Conclusion:Male patients and those with a higher body weight were more likely to receive non-standard doses of RBV, likely reflecting the perception that this may lead to higher rates of SVR.The impact of higher RBV doses on relapse and SVR will be determined after ongoing follow-up in this study.

Treatment of chronic hepatitis C (CHC) with nitazoxanide (NTZ) and peginterferon (PegIFN) with or without ribavirin (RBV) improves sustained virologic response (SVR) rates in naïve genotype 4 patients (Gastroenterology 2009;136:856). The aim of this study was to determine the efficacy of NTZ plus PegIFN and RBV in naïve patients with CHC genotype 1 infection; the final sustained viral response (SVR) rates are reported.

Methods: Results from two Phase 1 studies were pooled for the analysis.Study 1 investigated the antiviral activity of oral filibuvir doses of 100, 300 and 450 mg BID and 300 mg TID or placebo, for 8 days in treatment naïve patients.In the second study, the antiviral activity of filibuvir 450 mg BID in treatment experienced patients dosed for 10 days and 700 mg BID in treatment naïve patients dosed for 3 days was evaluated.Filibuvir exposures achieved over 24 hours (AUC24) were utilized to inform the ER analysis of the maximum log change in viral load from baseline.The relationship was described by an inhibitory E max model using a non-linear mixed effects model.Effects of food, baseline viral load (BVL) and genotype (1a/1b) on relevant model parameters were also evaluated.The antiviral response for a range of doses was simulated from the model. Results:The ER data from 52 subjects were adequately described by the E max model with E max (95% CI) = -2.14(-2.54, -2.02) IU/ml and AUC24 50 (95% CI) = 54,176 (44,606, 102,006) ng•hr/ml.BVL was the only influential covariate which described the maximal response (E max ).The analysis indicated that doses in excess of 300 mg BID were expected to achieve atleast 70% of E max .Furthermore, filibuvir exposures resulting from doses greater than 600 mg BID produced responses close to E max indicating that higher doses (>600 mg BID) are unlikely to provide additional efficacy.Conclusions: Filibuvir exposures adequately described the maximum log change in viral load relative to baseline.The above analysis in conjunction with results from a Phase 2a study (200/300/500 mg BID+SOC, rapid viral response rates of 60-75%) suggests that filibuvir doses of 300 and 600 mg BID are expected to be efficacious when combined with SOC and will be further investigated in Phase 2b studies.

Background: HCV infection is a leading cause of liver transplantation and there is an urgent need to develop therapy to reduce rates of re-infection of transplanted livers.Methods: Using transgenic mice (HuMAb, Medarex), we have developed a fully human monoclonal antibody to a linear epitope of HCV E2 glycoprotein MBL-HCV1 that neutralizes pseudoviruses from multiple HCV genotypes.We then tested the ability of MBL-HCV1 to neutralize infectious, replication competent HCV in a cell culture assay using HCVcc 2a strain JFH1/J6.Concentrated cell culture supernatants of JFH1/J6 virions were pre-incubated with MBL-HCV1, applied to Huh 7.5 cells and HCV RNA infection measured by qRT-PCR.MBL-HCV1 completely neutralized HCVcc at concentrations as low as 0.15mg/ml.Based on these in vitro results, the ability of MBL-HCV1 to prevent HCV infection in uninfected chimpanzees was assessed.Three chimpanzees received a single dose of 0 mg/kg, 50 mg/kg or 250 mg/kg of MBL-HCV1 intravenously before challenge with 32 CID of HCV 1a strain H77.Animals were followed for 20 weeks with weekly PCR based viral loads [Lower Limit of Quantification (LLQ) = 500 Genomes/mL (Ge/mL)] as well as clinical and safety laboratory assessments.Results: Infusion of MBL-HCV1 was safe and well tolerated.No HCV RNA was detected in the serum of the 250 mg/kg dosed chimp through week 20.A subset of samples through day 56 was also measured in a transcription-mediated amplification assay (LLQ = 50 Ge/mL) and none of these tested positive.In contrast, the 0 mg/kg and 50 mg/kg dosed chimps both became infected by Day 14.To investigate the impact of MBL-HCV1 on viral clearance, the 0 mg/kg dosed chimp was administered 250 mg/kg of MBL-HCV1 at day 42 when viral load measured 1.0×10 5 Ge/mL.At day 49, the viral load was undetectable before rebounding at day 56 to 2.8×10 4 Ge/mL.Conclusions: These findings suggest that a human monoclonal antibody directed to a conserved epitope of HCV E2 glycoprotein neutralizes infectious, replication competent HCV and prevents infection in the chimpanzee model of HCV disease.A phase I study is planned.

Background: Previously, we analyzed VEGF, sVEGFR-2, sVEGFR-3, s-c-Kit, HGF, and Ras p21 to identify predictors of survival or clinical correlates of sorafenib treatment response (Llovet et al, AASLD 2008).Here we include angiopoietin-2 (Ang2), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and insulin-like growth factor-2 (IGF-2) to provide a final report on biomarkers correlating with outcome.Methods: Patients with advanced HCC (N=602) in the randomized SHARP trial received sorafenib 400 mg bid or placebo.ELISAs for biomarkers were performed on plasma samples at baseline and 12 weeks.Results: Biomarker data were available for ~81% and ~50% of patients at baseline and 12 weeks, respectively.High baseline Ang2 (>6061.1 pg/mL, median) was associated with shorter overall survival (OS) (HR=2.42,P < 0.0001) and time to progression (TTP) (HR=1.52,P=0.016) than low baseline Ang2.Upon multivariate analysis, VEGF and Ang2-in addition to ECOG performance status (PS), macrovascular invasion, AFP, and alkaline phosphatase-were independently associated with overall survival in the whole cohort of patients (VEGF, P=0.017; Ang2, P=0.002) as well as in those who received placebo (with the exception of ECOG PS; VEGF, P=0.002; Ang2, P=0.002).None of the baseline biomarkers were significantly associated with greater benefit, yet there was a trend toward enhanced OS benefit in patients with high c-Kit (P=0.081) or low IGF-2 (P=0.130) or low HGF (P=0.073).Changes in Ang2 levels at 12 weeks after treatment were significantly different in the sorafenib group (no changes from baseline) than in the placebo group (increased by 35.6%; P < 0.0001).Patients in both groups with increase in Ang2 at 12 weeks had shorter OS/TTP compared with those who did not (P 0.005, all comparisons).Patients in both groups who had a decrease in IGF-2 of at least 94.3 ng/mL (median) had shorter OS/TTP than those who did not (P < 0.03, all comparisons).Conclusions: Baseline VEGF and Ang2 emerge as independent predictors of survival in patients with HCC.A trend towards improved clinical benefit with sorafenib was identified in patients with high c-Kit, low IGF-2, and low HGF at baseline.Increase in Ang2 levels at 12 weeks in either group correlated with worse survival outcome.

BACKGROUND Patients infected with hepatitis C virus (HCV) genotype 2 or 3 have sustained virologic response rates of approximately 80% after receiving treatment with peginterferon and ribavirin for 24 weeks. We conducted a large, randomized, multinational, noninferiority trial to determine whether similar efficacy could be achieved with only 16 weeks of treatment with peginterferon alfa-2a and ribavirin. METHODS We randomly assigned 1469 patients with HCV genotype 2 or 3 to receive 180 mug of peginterferon alfa-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks. A sustained virologic response was defined as an undetectable serum HCV RNA level (<50 IU per milliliter) 24 weeks after the end of treatment. RESULTS The study failed to demonstrate that the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks (62% vs. 70%; odds ratio for 16 weeks vs. 24 weeks, 0.67; 95% confidence interval, 0.54 to 0.84; P<0.001). In addition, the rate of relapse (a detectable HCV RNA level during follow-up in patients who had undetectable HCV RNA at the end of treatment) was significantly greater in the 16-week group (31%, vs. 18% in the 24-week group; P<0.001). The sustained virologic response rates in patients with a pretreatment serum HCV RNA level of 400,000 IU per milliliter or less was 82% with the 16-week regimen and 81% with the 24-week regimen. Among patients with a rapid virologic response (an undetectable HCV RNA level by week 4), sustained virologic response rates were 79% in the 16-week group and 85% in the 24-week group (P=0.02). CONCLUSIONS Treatment with peginterferon and ribavirin for 16 weeks in patients infected with HCV genotype 2 or 3 results in a lower overall sustained virologic response rate than treatment with the standard 24-week regimen. (ClinicalTrials.gov number, NCT00077636 [ClinicalTrials.gov].).

A 64-year-old male renal transplant recipient developed rectal bleeding caused by a primary lymphoma of the colon, an unusual site for initial disease involvement. Renal transplant recipients may be at increased risk for the development of primary colonic lymphoma, a diagnosis that should be considered in transplant patients who develop abdominal pain, rectal bleeding, or intestinal perforation. The unique clinical features and special management considerations of colonic lymphoma in the renal transplant recipient are discussed.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. Correspondence to Emmet B. Keeffe, MD, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509, USA; e-mail: [email protected]