fibrosis. The aim of this study was to evaluate the effects of hepatitis activity and antiviral therapy on LSM in cirrhotic patients. Consecutive patients with compensated hepatic cirrhosis were enrolled for LSM. The medical records of hepatitis activity and antiviral therapy before enrollment were reviewed. Patients were stratified into inactive, fluctuating, and active groups by serial change of alanine transaminase level. For chronic hepatitis C, patients were stratified into sustained virological response (SVR) and non-SVR (NSVR) by effect of antiviral treatment. LSM results were compared among different groups. A total of 163 patients (mean age = 57.2 ± 11.0 years) were enrolled. The median (range) LSM values were 9.6 (4.2–20.6), 10.25 (3.9–49.6), and 15.75 (4.8–61.5) kPa in the inactive, fluctuating, and active groups, respectively. Patients in the active group had significantly higher LSM values. For chronic hepatitis C, median (range) LSM values were 16.6 (8.1–61.5), 22.9 (11.1–37.4), and 11.2 (3.9–27.0) kPa in patients without antiviral therapy, in NSVR, and in SVR groups, respectively. Patients with SVR had significantly lower LSM values. For chronic hepatitis B, median (range) LSM values were 11.8 (5.1–46.6), 16.85 (4.2–48), and 10.6 (4.3–46.4 kPa) kPa in patients without oral nucleos(t)ide analogue (NA) therapy, with NA

It has been demonstrated that microRNA-122 (miR-122) plays key roles in the modulation of hepatitis B virus (HBV) replication. This study examined the role of miR-122 in patients with hepatitis C virus (HCV)-HBV dual infection with active hepatitis C who received pegylated interferon-α and ribavirin dual therapy. We enrolled 121 patients with HCV-HBV dual infection after dual therapy. Stored serum was collected before treatment. RT-PCR was used to analyze miR-122. HBsAg seroclearance was noted in 37 (30.1%) cases during a median follow-up period of 5.4 years. miR-122 was significantly lower in HBsAg seroclearance patients than in non-HBsAg seroclearance patients (P 100 IU/mL versus ≤100 IU/mL (P

Background and Aim Chronic hepatitis B infection remains a significant health issue worldwide. This study evaluated the efficacy and safety of combined therapy using lamivudine plus adefovir (LAM+ADV) versus telbivudine plus adefovir (LdT+ADV) and the corresponding renal function change and safety. Methods This study enrolled a total of 171 patients (110 patients received LAM+ADV and 60 patients received LdT+ADV). We analyzed the changes in renal function using the estimated glomerular filtration rate (eGFR). The DNA undetectable rate, hepatitis B e antigen (HBeAg) seroconversion rate, and alanine aminotransferase (ALT) normalization rate were analyzed. We checked the serum uric acid, phosphate and creatine kinase, and lactic acid levels to analyze safety. We observed these patients for 48 to 240 weeks and checked their serum profile every 6 months. Results There was no statistically significant difference between the two groups in anti-hepatitis B virus (HBV) efficacy in terms of DNA undetectable rate, ALT normalization rate, and HBeAg seroconversion rate. Both the LAM+ADV and LdT+ADV groups had stable or improved renal function. However, a higher eGFR was found in the LdT+ADV group with continuous serum fluctuation during 3 years of combined therapy as well as a higher serum creatine kinase level. Conclusions Long-term LdT+ADV combined therapy and LAM+ADV combined therapy were both associated with stable or improved renal function. The clinical efficacy was similar between the two groups, but the LdT group had a higher serum creatine kinase level. We need to monitor the data regularly in clinical practice.

This study aimed to assess the renal function in chronic hepatitis B (CHB) patients who received nucleos(t)ide analogues (NAs) therapy using estimated glomerular filtration rate (eGFR) titer. We performed a longitudinal observational study of 37 tenofovir-, 42 telbivudine-, and 62 entecavir-naive CHB patients, who had impaired renal function (eGFR, 90-30 ml/min/1.73m2) without history of diabetes, hypertension, and chemotherapy. Calculation and evaluation of eGFR was performed with the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault formula at pretreatment, at baseline, and after the 1st and 2nd year of treatment. The eGFR was significantly increased in patients given telbivudine or entecavir (p = 0.003 and p = 0.012, respectively), but the eGFR was decreased in patients given tenofovir (p = 0.001) after 2 years of treatment. Of all patients, eGFR was stable one year prior to treatment. If we analyzed the renal function by change of chronic kidney disease (CKD) category with a change of 25% of eGFR, the proportion of uncertain drop (drop in CKD category with

Objectives: Antiviral therapy can prevent the development of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients. However, HCC still develops in patients achieving sustained virological response (SVR). We proposed to evaluate the risk factors and derive a novel risk score for HCC (scoreHCC) by summation of products of clinical weights based on the regression coefficients in the final proportional hazards model. Methods: From March 2002 to October 2009, we enrolled 871 patients with biopsy-proven CHC, who received combined pegylated interferon and ribavirin therapy and achieved SVR. Results: Cox regression analysis showed that old age [hazard ratio (HR) 3.82, 95% CI 1.74‐8.37, P¼0.001], high a-fetoprotein levels (HR 3.15, 95% CI 1.60‐6.19, P¼0.001), low platelet counts (HR 2.81, 95% CI 1.22‐6.44, P¼0.015) and high fibrotic stage (HR 3.95, 95% CI 1.46‐10.70, P¼0.007) were independent risk factors. The cut-off level of risk scores was a derived value of 10 and was able to predict the HCC risk with 89.2% sensitivity and 69.5% specificity. The AUC value for the prediction was 0.848. The scoreHCC values were further categorized into three risk groups: low risk (scoreHCC ≤10), intermediate risk (scoreHCC 11‐15) and high risk (scoreHCC ≥16). The proportion of HCC development increased from 1.37% (9/657) in the low-risk group to 9.14% (16/175) in the intermediate-risk group and 30.77% (12/39) in the high-risk group (P,0.001). Conclusions: With the novel risk scores, we can estimate the chance of HCC development more exactly and practically. This approach can be used for HCC screening in CHC patients achieving SVR.

Background and Aim: Transient elastography (TE) has been useful in esophageal varices (EV) diagnosis for chronic hepatitis C patients. In the present study, we evaluate the usefulness of TE and simple blood markers in the EV diagnosis of patients with hepatitis B virus (HBV)-related cirrhosis, prospectively. Methods: Consecutive patients with compensated cirrhosis and positive HBV surface antigen were enrolled, prospectively. At enrollment, the aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR) and the AST to platelet ratio index (APRI) were recorded, and TE was performed. Two experienced endoscopists assessed EV independently. High-risk EV was defined as small size with a red color sign, and medium or large in size. The diagnostic performances, optimal cut-offs, and the validities of TE, APRI, platelet count (PLT), and AAR in EV diagnosis were assessed. Results: A total of 126 patients (male/female: 93/33; mean age: 54.5 years) with reliable TE results were analyzed. There was good agreement between two endoscopists in assessing the presence of EV and high-risk EV (kappa value: 0.82 and 0.96). Forty-eight (38.1%) patients had EV (small: 35; high risk: 13). There was correlation between TE result and EV size (r = 0.515, P

Background and Aim: Long-term trends of anti-hepatitis C virus (HCV) antibody titer and their associated factors in patients with sustained virological response (SVR) were investigated. Methods: From May 1999 to July 2005, a total of 166 SVR consecutive patients (M/F: 86/80) were enrolled. Anti-HCV titer, samples to cut-off (S/CO) ratios, were measured with AxSYM HCV version 3.0. Their S/CO ratios were followed every 6 months after SVR and the patterns over time were identified by trajectory analyses. Changes of recombinant immunoblot assay (RIBA) pattern before treatment and end of follow-up were compared (n = 64). Results: The mean duration of follow-up was 4.7 ± 1.5 years (median 4.3; range 3–9 years). The rates of S/CO ratios decreased annually (P

Background: Classical second-line anti-Helicobacter pylori includes proton-pump inhibitor, tetracycline, metronidazole, and bismuth salts, but alternative therapies are required owing to the restricted availability of the latter. Levofloxacin-containing triple therapy is recommended but is expensive. Besides, quinolone resistance in an endemic tuberculosis infection area like Taiwan is concerned. The low in vitro antibiotic resistance to amoxicillin and tetracycline in Taiwanese H. pylori strains implies that in vivo esomeprazole/amoxicillin/tetracycline (EAT) second-line rescue therapy may be effective. This study compared the efficacy of esomeprazole/amoxicillin/levofloxacin (EAL) and EAT second-line eradication therapies and determines the clinical factors influencing the efficacy of salvage regimens. Materials and methods: One hundred and twenty-eight patients who failed H. pylori eradication using the standard triple therapy for 7 days are randomly assigned to either EAL group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) for 7 days or EAT group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily) for 14 days. Follow-up endoscopy or urea breath test was performed 8 weeks later to assess treatment response. Results: The eradication rates of EAL and EAT groups were 78.1 versus 75.0%, p = .676 (in intention-to-treat analysis) and 80.3 versus 80%, p = .0964 (per-protocol analysis). Both groups exhibited similar drug compliance (95.3 vs 96.9%, p = .952) but more adverse events in the EAT group (6.3 vs 12.5%, p = .225). Conclusions: Despite low in vitro drug resistances to amoxicillin and tetracycline, the efficacy of 14-day EAT regimens attained an unacceptable report card of 75% eradication rates in intention-to-treat analysis and was not even superior to the 7-day EAL regimen. Drug–drug interaction between combined antibiotics should be considered other than in vivo drug resistances.

Background and Study Aims. The optimal dose of intravenous proton-pump inhibitor (PPI) therapy for the prevention of peptic ulcer (PU) rebleeding remains controversial. This study aimed to understand the real world experiences in prescribing high-dose PPI and non-high-dose PPI for preventing rebleeding after endoscopic treatment of high-risk PU.Patients and Methods. A total of 220 subjects who received high-dose and non-high-dose pantoprazole for confirmed acute PU bleeding that were successfully treated endoscopically were enrolled. They were divided into rebleeding (n=177) and non-rebleeding groups (n=43). Randomized matching of the treatment-control group was performed. Patients were randomly selected for non-high-dose and high-dose PPI groups (n=44in each group).Results. Univariate analysis showed, significant variables related to rebleeding were female, higher creatinine levels, and higher Rockall scores (≧6). Before case-control matching, the high-dose PPI group had higher creatinine level, higher percentage of shock at presentation, and higher Rockall scores. After randomized treatment-control matching, no statistical differences were observed for rebleeding rates between the high-dose and non-high-dose groups after case-control matching.Conclusion. This study suggests that intravenous high-dose pantoprazole may not be superior to non-high-dose regimen in reducing rebleeding in high-risk peptic ulcer bleeding after successful endoscopic therapy.

Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB).We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2 years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104 weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed.HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104 weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P = 0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65 weeks.The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Background and Aim: The aim of the present study was to elucidate a reasonable model and the efficacy of hepatocellular carcinoma (HCC) screening on an elderly population. Methods: Two-stage HCC screening was conducted in a hepatitis C virus (HCV)-endemic area. First, participants underwent blood tests for hepatitis B surface antigen (HBsAg), anti-HCV antibody, serum a-fetoprotein (AFP), aspartate aminotransferase, alanine ami- notransferase, and platelet count. Patients who were abnormal for any of the six markers were enrolled for second-stage ultrasonography. Suspected cases were referred for confir- mation. HCC cases were followed for 4 years.All patients were linked to national mortality and cancer register databases to identify newly-developed HCC, 30 months after screening. Results: Atotal of 461 males and 541 females were screened for HCC, with 15.1% testing positive for HBsAg and 44.3% positive for anti-HCV. Among them, 619 (61.8%) met the criteria of ultrasonographic screening; 527 (85.1%) responded, and 16 confirmed HCC (male/female = 8/8, 68.8 8 years) cases were detected. All tumor diameters were less than 5 cm, and six were less than 2 cm. AFP and thrombocytopenia were two independent predictive factors of HCC. The overall survival rates of detected cases were 93.8% and 56.3% was 1 and 4 years, respectively. The only good prognostic predictor was "underwent curative treatment".Another seven non-HCC residents developed HCC after screening, and five of these were with either thrombocytopenia or AFP elevation. Conclusion: Under economical consideration, AFP and platelet count should be feasible screening markers of risk identification. Early detection and prompt treatment results in good prognosis in an aged population.

Background: HBsAg and anti-hepatitis C virus (anti-HCV) are stable markers and widely used. The seroconversion and seroclearance of HBsAg and anti-HCV are important for disease control and prognosis of diseases. Aims: To investigate acquirement and disappearance of HBsAg and anti-HCV in an endemic area. Methods: Seven years after a community screening, 1002 of 2909 residents of Tzukuan Township were recruited. HBsAg, anti-HCV and alanine transaminase (ALT) were checked in all who participated and hepatitis B virus (HBV) DNA, anti-HBs, anti-HBc, HCV RNA, anti-HDV and upper abdominal ultrasonography were studied in different groups. Results: There were 461 male and 541 female residents with a mean age of 66.7±8.6 years. No new HBsAg carrier was noted and the HBsAg clearance rate was 1.58% per year. One of the 17 cases with HBsAg clearance had positive HBV DNA, three had ALT elevation, two had cirrhosis and seven had anti-HBs seroconversion. Quantitative of HBsAg and HBV DNA were concordant and 78.1% subjects had low levels of titration. Anti-HBc alone contributed to 32.1% and was prominent in old age and the anti-HCV-positive group. The anti-HCV seroconversion rate was only 0.74% per year and household transmission was the only risk factor. Only 37.5% of cases with anti-HCV seroconversion had HCV viraemia and the anti-HCV seroreversion rate was 0.63% per year. The anti-HDV seroconversion rate was 0.72% per year and no subject showed anti-HDV clearance. Conclusions: Much higher rates of HBsAg seroclearance, anti-HCV seroreversion and anti-HBc alone were noted in this endemic area and no subject showed anti-HDV clearance.

BACKGROUND AND AIM:The aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are commonly used compound surrogates for advanced fibrosis in chronic hepatitis C (CHC) patients. However, the use of APRI and FIB-4 entails a risk of overestimating the fibrosis stage due to the impact of necroinflammatory activity on transaminases. We sought to investigate the optimal cutoff values of the two compound surrogates for predicting cirrhosis stratified by AST level. METHODS:This retrospective study enrolled 1716 treatment-naive CHC patients who underwent liver biopsy prior to interferon therapy from 1997-2010. Fibrosis was scored according to the modified Knodell classification. The upper limit for normal AST in our hospital is 37 IU/L. We stratified the enrolled patients into the categories of AST≤37 IU/L (N = 132), 37148 IU/L (N = 346). RESULTS:436 patients had cirrhosis (F4). The area under receiver operating characteristic (AUROC) analysis results distinguishing cirrhosis (F4) from non-cirrhosis (F0-F3) were 0.81 for APRI and 0.85 for FIB-4 in patients with AST≤37 IU/L; 0.71 for APRI and 0.72 for FIB-4 in patients with 37148 IU/L. The optimal cutoff values of APRI and FIB-4 for the diagnosis of cirrhosis were 0.6 and 1.4, respectively, in patients with AST≤37 IU/L; 1.1 and 2.2, respectively, in patients with 37148 IU/L. CONCLUSIONS:We provide optimal cutoff values of both APRI and FIB-4 to predict cirrhosis stratified by AST levels, which should be more feasible compared with the single cutoff values proposed in previous studies.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are well-known risk factors for hepatocellular carcinoma, and diabetes mellitus (DM) and overweight have also been reported as risk factors for hepatocellular carcinoma (HCC). We tried to elucidate the roles of DM and overweight in HCC development in a dual HBV and HCV endemic area of southern Taiwan.In 2004, a community-based comprehensive screening program was conducted in Tainan County. Hepatitis B surface antigen (HBsAg), anti-HCV, alpha-fetoprotein, complete blood counts, triglyceride, cholesterol, and glucose levels were examined. DM was defined as fasting blood sugar126 mg per 100 ml, and overweight was defined as a body mass index24 kg m(-2). Subjects with thrombocytopenia (platelet count150 x 10(9) l(-1)) and elevated alpha-fetoprotein (20 ng ml(-1)) underwent ultrasonographic screening for HCC. A total of 56,307 adults (40 years old) participated, and 72 new HCC cases were detected and confirmed.In comparisons of all 72 HCC cases with the other 144 individual age-, sex-, residency-, HBsAg-, and anti-HCV-matched controls, only thrombocytopenia and high alanine transaminase (ALT) levels were shown to be independent risk factors. Neither DM nor overweight was shown to be significant in any of the analyses.On the basis of the community-based cross-sectional and case-controlled studies, neither DM nor overweight was a risk factor for HCC in a dual HBV and HCV endemic area. However, male gender, age (or =65 years), HBsAg, anti-HCV, thrombocytopenia, and high ALT levels were independent risk factors for HCC.

Background and Aim: To evaluate the association of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with hypercholesterolemia and hypertriglyceridemia. Methods: We analyzed the computerized health datasets of 56 336 residents from a community-based comprehensive screening in Tainan County in southern Taiwan. The overall prevalence rates of HBV surface antigen (HBsAg) and anti-HCV were 10.9% and 10.2%, respectively. Anti-HCV, HBsAg, platelet counts, albumin/globulin ratio (A/G ratio), fasting glucose, triglyceride, cholesterol levels, and body mass index (BMI) were abstracted for analyses. Multivariate logistic analysis was used for identification of the independent factors of hypercholesterolemia and hypertriglyceridemia. Results: The prevalence of hypercholesterolemia and hypertriglyceridemia were 48.9% and 28.0%, respectively. Hypercholesterolemia and hypertriglyceridemia were associated with each other. Older age, negativity for HBsAg and anti-HCV, normal platelet counts, A/G ratio ≥ 1, higher BMI, and being diagnosed as diabetic were common independently associated factors of both hypercholesterolemia and hypertriglyceridemia. Men had higher risk for hypertriglyceridemia, while women had higher risk for hypercholesterolemia. Conclusions: This large scale community-based study demonstrated that subjects with seropositivity for Hepatitis C not only had lower prevalence of hypercholesterolemia and hypertriglyceridemia but subjects with seropositivity for Hepatitis B had the same trend.

Background and Aim: The early detection of hepatocellular carcinoma (HCC) and opportunity to select appropriate treatment are important benefits of HCC screening. Our aim in the present study was to investigate the survival rate, prognostic factors and treatment effects in HCC patients of community-based screening. Methods: Community-based ultrasound (US) screening for HCC in adults with platelet counts ( 20 ng/mL was conducted in 2002 and 2004. As per the Barcelona Clinic Liver Cancer (BCLC) stage, 90 cases of intermediate or earlier stage HCC were detected and 88 cases had sufficient information for analysis (49 men and 39 women, aged 65.8 ± 9.6 years). The tumor diameter was mostly less than 5 cm (76.1%). The follow up was continued until June 2008. Results: The 4-year overall survival rate was 46.8%. Old age (≥ 70 years) (P = 0.046), later stage of HCC (intermediate vs earlier) (P = 0.012), low platelet count (