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Simple Summary: Cost-effective, Hepatocellular carcinoma (HCC) risk-based surveillance strategies should be established after achieving sustained virologic response (SVR). Circulating microRNAs are considered stable serum markers for early cancer diagnosis and prognosis and treatment response prediction. The aim of our longitudinal follow-up study was to assess whether Let-7 family members can predict HCC risk in CHC patients. We assessed the sera of 54 patients with CHC who developed HCC and 173 patients with CHC who did not develop HCC after antiviral therapy. Cox's regression model revealed the independent role of let-7i as an effective surrogate biomarker for predicting HCC development in patients with CHC. 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 <0.0001). After Cox's regression model was used to adjust for age, sex, HCV genotype, and FIB-4 ≥ 3.25, patients with CHC with let-7i median ≥ −1.696 (adjusted hazard ratio [aHR] = 0.31, 95% CI: 0.08–0.94, p = 0.0372) in the sustained virologic response (SVR) groups and ≥−1.696 (aHR = 0.09, 95% CI: 0.08–0.94, p = 0.0022) in the non-SVR group were less likely to develop HCC. Thus, circulating let-7i can be used for early CHC surveillance in patients with HCC risk after antiviral treatment. [ABSTRACT FROM AUTHOR]

Hepatitis C virus genotype and viral loads are important predictors for sustained virologic response (SVR) to interferon-alpha therapy for chronic hepatitis C (CHC). We have conducted a prospective study on treatment of 90 patients with a tailored-dose and extended interferon-alpha regimen according to pretreatment virologic factors (low-risk, genotype non-1b/viral loads≤0.65 Meq./ml, 6 million units thrice weekly for 12 weeks (6 MU×12 weeks) followed by 3 MU×24 weeks; high-risk, genotype 1b/viral loads>0.65 Meq./ml, 6 MU×24 weeks followed by 3MU×24 weeks; medium-risk, the others, 6MU×12 weeks followed by 3 MU×36 weeks), and compared to 123 patients with fixed-dose regimen (6 MU×24 weeks). Patients with tailored-dose regimen had a significantly higher rate of SVR than those receiving fixed-dose interferon-alpha (46.7% versus 29.3%, P<0.01, intention-to-treat analysis). Improved efficacy was mainly seen in the medium-risk (48.9% versus 26.6%, P=0.02) and the high-risk groups (26.1% versus 8.3%, P=0.06), but not in the low-risk group. By using multivariate logistic regression, low pretreatment viral loads and tailored-dose IFN regimens were significantly associated with higher SVR in both the high- and medium-risk groups. There were no differences in the tolerability and in the incidence of adverse effects between fixed-dose and tailored-dose groups. In conclusion, our results demonstrate the efficacy of tailored-dose interferon-alpha therapy for CHC; these could provide decision-making information for standard/pegylated interferon-alpha combining ribavirin therapy according to baseline predictors. [Copyright &y& Elsevier]

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]

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 < 0.001) and NBNC groups (2.9 ± 1.5, P = 0.004), mainly due to the higher prevalence of ischemic heart disease, respiratory disorders, and mental/behavioral disorders. The HBV and NBNC groups exhibited comparable burdens of comorbidities. Conclusions: Hemodialysis patients had a high prevalence of multiple comorbidities. Hemodialysis patients with HCV exhibited a higher burden of comorbidities, especially ischemic heart diseases, respiratory disorders, and mental/behavioral disorders, than HBV and NBNC patients did. [ABSTRACT FROM AUTHOR]

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 <.001). The HCV treatment rate increased from 2.3% (5/217) in 2012 to 21.7% (49/226) in 2019 (P <.001). In the sequential analysis of the 490 patients who participated in both screens, 17 of the 55 HCV‐viremic patients became HCV RNA seronegative, including 13 by antivirals and four spontaneously. By contrast, one anti‐HCV‐seropositive but nonviremic patient became viremic, and six anti‐HCV‐seronegative patients became anti‐HCV‐seropositive in 2019. The annual incidence of new HCV was 0.2%/year. Seven HBsAg‐seropositive patients experienced HBsAg loss (1.25%/year). Two patients had new anti‐HBc seropositivity (new HBV exposure: 0.57%/year). The seroprevalence of viral hepatitis decreased in an 8‐year follow‐up but remained prevalent, and the treatment of HCV infection was underutilized in uraemic patients. Additional efforts are needed to enhance the HCV treatment uptake of uraemic patients. Clinical Trial IDs: NCT03803410, NCT01766895. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35–24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03–6.54, P < 0.001), male gender (HR/CI 2.69/1.29–5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03–1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04–19.09, P = 0.04) and BMI (HR/CI 1.11/1.03–1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aim: The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are elusive. Methods: Serum anti‐HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti‐HBV therapy and subsequently during the follow‐up period. Results: The seropositive rate of anti‐HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti‐HDV seropositivity were platelet counts (odds ratio [OR]/95% confidence intervals [CI]: 0.995/0.992–0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70–0.94; P = 0.005), and hepatitis B e‐antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05–0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti‐HDV seropositive patients was age (OR/CI: 0.95/0.90–1.00; P = 0.03). The spontaneous clearance rate of serum anti‐HDV antibody was 3.0 per 100 person‐years with a median follow‐up period of 3.5 years (range 2–12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person‐years among anti‐HDV seropositive patients after a median follow‐up period of 6.0 years (range 2–11 years). A baseline anti‐HDV titer < 0.5 cut‐off index was the only factor predictive of anti‐HDV seroclearance (hazard ratio [HR]/CI: 30.11/3.73–242.85; P = 0.001). Conclusions: HDV infection was not common among patients treated for HBV in Taiwan. Seroclearance of anti‐HDV and HDV RNA did occur over time, albeit the chance is rare. [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]

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]

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]

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: 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 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 < 0.001). Patients without HCC development showed a significantly reduced trend of sMICA levels during follow‐up (trend P = 0.001), which was observed only in GG genotype (trend P < 0.001) but not A allele carriers (P = 0.88). In contrast, patients with HCC showed an increased trend of sMICA levels (trend P = 0.024). However, only the GG genotype "high expressors" (trend P = 0.06) but not A allele carriers (P = 0.18) showed a correlation of substantially increased trend of sMICA levels and HCC development. Conclusions: Serial sMICA levels were associated with HCC development in SVR patients. The clinical utility of this finding is restricted to MICA rs2596542 GG genotype carriers. [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]

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: Transfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan. Methods: A total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance. Results: The seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07–1.18, P<0.001), serum alanine aminotransferase (ALT) (OR/CI: 1.04/1.02–1.06, P<0.001) and platelet counts (OR/CI: 0.995/0.991–0.998, P = 0.002). Age was the only factor independently associated with HBsAg seropositivity (OR/CI: 1.08/1.02–1.14.4, P = 0.007). Compared to patients born before 1992, the seroprevalence of HCV among thalassemic patients decreased dramatically in those born after 1992 (46.0% vs. 11.8%, p = 0.012). The seroprevalence of HCV among hemophilic patients also decreased significantly when comparing patients born before 1987 to those born after 1987 (79.5% vs. 11.5%, p<0.001). Similarly, the seroprevalence of HBV decreased significantly in the post-vaccination cohort compared to its counterpart (13.1%, vs. 1.3%, p = 0.005). The spontaneous clearance of HCV was observed in 25.4% (15/59) of patients, and ALT was the only factor associated with it (OR/CI 0.98/0.96–1.00, P = 0.02). Conclusions: Both HBV and HCV infections are prevalent among transfusion-dependent thalassemic and hemophilic patients in Taiwan. Nevertheless, seroprevalence decreased significantly and dramatically for HCV after universal blood screening and for HBV after implementation of a universal mass vaccination program. [ABSTRACT FROM AUTHOR]

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

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: 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 & Aims Genetic variants of patatin-like phospholipase domain-containing 3 ( PNPLA3 ) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. Methods The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. Results Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p = 0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p = 0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008–1.037, p = 0.002), diabetes (OR: 1.81, CI: 1.236–2.653, p = 0.002), α-fetoprotein (OR: 1.006, CI: 1.001–1.01, p = 0.01), platelet counts (OR: 1.009, CI: 1.006–1.012, p < 0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006–1.785, p = 0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356–15.106, p = 0.014) or the dominant model (OR: 2.20, CI: 1.026–4.734, p = 0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889–26.719, p < 0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048–2.286, p = 0.03). Conclusions The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic–environmental interaction contributed to the high risk of advanced liver disease in CHC patients. [ABSTRACT FROM AUTHOR]

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 The treatment efficacy of patients with mixed hepatitis C virus ( HCV) genotype 1/genotype 2 ( HCV-1/2) remains unknown. We aimed to elucidate the sustained virological response ( SVR) rate in patients with HCV-1/2 infection. Methods One hundred and ten HCV-1/2 patients treated with response-guided peginterferon/ribavirin therapy (24 weeks for patients with a rapid virological response [ RVR] and low viral loads; 48 weeks for patients without a RVR or high viral loads) were allocated. Two hundred HCV-1 patients were selected as a historical control. Interleukin-28B ( IL-28B) rs8099917 genotype was tested for the association with an SVR. Results The rates of RVR, sustained virologic response ( SVR), and relapse rate were 71.8%, 87.3%, and 11.1%, respectively. The SVR rate was significantly higher in patients with an abbreviated regimen as compared with those with 48-week regimen (95.5% vs 75.0%, P = 0.002), and both were similar to the HCV-1 historical control. Stepwise logistic regression analysis revealed that lower baseline viral loads were the single factor predictive of an RVR (odds ratio/95% confidence intervals [ OR/ CI] of 41.62/9.72-178.19, P < 0.001). The achievement of an RVR was the single best factor predictive of an SVR ( OR/ CI: 7.5/1.33-42.27, P = 0.02). Nevertheless, an abbreviated regimen became the single factor associated with an SVR if treatment regimen was taken into consideration ( OR/ CI: 11.0/1.25-96.79, P = 0.03). The SVR rate did not differ between patients with rs8099917 TT and TG/ GG genotype (91.7% vs 87.5%, P = 0.63). Conclusions The treatment efficacy of patients with HCV-1/2 was satisfactory. The role of IL-28B genetic variants in the population with response-guided therapy was limited. [ABSTRACT FROM AUTHOR]

Highlights: [•] PBMC–miR125b is inversely associated with treatment outcome in HCV-1 patients. [•] PBMC–miR125b is independent to the most important baseline factor IL28B genotype. [•] PBMC–miR125b is the only factor associated with treatment success in nonRVR patients. [ABSTRACT FROM AUTHOR]

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: Viral kinetics and host interleukin 28B (IL-28B) genotype determine treatment outcome in hepatitis C virus genotype 1 (HCV-1) infection. Objectives: We aimed to explore the interplay between interferon responsiveness at treatment week 4 and IL28B genotype in the achievement of a sustained virological response (SVR; undetectable HCV RNA 24-weeks after end-of-treatment). Study designs: Rs8099917 genotypes were determined in 528 HCV-1 patients with peginterferon/ribavirin. Interferon responsiveness were evaluated by the degree of week 4 viral reduction: <1 log10 IU/mL, 1–2 logs10 IU/mL, 2–3 logs10 IU/mL, 3–4 logs10 IU/mL and ≥4 logs10 IU/mL reduction and/or undetectable HCV RNA, respectively. Results: The SVR rate was significantly higher in patients with great interferon responsiveness at week 4. A great interferon responsiveness was associated with younger age (P <0.0001), lower body mass index (P =0.0056), lower aspartate aminotransferase levels (P =0.0009), higher hemogloblin concentration (P =0.0033), higher platelet counts (P <0.0001), male gender (P <0.0001) and rs809997 TT-genotype (P <0.0001). Comparing to non-TT genotype patients, TT genotype patients had a significantly higher SVR rate with moderate viral reduction (1–3 logs10 IU/mL) at week 4 (58.9% vs. 18.2%, P <0.001), and the SVR rate did not differ between TT/non-TT patients on the extreme ends (<1 or >3 log10 IU/mL reduction) of week 4 interferon responsiveness. For non-TT genotype carriers who were with <3 logs10 reduction, none (0/15) could have a complete early virological response and only 10.9% (7/64) of the patients had an SVR. Conclusions: More profound interferon responsiveness is mandatory for HCV-1 patients with unfavorable IL-28B genotype. [Copyright &y& Elsevier]

Background/Aims: The impact of virological factors and interleukin-28B (IL-28B) genetic variants on retreatment of hepatitis C virus genotype 2 (HCV-2) treatment-experienced patients remains unknown. Methods: On-treatment virological responses and IL-28B rs8099917 genotype were determined in 46 HCV-2 treatment-experienced patients (42 previous relapsers; four previous non-responders) retreated with 24-week peginterferon/ribavirin. Results: Forty (87.0%) patients carried the rs8099917 TT genotype and 6 patients (13.0%) carried the TG/GG genotype. The sustained virological response (SVR; seronegativity of HCV RNA throughout 24 weeks of the post-treatment follow-up period) rate was 71.7%. Compared with previous non-responders, previous relapsers had a significantly higher SVR rate (78.6% vs. 0%, P = 0.004) and a lower relapse rate (17.5% vs. 100%, P = 0.04). All the previous non-responders were with the rs8099917 TT genotype. As for those who relapsed, treatment responses, including the rates of rapid virological response (RVR, 80.6% vs. 66.7%, P = 0.59), early virological response (EVR, 97.2% vs. 83.3%, P = 0.27), end-of-treatment virological response (97.2% vs. 83.3%, P = 0.27) and SVR (80.6% vs. 66.7%, P = 0.59) and relapse rate (17.1% vs. 20.0%, P = 1) did not differ significantly between patients with the rs8099917 TT and those with the non-TT genotype. Multivariate analysis revealed that the most important factor predictive of an SVR in the retreatment of HCV-2 was previous relapse; the only factor predictive of an SVR for previous relapsers was the achievement of an EVR. Compared with the achievement of a RVR, the attainment of an EVR was more accurate in predicting an SVR (88% vs. 74%). Conclusions: Peginterferon/ribavirin is effective in the retreatment of HCV-2 relapsers, especially among those who achieved an EVR. [ABSTRACT FROM AUTHOR]

Background: The current stopping rule for peginterferon/ribavirin therapy in hepatitis C virus genotype-1 (HCV-1) patients is based on an early virological response (EVR, defined as >2 log10 viral reduction at treatment week 12). We aimed to explore rapid stopping rules at week 4. Methods: We randomly allocated 528 HCV-1 patients into training and validation sets (at a 1:2 ratio). The interleukin-28B rs8099917 genotypes and on-treatment virological responses were evaluated to determine the negative predictive value (NPV) for achieving a sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks after end-of-treatment). The study was approved by the ethics committees of the participating hospitals. All of the patients gave written informed consent before enrollment. Results: A poor week 4 response (W4R), defined as a HCV RNA reduction of <1 log10 IU/mL at week 4 or a week 4 HCV RNA>10,000 IU/mL with interleukin-28B non-TT genotype, had the highest NPV (95%). In the complete sample, poor W4R could identify 43.4% (59/136) of the non-responders, with an NPV of 95% and a false negative rate of only 0.8% (3/396). The multivariate analysis revealed that a poor W4R was the most important negative predictor (odds ratio/95% confidence intervals: 49.01/13.70-175.37), followed by the lack of an EVR. In addition to HCV RNA<1 log10 IU/mL reduction, using the criteria of HCV RNA>10,000 IU/mL/non-TT genotype helped identifying an additional one-third of non-SVR patients at W4.Using the strategy of sequential rapid stopping rule strategy could identify 53.7% (73/136) of the non-responders (43.4% at week 4 and an addition 11.3% at week 12), as compared to 40.4% for the classical week-12 early stopping rule. Conclusions: Sequential rapid stopping rules using on-treatment virological responses and interleukin-28B genotype can rapidly identify additional peginterferon/ribavirin non-responders. [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]

Background & Aims: A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24weeks of post-treatment follow-up) after 24weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen. Methods: Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24weeks peginterferon/ribavirin. Results: Compared to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, p <0.001) and SVR (64.7% vs. 25.6%, p <0.001) rates, and lower relapse rate (28.0% vs. 54.5%, p =0.01). Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/ 95% confidence intervals [OR/CI]: 6.24/2.34–16.63), followed by lower viral loads (OR/CI: 5.29/2.81–9.93) and age (OR/CI:0.94/0.91–9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22–53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18–9.65), lower viral loads (OR/CI: 2.23/1.00–4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06–1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%. Conclusions: Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: The adiponutrin/patatin-like phospholipase-3 ( PNPLA3) I148M polymorphism has recently been found to contribute to differences in hepatic lipid content. Nonalcoholic fatty liver disease (NAFLD) has recently been considered a hepatic component of insulin resistance and a risk factor in the emergence of type 2 diabetes. However, whether there is an association between PNPLA3 I148M and insulin resistance and NAFLD in a normoglycaemic population is still unknown. Methods: This study enrolled 156 normoglycaemic individuals with NAFLD and 723 controls. All participants received complete biochemical and clinical workups including liver ultrasonography. They were then genotyped for the PNPLA3 I148M polymorphism. Results: We found significant differences in the genotype and the dominant model of the PNPLA3 I148M polymorphism between the NAFLD groups and the controls ( P=0.018 and P=0.01 respectively). Furthermore, there was a dose effect of the PNPLA3 I148M genotype, in that CG heterozygotes had a risk of NAFLD between CC and GG homozygotes [adjusted odds ratio (OR)=2.03, 95% confidence interval (CI)=1.23-3.375 for the GG genotype and adjusted OR=1.55, 95% CI=1.02-2.35 for the CG genotype]. The dominant model of the PNPLA3 I148M polymorphism showed higher waist circumference, fasting insulin, Homeostasis Model Assessment (HOMA-IR), alanine aminotransferase concentrations and ferritin level. Multivariate analysis showed the PNPLA3 I148M polymorphism to be independently and significantly associated with NAFLD in our normoglycaemic participants. Conclusion: This study reports an association between the PNPLA3-I148M polymorphism and insulin resistance and NAFLD in a normoglycaemic population. [ABSTRACT FROM AUTHOR]

Background & Aims: Evidence on the efficacy of antiviral treatment in chronic hepatitis C (CHC) patients with hepatocellular carcinoma (HCC) after curative treatment is scarce. We aimed to evaluate the efficacy and safety of pegylated interferon-alpha plus ribavirin (pegIFN/RBV) combination therapy in these patients, compared to cirrhotic patients. Methods: This prospective, multicenter, case–control study recruited 82 consecutive CHC patients with HCC after curative management and 87 sex/age-matched cirrhotic patients. All patients received pegIFN-alpha-2a and weight-based RBV according to current treatment recommendations. The primary outcome measurement was sustained virological response (SVR, seronegative of hepatitis C virus RNA throughout the 6-month post-treatment follow-up period). Results: The SVR rate was significantly lower in the HCC group compared to the cirrhosis group (48.8% vs 64.4%, p =0.04). However, the significantly lower rate of SVR in the HCC group was observed among genotype-1 patients (33.3% vs 60.7%, p =0.005) but not among genotype-2/3 patients (70.6% vs 71.0%, p =0.88). In patients who achieved 80/80/80 adherence, there was no significant difference of SVR rate between groups (50.7% vs 64.2%, p =0.12) Multivariate logistic regression analysis demonstrated that rapid virological response (viral clearance during the first 4weeks of treatment, odds ratio=22.1, p <0.001) and adherence (odds ratio=3.1, p =0.05) were predictive factors associated with SVR, whilst previous occurrence of HCC was not associated with SVR (Odds ratio=0.4, p =0.09). The incidence of severe adverse events did not differ between the two groups. Conclusions: The study proved the feasibility of pegIFN/RBV therapy with current treatment guidelines in CHC patients after successful eradication of HCC, with careful monitoring. [ABSTRACT FROM AUTHOR]

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

Abstract: Human leukocyte antigens (HLAs) may play a role in the clinical evolution of hepatitis C virus (HCV) infection. The present study was aimed at elucidating the association between the HLA loci and responses to combination therapy with pegylated interferon-alpha 2a (PEG-IFN) and ribavirin in Taiwanese. We enrolled a total of 208 treatment-naïve Taiwanese chronic hepatitis C (CHC) patients treated with combination therapy. Patients with sustained virological response (SVR) had a significantly higher frequency of genotype non-1b infection, lower pretreatment HCV RNA levels and a higher frequency of mild hepatic fibrosis (fibrosis score: F: 0–2). The HLA A24 and B40 alleles were significantly associated with SVR after adjusted for the other three confounding factors including HCV genotype, hepatic fibrosis and pretreatment serum HCV RNA levels. Haplotypes (B40-DRB1*3, B46- DRB1*9, Cw1- DQB1*3, and Cw1- DRB1*9) were significantly associated with SVR to combination therapy. For 167 patients with genotype 1b infection and viral load < or =5.6logIU/ml or genotype non-1b infection, the B46 was significantly associated with sustained response with OR (odds ratio) [95% CI (confidence interval) of 0.047 (0.168–0.988)]. Haplotypes B40-DRB1*3, B46- DRB1*9, Cw1- DQB1*3, Cw1- DRB1*9 and DQB1*3- DRB1*9 were found to be associated with SVR to PEG-IFN/ribavirin therapy with OR (95% CI) of 0.179 (0.032–0.989), 0.313 (0.107–0.918), 0.350 (0.145–0.845), 0.282 (0.105–0.759) and 0.412 (0.174–0.978), respectively. We concluded that the virological and the host immunogenetic factors may possibly predict the response to combination therapy in CHC patients. [Copyright &y& Elsevier]

Abstract: Objectives: Hepatitis B virus infection is hyperendemic in Taiwan. In the past, the infection rate has been higher in indigenous villages. The prevalence of chronic HBV infection among indigenous children after immunization remains unknown. Methods: A total of 843 indigenous children were checked for the hepatitis B seromarker. Another 606 metropolitan children were enrolled for comparison in 2005. Results: The seroprevalences (%) of HBsAg, (hepatitis B surface antigen) anti-HBs, (antibody to hepatitis B surface antigen) and anti-HBc (antibody to hepatitis B core antigen) among indigenous and metropolitan children were 3.2 vs. 0.17 (p <0.001), 47.4 vs. 51.2 (p =0.164), and 10.7 vs. 1.7 (p <0.001), respectively. Among the indigenous children, who were divided into three age groups, the prevalences of HBsAg and anti-HBc increased with age, while anti-HBs decreased significantly (p =0.025, 0.002, and <0.001, respectively). Children with positive HBsAg had a significantly higher mean (SD) age (10.2 (2.2) vs. 9.2 (2.1) years, p =0.024) and a higher ALT value (16.4 (8.0) vs. 10.6 (8.3) IU/L, p =0.001). In a multivariable analysis, indigenous residency, older age group and abnormal ALT value were independent factors associated with positive HBsAg. Conclusions: The seroprevalence of hepatitis B infection has obviously declined among indigenous children 20 years after mass immunization programs launched in Taiwan. However, it is still higher than that of metropolitan children. Higher rates of chronic HBV infection in the mothers might be one important explanation for this finding. [Copyright &y& Elsevier]

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

Abstract: Adefovir dipivoxil (ADV)-resistant mutations have been identified in treating hepatitis B virus (HBV) infection. This study aimed to analyze the response, the incidence of ADV resistance and the virologic characteristics of ADV therapy. A total of 29 CHB patients with confirmed lamivudine (LAM)-resistant HBV were treated with ADV for more than 52 weeks. Serum HBV DNA, HBV genotypes and sequences of HBV polymerase reverse-transcriptase domain were determined. Rates for the biochemical response, HBeAg loss, HBeAg seroconversion and virologic response (<200copies/mL of HBV DNA) were 82.8, 23.5, 11.8, and 48.3%, respectively, at week 52 of treatment. Lower pre-treatment mean HBV DNA level was the only significant factor associated with negative HBV DNA after ADV therapy. Six (20.7%) patients had clearance of LAM-resistant YMDD variants with replacement by the wild type HBV at week 52. The rtN236T, rtA181V/T and rtI233V were not identified before ADV therapy and the genotypic mutation of rtN236T was detected in one (3.4%) patient. In conclusion, the 52-week ADV treatment for patients with LAM-resistant HBV variants significantly achieved normalization of ALT levels, reduced serum HBV DNA levels and induced HBeAg loss and seroconversion. The emergence of ADV-resistant mutations seemed rare at weeks 52. [Copyright &y& Elsevier]

We aimed to evaluate the efficacy, advantage, and safety of a 24-week regimen with high-dose interferon-α (INF-α; 6 million units thrice weekly) plus ribavirin (1000–1200 mg/day) combination therapy for 46 Taiwanese chronic hepatitis C (CHC) patients with persistently normal or near-normal alanine aminotransferase (PNALT) levels. Methods: Ninety-two age- and sex-matched CHC patients with elevated ALT levels (>2 times the upper limit of normal range) with a ratio of 1:2, treated with the same regimen, served as a control. Results: The sustained virologic response (SVR) rate was comparable between PNALT (67.4%) and elevated ALT (65.2%) groups (intention-to-treat analysis). The two groups had similar rates of discontinuation and incidence of adverse effects. Viral genotype 1b, baseline viral loads, body mass index, and age were significant factors negatively associated with SVR. Further decline of ALT levels throughout the follow-up period was observed in sustained responders of the PNALT group. None of the eight patients with ALT flares developed icteric hepatitis. The virologic efficacy was sustained in a 3-year extended follow-up period. Conclusion: high-dose INF-α with ribavirin combination therapy is effective, safe, and well tolerated in CHC patients with PNALT levels. The ALT assay might not be used as a single biochemical marker for determination of treatment consideration. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Both Model for End-stage Liver Disease (MELD) and Index scores have been used to predict mortality in patients with end-stage liver disease and cirrhosis in Western countries. Objectives:: This study aimed to determine mortality rates, identify prognostic indicators, and determine the usefulness of these 2 scoring systems in predicting short-term (6-month) survival in Taiwanese patients with chronic hepatitis B (CHB)-related decompensation who were treated with lamivudine. Methods:: This study was conducted at the Kaohsiung Medical University Hospital and the Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. Eligible patients were aged 18 to 85 years with CHB with related decompensation (with either serum total bilirubin level, ≥3 mg/dL or prolonged prothrombin time, ≥3 seconds) and were treatment naive. All patients were treated with lamivudine 100 mg PO (tablet) once daily; surviving patients were treated for at least 6 months. The clinical data, including hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B virus (HBV) DNA, were measured before treatment. Pre-treatment MELD and Index scores were calculated for all patients. Results:: Ninety-six patients were enrolled (79 men, 17 women; mean [SD] age, 44.5 [15.2] years). Thirteen (13.5%) patients died within 6 months. Higher international normalized ratio (INR) for prothrombin time, lower albumin level, and higher HBV DNA level (≥105 copies/mL) were factors significantly associated with death. The areas under the receiver operating characteristic curve for predicting survival by the MELD and Index scores were 0.822 and 0.788, respectively. Albumin level, which was not included in the scoring systems, also was found to be a significant predictor. Conclusions:: We found that with a 13.5% mortality rate, albumin, INR, and HBV DNA levels were good prognostic indicators in Taiwanese patients with CHB-related decompensation treated with lamivudine therapy. The MELD and Index scoring systems were good predictors of 6-month survival in the patients in this study. [Copyright &y& Elsevier]

Abstract: To investigate the influence of the T-to-A polymorphic sequence at position +874 in the interferon (IFN)-γ gene (+874 IFN-γ) on the response to combination therapy with high-dose interferon and ribavirin, the single nucleotide polymorphisms were determined by using a polymerase chain reaction sequence-specific primers approach in 150 histologically proved chronic hepatitis C (CHC) patients. The distribution of genotypes for +874 IFN-γ were T/T: 6 (4.0%), T/A: 31 (20.7%) and A/A: 113 (75.3%) and 24.7% (37/150) of patients were inherited T allele. After undergoing combination therapy with high-dose IFN-α and ribavirin, 70.7% (106/150) of patients achieved sustained viral response (SVR). Based on multivariate regression analyses, the independent factors predicting HCV SVR after combination therapy were HCV genotype non-1b (P &#60;0.001) and low pretreatment HCV RNA levels (P =0.041) (odds ratios/95% C.I.: 10.150/4.023–25.609 and 0.581/0.345–0.979, respectively). No association between genotypes, A or T alleles of +874 IFN-γ and response to combination therapy with high-dose IFN-α and ribavirin. In conclusion, we found that with high SVR rates after combination therapy with high-dose IFN-α and ribavirin, HCV genotypes and pretreatment serum HCV RNA levels, but not inheritance of the IFN-γ polymorphism at the position +847, were predictors for SVR. [Copyright &y& Elsevier]

Abstract: Objective.: This study was to clarify the safety of fine-needle aspiration of small hepatocellular carcinoma (HCC). Methods.: Ninety consecutive patients with small hepatocellular carcinoma (46 with single nodule, 44 with multiple nodules, all ≤3cm) who had a comparative angiography performed within 50 days (median 16 days) after aspiration were included. Results.: The angiographic detection of hepatocellular carcinoma was not influenced by the procedure of aspiration except in one (1.1%) with small arterioportal shunt. The newly developed nodules of hepatocellular carcinoma were not localized in the segment of aspirated nodule located. None of the new nodules was located along the needle tract. Patients with single nodule caused by hepatitis C had a significantly higher incidence of appearance of new nodule than those caused by hepatitis B (38.46% versus 4.35%, p =0.0159). Patients with multiple nodules had a significantly higher incidence of appearance of new nodule than patients with single nodule (60% versus 18.18%, p &#60;0.005). These results indicated that the newly developed nodules were related to the disease process rather than the procedure of aspiration. Conclusions.: Fine-needle aspiration is a safe procedure in the collection of specimens for the diagnosis of small hepatocellular carcinoma. [Copyright &y& Elsevier]

The clinical significance of coinfection of SENV-H among patients with chronic hepatitis C (CHC) and the response to combination therapy with high-dose interferon-alpha (IFN) plus ribavirin in Taiwan are uncertain. A total of 151 (120 histologically proved) naïve CHC patients who received 6 MU IFN thrice a week plus ribavirin for 24 weeks therapy were enrolled in this study. SENV-H DNA was tested by PCR method. Of 151 patients, 29 (19.2%) were positive for SENV-H DNA. The positive SENV-H DNA was significantly associated with HCV genotype 1b than non-1b infection (69.0% versus 43.4%; P = 0.011). No other clinical, histopathological and virological factor was related to positive SENV-H DNA. After combination therapy, the rate of sustained viral response (SVR) of HCV and SENV-H were 66.9 and 78.3%, respectively. By multivariate analyses, the significant factors associated with HCV SVR after combination therapy were HCV genotype non-1b, pretreatment HCV RNA levels less than 200,000 IU/mL, and younger age. We conclude that coexistent SENV-H infection, apparently associated with HCV genotype 1b, is found among 19.2% of Taiwanese CHC patients. Both HCV and SENV-H are highly susceptible to combination therapy with high dose IFN and ribavirin and SENV-H coinfection does not affect the HCV response. [Copyright &y& Elsevier]

: Background/AimsFamilial clustering of hepatitis B virus (HBV) infection is related to perinatal transmission, and is the main cause of familial-type hepatocellular carcinoma (HCC). The route of HBV transmission differs between the children and siblings of patients with HCC. This study examined the differences in HBV carrier rates and HCC-related mortality between two generations in HCC families.: MethodsFrom 1992 to 1997, relatives of individuals with HCC were screened prospectively with ultrasonography, alpha-fetoprotein, liver biochemistry tests and viral markers. Total HCC-related deaths during a 9-year period were compared between the generations of index patients and their children.: ResultsThe study included a total of 13 676 relatives in two generations. More HCC-related deaths occurred in the index patient generation than in the child generation. Furthermore, children of female index patients had higher rates of liver cancer related mortality than children of male index patients. The same was true when the analysis was limited to male HBV carriers. The prevalence of HBsAg in the offspring of HBsAg positive mothers was 66% in the child generation and 72% in the index patient generation. These high prevalences indicated high maternal HBV replication status.: ConclusionsPerinatal transmission and maternal viral load are important risk factors in hepatocarcinogenesis. [Copyright &y& Elsevier]

Background: The clinical significance of TT virus (TTV) coinfection in chronic hepatitis C (CHC) patients and influence of TTV viremia on hepatitis C virus (HCV) response to high dose interferon-alpha therapy in Taiwan were investigated. Materials and Methods: Total 102 HCV RNA-positive CHC patients were enrolled. TTV DNA (using polymerase chain reaction primers derived from 5′ non-coding region and open reading frame 2), alanine aminotransferase (ALT), GB virus-C/hepatitis G virus (GBV-C/HGV) RNA, anti-E2 antibody, genotype and RNA levels of HCV were tested. Results: The prevalence of TTV DNA was 51.0%. The mean age of TTV viremic CHC patients was significant higher than non-viremic ones (P<0.05). HCV sustained viral response (SVR) was achieved in 42 (41.2%) patients. Based on multivariate regression analyses, SVR were significantly associated with low pretreatment HCV RNA levels, HCV genotype non-1b and high pretreatment levels of ALT but not TTV viremia. Conclusions: TTV viremia is highly prevalent among Taiwanese CHC patients and related to increased ages. Neither severity of liver disease nor replication and genotype distribution of HCV was affected by concurrent TTV infection. With high HCV SVR rate associated with pretreatment HCV RNA and ALT levels and HCV genotype, TTV viremia did not influence the HCV response. [Copyright &y& Elsevier]

A G-to-A polymorphic sequence at position −308 in the tumor necrosis factor alpha promoter (TNF308.2) might be associated with disease susceptibilities. To investigate the association between −308 TNF-α variants and pathogenesis of hepatitis C virus (HCV) infection and response to interferon-alpha (IFN-α) treatment for chronic hepatitis C (CHC), −308 TNF-α genotypes were determined in 100 unrelated Taiwanese CHC patients treated with IFN-α and in 100 unrelated healthy subjects. The distribution of −308 TNF-α genotypes did not differ between CHC patients and controls. Age, sex, HCV genotype, and the necroinflammatory activity of liver histopathology did not differ among CHC patients with different −308 TNF-α genotypes. Although pretreatment HCV RNA serum levels, aminotransferase and the rate of severe fibrosis decreased with the copy number of TNF308.2, the difference did not reach significance. We failed to demonstrate any association between −308 TNF-α promoter polymorphisms and response to IFN therapy, which was inversely correlated to liver cirrhosis, pretreatment serum HCV RNA levels and genotype 1b by using multivariate analysis. In conclusion, our findings suggest that −308 TNF-α promoter polymorphisms do not play a direct role in the susceptibility and pathogenesis of HCV infection, and in the response to interferon-alpha therapy for CHC. [Copyright &y& Elsevier]