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

Background & AIMS Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. Methods We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. Results The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. Conclusion There is great variability in CHB disease progression rates even among “lower-risk” populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

BACKGROUND The World Health Organization (WHO) set out to eliminate hepatitis C virus (HCV) infection by 2030, a goal Taiwan might achieve before 2025. Using effective direct antiviral agents (DAAs) against chronic hepatitis C (CHC) in Taiwan, the treatment of CHC has been initiated in rural areas. Here, we aimed to elucidate the clinical and virological characteristics of HCV infection, and the treatment efficacy of DAAs in patients from Pingtung county in southern Taiwan. METHODS A total of 152 chronic hepatitis patients treated with DAAs were consecutively enrolled. Baseline characteristics and therapeutic efficacy were evaluated. RESULTS HCV genotype 2 was the most common viral genotype (39.5%), followed by 1b (36.8%), 6 (10.5%), and 1a (9.2%). The sustained virological response (SVR) rate was 98.7%. Hakka patients accounted for 22.4% of the study cohort, of which 14.7% had HCV genotype 6. There were no differences in clinical characteristics between Hakka and non-Hakka patients. Patients with HCV genotype 6 were younger in age (OR/CI: 0.95/0.91-1.00, p = 0.04) and composed of more people who inject drugs (PWID) (OR/CI: 17.6/3.6-85.5, p

Previous in vitro and in vivo experiments had demonstrated dose‐dependent anti‐cancer effects of clinical plasma colchicine concentrations on hepatocellular carcinoma (HCC) cells. This phase IIa trial was to evaluate the potential efficiency and safety of our novel colchicine dosage schedule for the palliative treatment of advanced HCC. The dosage schedule started from oral intake of 1 mg colchicine three times per day for 4 days and discontinuation in the following 3 days (one cycle). The treatment cycle was repeated and the dosage was adjusted ranging from 3 to 1.5 mg/day according to the condition of the participant. The control group was originated from chart review of 86 HCC patients treated by sorafenib for more than 2 months. Fifteen participants signed the inform consent. Two participants were excluded due to screening failure in one and less than four treatment cycles in another. For severe adverse events, the colchicine group demonstrated higher incidence of biliary tract obstruction (p = 0.0184) than the sorafenib group. Comparison grade 1 or 2 adverse events between two groups, the colchicine group had higher incidence of diarrhea (p = 0) and the sorafenib group had higher incidence of palmar‐plantar erythrodysesthesia syndrome (p = 0.0045). There was no significant difference in mortality, median survival, and overall survival between two groups (all p > 0.2). In conclusion, our novel colchicine dosage schedule is clinically feasible and has the potential to be applied in the palliative treatment of advanced HCC especially based on the cost‐effectiveness consideration.

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 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.

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

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

Uraemic patients undergoing haemodialysis are at high risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We aimed to evaluate the evolutionary seroprevalence of viral hepatitis and the gap in HCV care cascades in this special population by a large-scale surveillance study in Taiwan. Uraemic patients on maintenance haemodialysis from 22 sites (FORMOSA-LIKE group) in 2012 (n = 1,680) and 2019 (n = 2,326) were recruited for this study. The distributions and sequential changes of viral hepatitis markers were analysed. The prevalence of anti-HCV antibody and hepatitis B surface antigen (HBsAg) seropositivity was 13.6% (316/2326) and 11.5% (267/2326), respectively, in 2019 compared with 17.3% (290/1680, P = .002) and 13.6% (229/1680, P = .046), respectively, in 2012. The HCV-viremic rate among anti-HCV-seropositive patients was significantly lower in 2019 than in 2012 (56.3% [178/316] vs. 73.8% [214/290], P

Patients with Barcelona Clinic Liver Cancer Stage C (BCLC-C) hepatocellular carcinoma (HCC) can be markedly heterogeneous with varying prognosis. This study aims to establish a new subclassification system for BCLC-C HCC to better predict overall survival (OS) and to tailor therapy. We retrospectively studied 1856 BCLC-C HCC patients between 2006 and 2017 from E-Da Hospital, Taiwan (n = 622, training cohort), Kaohsiung Medical University Hospital, Taiwan (n = 774, Taiwan validation cohort), and Stanford University Medical Center and Mayo Clinic (United States), Hanyang University Hospital (South Korea), and Ogaki Municipal Hospital (Japan) to make up the international validation cohort (n = 460). In the training cohort, significant factors associated with OS were largest tumor size ≥ 10 cm, extrahepatic spread, macrovascular invasion, and Child–Pugh class, which provided the basis, together with aged ≥ 75 years, for the substaging, through C0 to C4, of BCLC-C HCC patients. The median OS for substages C0, C1, C2, C3, and C4 were 43.8 months (95% confidence interval [CI] 32.2–53.7), 20.6 months (CI 14.1–25.9), 11.5 months (CI 8.02–14.1), 5.7 months (CI 4.02–5.98), and 3.2 months (CI 2.41–3.59), respectively, (p

ObjectiveHCV prevails in uremic haemodialysis patients. The current study aimed to achieve HCV microelimination in haemodialysis centres through a comprehensive outreach programme.DesignThe ERASE-C Campaign is an outreach programme for the screening, diagnosis and group treatment of HCV encompassing 2323 uremic patients and 353 medical staff members from 18 haemodialysis centres. HCV-viremic subjects were linked to care for directly acting antiviral therapy or received on-site sofosbuvir/velpatasvir therapy. The objectives were HCV microelimination (>80% reduction of the HCV-viremic rate 24 weeks after the end of the campaign in centres with ≥90% of the HCV-viremic patients treated) and ‘No-C HD’ (no HCV-viremic subjects at the end of follow-up).ResultsAt the preinterventional screening, 178 (7.7%) uremic patients and 2 (0.6%) staff members were HCV-viremic. Among them, 146 (83.9%) uremic patients received anti-HCV therapy (41 link-to-care; 105 on-site sofosbuvir/velpatasvir). The rates of sustained virological response (SVR12, undetectable HCV RNA 12 weeks after the end of treatment) in the full analysis set and per-protocol population were 89.5% (94/105) and 100% (86/86), respectively, in the on-site treatment group, which were comparable with the rates of 92.7% (38/41) and 100% (38/38), respectively, in the link-to-care group. Eventually, the HCV-viremic rate decreased to 0.9% (18/1,953), yielding an 88.3% reduction from baseline. HCV microelimination and ‘No-C HD’ were achieved in 92.3% (12/13) and 38.9% (7/18) of the haemodialysis centres, respectively.ConclusionOutreach strategies with mass screenings and on-site group treatment greatly facilitated HCV microelimination in the haemodialysis population.ClinicalTrials.gov identifierNCT03803410 and NCT03891550

Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients.To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups.In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005).Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.

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

Background Chronic hepatitis C (CHC) has been associated with major psychoses, and interferon (IFN)-based therapy may cause psychiatric sequelae. We aimed to evaluate the effects of sustained virological response (SVR) on the incidence of major psychoses in a nationwide Taiwanese CHC cohort. Methods Fifteen thousand eight hundred thirty-six CHC Taiwanese who received IFN-based therapy were enrolled between 2003 and 2015. Of those, 12 723 patients were linked to the National Health Insurance Research Databases for the incidence of major psychoses. Death before major psychoses was considered a competing risk. Results Twenty-four patients developed new-onset major psychoses during 67 554 person-years (3.6 per 10 000 person-years), including 16 affective psychoses, 7 schizophrenia, and 1 organic psychotic condition. The incidence of major psychoses and affective psychoses did not differ between the SVR and non-SVR groups. The 10-year cumulative incidence of schizophrenia were significantly higher in the non-SVR than in SVR patients (0.14% vs 0.04%, P = .036). Cox subdistribution hazards showed that SVR and older age were associated with a significantly lower risk of schizophrenia (hazard ratio = 0.18 and 0.17). Sustained virological response was associated with decreased incidence of schizophrenia and majorly observed among patients with age Conclusions Successful IFN-based therapy might reduce the incidence of schizophrenia among CHC patients, especially among younger patients.

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.

Both dengue virus (DENV) and hepatitis C virus (HCV) belong to the Flaviviridae family and could induce hepatitis. We aimed to investigate the interference between them. In total, 515 patients confirmed with dengue fever (DF) were enrolled. Thirty-two patients (6.21%) were seropositive for anti-HCV; 12 of 32 anti-HCV-positive patients had detectable HCV-RNA at presentation of DF. The proportion of dengue hemorrhagic fever was comparable between patients with or without anti-HCV and between those with or without HCV-RNA. Eleven of 32 patients received HCV-RNA testing during a median interval of 23 months after DF, which revealed significantly increased HCV-RNA levels (5.43 ± 0.77 vs 3.09 ± 1.24 log IU/mL, follow-up vs acute-DF phase; P = .003). Four of 11 patients with baseline HCV-RNA values before DF demonstrated a nadir viremia during acute DF. We also included age-, sex-, and follow-up duration–matched HCV-monoinfected patients as controls; higher delta HCV-RNA changes were demonstrated in patients with DF than in controls during the follow-up period (2.34 ± 1.15 vs –0.27 ± 0.76 log IU/mL; P

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

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 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.

Background: The biochemical response is a crucial indicator of prognosis in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs). The impact of hepatitis D virus (HDV) infection on alanine aminotransferase normalization is elusive. Methods: The longitudinal study recruited 1185 CHB patients who received NAs. These patients were tested for anti-HDV antibody and HDV RNA at the initiation of anti-hepatitis B virus (HBV) therapy and annually for patients who were HDV-seropositive. ALT levels were examined at the first and second year of anti-HBV therapy. ALT abnormality was defined as ALT levels above 40 IU/mL in both male and female, and the risk factors associated with ALT abnormality were analysed. Results: Rates of seropositivity for anti-HDV and HDV RNA were 2.0% and 0.8% among 1185 NA-treated CHB patients, respectively. The strongest factor associated with ALT abnormality (>40 IU/mL) after first year treatment with NAs was HDV RNA seropositivity at year 1 (odds ratio [OR]/95% confidence interval [CI]: 31.44/3.49–283.56, P = 0.002), followed by liver cirrhosis (2.18/1.51–3.15, P

Mac‐2 binding protein glycosylation isomer (M2BPGi) is a novel glycoprotein biomarker that correlates with liver fibrosis. It has been investigated in East Asian populations as a hepatocellular carcinoma (HCC) biomarker. We assessed M2BPGi as an HCC biomarker in an ethnically diverse cohort of patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We enrolled 947 treatment‐naive patients mono‐infected with HBV or HCV without HCC at baseline. Biomarker levels were measured from baseline sera and correlated with longitudinal clinical data. The primary outcome was HCC occurrence during long‐term follow‐up. Median M2BPGi was significantly higher among patients with cirrhosis (2.67 versus 0.80; P < 0.001) and patients who developed HCC (3.22 versus 1.16; P < 0.001). The area under the receiver operating characteristic (AUROC) for M2BPGi and alpha‐fetoprotein (AFP) was similar overall (0.77 versus 0.72; P = 0.15), but M2BPGi outperformed AFP among patients with HBV (0.84 versus 0.75; P = 0.02). M2BPGi performed poorly among patients with HCV (AUROC, 0.51). M2BPGi was an independent predictor of HCC among patients with HBV but not among patients with HCV. M2BPGi performed better in patient subgroups with a lower prevalence of cirrhosis. Conclusion: In our HBV cohort, M2BPGi was more effective than AFP in predicting HCC and was an independent predictor of HCC. However, M2BPGi had limited predictive value in our HCV cohort, likely due to a high cirrhosis burden in this cohort. Further studies are needed to evaluate M2BPGi as an HCC biomarker in broader patient populations with more diverse disease etiology, non‐Asian ethnicity, and more advanced fibrosis.

BACKGROUND Serum ferritin is an indicator of iron accumulation in a human body, and it is frequently elevated in patients with systemic inflammatory state in chronic hepatitis C (CHC). Iron accumulation is associated with hepatic fibrosis, steatosis, and unfavorable outcome in CHC patients. We studied the status of elevated serum ferritin level and its association with the liver fibrosis or steatosis in Taiwanese CHC patients. METHODS Seven hundred and thirty-eight Taiwanese CHC patients were consecutively included in this study. Laboratory analysis, four indexes of fibrosis (FIB4), histological assessment of fibrosis, and steatosis were assessed by appropriate elevation of serum ferritin level. RESULTS Three hundred and one patients (40.8%) had elevated serum ferritin level (sex-specific threshold >1.5 × upper limit of normal). Serum iron level (odds ratio [OR], 1.02; 95% CI, 1.01%-1.03%, p 5%) were associated with older age (OR, 1.01; 95% CI, 1.00%-1.03%, p = 0.015), body mass index (OR, 1.10; 95% CI, 1.05%-1.15%, p < 0.001), and elevated serum ferritin level (OR, 1.001; 95% CI, 1.00%-1.001%, p = 0.024) by multivariate logistic regression analysis. Serum ferritin level also associated with high FIB4 (≥3.25) (OR, 1.001; 95% CI, 1.001%-1.002%, p = 0.010) when multivariate model adjusted together with advanced liver fibrosis by biopsy. CONCLUSION Elevated serum ferritin level was noted in 40.8% of Taiwanese CHC patients, and the serum ferritin level was associated with liver steatosis and high FIB4.

Introduction Chronic hepatitis C virus (HCV) infection is associated with nonhepatocellular carcinoma malignancies. We aimed to evaluate whether achieving a sustained virological response (SVR, defined as HCV RNA seronegativity throughout posttreatment 24-week follow-up) could reduce the risk of non-hepatocellular carcinoma malignancy in a real-world nationwide Taiwanese Chronic Hepatitis C Cohort (T-COACH). Methods A total of 10,714 patients with chronic hepatitis C who had received interferon-based therapy (8,186 SVR and 2,528 non-SVR) enrolled in T-COACH and were linked to the National Cancer Registry database for the development of 12 extrahepatic malignancies, including those with potential associations with HCV and with the top-ranking incidence in Taiwan, over a median follow-up period was 3.79 years (range, 0-16.44 years). Results During the 44,354 person-years of follow-up, 324 (3.02%) patients developed extrahepatic malignancies, without a difference between patients with and without SVR (annual incidence: 0.69% vs 0.87%, respectively). Compared with patients with SVR, patients without SVR had a significantly higher risk of gastric cancer (0.10% vs 0.03% per person-year, P = 0.004) and non-Hodgkin lymphoma (NHL) (0.08% vs 0.03% per person-year, respectively, P = 0.03). When considering death as a competing risk, non-SVR was independently associated with gastric cancer (hazard ratio [HR]/95% confidence intervals [CIs]: 3.29/1.37-7.93, P = 0.008). When patients were stratified by age, the effect of SVR in reducing gastric cancer (HR/CI: 0.30/0.11-0.83) and NHL (HR/CI: 0.28/0.09-0.85) was noted only in patients aged 65 years. Discussion HCV eradication reduced the risk of gastric cancer and NHL, in particular among younger patients, indicating that patients with chronic hepatitis C should be treated as early as possible.

HCC, a leading cause of cancer-related mortality, is diagnosed at advanced stages. Although antiviral therapy has reduced the risk of HCC among chronic hepatitis C (CHC) patients, the risk of HCC remains, thus, highlighting the unmet need for continuous surveillance. Therefore, stable and cost-effective biomarkers, such as circulating microRNAs, must be identified. We aimed to clarify whether serum levels of the Let-7 family can predict HCC risk in patients with CHC using univariate and multivariate Cox’s proportional hazards model. We analyzed the sera of 54 patients with CHC who developed HCC after antiviral therapy and compared the data with those of 173 patients without HCC development. The Let-7 family (except for let-7c) exhibited significant negative correlations with the fibrosis score (r = −0.2736 to −0.34, p = 0.0002 to

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.

Liver fibrosis determined hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C patients with sustained virological response (SVR). We aimed to determine whether post-treatment fibrotic modification overwhelmed pretreatment fibrotic status in terms of long-term HCC prediction. 265 SVR patients with paired biopsies before and after antiviral therapy were enrolled for analysis of the association of fibrotic changes with HCC. Eighteen (6.8%) of the 265 patients developed HCC over 1931 person-years. Cox regression analysis without post-treatment fibrosis as a covariant revealed that factors predicted HCC included age (hazard ratio [HR]/confidence intervals [CI] 1.07/1.01–1.13, p = 0.01), male gender (HR/CI 4.57/1.45–14.36, p = 0.009), diabetes (HR/CI 3.60/1.32–9.85, p = 0.01) and pretreatment advanced fibrosis (HR/CI 2.73/1.05–7.07, p = 0.039). Advanced fibrosis in post-treatment status replaced pretreatment fibrosis as the most critical determinant of HCC when it was included for analysis (HR/CI 3.53/1.34–9.30, p = 0.01). The incidences of HCC among patients with fibrotic modification from F0–2 to F0–2, F34 to F0–2, F0–2 to F34 and F34 to F34 were 0.41%, 0.84%, 1.68%, and 3.05%, respectively (p = 0.004). Compared to patients whose fibrotic stage remained at F0–2 before and after treatment, the HCC risk decreased and did not differ among those whose fibrotic stage improved from F34 to F0–2. However, HCC risk increased significantly and gradually in patients whose fibrotic stages changed from F0–2 to F34 (HR/CI 4.13/1.11–15.36, p = 0.035) and whose fibrotic stages remained at F34 before and after treatment (HR/CI 7.47/2.37–23.55, p = 0.001) (trend p = 0.003). Post-treatment fibrotic modifications overwhelmed pretreatment fibrotic statuses in predicting HCC.

MHC class I chain-related gene A (MICA) variants have been associated with hepatocellular carcinoma (HCC). Their association with MICA expression in cancer cells and cancer recurrence is unknown. SNP rs2596542 of MICA was tested in 193 HCC patients with surgical resection. The corresponding MICA expression in the cancer tissue was measured by immunochemistry microarray. Patients with the SNP rs2596542 A allele had significantly lower MICA expression in tumor tissue than did those with the GG genotype (24.7 ± 15.1% vs. 41.5 ± 23.4%, P 30%, patients with either one and both two risk factors had HCC HRs of 9.76 (C.I. 1.27–75.03, P = 0.03) and 27.30 (C.I. 3.46–215.6, P = 0.002), respectively. We concluded that low cellular MICA expressions were at a greater risk of HCC recurrence after curative treatment.

Background: A direct-acting antiviral (DAA) era in hepatitis C virus (HCV) treatment is fast approaching; unfortunately, the availability and affordability of DAAs in Asia–Pacific areas vary, making it difficult to develop universal HCV practice guidelines appropriate for the all Asian populations. This study aimed to evaluate the real-world cost-effectiveness of IFN-based therapy according to the current strategies with PegIFN/RBV for “easy-to-treat” to provide a reference for application of future DAA development for IFN-eligible, treatment naïve HCV patients. Methods: A total of 1032 chronic hepatitis C treatment-naïve patients who corresponded to response-guided therapy (RGT) guidelines of PegIFN/RBV regimens were linked to the entire population of expenditures and order in the National Health Insurance Research Database of Taiwan. The average total cost per SVR achieved was calculated as the summation of the total cost for all treated patients/number of SVR cases. Results: Current RGT suggested 24 weeks of PegIFN/RBV for G1 naïve patients with baseline LVL and RVR at treatment week 4 achieved an average treatment cost per SVR of $5090 ± 2400. This was of superior cost-effectiveness compared with those other subgroups of G1 patients. In terms of G2 patients, according to current RGT of 16 weeks of treatment duration, PegIFN/RBV treatment with RVR achieved was of a very competitive cost per SVR ($3237 ± 488). Conclusion: For a naïve patient in the new DAA era, the PegIFN/RBV treatment might be conserved for those with all favorable risk parameters, considering the treatment duration and cost per SVR, in the resource-constrained countries. Keywords: Chronic hepatitis C, Cost-effectiveness analysis, Naïve, Pegylated interferon, Response-guided therapy

BACKGROUND AND AIM Major histocompatibility complex class I chain-related A (MICA) genetic variants and their serum levels (sMICA) were associated with the development of hepatitis C virus-related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes in serial sMICA levels and their association with HCC in the post-curative status are elusive. METHODS Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were analyzed in chronic hepatitis C patients with a sustained virologic response after antivirals. Forty-two patients who developed HCC and 84 age-matched, gender-matched, and cirrhosis propensity score-matched non-HCC controls were compared. Serial sMICA levels were measured within 6 months before treatment initiation (pre-sMICA), 6 months after the end of treatment (post-sMICA), and on the last visit before the development (or not) of HCC (last-sMICA). RESULTS Cox regression analysis revealed that last-sMICA was the only predictive factor of HCC development (hazard ratio/95% confidence interval: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P

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

Background/aims: The registered trial has demonstrated that paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD) with ribavirin was effective for recurrent hepatitis C virus genotype 1 (HCV-1) infection after liver transplantation in patients with mild fibrosis; however, the real-world efficacy and safety of this regimen have not been determined. Methods: The efficacy (sustained virological response, SVR12, undetectable HCV RNA 12 weeks post-treatment) and safety were evaluated in 12 patients with recurrent HCV-1 infection after liver transplantation. Results: Nine patients were treated for 24 weeks, and three patients (two treatment-naïve patients and one interferon-intolerant patient) were treated for 12 weeks. HCV RNA was undetectable at treatment day 1, week 1, week 4, week 12, and at the end of treatment in 8.3% (n = 1), 25% (n = 3), 83.3% (n = 10), 100% (n = 12), and 100% (n = 12) of patients, respectively. All twelve patients achieved SVR12. Treatment was temporarily stopped in one patient because of leucopenia. The other patient with minimal fibrosis experienced an elevation in alanine aminotransferase concentration, which returned to normal levels after dose reduction. Seven (58.3%) patients required RBV dose reduction and two (16.7%) required transient RBV discontinuation during treatment. There were no serious adverse events, and most adverse events were related to ribavirin. No patient developed graft rejection or deterioration in hepatic or renal function during treatment. Treatment efficacy and safety were comparable between patients with and without advanced liver fibrosis. Conclusion: PrOD plus ribavirin had a highly satisfactory real-world efficacy and safety profile in the treatment of recurrent HCV-1 infection after liver transplantation in Asian patients. Keywords: HCV, DAA, Liver transplantation, PrOD, Real-world

BACKGROUND Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P

// Batbold Batsaikhan 1, 2 , Ching-I Huang 3 , Ming-Lun Yeh 3, 4 , Chung-Feng Huang 3, 4, 5 , Nei-Jen Hou 3 , Zu-Yau Lin 3, 4 , Shinn-Cherng Chen 3, 4 , Jee-Fu Huang 3, 4 , Ming-Lung Yu 3, 4 , Wan-Long Chuang 3, 4 , Jin-Ching Lee 5 and Chia-Yen Dai 1, 3, 4, 6 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia 3 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Chia-Yen Dai, email: daichiayen@gmail.com Keywords: HCV; lipid profiles; triglycerides; FIB4; antiviral treatment Received: December 14, 2017 Accepted: March 22, 2018 Published: April 20, 2018 ABSTRACT Background: Low lipid profile is associated with hepatitis C virus (HCV) infection. Chronic HCV infection is the main cause of liver injury and serum lipid levels during antiviral treatment. We aimed to evaluate the effect of antiviral treatment on the change of lipid profiles during HCV treatment. Methods: Total 863 patients who complete the interferon-based therapy in Kaohsiung Medical University Hospital were included in this study. The lipid profile measured and evaluated in baseline and after 6 months of the treatment. Results: Sustained virological response (SVR) was achieved in 81.2% of all patients. The baseline triglycerides (TG) levels in the SVR group and non SVR groups were similar. The TG levels at 6 months after cessation of the treatment was significantly elevated in SVR group (102.9±57.0 mg/dL, p=0.0001) but did not elevated in non SVR group (94.5±45.6 mg/dL, p=0.690) compared with baseline TG levels. After adjusting patients by four indexes for fibrosis (FIB4) in cut-off point 3.25, serum TG levels significantly increased in low FIB4 group (103.2±57.9 mg/dL, p=0.0001) but not in high FIB4 group (98.1±49.6 mg/dL, p=0.095) after 6 months end of the treatment. Serum TG level was increased greater in patients who had low FIB4 score and patients who achieved SVR (baseline 89.1±34.8 mg/dL; 6 months after treatment 104.3±59.3 mg/dL, paired T test p=0.0001). Conclusion: The clearance of the HCV RNA is the main determinant of the increase of lipids after PegIFN/RBV treatment. However advanced fibrosis also has an effect in increase of lipids after the treatment.

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

Background: Health burdens of hepatocellular carcinoma (HCC) are emerging quickly in the world, including in Taiwan. Surgical resection has been recognized as the first-line treatment for early tumors. This study aimed to investigate the prognostic risk factors for mortality and recurrence rate in Taiwan, which has a high prevalence of chronic viral hepatitis. Methods: A total of 397 HCC patients receiving tumor resection were consecutively examined in central Taiwan from 2008 to 2014. A hospital-based patient cohort was designed to collect serological markers to further assess liver function. We modified the Kaplan–Meier method according to the competing death risks for comparing recurrence and used multivariate Cox proportional hazard regression to adjust for significant risk factors. Results: In addition to advanced fibrosis, tumor size ≥5 cm was significantly associated with higher mortality within the 5-year period when compared with

// Ming-Lun Yeh 1, 2, 3 , Ching-I Huang 2 , Chung-Feng Huang 2, 3 , Meng-Hsuan Hsieh 2, 3, 5 , Ming-Yen Hsieh 2 , Zu-Yau Lin 2, 3 , Shinn-Cherng Chen 2, 3 , Jee-Fu Huang 2, 3 , Po-Lin Kuo 1 , Hsing-Tao Kuo 6, 7, * , Chia-Yen Dai 1, 2, 3, 4, 5, * , Ming-Lung Yu 2, 3, 4, 8 and Wan-Long Chuang 2, 3, 4 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 6 Division of Hepatogastroenterology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan 7 Department of Senior Citizen Service Management Chia Nan University of Pharmacy and Science, Tainan, Taiwan 8 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan * These authors contributed equally to this work Correspondence to: Chia-Yen Dai, email: d820195@gmail.com Hsing-Tao Kuo, email: kht@mail.chimei.org.tw Keywords: hepatocellular carcinoma, incidence, hepatitis B virus, hepatitis C virus, dual infection Received: August 02, 2017 Accepted: September 21, 2017 Published: January 13, 2018 ABSTRACT We investigated the long-term risk of hepatocellular carcinoma (HCC) in dual-infected hepatitis B and C patients after eradication of hepatitis C virus (HCV). A total of 164 (62% male, median age, 50.5 years) hepatitis B and C dual-infected patients who achieved HCV sustained virological response were recruited. Half the patients were HCV genotype 1 with a median viral load of 5.5 log10 IU/mL, and 22.6%had an HBV DNA level ≥ 2000 IU/mL before therapy. HCC developed in 14 patients (8.5%), with an annual incidence of 1.38% per person-year. The 3-year, 5-year, 10-year, and 15-year cumulative probabilities were 2.5%, 5.1%, 12.6%, and 22.7%, respectively. Six months after treatment, a Cox regression hazard analysis revealed platelet level (HR: 0.98, 95% CI: 0.957–0.999, P = 0.038) and AFP level (HR: 1.20, 95% CI: 1.031–1.400, P = 0.019) to be independent factors in HCC. A higher 10-year cumulative risk of HCC was detected in patients with 6-month post-treatment AFP levels > 5.0 ng/mL and platelet levels < 130 x1000/μL (54.9%), compared to patients with neither (8.6%). Although the risk of HCC is low, surveillance of HCC is encouraged in dual-infected patients after eradication of HCV. Post-treatment AFP and platelet levels predict HCC development.

// Chia-Yen Dai 1, 2, 3, 4, 5, 6, * , Yi-Shan Tsai 1, * , Wen-Wen Chou 1 , Tawei Liu 1 , Chung-Feng Huang 1, 2, 4 , Shu-Chi Wang 3 , Pei-Chien Tsai 1 , Ming-Lun Yeh 1, 4, 5 , Ming-Yen Hsieh 1 , Ching-I Huang 1, 5 , Shang-Yin Vanson Liu 7 , Jee-Fu Huang 1, 4 , Wan-Long Chuang 1, 4, 6 and Ming-Lung Yu 1, 2, 3, 4, 5, 6, 8 1 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2 Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 3 Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Faculty of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan 7 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan 8 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan * These authors contributed equally to this work Correspondence to: Ming-Lung Yu, email: fish6069@gmail.com Keywords: miR-125b; HCV; IL-6; STAT3; HCV Received: July 28, 2017 Accepted: December 01, 2017 Published: January 10, 2018 ABSTRACT Background/Aims: MicroRNA-125b (miR-125b) has been found to regulate inflammation and acts as an oncogene in many cancers. The mechanisms of miR-125b expression during hepatitis C virus (HCV) infection remain to be clarified. The present study aims to identify the factors that might regulate miR-125b expression in HCV infection. Results: High expression of miR-125b was found to correlate with HCV infection in replicon cells and in sera from HCV-infected patients, whereas the miR-125b inhibitor reduced HCV gene expression. The interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway plays an inducible effect on miR-125b gene expression. STAT3 siRNA or inhibitor could reduce HCV replication. Materials and Methods: HCV replicon cells Con1 (type 1b) and Huh7/Ava5 (type 1b) were treated with 17-hydroxy-jolkinolide B (HJB) or STAT3 siRNA. Cell viability assay and Renilla Luciferase Assay were used. Fragments of the miR-125b-1 promoter were constructed for the luciferase reporter assay. PSMB8, PSMB9, miR-125b-1, and miR-125b-2 expression was determined using TaqMan ® Gene Expression Assays. Western blot analysis was performed to assess protein abundance. Conclusions: This study elucidates a novel pathway for miR-125b in the pathogenesis of chronic HCV infection and suggests it as a possible target for treating HCV infection.

Direct-acting antiviral agents (DAAs) have been widely used for chronic hepatitis C (CHC) treatment recently. The characteristics of glucose abnormalities after DAAs therapy however, remain elusive. We aimed to elucidate the mutual impact between treatment response and parameters of glucose abnormalities after DAAs therapy in CHC patients. CHC patients who received DAAs therapy were recruited. The primary outcome measurements were their insulin resistance (IR) and beta-cell function assessed by the homeostasis model assessment (HOMA) method before treatment and at end-of-follow-up (EOF). Sixty-five CHC patients (19 males, mean age = 59.8 ± 10.3 years) were consecutively enrolled. They included 47 (72.3%) patients of genotype-1 infection. The treatment regimens among patients were sofosbuvir in 30 patients, paritaprevir-ritonavir/ombitasvir/dasabuvir in 23 patients, and asunaprevir/daclatasvir in 12 patients respectively. The overall sustained virological response rate was 98.5%. The mean IR at EOF was 2.6 ± 1.8, which was not significantly different from baseline level (2.7 ± 2.9, P = 0.75). There was a significant improvement of beta-cell function at EOF compared to baseline (107.7 ± 86.8 to 86.7 ± 44.5, P = 0.05). The amelioration of beta-cell function at EOF was significantly observed among 23 patients of high baseline IR (166.7 ± 111.3 of baseline vs 105.7 ± 48.2 of EOF, P = 0.04). Six (60%) of the 10 pre-diabetic patients at baseline achieved a normoglycemic state at EOF. Successful eradication of HCV by DAAs might improve glucose abnormalities in CHC patients, particularly among those who had high IR.

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.

Posttransplant hepatitis C virus (HCV) recurrence is universal in chronic hepatitis C recipients. Antiviral therapy is suggested after liver transplant to halt disease progression. Pegylated interferon plus ribavirin therapy remains the standard of care in many areas where direct antiviral agents are poorly accessible. This study aimed to assess the treatment efficacy and safety of the regimen for Taiwanese patients with post-transplant HCV recurrence. Nine patients with HCV recurrence postliver transplantation were allocated. Patients received either pegylated interferon α-2a 180 μg/wk or pegylated interferon α-2b 1.5 mg/kg/wk plus ribavirin for 24–48 weeks. The primary endpoint was the achievement of sustained virological response (SVR), defined as undetectable HCV RNA throughout 6 months of follow-up after the end of treatment. The safety profiles were also documented. The rates of rapid virological response, early virological response, end-of-treatment virological response, and SVR were 33%, 63%, 75%, and 56% respectively. Of the four patients who failed antiviral treatment, the treatment responses were nonresponse ( n = 1), loss of follow-up ( n = 1), and relapse ( n = 2). Three patients terminated therapy early due to severe adverse events, including severe anemia, intra-abdomen infection, and hepatocellular carcinoma recurrence. One of the three patients who terminated treatment early at Week 6 experienced rapid virological response followed by SVR. Pegylated interferon/ribavirin combination allowed a chance for cure with a fair SVR rate in Taiwanese chronic hepatitis C patients postliver transplantation. Early identification of side effects and careful monitoring during therapy might enhance the treatment efficacy.

BACKGROUND/AIMS The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients. METHODS The red blood cell (RBC) components, serum erythropoietin (EPO) levels, and their relationship to clinical characteristics were evaluated between 124 age-matched and sex-matched healthy controls and 248 histology-proven CHC patients. RESULTS Chronic hepatitis C patients had significantly higher serum levels of EPO (1.44 ± 0.36 log mIU/mL versus 1.03 ± 0.31 log mIU/mL, P

AIM 25-Hydroxy vitamin D (Vit D) plays a role in treatment outcomes in chronic hepatitis C virus (HCV) infection. We aimed to clarify whether HCV replication is inhibited by Vit D in HCV replicon cells. Clinical implication was assessed for rapid virological response (RVR) and sustained virological response (SVR) among those patients receiving antiviral therapy. METHODS Cell survival and viral loads were observed in Con1 (genotype 1b) and J6/JFH (genotype 2a) cells treated with different doses of Vit D. Three groups of patients with different treatment responses were recruited to assess their Vit D levels: group A, RVR-/SVR-; group B, RVR+/SVR-; and group C, RVR+/SVR+. RESULTS The viral load of Con1 cells decreased by 69%, 80%, and 86% following treatment with 1 μM, 5 μM, and 10 μM Vit D, respectively (P

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.