Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients.

BACKGROUND & AIMS: Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients. METHODS: The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective-prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort. RESULTS: In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development. CONCLUSIONS: Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.

Advanced hepatic fibrosis and steatosis are associated with persistent alanine aminotransferase elevation in chronic hepatitis C patients negative for hepatitis C virus RNA during pegylated interferon plus ribavirin therapy.

BACKGROUND: Clinical implications of persistent alanine aminotransferase (ALT) elevation and associated factors in chronic hepatitis C (CHC) patients who achieved undetectable hepatitis C virus (HCV) RNA during pegylated interferon plus ribavirin (peg-IFN/RBV) therapy remain unknown. METHODS: A total of 1113 CHC patients with undetectable HCV RNA during peg-IFN/RBV therapy were enrolled. Baseline characteristics associated with persistent on-treatment ALT elevation (POAE), and its impact on treatment outcomes, were investigated. RESULTS: Of 1113 CHC patients, 254 (22.8%) had POAE. Among patients with HCV genotype 1 (HCV-1) who had complete early virologic response (EVR) and received 48 weeks of therapy, patients with POAE had a lower rate of sustained virologic response (SVR) than those without POAE (44.1% vs 74.0%; P = .0002). Multivariate analyses showed that body mass index ≥ 27 kg/m(2), ALT level ≥3 times the upper limit of normal, aspartate aminotransferase to platelet ratio index score ≥1.5, hepatic fibrosis ≥F3, and hepatic steatosis ≥S2 were independent factors associated with POAE after viral clearance. CONCLUSIONS: POAE is common in CHC patients during therapy. HCV-1 patients with POAE have a lower SVR rate to 48-week therapy if they achieve complete EVR. Advanced hepatic fibrosis, obesity, and steatosis are factors associated with POAE in these patients.

Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial.

OBJECTIVE: Data comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited. DESIGN: In this randomised trial, 172 patients received 24 weeks of peginterferon alfa-2a 135 µg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 µg/week (n=86). The efficacy and safety endpoints were sustained virological response (SVR) rate and adverse event (AE)-related withdrawal rate. RESULTS: Compared with monotherapy, combination therapy had a greater SVR rate (74% vs 44%, relative risk (RR): 1.68 [95% CI 1.29 to 2.20]; p<0.001). The beneficial effect of combination therapy was more pronounced in patients with baseline viral load ≥800,000 IU/mL than those with baseline viral load <800,000 IU/mL (RR: 3.08 [95% CI 1.80 to 5.29] vs. RR: 1.11 [95% CI 0.83 to 1.45]; interaction p=0.001). Patients receiving combination therapy were more likely to have a haemoglobin level of <8.5 g/dL (70% vs. 8%, risk difference (RD): 62% [95% CI 50% to 73%]; p<0.001) and required a higher dosage [mean: 13,417 vs. 6667 IU/week, p=0.027] of epoetin ß to manage anaemia than those receiving monotherapy. The AE-related withdrawal rates were 6% and 3% in combination therapy and monotherapy groups, respectively (RD: 2% [95% CI -4% to 9%]). CONCLUSIONS: In treatment-naive haemodialysis patients with HCV-2 infection, combination therapy with peginterferon plus low-dose ribavirin achieved a greater SVR rate than peginterferon monotherapy. Most haemodialysis patients can tolerate combination therapy. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov number, NCT00491244.

Comparison of Abbott RealTime HCV Genotype II with Versant line probe assay 2.0 for hepatitis C virus genotyping.

Genotyping and subtyping of 225 samples with hepatitis C virus (HCV) genotype 1, 2, 3, or 6 infection were done with Versant LiPA 2.0 and Abbott RealTime HCV Genotype (GT) II by using direct sequencing of the NS5B and 5' untranslated regions as the reference standards. The concordance rates were >99.2% for genotypes and 96.1% for subtypes 1a and 1b. Both the Abbott RealTime and Versant LiPA assays can accurately determine hepatitis C virus genotypes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00979979.).

Serum Biomarkers Predictive of Significant Fibrosis and Cirrhosis in Chronic Hepatitis B.

GOALS/BACKGROUND: Aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 index are noninvasive biomarkers to evaluate hepatic fibrosis. However, their usefulness in chronic hepatitis B (CHB) patients remains unclear. METHODS: A total of 631 CHB patients were enrolled and randomly divided into a training set (n=420) and a validation set (n=211). Areas under receiver operating characteristic (AUROC) curves for FIB-4 index and APRI were compared to evaluate their diagnostic values in identifying significant fibrosis and cirrhosis. RESULTS: The AUROC of FIB-4 index for the diagnosis of significant fibrosis and cirrhosis in the entire cohort was higher than that of APRI (0.769 vs. 0.704, P=0.0003 and 0.869 vs. 0.706, P<0.0001). By using cutoff APRI of 0.38 and 4.04 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 67.7% and 76.8%. At cutoff FIB-4 index of 0.87 and 3.40 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 69.2% and 84.4%. Compared with patients with concordance, patients with overestimated score by FIB-4 index had a significantly higher serum alanine aminotransferase (ALT) level (299±245 vs. 168±196 U/L, P=0.001) as well as a higher ratio of hepatitis flare (ALT>400 U/L) (25% vs. 7.9%, P=0.008). CONCLUSIONS: FIB-4 index proves to be more reliable than APRI in predicting significant fibrosis and cirrhosis in CHB patients. By using FIB-4 index, a substantial proportion of patients could be identified correctly as significant fibrosis and cirrhosis without further invasive liver biopsy.

Increasing biopsy number and sampling from gastric body improve the sensitivity of rapid urease test in patients with peptic ulcer bleeding.

BACKGROUND: Previous studies demonstrated that the sensitivity of rapid urease test (RUT) for diagnosis of Helicobacter pylori infection decreased during peptic ulcer bleeding. AIM: We designed this study and tried to find a better method to improve the detection rate of H. pylori infection at the same session of endoscopic diagnosis of peptic ulcer bleeding. METHODS: We prospectively enrolled 116 patients with peptic ulcer bleeding. These patients received intravenous proton pump inhibitor and then received upper gastrointestinal endoscopy within 24 h after arrival. We took one piece of biopsy from gastric antrum (Group 1), four pieces from gastric antrum (Group 2), and one piece from the gastric body (Group 3) for three separate RUTs, respectively. (13)C-urease breath test was used as gold standard for diagnosis of H. pylori infection. RESULTS: There were 74 patients (64 %) with positive (13)C-urease breath test. Among these 74 patients, 45 patients had positive RUT (sensitivity: 61 %) in Group 1; 55 patients had positive RUT (sensitivity: 74 %) in Group 2; 54 patients had positive RUT (sensitivity: 73 %) in Group 3. There were significant differences between Group 1 and Group 2 (p = 0.02) and between Group 1 and Group 3 (p = 0.022). CONCLUSIONS: The sensitivity of RUT was 61 % during peptic ulcer bleeding. The sensitivity of RUT can be increased significantly by increased biopsy number from gastric antrum or biopsy from gastric body.

Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial.

BACKGROUND: Data are limited on the efficacy and safety of pegylated interferon plus ribavirin for patients with hepatitis C virus genotype 1 (HCV-1) receiving hemodialysis. OBJECTIVE: To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis. DESIGN: Open-label, randomized, controlled trial. (ClinicalTrials.gov: NCT00491244). SETTING: 8 centers in Taiwan. PATIENTS: 205 treatment-naive patients with HCV-1 receiving hemodialysis. INTERVENTION: 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102). MEASUREMENTS: Sustained virologic response rate and adverse event-related withdrawal rate. RESULTS: Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001). More patients receiving combination therapy had hemoglobin levels less than 8.5 g/dL than those receiving monotherapy (72% vs. 6%; risk difference, 66% [CI, 56% to 76%]; P < 0.001). Patients receiving combination therapy required a higher dosage (mean, 13 946 IU per week [SD, 6449] vs. 5833 IU per week [SD, 1169]; P = 0.006) and longer duration (mean, 29 weeks [SD, 9] vs. 18 weeks [SD, 7]; P = 0.004) of epoetin-ß than patients receiving monotherapy. The adverse event-related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, -3% to 9%]). LIMITATION: Open-label trial; results may not be generalizable to patients on peritoneal dialysis. CONCLUSION: In treatment-naive patients with HCV-1 receiving hemodialysis, combination therapy with pegylated interferon plus low-dose ribavirin achieved a greater sustained virologic response rate than pegylated interferon monotherapy. PRIMARY FUNDING SOURCE: National Center of Excellence for Clinical Trial and Research.

Functional impairment of dendritic cells in patients infected with hepatitis C virus genotype 1 who failed peginterferon plus ribavirin therapy.

Although chronic hepatitis C patients have a lower frequency and functions of dendritic cells (DCs) than healthy subjects, little is known about the serial changes in frequency and functions of DCs following anti-viral treatment and the relationship with treatment outcomes. Twenty patients with hepatitis C virus genotype 1 receiving peginterferon (PEG-IFN) and ribavirin for 24 weeks were enrolled. The frequency and functions of DCs were assayed at baseline and 24 weeks post-treatment. Ten sex and age-matched healthy adults served as controls. Nineteen of the 20 chronic hepatitis C patients completed 24 weeks of combination therapy. Fifteen patients achieved rapid virologic response and 12 achieved sustained virologic response (SVR). The baseline frequency of peripheral blood myeloid DCs and plasmacytoid DCs was significantly lower in chronic hepatitis C patients than in healthy controls. In patients who achieved SVR, the frequency of DCs subsets at the end of follow-up increased to a level comparable to healthy controls. Although no functional defects of DCs was found in chronic hepatitis C patients in comparison with healthy controls, in patients without SVR had a lower CD83 expression and higher interleukin-10 production of DCs than SVR patients. The results suggest that low CD83 expression and high IL-10 production of DCs at the baseline may predict a poor virologic response to 24-week PEG-IFN plus ribavirin therapy in HCV genotype 1 patients.

Acute hemorrhagic rectal ulcer: an important cause of lower gastrointestinal bleeding in the critically ill patients.

BACKGROUND AND AIM: The occurrence of acute hemorrhagic rectal ulcer (AHRU) in patients in the intensive care unit (ICU) has not been well investigated. The aims of this study were to evaluate the clinical manifestations and outcomes in these patients. METHOD: The patients developing significant acute lower gastrointestinal (LGI) bleeding after ICU admission from July 2002 to December 2007 were retrospectively reviewed. Bedside colonoscopy was performed within 24 h of bleeding, and those patients with bleeding from AHRU were studied. Ulcers with stigmata of recent bleeding were treated with endoscopic hemostasis, and the outcome of these patients was analyzed. RESULTS: AHRU occurred in 36 of 114 patients (31.6%) and was the most common cause of acute LGI bleeding after ICU admission. Most patients had comorbidities, such as respiratory failure, renal failure, diabetes mellitus, or atherosclerosis. Fourteen patients (38.9%) developed hypovolemic shock after the onset of bleeding. Endoscopic therapy was performed in 29 patients with 97.2% success rate for hemostasis. Fourteen patients (48.3%) developed rebleeding within 4 weeks. This was controlled by repeated endoscopic intervention. Anticoagulant use was the risk factor for rebleeding after treatment. The survival rate at 4 weeks after bleeding was 52.8%. Logistic regression analysis revealed thrombocytopenia (platelet count <150,000/mm(3)) and more than one comorbidity were independent predictors for mortality. CONCLUSIONS: AHRU is an important etiology of acute LGI bleeding in the patients with critical illness. Bedside colonoscopy is helpful for early diagnosis and treatment. The underlying comorbidities of the patients influence the outcome after bleeding.

Pegylated interferon alfa-2a monotherapy for hemodialysis patients with acute hepatitis C.

BACKGROUND: Hemodialysis patients are at risk of hepatitis C virus (HCV) infection. However, little is known about the efficacy and safety of pegylated interferon (IFN) therapy for hemodialysis patients with acute hepatitis C. METHODS: From 2005 through 2008, 35 hemodialysis patients with acute hepatitis C who did not have spontaneous clearance of HCV by 16 weeks were treated with pegylated IFN alfa-2a at a dosage of 135 microg weekly for 24 weeks. In contrast, 7 patients with clearance of HCV by 16 weeks were under observation only. Thirty-six hemodialysis patients from 2002-2005 who had acute hepatitis C but did not receive treatment served as historical controls. The primary efficacy and safety end points were sustained virologic response (undetectable HCV RNA levels at 24 weeks after therapy) by intention-to-treat analysis and treatment-related withdrawal. RESULTS: The rate of sustained virologic response in the treatment group was significantly higher than the rate of spontaneous HCV clearance in the control group (88.6% vs 16.7%; P < .001). Two patients (5.7%) prematurely terminated treatment at 8 and 10 weeks because of constitutional symptoms, and both did not have sustained virologic response. All but one patient had rapid virologic response (undetectable HCV RNA levels at 4 weeks of therapy), and all patients who received >12 weeks of therapy had early and end-of-treatment virologic responses. All patients who had clearance of HCV by 16 weeks had undetectable HCV RNA levels until the end of follow-up. CONCLUSIONS: Pegylated IFN alfa-2a monotherapy is safe and efficacious for hemodialysis patients with acute hepatitis C. It is suggested that patients without spontaneous clearance of HCV by week 16 should receive therapy.

The ratio of aminotransferase to platelets is a useful index for predicting hepatic fibrosis in hemodialysis patients with chronic hepatitis C.

Percutaneous liver biopsy is the gold standard for staging hepatic fibrosis of hemodialysis patients with chronic hepatitis C before renal transplantation or antiviral therapy. Concerns exist, however, about serious post-biopsy complications. To evaluate a more simple approach using standard laboratory tests to predict hepatic fibrosis and its evolution, we studied 279 consecutive hemodialysis patients with chronic hepatitis C and a baseline biopsy. Among them, 175 receiving antiviral therapy underwent follow-up biopsy to evaluate the histological evolution of fibrosis. Multivariate analysis of routine laboratory tests at baseline showed the aspartate aminotransferase-to-platelet ratio index was an independent predictor of significant hepatic fibrosis. The areas under curves of this ratio to predict fibrosis stages F2-4 were 0.83 and 0.71 in the baseline and follow-up sets; and 0.75 and 0.80 respectively, for patients with sustained or non-sustained virological response groups in the follow-up sets. By a judicious setting of cut-off levels for the baseline and non-sustained groups, and the sustained virological response group, almost half and 60 percent of the baseline and follow-up sets could be correctly diagnosed without biopsy. Our study found the aminotransferase-to-platelet ratio index is accurate and reproducible for assessing hepatic fibrosis in hemodialysis patients with chronic hepatitis C. Applying this simple index could decrease the need of percutaneous liver biopsy in this clinical setting.

Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial.

BACKGROUND: Comparable sustained virologic response (SVR) rates have been documented between Asian patients who received 24 weeks of pegylated interferon (IFN) plus ribavirin and white patients who received 48 weeks of combination therapy for hepatitis C virus genotype 1 (HCV-1) infection. Whether a 48-week course of combination therapy shows a better SVR rate than a 24-week course of such therapy among Asian patients with HCV-1 infection has not been confirmed in multicenter, randomized studies. METHODS: In this multicenter, randomized trial, 308 treatment-naive HCV-1-infected Asian patients were randomly assigned to receive either 24 or 48 weeks of pegylated IFN-alpha-2a (180 microg per week) plus ribavirin (1000-1200 mg/day) therapy. The primary end point was SVR, defined as an undetectable serum HCV RNA level 24 weeks after discontinuation of therapy. In addition, rapid virologic response (RVR) was defined as an undetectable serum HCV RNA level at week 4 of therapy, and complete early virologic response was defined as an undetectable serum HCV RNA level at 12 weeks of therapy in the absence of RVR. RESULTS: By intention-to-treat analysis, patients who received 48 weeks of therapy had a significantly higher SVR rate than did those who received 24 weeks of therapy (76% vs. 56%; P < .001). Among patients with a baseline serum HCV RNA level <800,000 IU/mL and RVR, SVR rates were comparable between 24- and 48-week courses of therapy (94% vs. 100%; P = .13). In contrast, 48 weeks of therapy was associated with a significantly higher SVR rate than was 24 weeks of therapy among patients without RVR (39% vs.16%; P = .01) and among those who achieved a complete early virologic response (44% vs. 20%; P = .02). CONCLUSIONS: In treatment-naive Asian patients with HCV-1 infection, 48 weeks of pegylated IFN-alpha-2a plus ribavirin therapy is associated with a higher SVR rate, compared with 24 weeks of such therapy. Patients with a baseline serum HCV RNA level <800,000 IU/mL and who have achieved an RVR can receive a 24-week course of therapy without compromising the SVR rates; however, those who have not achieved an RVR but who have achieved a complete early virologic response should receive a 48-week course of therapy.

Esophageal varices: noninvasive diagnosis with duplex Doppler US in patients with compensated cirrhosis.

PURPOSE: To prospectively develop and evaluate the accuracy of a duplex Doppler ultrasonographic (US) index for predicting the presence or absence of esophageal varices in patients with compensated cirrhosis (Child-Pugh class A) by using endoscopy as the reference standard. MATERIALS AND METHODS: The study had institutional review board approval; all participants gave informed consent. Data in a total of 383 prospectively enrolled patients who underwent duplex Doppler US and screening endoscopy were divided into training (n = 240) and validation (n = 143) sets. Duplex Doppler US indexes, including mean portal vein velocity (PVV), hepatic impedance indexes, splenic impedance indexes, and the splenic index were evaluated with univariate and multivariate logistic regression analyses to find the independent factors predictive of the presence of esophageal varices. Receiver operating characteristic (ROC) curves were constructed for these factors to evaluate diagnostic accuracy in the training set and reproducibility in the validation set. RESULTS: Multivariate logistic regression analysis showed that splenic index and mean PVV were predictive of the presence of esophageal varices in the training set. A splenoportal index (SPI) was calculated as the splenic index divided by mean PVV to amplify the opposite effects on esophageal varices. Areas under ROC curves for SPI were significantly higher than those for the splenic index (0.93 vs 0.90, P = .02) and mean PVV (0.93 vs 0.67, P < .001) in the training set and in the validation set (0.96 vs 0.91 for splenic index, P = .01; 0.93 vs 0.80 for mean PVV, P < .001). An SPI threshold of 3.0 had 92% sensitivity, 93% specificity, 91% positive predictive value, and 94% negative predictive value for esophageal varices. Applying this cutoff value correctly predicted the presence or absence of esophageal varices in 92% of the patients without screening endoscopy. CONCLUSION: SPI can serve as a useful noninvasive index to predict the presence or absence of esophageal varices.

Peginterferon alfa-2a plus Weight-Based or Flat-Dose Ribavirin for Treatment-Naïve Hepatitis C Virus Genotype 2 Rapid Responders: A Randomized Trial.

The impact of ribavirin (RBV) dosage on sustained virologic response (SVR) rates remains elusive in hepatitis C virus genotype 2 (HCV-2) rapid responders receiving 16 weeks of peginterferon (Peg-IFN) plus RBV. Treatment-naïve HCV-2 patients with rapid virologic response (RVR) received Peg-IFN alfa-2a 180 µg/week plus weight-based RBV (1,000 or 1,200 mg/day; cut-off body weight: 75 kg) for 6 weeks, and then randomly received Peg-IFN alfa-2a 180 µg/week plus weight-based (1,000 or 1,200 mg/day; n = 247) or flat-dose (800 mg/day; n = 246) RBV for additional 10 weeks. The primary endpoint was SVR24. Patients receiving weight-based and flat-dose RBV therapies had comparable SVR24 rates (93.5% versus 91.9%, P = 0.49). The risk differences (RDs) of SVR24 receiving weight-based and flat-dose RBV arms were 7.1% [95% CI: 0.7% to 13.6%] in males, and -5.8% [95% CI: -12.1% to 0.5%] in females (interaction P = 0.01). The SVR24 rate was higher in males receiving ≥13 mg/kg/day than those receiving <13 mg/kg/day (96.3% versus 85.1%, P = 0.001). In conclusion, Peg-IFN alfa-2a plus weight-based or flat-dose RBV for 16 weeks provides comparable SVR24 rates in treatment-naïve HCV-2 rapid responders. However, males should receive weight-based RBV to achieve a high SVR24 rate.

Peginterferon plus weight-based ribavirin for treatment-naïve hepatitis C virus genotype 2 patients not achieving rapid virologic response: a randomized trial.

Hepatitis C virus genotype 2 (HCV-2) slow responders poorly respond to 24 weeks of peginterferon (Peg-IFN) plus ribavirin (RBV). We evaluated the efficacy of extended 48-week regimen and the role of interleukin-28B (IL-28B) genotype in this clinical setting. Treatment-naïve HCV-2 patients not achieving rapid virologic response (RVR) by Peg-IFN alfa-2a 180 µg/week plus weight-based RBV (1,000-1,200 mg/day, cutoff body weight of 75 kg) were randomly assigned to receive a total duration of 48 (n = 94) or 24 (n = 93) weeks of therapy. The primary endpoint was sustained virologic response (SVR). Baseline patient characteristics to predict SVR were analyzed. Patients receiving 48 weeks of treatment had a greater SVR rate than those receiving 24 weeks of treatment (70.2% versus 46.2%, P = 0.001). Compared to patients treated for 24 weeks, the SVR rate in those treated for 48 weeks increased by 10.9% [95% CI: -5.9% to 27.7%] and 65.6% [95% CI: 44.5% to 86.7%] if they had IL-28B rs8099917 TT genotype, and GT/GG genotype, respectively (interaction P = 0.002). In conclusion, 48-week treatment with Peg-IFN plus weight-based RBV provides a greater SVR rate than 24-week treatment in treatment-naïve HCV-2 patients with unfavorable IL-28B genotypes who fail to achieve RVR.

Enterovirus-71 virus-like particles induce the activation and maturation of human monocyte-derived dendritic cells through TLR4 signaling.

Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation.

Interleukin 28B genetic polymorphisms and viral factors help identify HCV genotype-1 patients who benefit from 24-week pegylated interferon plus ribavirin therapy.

BACKGROUND: Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and viral factors can predict sustained virological response (SVR) in HCV genotype-1 (HCV-1) patients receiving 48 weeks of pegylated interferon and ribavirin. Whether these factors would identify those patients who can benefit from a shorter duration of therapy remains unclear. METHODS: Treatment-naive HCV-1 patients (n=662) receiving 24 or 48 weeks of combination therapy were enrolled. Baseline demographic data, HCV viral load, IL28B SNP genotypes (rs8099917), duration of therapy and rapid virological response (RVR) were evaluated to predict SVR. The SVR rates were further stratified by the independent factors and compared. RESULTS: The IL28B rs8099917 TT genotype, low baseline viral load (HCV RNA≤600,000 IU/ml), RVR and 48-week therapy independently predicted SVR. In RVR patients with the IL28B rs8099917 TT genotype, the SVR rate of 24-week therapy was comparable to 48-week therapy (95% versus 99%; P=0.21) at low baseline viral load, but was inferior to 48-week therapy (70% versus 97%; P<0.001) at high baseline viral load. In non-RVR patients, the SVR rate of 24-week therapy was inferior to 48-week therapy for those with the IL28B rs8099917 TT genotype but high baseline viral load (23% versus 62%; P<0.001), and those with the IL28B rs8099917 GT/GG genotype but low baseline viral load (0% versus 33%; P=0.02). CONCLUSIONS: HCV-1 patients simultaneously bearing the IL28B rs8099917 TT genotype, low baseline viral load and RVR can benefit from a shorter duration of combination therapy.

Interleukin 28B genetic polymorphisms play a minor role in identifying optimal treatment duration in HCV genotype 1 slow responders to pegylated interferon plus ribavirin.

BACKGROUND: Pegylated interferon and ribavirin for 72 weeks improve sustained virological response (SVR) in HCV genotype 1 (HCV-1) slow viral responders. Whether interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and on-treatment viral responses can identify non-rapid virological response (RVR) patients who benefit from 48 or 72 weeks of therapy remains unclear. METHODS: Treatment-naive HCV-1 patients who failed to achieve RVR were randomly assigned to receive 48 (n=168) or 72 (n=167) weeks of therapy. Baseline factors and on-treatment virological responses at weeks 8 and 12 were evaluated for SVR in 289 compliant patients who received ≥80% of drug dosages and treatment duration, and had end of follow-up viral response. The stratified SVR rates for independent factors were compared by treatment duration. RESULTS: Treatment duration, IL28B rs8099917 genotypes, cirrhosis, week-8 viral response (undetectable HCV RNA at treatment week 8) and complete early virological response (cEVR) predicted SVR. In week-8 viral response patients, the SVR rates of 72-week and 48-week treatment were similar (75-88%), regardless of IL28B SNP genotypes or cirrhosis. In non-week-8 viral response patients who achieved cEVR, the SVR rate of 72-week treatment was higher than that of 48-week treatment for non-cirrhotic patients, regardless of IL28B SNP genotypes (91-100% versus 13-44%; P=0.001). CONCLUSIONS: Although IL28B SNP genotypes predict SVR, they play a minor role when on-treatment viral responses are taken into consideration. On-treatment viral responses at weeks 8 and 12 are the key determinants to decide the optimal treatment duration in HCV-1 patients without RVR.

Transient elastography to assess hepatic fibrosis in hemodialysis chronic hepatitis C patients.

BACKGROUND AND OBJECTIVES: Although percutaneous liver biopsy (PLB) is the gold standard for staging hepatic fibrosis in hemodialysis patients with chronic hepatitis C (CHC) before renal transplantation or antiviral therapy, concerns exist about serious postbiopsy complications. Using transient elastography (TE, Fibroscan(®)) to predict the severity of hepatic fibrosis has not been prospectively evaluated in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 284 hemodialysis patients with CHC were enrolled. TE and aspartate aminotransferase-to-platelet ratio index (APRI) were performed before PLB. The severity of hepatic fibrosis was staged by METAVIR scores ranging from F0 to F4. Receiver operating characteristic curves were used to assess the diagnostic accuracy of TE and APRI, taking PLB as the reference standard. RESULTS: The areas under curves of TE were higher than those of APRI in predicting patients with significant hepatic fibrosis (≥F2) (0.96 versus 0.84, P<0.001), those with advanced hepatic fibrosis (≥F3) (0.98 versus 0.93, P=0.04), and those with cirrhosis (F4) (0.99 versus 0.92, P=0.13). Choosing optimized liver stiffness measurements of 5.3, 8.3, and 9.2 kPa had high sensitivity (93-100%) and specificity (88-99%), and 87, 97, and 93% of the patients with a fibrosis stage of ≥F2, ≥F3, and F4 were correctly diagnosed without PLB, respectively. CONCLUSIONS: TE is superior to APRI in assessing the severity of hepatic fibrosis and can substantially decrease the need of staging PLB in hemodialysis patients with CHC.