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Simple Summary: The long-term benefits of lenvatinib on the treatment of advanced hepatocellular carcinoma (HCC) are still unsatisfactory. The search for a new drug to promote lenvatinib's anti-cancer effect is an urgent issue. Whether the response of HCC to lenvatinib is dose-dependent also still needs to be clarified. The aims of this study were to investigate the dose-dependent anti-cancer effect of lenvatinib on HCC cells and the potential benefit of combined colchicine therapy. Four primary cultured HCC cell lines were applied for experiments. Combined analysis of the results of differential expressions of the genes (11 lenvatinib target genes and NANOG) and the anti-proliferative effect indicated that the anti-cancer effect of lenvatinib on HCC was not dose dependent. Combined clinically achievable plasma colchicine concentration with lenvatinib can promote the total anti-cancer effects on HCC. Purpose: The dose-dependent anti-cancer effect of lenvatinib on hepatocellular carcinoma (HCC) cells and the potential benefit of combined colchicine therapy were investigated. Methods: Four primary cultured HCC (S103, S143, S160, S176) cell lines were investigated by differential expressions of genes (11 lenvatinib target genes and NANOG) and anti-proliferative effect using clinically achievable plasma lenvatinib (250, 350 ng/mL) and colchicine (4 ng/mL) concentrations. Results: Colchicine showed an anti-proliferative effect on all cell lines. Lenvatinib at 250 ng/mL inhibited proliferation in all cell lines, but 350 ng/mL inhibited only three cell lines. For lenvatinib target genes, colchicine down-regulated more genes and up-regulated less genes than lenvatinib did in three cell lines. Lenvatinib up-regulated NANOG in all cell lines. Colchicine down-regulated NANOG in three cell lines but up-regulated NANOG with less magnitude than lenvatinib did in S103. Overall, combined colchicine and 250 ng/mL lenvatinib had the best anti-cancer effects in S143, with similar effects with combined colchicine and 350 ng/mL lenvatinib in S176 but less effects than combined colchicine and 350 ng/mL lenvatinib in S103 and S160. Conclusions: Lenvatinib does not show a dose-dependent anti-cancer effect on HCC. Combined colchicine and lenvatinib can promote the total anti-cancer effects on HCC. [ABSTRACT FROM AUTHOR]

Background: Long-term incidences and baseline determinants of functional cure (hepatitis B surface antigen [HBsAg] seroclearance) during entecavir (ETV) or tenofovir disoproxil fumarate (TDF) treatment are incompletely understood.Methods: This is an international multicenter cohort study of treatment-naive patients with chronic hepatitis B who started ETV or TDF treatment without baseline cancer. Patients were observed for HBsAg seroclearance until death or loss to follow-up. We calculated the incidences and explored the baseline determinants of HBsAg seroclearance using competing risk regression.Results: The analysis included 4769 patients (median age, 50 years; 69.05% male), with a median follow-up of 5.16 years (26 614.47 person-years). HBsAg clearance occurred in 58 patients, yielding a 10-year cumulative incidence of 2.11% (95% confidence interval, 1.54%-2.88%) and an annual rate of 0.22% (.17%-.28%). Baseline predictors included low-level viremia with hepatitis B virus DNA <2000 IU/mL (adjusted subdistribution hazard ratio, 3.14 [95% confidence interval, 1.80-5.49]), elevated serum alanine aminotransferase >200 U/L (3.68 [2.07-6.53]), serum bilirubin (1.11 per mg/dL; [1.06-1.17 mg/dL]), and fatty liver (1.84 [1.03-3.29]).Conclusion: HBsAg seroclearance rarely occurs in patients with chronic hepatitis B treated with ETV or TDF and is associated with low-level viremia, alanine aminotransferase flare, bilirubin level, and fatty liver.Functional cure of hepatitis B virus infection rarely occurred at an average annual rate of 0.22% during first-line oral antiviral treatment, with higher chances observed in patients with low-level viremia, high-level aminotransferase flare, elevation of serum bilirubin, and fatty liver. [ABSTRACT FROM AUTHOR]

Background and Aim: Hepatitis B virus (HBV) surface antigen (HBsAg) seroreversion usually occurs during immunosuppressive therapy. The risk and factors of HBsAg seroreversion from resolved HBV infection in the general population remained unclear. Methods: This retrospective study enrolled subjects with resolved HBV infection and who had received at least two times of screening in a longitudinal community screening program. HBsAg, hepatitis B surface antibody (anti‐HBs), and hepatitis C virus antibody (anti‐HCV) were tested every time in all subjects. The primary endpoint was HBsAg seroreversion. Results: Of the 7630 subjects enrolled, 5158 (67.6%) subjects had positive anti‐HBs at baseline. HBsAg seroreversion occurred in 84 subjects during 42 815‐person‐year follow‐up with an annual incidence of 0.2% and a 10‐year cumulative risk of 1.9%. Anti‐HBV treatment‐experienced subjects had a significantly higher risk of HBsAg seroreversion than anti‐HBV treatment‐naive subjects (83/310 [26.8%] vs 1/7320 [0.01%], P < 0.001). Lower rates of positive anti‐HBs and anti‐HCV were observed in anti‐HBV treatment‐experienced subjects who developed HBsAg seroreversion. Both positive anti‐HBs (hazard ratio/95% confidence interval: 0.56/0.348–0.903, P = 0.017) and positive anti‐HCV (hazard ratio/95% confidence interval: 0.08/0.030–0.234, P < 0.001) were independent factors of HBsAg seroreversion in anti‐HBV treatment‐experienced subjects. Less than 5% of the HBsAg seroreverters had clinical hepatitis flare at HBsAg seroreversion. The HBsAg titer was low, and only transient reappeared in most of the HBsAg seroreverters. Conclusions: Subjects with resolved HBV infection were at a minimal risk of HBsAg seroreversion, unless with prior anti‐HBV treatment experience. Fortunately, even with a reappearance of HBsAg, it was transient and clinically non‐relevant. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. 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. • HBsAg levels decline during DAA therapy and rebound post-DAA therapy in HBV/HCV coinfected patients. • HBsAg loss can occur in HBV/HCV coinfected patients on DAA therapy at a frequency seen in HBV monoinfection. • HBV/HCV-coinfected patients are at risk of HBV reactivation after DAA, especially in those with higher HBsAg levels. • HBV/HCV coinfected cirrhotic patients on DAAs should undergo HBV prophylaxis to reduce risk of hepatic failure and death. • Quantitative HBsAg measurement could guide decision-making in HBV/HCV coinfected patients on DAA therapy. [ABSTRACT FROM AUTHOR]

Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. [Display omitted] • Among 12,566 patients with chronic HBV infection, about one-quarter were not adequately evaluated. • Among adequately evaluated patients, about one-third were treatment eligible by international guidelines. • Among those who were treatment eligible, about 80-85% were treated. • Treatment rates were lower in females and Asian Americans (vs. Asians from the East or non-Asians). [ABSTRACT FROM AUTHOR]

Background: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort.Methods: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score.Results: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001).Conclusions: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy. [ABSTRACT FROM AUTHOR]

Background and Aim: Ribavirin (RBV) remains crucial in difficult‐to‐cure chronic hepatitis C patients receiving directly acting antivirals (DAAs). The current study aimed to address whether RBV enhanced early viral kinetics in patients with DAAs. Methods: Hepatitis C virus (HCV) genotype‐1b patients were allocated to daclatasvir/asunaprevir +weight‐based RBV (1000–1200 mg/day) for 12–24 weeks. HCV RNA levels were compared at day 1, week 1, week 2, and week 4 of treatment. Results: The sustained virological response rate was 100% (67/67) and 96.7% (59/61) in the RBV and non‐RBV group, respectively. The HCV RNA levels at treatment week 2 (W2) were significantly lower in the RBV group than in the non‐RBV group (0.42 ± 0.81 log IU/mL vs 0.79 ± 1.03 log IU/mL, P = 0.04). Among the intermediate responders who remained to have detectable RNA after W1 of treatment, patients with RBV had a significantly higher rate of undetectable HCV RNA (71.4% vs 36.0%, P = 0.003) and lower HCV RNA level at W2 (0.55 ± 0.89 log IU/mL vs 1.32 ± 1.04 log IU/mL, P = 0.001). A more significant magnitude of HCV RNA reduction was also noted from baseline to day 1 (3.15 ± 0.38 log IU/mL vs 2.80 ± 0.70 log IU/mL, P = 0.009) and W1 to W2 (1.40 ± 0.65 log IU/mL vs 0.88 ± 0.78 log IU/mL, P = 0.007) in the RBV group compared to the non‐RBV group among the intermediate responders. Logistic regression analysis revealed that adding RBV independently predicted undetectable HCV RNA at W2 (odds ratio/confidence interval: 4.74/1.54–14.57, P = 0.007) in the intermediate responders. Conclusions: Adding RBV to DAAs improved early viral kinetic, in particular, for intermediate responders. [ABSTRACT FROM AUTHOR]

Background: Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) was a novel marker of liver fibrosis. We aimed to investigate WFA+-M2BP level in assessing liver fibrosis in patients with chronic hepatitis B (CHB) infection. Methods: A total of 160 CHB patients, who received a liver biopsy, were consecutively recruited. Serum WFA+-M2BP level was quantified at the time point of biopsy. The results were compared with histopathological manifestations and clinical characteristics of the patients. Results: The median WFA+-M2BP level, aspartate aminotransferase-to-platelet ratio (APRI) and Fibrosis-4 (FIB-4) index were 1.20 COI, 1.19, and 1.63, respectively. Fifty-one (31.9%) patients had advanced fibrosis. There was a significant increase of WFA+-M2BP levels in parallel to necroinflammation/fibrosis stages. The areas under the receiver operating characteristic curve (AUROC) of WFA+-M2BP level for predicting fibrosis stages were 0.780 of F2, 0.785 of F3, and 0.769 of F4, respectively (all p <0.001). The multivariate analysis identified age (Odds ratio [OR] 1.05, 95% confidence interval [CI]: 1.010–1.092, p = 0.014), platelet (OR: 0.99, 95%CI: 0.980–0.998, p = 0.013), and WFA+-M2BP level (OR: 1.97, 95% CI: 1.299–2.984, p = 0.001) as independent factors associated with advanced fibrosis. Combination of age, platelet and WFA+-M2BP level achieved a better diagnostic performance for advanced fibrosis (AUROC: 0.732, accuracy: 81.3%) than APRI (AUROC: 0.577, accuracy: 63.8%) or FIB-4 index (AUROC: 0.691, accuracy: 75.6%). Conclusion: WFA+-M2BP had a good performance indistinguishing liver fibrosis in CHB patients. The combination of age, platelet, and WFA+-M2BPaddressed more accuracy in identifying patients with advanced fibrosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/aims: Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as metabolic abnormalities. The association between chronic hepatitis C (CHC) and uric acid levels has rarely been investigated. We aimed to evaluate the levels of serum uric acid in CHC patients. Methods: Three hundred and seventy-three histologically confirmed CHC patients who were scheduled to receive antiviral therapy were consecutively enrolled, and 746 age- and sex-matched uninfected controls were included for comparison. Hyperuricemia was defined as a uric acid level > 7 mg/dL in men and > 6.0 mg/dL in women. Results: Hyperuricemia was identified in 15.8% of the CHC patients. The uric acid levels did not differ between the CHC patients and the controls (5.54 ± 1.20 mg/dL vs. 5.45 ± 1.45 mg/dL, P = 0.3). Among the 373 CHC patients, the factors associated with hyperuricemia included body mass index (BMI) (OR/CI: 1.13/1.04–1.21, P = 0.003) and estimated glomerular filtration rate (eGFR) (OR/CI: 0.98/0.97–1.00, P = 0.02). Logistic regression analysis revealed that the factors associated with hyperuricemia in male patients included BMI (OR/CI: 1.12/1.05–1.30, P = 0.006) and advanced fibrosis (F3-4) (OR/CI: 0.27/0.09–0.83, P = 0.02), whereas the factors associated with hyperuricemia in female patients included eGFR (OR/CI: 0.97/0.95–0.99, P = 0.02) and diabetes (OR/CI: 3.03/1.11–8.25, P = 0.03). There was a significant decreasing trend of serum uric acid levels with the progression of fibrotic stages among male patients (6.21 ± 1.03 mg/dL 5.82 ± 1.16 mg/dL and 5.44 ± 1.28 mg/dL in stages F0-2, F3, and F4, respectively, trend P = 0.01). Conclusions: Hyperuricemia was inversely associated with liver disease severity in CHC male patients. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Hepatitis C virus infection is associated with thrombocytopenia. Thrombocytopenia recovers after viral eradication. The current study explored the rate and factors associated with platelet (PLT) recovery, which may represent the degree of liver fibrosis regression. Methods: A total of 466 patients who achieved a sustained virological response were enrolled to compare the PLT change after a mean follow‐up period of 85.5 months (range 12–163 months). Results: Platelet counts increased significantly after achieving sustained virological response (from 166 ± 55 × 103 to 201 ± 61 × 103 u/L, P < 0.001). The median PLT count increment was 5.03 × 103 u/L per year. Logistic regression analysis revealed that factors associated with slow PLT count recovery were high pretreatment PLT counts (odds ratio [OR]/ 95% confidence intervals [CI]: 0.992/0.989–0.996, P < 0.001) and hepatitis B virus (HBV) co‐infection (OR/CI: 0.416/0.220–0.785, P = 0.007). High PLT counts were the only factor associated with slow PLT recovery in patients with mild liver disease (F0–2) (OR/CI: 0.992/0.987–0.996, P < 0.001). On the other hand, HBV co‐infection was the only factor associated with slow PLT recovery in patients with advanced fibrosis (OR/CI: 0.207/0.054–0.789, P = 0.02). Linear regression analysis of factors correlated to the delta PLT count change per year in patients with F0–2 included pretreatment white blood cell (β: −0.001; CI: −0.002–0.000; P = 0.01) and pretreatment PLT counts (β: −0.037; CI: −0.061 to −0.013; P = 0.003). HBsAg seropositivity was the only factor correlated to the delta PLT count change per year (β: −10.193; CI: −16.752–3.635; P = 0.003) among patients with F3–4. Conclusions: Platelet counts recovered after hepatitis C virus eradication. HBV dual infection disrupted PLT count recovery, especially in CHC patients with advanced liver disease. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non‐viral causes of HCC, particularly non‐alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC. Methods: We conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878). Results: Cirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV‐related HCC (HBV‐HCC) (P = .001) and 85.9% of HCV‐HCC (P < .001). Compared to viral HCC, cryptogenic HCC patients presented with larger tumours and at later stages of disease. Five‐year overall survival was 16.3% among cryptogenic HCC patients compared with 31.9% among HBV‐HCC patients and 27.7% among HCV‐HCC patients (P < .001 for both by the log‐rank test). HCC aetiology was not an independent predictor of survival, though ethnicity, cirrhosis status, meeting Milan criteria and treatment allocation were. Conclusions: Compared with viral HCC patients, those with cryptogenic HCC had lower prevalence of cirrhosis, were diagnosed with larger tumours at more advanced stages of disease, and had poorer overall survival. Additional efforts are needed to identify patients at risk of cryptogenic HCC and to identify cryptogenic HCC at earlier stages of disease. [ABSTRACT FROM AUTHOR]

Background and Aim 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. Methods 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. Results The overall SVR12 rate was 96.9%, and two patients, one with positive HBsAg, had a relapse of HCV. No episodes of HBV virological reactivation were observed among the patients with a past HBV infection. For the seven patients with a current HBV infection, HBV virological reactivation was found in four (57.1%) of the seven patients. Clinical reactivation of HBV was observed in one patient with pretreatment detectable HBV DNA and recovered after entecavir administration. For the other three patients with HBV virological reactivation, the reappearance of low level HBV DNA without clinical reactivation was observed. HBsAg levels demonstrated only small fluctuations in all the patients. Conclusions There 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. [ABSTRACT FROM AUTHOR]

Background: The impact of additional extra-hepatic primary cancer (EHPC) on the outcomes of patients with hepatocellular carcinoma (HCC) remains uncertain. Methods: We retrospectively analyzed the cancer registration database from a tertiary hospital in Southern Taiwan. Patients who were diagnosed with HCC from 2008 to 2012 were enrolled. Overall survival (OS), HCC-specific survival and recurrence after curative therapy were analyzed and compared between the patients with and the patients without EHPC. Results: EHPC was found in 121/1506 (8.0%) patients. HCC patients with EHPC were older, more likely to be classified as Child-Pugh A, less likely to have viral hepatitis B or C, more likely to be single, had early stage HCC and received curative therapy for HCC. The OS did not significantly differ between the patients with and without EHPC(p = 0.061). However, significantly higher HCC-specific survival was observed in patients with EHPC (p<0.001), and a higher rate of non-HCC mortality was demonstrated in patients with EHPC (54.4% vs 9.3%). The subgroup analysis revealed better OS in patients with EHPC who were older than 65, had viral hepatitis B or C, had non-stage 1 HCC, had non-early stage BCLC and received non-curative therapy. Conversely, patients with HCC stage 1 who received curative therapy exhibited worse OS if they also had EHPC. The analysis of recurrence after curative therapy showed no difference between the two groups. Conclusions: Our results implied that EHPC did not affect OS, but HCC-related survival was better in patients with EHPC. Based on these findings, the management of additional primary cancer is warranted. [ABSTRACT FROM AUTHOR]

Background & aims: Identification of disease severity remains a challenge in the management of non-alcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18), is a recently developed non-invasive biomarker for NASH. We aimed to assess the performance of CK18 in disease severity prediction among Taiwanese NASH patients. Methods: A total of 76 biopsy-proven NASH patients (54 males, age = 41.0 ± 13.5 years) were consecutively recruited. The optimal cutoff values of CK18 for each stage of fibrosis were correlated with their histopathological manifestations. Results: There were 23 (30.3%) patients of Metavir fibrosis stage 0 (F0), 32 (42.1%) patients of F1, 14 (18.4%) patients of F2, and 7 (9.2%) patients of F3-4, respectively. The CK18 levels among those patients of F0, F1, F2, F3-4 were 86.7 ± 75.6 U/L, 122.4 ± 123.8 U/L, 160.7 ± 120.4 U/L, and 507.3 ± 343 U/L, respectively (trend for P<0.001). The adjusted optimal cutoff value for F2 prediction was 312.5 U/L, yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the accuracy of 96.4%, 28.6%, 77.9%, 75%, and 77.6%, respectively (P = 0.009). For the prediction of advanced fibrosis (F3-4), the adjusted optimal cutoff value was 374.5 U/L, yielding the sensitivity, specificity, PPV, NPV, and the accuracy of 97.1%, 54.1%, 95.7%, 66.7%, and 77.6%, respectively (P = 0.003). Among those patients without hyperuricemia, the PPV, NPV, and accuracy of CK18 reached 100%, 95.8%, and 96%, respectively (P<0.001). Conclusions: CK18 combined with uric acid measurement is a promising non-invasive biomarker for prediction of disease severity in NASH patients. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The advantage of colchicine to promote sorafenib or regorafenib anti-cancer effects on hepatocellular carcinoma (HCC) was investigated. Four primary cultured HCC cell lines (S103, S143, S160, S176) were studied by clinically achievable plasma sorafenib (5, 10 μg/mL), regorafenib (2, 4 μg/mL) and colchicine (4 ng/mL) concentrations. Sorafenib and regorafenib target genes and cancer stem cell markers (NANOG , POU5F1) were selected for experiments. Colchicine inhibited proliferation in all cell lines. Sorafenib inhibited proliferation only in S143 (5 μg/mL). Combined colchicine with sorafenib reversed the sorafenib effect on cellular proliferation from promotive to inhibitory in S103, and demonstrated anti-proliferative effects on other cell lines. Regorafenib inhibited proliferation in S103 (2 μg/mL), S176 (2 μg/mL) and S160 (4 μg/mL). Combined colchicine with regorafenib demonstrated equal or stronger anti-proliferative effects than regorafenib alone in all cell lines except S160. Combined colchicine obliterated or reduced the number of up-regulated target genes induced by sorafenib, and demonstrated equal or increased number of down-regulated target genes as compared with regorafenib alone. However, combined colchicine with regorafenib increased one up-regulated target gene in three cell lines. Colchicine obliterated or decreased the magnitude of up-regulated NANOG induced by sorafenib (S103, S143, S176) or regorafenib (S143), and combined with regorafenib could down-regulate NANOG (S160, S176). Adding colchicine to sorafenib or regorafenib showed inconsistent influence on POU5F1 expression as compared with sorafenib or regorafenib alone. The above results suggest that the anti-cancer effects of combined sorafenib with colchicine may be better than sorafenib alone. Colchicine may be added to regorafenib non-responders. [Display omitted] • Hepatocellular carcinoma is composed by cancer cells with various characters. • Multikinase inhibitor resistant cells will replace sensitive cells after treatment. • Colchicine can inhibit proliferation in cancer cells with different characters. • Combined sorafenib with colchicine may be better than sorafenib alone. • Colchicine may be added to regorafenib non-responders. [ABSTRACT FROM AUTHOR]

Background: The optimal therapeutic strategy for hepatitis B virus (HBV) e antigen (HBeAg)-seropositive and hepatitis C virus (HCV) dually infected patients remains unknown. We aimed to elucidate the effectiveness of peginterferon (Peg-IFN)/ribavirin (RBV) with and without lamivudine (LAM) combination therapy in the clinical settings. Patients and Methods: Nine patients seropositive for HBV surface antigen, HBeAg, antibodies to HCV and HCV RNA for >6 months were treated with Peg-IFN/RBV with ( n = 5) and without ( n = 4) a 12-month LAM add-on therapy at treatment week 12. The treatment duration of Peg-IFN/RBV was 24 weeks (HCV genotype 1 [HCV-1] with rapid virological response [RVR] or HCV-2) or 48 weeks (HCV-1 without RVR). Primary endpoints included HBeAg loss and HCV-sustained virological response (SVR). Results: All of the nine patients had undetectable HCV RNA at treatment weeks 4 and 12 and end-of-Peg-IFN/RBV therapy. However, SVR was achieved in 100% of patients treated with triple therapy, compared with only 50% in those with Peg-IFN/RBV therapy ( P = 0.167). The 3-year durability of HCV SVR was 100%. HBeAg loss and HBV DNA <2000 IU/mL at 6 months post-LAM treatment were found in 100% and 40% of patients treated with triple therapy, compared with none of the four patients with Peg-IFN/RBV therapy achieved any HBV responses. Of the five patients with triple therapy, four had persistent HBeAg loss during 3-year follow-up period; one developed HBeAg seroreversion 15 months after treatment. Conclusion: For HBeAg-positive HBV/HCV dually infected patients, Peg-IFN/RBV was effective for HCV eradication. Add-on LAM might promote HBeAg loss in the clinical setting. [ABSTRACT FROM AUTHOR]

Background and Aim: Pegylated interferon-alpha plus ribavirin combination (PegIFN/ RBV) therapy possesses positive effect in the secondary prevention of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients. The current study aimed to assess its efficacy in the tertiary prevention and to validate the performance of the MHC class I polypeptide-related chain A (MICA) level in the prediction of hepatocellular carcinoma (HCC) recurrence. Methods: A multi-center study enrolling 105 consecutive HCC patients post curative therapies were prospectively recruited. The primary outcome measurement was recurrence of HCC. Results: The mean observational period was 52.7 months (range = 3.9-121.5 months). Fifty-six (53.3%) patients achieved sustained virological response (SVR). After completion of treatment, 43 (41.0%) patients developed HCC recurrence, and 24 (55.8%) of them had their recurrence within 6 months after completion of therapy. Thirty-three (76.7%) of the patients with HCC recurrence were of de novo pattern. Those responders tended to have a lower cumulative incidence of recurrence than those non-responders (43.2 vs 84.8/100 person-month, log-rank P = 0.13). Those non-responders with a high MICA level (>100 pg/mL) carried the lowest cancer-free survival than those non-responders with a low MICA level and those responders (P = 0.002). Cox regression hazard analysis showed high baseline MICA level (Odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.1-20.8, P = 0.04) and a low platelet count (<100 000/mm³) (OR=5.4, 95% CI=1.1-27.0, P=0.04) predicted HCC recurrence. Conclusions: PegIFN/RBV therapy carried a limited effect in the tertiary prevention of HCC. A high MICA level predicted HCC recurrence, particularly among those nonresponders. [ABSTRACT FROM AUTHOR]

Background & Aims: Asians are more susceptible to non-alcoholic steatohepatitis (NASH) as well as metabolic disorder than other ethnicities. We aimed to assess the interaction between metabolic factors and fibrosis in Taiwanese NASH patients. Methods: A total of 130 biopsy-proven Taiwanese NASH patients (94 males, age = 43.0 ± 13.0 years) were consecutively enrolled. Their demographic, metabolic profiles and histopathological manifestations were analyzed. Results: Twenty-four (18.5%) NASH patients were non-obese. Thirty-three (25.4%) patients had significant fibrosis (F2) or more: 22 (16.9%) patients were of F2, whilst 11 (8.5%) patients were of advanced fibrosis (F3-4). The prevalence of metabolic syndrome, diabetes and hypertension were 60.8%, 39.4%, and 61.5%, respectively. There was a significant inverse correlation between hyperuricemia and fibrosis stages, ranging from 48.4% of F0-1, 33.3% of F2, and 9.1% of F3-4, respectively (P = 0.01, linear trend). Multivariate logistic regression analysis showed that a decreased serum albumin level (OR = 40.0, 95% CI = 4.5–300, P = 0.001) and normal uric acid level (OR = 5.6, 95% CI = 1.5–21.7, P = 0.01) were the significant factors associated with significant fibrosis. Conclusions: Hyperuricemia inversely predicts fibrosis stages. Females might carry a more disease severity than males in Taiwanese NASH patients. [ABSTRACT FROM AUTHOR]

Background and Aim Chronic hepatitis C virus ( HCV) infection has been suggested to be associated with non-insulin-dependent diabetes mellitus and lipid profiles. This study aimed to investigate the possible relationships of insulin resistance ( IR) and lipid profiles with chronic hepatitis C ( CHC) patients in Taiwan. Methods We enrolled 160 hospital-based CHC patients with liver biopsy and the 480 controlled individuals without CHC and chronic hepatitis B from communities without known history of non-insulin-dependent diabetes mellitus. Fasting plasma glucose, total cholesterol, high-density lipoprotein cholesterol ( HDL- C), low-density lipoprotein cholesterol ( LDL- C), triglycerides ( TGs), alanine aminotransferase, and serum insulin levels, and homeostasis model assessment ( HOMA-IR) were tested. Results When comparing factors between CHC patients, and sex- and age-matched controls who had no HCV infection, patients with HCV infection had a significantly higher alanine aminotransferase level, fasting plasma glucose level, insulin level, and HOMA-IR ( P < 0.001, P = 0.023, P = 0.017, and P = 0.011, respectively), and significantly lower TG level ( P = 0.023), total cholesterol, and HDL- C and LDL- C levels (all P < 0.001) than 480 controls. In multivariate logistic regression analyses, a low total cholesterol, a low TGs, and a high HOMA-IR are independent factors significantly associated with chronic HCV infection. In the 160 CHC patients (41 patients with high HOMA-IR [> 2.5]), a high body mass index, TGs, and HCV RNA level are independent factors significantly associated with high HOMA-IR in multivariate logistic analyses. Conclusions Chronic HCV infection was associated with metabolic characteristics including IR and lipid profile. IR was also associated with virological characteristics. [ABSTRACT FROM AUTHOR]

Background: Studies are limited on pegylated interferon (Peg-IFN) therapy for chronic hepatitis B (CHB) patients who failed or relapsed on previous antiviral therapy. Objectives: We aimed to investigate the effect of Peg-IFN therapy in treatment-experienced CHB patients. Study Design: A total of 57 treatment-experienced CHB patients at two medical centers were enrolled. All of the patients were treated with Peg-IFN α-2a at 180 μg weekly for 24 or 48 weeks. The hepatitis B serological markers and viral loads were tested every 3 months until 1 year after stopping Peg-IFN therapy. The endpoints were HBV DNA <2000IU/mL, hepatitis B e antigen (HBeAg) seroconversion, and a hepatitis B surface antigen (HBsAg) loss at 12 months post-treatment. Results: In HBeAg-positive patients, 25.0%, 29.2%, and 12.5% of the patients achieved HBeAg seroconversion, HBV DNA <2000 IU/mL and a combined response, respectively, at 12 months post-treatment. Prior IFN therapy, a high baseline ALT level, a low creatinine level, undetectable HBV DNA at 12 weeks and a decline in HBV DNA >2 log10 IU/mL at 12 weeks of therapy were factors associated with treatment response. In HBeAg-negative patients, 9.1%, 15.2%, and 6.1% of the patients achieved undetectable HBV DNA, HBV DNA <2000 IU/mL, and an HBsAg loss, respectively, at 12 months post-treatment. No factor was significantly associated with the treatment response in the HBeAg-negative patients. The median HBsAg level declined from 3.4 to 2.6 log10 IU/mL in all the patients, and the 5-year cumulative rate of the HBsAg loss was 9.8% in the HBeAg-negative patients. Overall, none of the patients prematurely discontinued the Peg-IFN therapy. Conclusions: Peg-IFN re-treatment is effective for a proportion of HBeAg-positive treatment-experienced patients; it has limited efficacy for HBeAg-negative treatment-experienced patients. Peg-IFN might facilitate HBsAg loss in HBeAg-negative treatment-experienced patients. [ABSTRACT FROM AUTHOR]

Background: Selection of drug-resistant strains may lead to failure of HBV antiviral therapy. There is little information whether there is detection difference in drug resistant mutations between different viral load assays of HBV. Objectives: This study is aimed to investigate whether there is drug-resistant strains related detection difference between Abbott RealTime HBV (RealTime) and CobasAmpliPrep/CobasTaqMan HBV assays 2.0 (TaqMan). Study Design: One hundred and thirty-four CHB patients who received HBV anti-viral therapy were enrolled. HBV virological markers were tested 3 months apart regularly. Serum HBV DNA levels were determined using the TaqMan and RealTime. YMDD (rt180M and rt204V) mutation was checked in patients who experienced virologic breakthrough (VBT). Results: The correlation of HBV DNA observed between the RealTime and TaqMan was good for all 571 samples (R2 = 0.797; P<0.001). However, the correlation in the 434 samples with HBV DNA level <3 log10 IU/ml was not as good as in all samples (R2 = 0.457). Overall, 21.5% of samples had a detection difference of ≥1 log10 IU/ml with 91.9% of these having HBV DNA level <3 log10 IU/ml. Twenty-four patients experiencedVBT. Three of these patients had acquired the YMDD mutation and exhibited discordant viral load results between the two methods tested. In each case, persistent HBV DNA was detected by RealTime and undetectable with TaqMan. Of the patients who experienced a VBT and had acquired YMDD mutation, 4.7% had undetectable HBV DNA by TaqMan while all were detectable with RealTime. Conclusions: RealTime assay is more sensitive and is little impacted by the development of drug resistant mutation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Measurement of hepatitis B virus (HBV) DNA levels is essential in the clinical management of patients with chronic HBV infection. Performance and accuracy of quantitation for HBV DNA are therefore critical in clinical practice. Objectives: We aimed to compare and evaluate the performance characteristics of two HBV DNA quantitative assays: Abbott RealTime HBV (RealTime assay) and Cobas AmpliPrep/Cobas TaqMan HBV assays 2.0 (TaqMan assay). Study design: Serum samples from 220 HBV-infected patients were collected. Performance characteristics of the HBV DNA quantitative assays, including sensitivity, linearity, and reproducibility were measured. The assays were compared based on the viral status, including HBeAg, genotype, core promoter and pre-core region mutations. Results: The RealTime assay had a sensitivity and specificity of 98.2% and 100%, respectively. The intra-assay coefficients of variation of serum samples ranged from 0.00% to 11.25% for the RealTime assay and 1.22% to 8.22% for TaqMan assay. Paired quantitative results showed excellent correlation by linear regression analysis (R 2 =0.961), good level of agreement with a mean difference of 0.31log10 IU/mL, and limits of agreement of −0.62 to 1.24log10 IU/mL, irrespective of HBeAg, genotype, core promoter and pre-core region mutation-specific differences. In this study, a difference of ≥1log10 IU/mL between the two assays was observed in 8.6% of the samples. Genotype B and average HBV DNA levels of <3log10 IU/mL were significant associated factors of this discordance. Conclusions: The Abbott assay delivered high performance for HBV DNA quantification and correlated extremely well with the TaqMan assay, irrespective of viral status. [Copyright &y& Elsevier]

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 53.0months (range: 6–133months). Results: Thirty-three of the 642 (5.1%) patients developed HCC over 2324.8 person-years of follow-up. Cox regression analysis revealed that the strongest predictive factor of HCC occurrence was liver cirrhosis (HR 4.98, 95% CI 2.32–10.71, p <0.001), followed by age (HR 1.06, 95% CI 1.02–1.11, p =0.005) and γGT levels (HR 1.008, 95% CI 1.004–1.013, p <0.001). The incidence of HCC did not differ between patients with high and low baseline γGT levels among patients with cirrhosis (p =0.53), but the incidence of HCC was significantly higher in non-cirrhotic patients with high γGT levels compared with those with low γGT levels (p =0.001). Cox regression analysis revealed that the strongest factors associated with HCC development in non-cirrhotic sustained responders were baseline γGT levels (HR 6.44, 95% CI 2.20–18.89, p =0.001) and age (HR 3.68, 95% CI 1.33–10.17, p =0.012). The incidence of HCC was not different between older non-cirrhotic patients with high γGT levels and cirrhotic patients (p =0.34). Conclusions: HCC remains a threat in non-cirrhotic patients with an SVR. Serum γGT levels helped to identify potential patients at high risk. [Copyright &y& Elsevier]

Background and Aim Host interleukin-28 B ( IL-28 B) genetic variants determine a sustained virological response ( SVR) in hepatitis C virus genotype 1 ( HCV-1) treatment-naïve patients. Its impact on treatment-experienced Asian patients with peginterferon/ribavirin in is to be elucidated. Methods IL-28 B rs8099917 genotype was determined in 70 HCV-1 treatment-experienced patients retreated with 48-week peginterferon/ribavirin. Results The SVR rate was 60.0% and was significantly higher in previous relapsers than in nonresponders (72.7% and 13.3%, P < 0.001). Multivariate analysis revealed that the most important factor predictive of an SVR was previous relapse (Odds ratio [ OR]/95% confidence interval [ CI]: 14.76/2.72-80.06, P = 0.002), followed by the carriage of rs8099917 TT genotype ( OR/95% C. I.: 7.67/1.27-46.49, P = 0.03). Comparing to patients with TG/ GG genotype, those with TT genotype had significantly higher rates of rapid virological response (29.3% vs 0%, P = 0.03), end-of-treatment virological response (86.2% vs 50.0%, P = 0.01), SVR (69.0% vs 16.7%, P = 0.002), and lower relapse rate (22.0 % vs 66.7%, P = 0.04). The SVR rate was similarly low between previous nonresponders with different rs8099917 genotypes (12.5% vs 14.3%, P = 1). On the contrary, previous relapsers with rs8099917 TT genotype had a significantly higher SVR rate than those who carried rs8099917 TG/ GG genotype (78.0 % vs 20.0%, P = 0.02). Stepwise logistic regression analysis revealed that the only factor predictive of an SVR in previous relapsers was the carriage of rs809997 TT genotype ( OR/95% CI:18.50/1.82-188.39, P = 0.014). Conclusions Host IL-28 B genetic variants played a role in Asian relapsers but not nonresponders retreated with peginterferon/ribavirin. Direct antiviral agents might be possibly avoidable in Asian relapsers with favorable IL-28 B genotype. [ABSTRACT FROM AUTHOR]

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

Simple Summary: It is important to understand the impact of viremia on the survival of hepatocellular carcinoma (HCC) in hepatitis C patients. This study aimed to investigate the characteristics and survival between hepatitis C patients with and without viremia at HCC diagnosis. We enrolled 1,389 HCC patients, including 301 with HCC developed after hepatitis C eradication (post-SVR HCC) and 1,088 with hepatitis C viremia (viremic HCC). Post-SVR HCC patients had better liver function, earlier tumor stages and higher median survival than viremic HCC patients. But post-SVR HCC was not independently associated with survival on further multivariate analysis. On sub-analysis, viremic HCC patients who subsequently eradicated hepatitis C had higher median survival and was also significantly associated with lower mortality as compared to post-SVR HCC. Therefore, the advantages in clinical and tumor characters determined the better overall survival of post-SVR HCC patients; however, eradication of hepatitis C after HCC also improved survival. The clinical presentation and survival of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication as compared to HCC in viremic patients are not well characterized. We aimed to investigate the characteristics and survival between HCV patients with and without viremia at HCC diagnosis.: We retrospectively analyzed overall survival outcomes in 1389 HCV-related HCC patients, including 301 with HCC developed after HCV eradication (post-SVR HCC) and 1088 with HCV viremia at HCC diagnosis (viremic HCC). We also evaluated overall survival in the two groups using propensity score-matching methods.: At HCC diagnosis, post-SVR HCC patients were older, less obese, less likely cirrhotic, with better liver function, lower alfa-fetoprotein levels, earlier BCLC stages, and higher rate of treatment with surgery. Overall, post-SVR HCC patients had higher median survival than viremic patients (153.3 vs. 55.6 months, p < 0.01), but post-SVR HCC was not independently associated with survival on multivariate analysis (adjusted HR: 1.05, 95% CI: 0.76–1.47). However, on sub-analysis, viremic HCC patients who subsequently received anti-viral treatment and achieved SVR had higher median survival than post-SVR HCC patients (p < 0.01). Viremic HCC with subsequent SVR was also significantly associated with lower mortality as compared to post-SVR HCC (adjusted HR: 0.18, 95% CI: 0.11–0.29). In addition, we observed similar findings in our analysis of the propensity score-matched cohorts.: The advantages in clinical and tumor characters at HCC diagnosis determined the better overall survival of post-SVR HCC patients; however, HCV eradication after HCC development was also associated with improved survival. [ABSTRACT FROM AUTHOR]

Introduction: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). Methods: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. Results: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. Conclusion: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Discussion This study estimated the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long‐term impacts of MASLD on all‐cause and cardiometabolic‐specific mortality were evaluated.We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self‐reported medication use and clinical seromarkers. All‐cause and cardiometabolic‐specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020.The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow‐up, patients with MASLD had a 9%–29% higher risk of all‐cause, cardiovascular‐related, or diabetes‐related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate‐adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05–1.25) and 1.10 (1.03–1.17), respectively, and those for diabetes deaths were 1.42 (1.05–1.93) and 1.24 (0.98–1.57), respectively, compared with those in the non‐MASLD group (Pfor trend < 0.001).Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all‐cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications. [ABSTRACT FROM AUTHOR]

Background: High dosage and longer duration of antiviral treatment has been suggested to treat cryoglobulinemia patients. We aimed to investigate the efficacy of antiviral treatment in cryoglobulinemia patients and analyze the associated factors of persistent cryoglobulinemia. Methods: Totally 148 patients after completion of anti-HCV treatment were enrolled in our study. Serum cryoglobulinemia precipitation was assessed and analyzed for the associated factors after antiviral therapy. Results: Fifty-one (34.5%) out of 148 patients were positive for serum cryoglobulinemia after completion of antiviral therapy. In multivariate analysis, advanced fibrosis (Odds Ratio [OR]– 4.13, 95% Confidence Interval [95% CI]– 1.53–11.17, p = 0.005) and platelet counts (OR-0.98, 95% CI– 0.97–0.99, p = 0.010) were independently and significantly associated with persistent cryoglobulinemia. The factors associated with the persistent cryoglobulinemia in SVR patients were advanced fibrosis (OR-1.93, 95% CI– 1.02–3.65, p = 0.041) and platelet count (OR-0.98, 95% CI– 0.96–0.99, p = 0.041) by multivariate analysis. Multivariate logistic regression analysis showed persistent (OR-4.83, 95% CI– 1.75–13.36, p = 0.002) was significantly associated with advanced fibrosis in patients with cryoglobulinemia follow up after antiviral therapy. Conclusions: The prevalence of the persistent cryoglobulinemia is 34.5% after completing antiviral therapy and it is associated with advanced fibrosis, also HCV clearance. [ABSTRACT FROM AUTHOR]

Firstly, it would indeed be of great benefit to know when and in whom anti-HBV nucleos(t)ide analogue (NUC) therapy should be initiated for HBV/HCV-coinfected patients receiving direct-acting antivirals (DAAs). All 3 major liver societies recommend prophylactic anti-HBV NUC therapy for HBV/HCV-coinfected patients commencing DAAs and fulfilling the criteria for HBV treatment.[[2]] In the current study, we observed that cirrhotic patients, irrespective of the presence of HBV viremia, were at high risk of HBV-related clinical reactivation with hepatic failure and even mortality. The results provide evidence that all cirrhotic HBV/HCV-coinfected patients should be treated with pre-emptive NUC therapy. [Extracted from the article]

Hepatitis C virus (HCV) infections can cause permanent liver-related diseases, including hepatocellular carcinoma (HCC). Low mortality and incidence of HCC have been observed in patients with chronic hepatitis C undergoing direct-acting antiviral therapy. Tumor suppressive let-7 family members are down-regulated in HCC. The present study, therefore, aimed to investigate whether expression levels for the full spectrum of let-7 family members (let-7a, 7b, 7c, 7d, 7e, 7f, 7g, 7i, and miR-98) in the circulatory system are useful as surveillance biomarkers for liver-related diseases to monitor treatment efficacy during HCV infection. To this end, we measured the levels of mature circulating let-7 family members using quantitative reverse transcription-PCR in 236 patients with HCV infection, and 147 age- and sex-matched controls. Using hierarchical cluster analysis and principal component analysis, three clusters were obtained after measuring expression levels of let-7 family members in the patients and controls. Cluster 1 included let-7a/d/e/g, Cluster 2 comprised let-7b and let-7i, and Cluster 3 comprised let-7c/f/miR-98. Let-7b/c/g represented the three clusters and showed the best survival response to liver cancer when analyzed with respect to patient data. Therefore, considering the circulating levels of let7 b/c/g as representatives of the let-7 family may facilitate effective monitoring of liver-related disease. [ABSTRACT FROM AUTHOR]

Summary: Volvulus of the sigmoid colon is rare in children although it is a common cause of large bowel obstruction in elderly people. We report a case of sigmoid volvulus in a 14-year-old girl with intellectual disability. She had a 1-year history of chronic diarrhea despite supportive treatment. She was brought to the emergency department because of intermittent abdominal pain associated with vomiting of bile and passage of bloody stools. A plain X-ray showed dilated bowel loops. A contrast-enhanced computed tomography (CT) scan showed both limbs of the distended loop tapering in size and forming a round soft-tissue mass with whirled configuration in the left colonic compartment. Preoperatively, volvulus was suspected. Exploratory laparotomy disclosed a markedly distended sigmoid colon packed with fecal material and a counterclockwise rotation of 720 degrees with strangulating gangrene. The volvulus was untwisted, and a 65-cm segmental resection of the colon and primary anastomosis were performed. The patient was discharged on the 19th day following an uneventful postoperative course. We believe that a contrast-enhanced CT scan is a useful tool in the diagnosis of sigmoid volvulus. [Copyright &y& Elsevier]

Spontaneous rupture of the kidney is uncommon; here we report a case of spontaneous rupture of the kidney due to a rhabdoid tumor. An 11-year-old boy presented with left flank pain and hematuria, was admitted to a hospital where he was found to have an abnormality of the left kidney on computed tomography (CT) scan. He was referred to our department for further evaluation and treatment on the next day. Spontaneous rupture of left renal tumor was suspected by a drop in hemoglobin level, hemoglobin decreased from 9.2 to 7.6 mg/dl within 72 h. The hemoglobin level continued to drop despite blood transfusion. Urgent trans-abdominal exploration of the left kidney was performed. During the operation, rupture of left renal tumor with massive bleeding was noted. Para-aortic lymph node metastasis is evident. The surgical specimen contained a large peri-renal hemorrhage and tumor rupture into peri-pelvic soft tissue. Histopathological diagnosis was rhabdoid tumor consisting of round nuclei, prominent nucleoli and eosinophic cytoplasm. Two courses of adjuvant chemotherapy with actinomycin D, vincristine and epirubicin and radiotherapy (1,200 cGY) were performed post-operatively. The patient died 5 months after operation due to metastasis of the tumor to the lung and intra-abdominal organs. [ABSTRACT FROM AUTHOR]

Summary: Background: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. Aim: To evaluate the impact of HCV treatment on such disparities. Methods: In a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. Results: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). Conclusion: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection. [ABSTRACT FROM AUTHOR]

Summary: Background: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. Aims: To assess the treatment and renal/bone safety outcomes following the switch to TAF. Methods: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T‐scores (L‐spine) by bone absorptiometry by 24 months after switch to TAF. Results: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T‐score improved significantly from −1.43 ± 1.36 to −1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9–89.5 ± 16.3 mL/min/1.73 m2, p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T‐score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T‐score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). Conclusions: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable. [ABSTRACT FROM AUTHOR]

Background and Aim: The prevalence of metabolic dysfunction‐associated fatty liver disease (MAFLD) and its interplay with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of liver disease severity is elusive. Methods: A mass surveillance program was conducted in a viral hepatitis endemic area. The objective was to identify MAFLD/non‐MAFLD subjects with advanced liver disease. Results: Two thousand two hundred and forty‐two (41.7%) of the 5378 subjects were identified as having MAFLD, and 375 (7.0%) had advanced liver disease. The proportions of anti‐HCV and HBsAg seropositivity were 19.3% and 9.7%, respectively. The proportions of advanced fibrosis in subjects with non‐viral hepatitis (NBNC), HBV and HCV infection were 2.8%, 5.7% and 23.4%, respectively. Subjects with MAFLD had a significantly higher proportion of advanced fibrosis (8.7% vs 5.7%, P < 0.001). Factors associated with advanced fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 4.8/3.7–6.0, P < 0.001), male sex (OR/CI: 1.3/1.0–1.7, P = 0.019), anti‐HCV seropositivity (OR/CI: 5.9/4.6–7.5, P = 0.019), MAFLD‐lean metabolic dysregulation (MS) (OR/CI: 2.6/1.3–5.2, P = 0.005; compared with the non‐MAFLD group) and MAFLD‐diabetes (OR/CI: 1.5/1.1–2.1, P = 0.008; compared with the non‐MAFLD group). MAFLD did not aggravate liver disease severity in patients with viral hepatitis. However, among NBNC subjects, factors associated with advanced liver disease included MAFLD‐lean MS group (OR/CI: 9.1/2.4–34.6, P = 0.001; compared with non‐MAFLD group) and MAFLD‐DM group (OR/CI: 2.0/1.2–3.2, P = 0.004; compared with non‐MAFLD group). Conclusions: MAFLD patients with diabetes and metabolic dysregulation had a higher risk of advanced liver disease. The effect was more significant in non‐viral hepatitis subjects in a community level. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B (CHB) and fatty liver (FL) are common, natural history data on concurrent FL and CHB (FL-CHB) are limited. This study aimed to evaluate the effect of FL on cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance incidence in CHB patients.Methods: In a retrospective cohort study of 6786 adult CHB patients, we used propensity score matching (PSM) to balance the FL-CHB and non-FL CHB groups. Kaplan-Meier methods were used to compare cumulative cirrhosis, HCC, and HBsAg seroclearance rates between subgroups.Results: Before PSM, compared to non-FL CHB, FL-CHB patients had lower 10-year cumulative rates of cirrhosis, HCC, and a higher HBsAg seroclearance rate. Similar results were found in the matched FL-CHB and non-FL CHB patients, as well as in the antiviral-treated PSM cohort. Cox proportional hazards model indicated FL to remain significantly and strongly associated with lower risk of cirrhosis and HCC (hazard ratio [HR], 0.19 [95% confidence interval {CI}, .12-.33], P < .001 and HR, 0.21 [95% CI, .09-.51], P = .001, respectively) in antiviral-treated patients but not in untreated patients.Conclusions: FL was significantly associated with lower cirrhosis and HCC risk and higher HBsAg seroclearance. Further studies are needed to confirm our funding and investigate the mechanisms underlying the impact of FL on CHB. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) eradication by antivirals promote fibrosis modification. Whether host genetics determined fibrosis regression in chronic hepatitis C (CHC) patients with sustained virological response (SVR) is to be determined. One hundred and fifty-six SVR patients with paired liver biopsy before and after antivirals were enrolled. Host genetic factors including single nucleotide polymorphism rs17047200 of tolloid-like 1(TLL-1) were analyzed for their association with fibrosis modification. The proportions of improved, unchanged and worsening fibrotic stags were 39.1% (n = 61), 39.1% (n = 61), and 21.8% (n = 34), respectively. The rate of annual fibrotic improvement was 0.16 ± 0.79. There was a significant trend of increased fibrotic improvement rate in patients from F01 to F4 (P < 0.001). However, the rate of improvement seemed more limited in cirrhotic patients among those with advanced liver disease. Patients with fibrotic improvement had a significantly higher proportion of TLL-1 rs17047200 AA genotype compared to those without (92.5% vs. 79.3%, p = 0.039). Logistic regression analysis revealed that the TLL-1 rs17047200 AA genotype was the only independent factor associated with fibrosis improvement (odds ratio/95% confidence intervals: 3.2/1.01-10.12, p = 0.047). Compared with TLL-1 rs17047200 non-AA carriers, a significantly higher proportion of fibrosis improvement in AA genotype carriers was observed among patients with F0-2 (33.3% vs. 0%, p = 0.005) but not with F34 (70% vs. 80%, p = 1). We concluded that TLL-1 genetic variants determined fibrotic improvement in CHC with curative antivirals, particularly in patients with mild liver disease. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B (CHB) can progress to cirrhosis, but there are limited noninvasive tools available to estimate cirrhosis risk, including in patients receiving antiviral therapy. This study developed and validated a simple model to assess risk in CHB patients.Methods: The derivation cohort included 3000 CHB patients from 6 centers in the United States, with 52.60% receiving antiviral therapy. External validation was performed for 4552 CHB individuals from similar cohorts in Taiwan, with 21.27% receiving therapy. Cox proportional hazards regression analyses were used to screen predictors and develop the risk score for cirrhosis. Areas under receiver operating characteristic curves (AUROCs) were calculated for predictive value.Results: Sex, age, diabetes, antiviral treatment status/duration, hepatitis B e-antigen, and baseline alanine aminotransferase/aspartate aminotransferase levels were significantly associated with increased cirrhosis risk. A 13-point risk score was developed based on these predictors. The AUROCs for predicting cirrhosis risk were 0.82 at 3 years, 0.85 at 5 years, and 0.89 at 10 years in the derivation cohort, and 0.82, 0.79, and 0.77 in the validation cohort, respectively.Conclusions: We developed and validated a simple cirrhosis prediction model with an independent external cohort that can be applied to both treatment-naive and treatment-experienced CHB patients in diverse settings and locations. [ABSTRACT FROM AUTHOR]

Background The World Health Organization has established interim guidance for hepatitis C virus (HCV) elimination. We aimed to prove the concept of "treatment as prevention" by conducting a prospective HCV elimination program for hemodialysis (HD) patients. Methods A universal HCV screen was launched in 22 HD centers in 2019. HCV-viremic patients were linked to care with direct-acting antivirals (DAAs). The second screen was performed in 2021 to evaluate the effect of link-to-care in lowering the prevalence of HCV viremia and the incidence of HCV new/re-infections. Results Of 2336 patients enrolled in the first screening in 2019, 320 (13.7%) were seropositive for anti-HCV and 181 (7.7%) were HCV-viremic. Of 152 patients successfully linked to treat with DAA, 140 (92.1%) patients achieved a sustained virological response. Of them, 1733 patients participated in the second surveillance. Five anti-HCV-negative patients experienced anti-HCV seroconversion. Of 119 DAA-cured patients and 102 spontaneous HCV clearance patients, none had HCV reinfection. The annual incidence of HCV new infection was 0.1%. Sixty-one of the 620 (9.8%) newly enrolled patients were anti-HCV-seropositive in the second survey. The overall HCV-viremic rate decreased from 7.7% in 2019 to 0.6% (15/2353) in 2021. At the institutional level, 45.5% (10/22) eradicated HCV and 82% (18/22) of HD units had no HCV new infections or reinfections. Conclusions The link-to-care project proved the concept of "treatment as prevention" by which HCV microelimination helps to prevent reinfection and new infections in the HD population. Trial registration: ClinicalTrials.gov identifier: NCT03803410 and NCT03891550. [ABSTRACT FROM AUTHOR]

Background and Aims: 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.Methods: We analyzed the etiologies, fibrosis stages, clinical data, and outcomes of newly diagnosed patients with HCC.Results: 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 < 0.05) and HCV-HCC (30.2%, p < 0.05) groups. Compared to patients from the viral-related HCC groups, patients with NBNC-HCC exhibited a significantly lower fibrosis stage. NBNC-HCC patients exhibited a higher proportion of Barcelona Clinic Liver Cancer (BCLC) classification stage C and stage D compared to patients from the HBV-HCC and HCV-HCC groups. With a mean of 2.33 ± 2.31 years of follow-up, the median survival of patients with NBNC-HCC was 1.75 (95% CI 1.33-2.17) years, which was significantly lower than that of patients with HBV-HCC (p = 0.041) and HCV-HCC (p < 0.001).Conclusions: Patients with NBNC-HCC have a higher risk of diabetes than patients with HCC of viral etiologies. Although patients with NBNC-HCC exhibited a milder fibrosis stage, their more advanced HCC stages and worse overall survival should be taken into consideration in clinical care. [ABSTRACT FROM AUTHOR]

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