Omar Massoud

Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C

BACKGROUND Asunaprevir is a selective NS3 protease inhibitor with in vitro activity against HCV genotypes 1 and 4. METHODS In this Phase IIa double-blind study, treatment-naive HCV genotype-1-infected patients in the United States and France were randomly assigned 1:1:1:1 to placebo or asunaprevir 200 mg twice daily, 600 mg twice daily or 600 mg once daily in combination with pegylated interferon (PEG-IFN)-α2a and ribavirin for 48 weeks. The primary efficacy end point was undetectable HCV RNA at weeks 4 and 12 (extended rapid virological response [eRVR]). Other end points included safety and undetectable HCV RNA at 24 weeks post-treatment (24-week sustained virological response [SVR24]). RESULTS A total of 47 patients were randomized and treated. eRVR was achieved by 75% (9/12), 75% (9/12) and 92% (11/12) of patients in the asunaprevir 200 mg twice-daily, 600 mg twice-daily and 600 mg once-daily groups, respectively, versus 0% (0/11) in the placebo group. Corresponding SVR24 rates were 83% (10/12), 83% (10/12) and 92% (11/12) in the asunaprevir groups and 46% (5/11) in the placebo group. There was no virological breakthrough in any asunaprevir group. Following the 12-week analysis, the 600 mg doses were reduced to 200 mg twice daily because of a greater frequency of transaminase elevations at the 600 mg dose. The most common grade 3-4 laboratory abnormalities were consistent with those reported for PEG-IFN and ribavirin. CONCLUSIONS Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies.

The use of Sirolimus should be restricted in liver transplantation

Sirolimus and mTOR inhibitors are important additions to the therapeutic armamentarium to prevent allograft rejection, but their role in liver transplantation is evolving. De novo use of Sirolimus in the early post-transplant period has undoubtedly been influenced by the high incidence of hepatic artery thrombosis and decreased patient and graft survival leading to a black box warning. The jury remains undecided on the role of conversion from CNIs to mTOR inhibitors in those developing renal insufficiency and it must be noted that a second warning was issued by the FDA because of decreased survival in those conversion studies. Finally, the anti-atherogenic, antiviral, and anti-neoplastic effects associated with Sirolimus, which might favor their use in certain liver transplant patients, need further evaluation before firm recommendations can be made.

Equivalent survival following liver transplantation in patients with non-alcoholic steatohepatitis compared with patients with other liver diseases

BACKGROUND Orthotopic liver transplantation (LT) in non-alcoholic steatohepatitis (NASH) is increasing in parallel with the obesity epidemic. METHODS This study retrospectively reviewed the clinical outcomes of LTs in NASH (n = 129) and non-NASH (n = 775) aetiologies carried out at a single centre between 1999 and 2009. RESULTS Rates of 1-, 3- and 5-year overall survival in NASH (90%, 88% and 85%, respectively) were comparable with those in non-NASH (92%, 86% and 80%, respectively) patients. Mortality within 4 months of LT was twice as high in NASH as in non-NASH patients (8.5% vs. 4.2%; P = 0.04). Compared with non-NASH patients, post-LT mortality in NASH patients was more commonly caused by infectious (38% vs. 26%; P < 0.05) or cardiac (19% vs. 7%; P < 0.05) aetiologies. Five-year survival was lower in NASH patients with a high-risk phenotype (age >60 years, body mass index >30 kg/m(2), with hypertension and diabetes) than in NASH patients without these characteristics (72% vs. 87%; P = 0.02). Subgroup analyses revealed that 5-year overall survival in NASH was equivalent to that in Laennecs cirrhosis (85% vs. 80%; P 0.87), but lower than that in cirrhosis of cryptogenic aetiology (85% vs. 96%; P = 0.04). CONCLUSIONS Orthotopic LT in NASH was associated with increased early postoperative mortality, but 1-, 3- and 5-year overall survival rates were equivalent to those in non-NASH patients.

Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: A proteomic signature validated by enzyme‐linked immunosorbent assay

The diagnosis of acute cellular rejection (ACR) requires liver biopsy with its attendant expense and risk. Our first aim was to prospectively determine in an exploratory analysis whether there is a serum proteome signature associated with histologically confirmed ACR. Our second aim was to use simpler and faster enzyme‐linked immunosorbent assay (ELISA)‐based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high‐abundance protein depletion and isobaric tag for relative and absolute quantitation liquid chromatography–tandem mass spectrometry to characterize the serum proteome in serum samples of patients with or without ACR. Seven of the 41 proteins identified as differentially abundant [serum amyloid A, complement component 4 (C4), fibrinogen, complement component 1q (C1q), complement component 3, heat shock protein 60 (HSP60), and HSP70] could be measured with ELISA‐based assays in a validation cohort consisting of patients with ACR (n = 25) and patients without ACR (n = 21). The mean alanine aminotransferase (ALT) levels in patients with ACR and in patients without ACR were 198 ± 27 and 153 ± 34 U/L, respectively. Among the 7 proteins for which ELISA assays were available, C4 and C1q were both independent predictors of ACR. C4 had the greatest predictivity for differentiating patients with or without ACR. A C4 level ≤ 0.31 g/L had a sensitivity of 97%, a specificity of 62%, a positive predictive value of 74%, and a negative predictive value of 94%. A C4 level ≤ 0.31 g/L and an ALT level ≥ 70 IU/mL together had a sensitivity of 96%, a specificity of 81%, a positive predictive value of 86%, and a negative predictive value of 94%. In summary, in this exploratory analysis, serum C4 and ALT levels were highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, and diverse population is needed. Liver Transpl 17:723‐732, 2011.

1195 BMS-650032, AN NS3 INHIBITOR, IN COMBINATION WITH PEGINTERFERON ALPHA-2A AND RIBAVIRIN IN TREATMENT-NAIVE SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION

3. PR plus BOC for 44 weeks (BOC/PR48). Primary endpoint was SVR 24 wks post-therapy (Roche TaqMan LLD = 9.3 IU/mL). Results: SVR was numerically higher in patients with G1a (66–73%) compared to G1b (59–64%) in the BOC arms of both studies. Similarly, the number of patients with RAVs was higher with G1a infection and the rate of detectable RAVs in all patients for whom RAV testing was performed was higher in G1a infected subjects in both studies (Table). Conclusions: BOC/PR therapy is associated with a small but consistently higher SVR rate and lower rate of development of RAVs in patients infected with G1b compared to G1a.

Hepatitis C Virus Antibody Positivity and Predictors Among Previously Undiagnosed Adult Primary Care Outpatients: Cross-Sectional Analysis of a Multisite Retrospective Cohort Study

BACKGROUND Hepatitis C virus (HCV) testing guidance issued by the Centers for Disease Control and Prevention in 1998 recommends HCV antibody (anti-HCV) testing for persons with specified risk factors. The purpose of this study was to determine the prevalence and predictors of anti-HCV positivity among primary care outpatients and estimate the proportion of unidentified anti-HCV-positive (anti-HCV+) persons using risk-based testing. METHODS We analyzed electronic medical record data from a 4-site retrospective study. Patients were aged ≥18 years, utilized ≥1 outpatient primary care service(s) between 2005 and 2010, and had no documented evidence of prior HCV diagnosis. Among persons tested for anti-HCV, we fit a multilevel logistic regression model to identify patient-level independent predictors of anti-HCV positivity. We estimated the proportion of unidentified anti-HCV+ persons by using multiple imputation to assign anti-HCV results to untested patients. RESULTS We observed 209 076 patients for a median of 5 months (interquartile range, 1-23 months). Among 17 464 (8.4%) patients who were tested for anti-HCV, 6.4% (n=1115) were positive. We identified history of injection drug use (adjusted odds ratio [95% confidence interval], 6.3 [5.2-7.6]), 1945-1965 birth cohort (4.4 [3.8-5.1]), and elevated alanine aminotransferase levels (4.8 [4.2-5.6]) as independently associated with anti-HCV positivity. We estimated that 81.5% (n=4890/6005) of anti-HCV+ patients were unidentified using risk-based testing. CONCLUSIONS In these outpatient primary care settings, risk-based testing may have missed 4 of 5 newly enrolled patients who are anti-HCV+. Without knowing their status, unidentified anti-HCV+ persons cannot receive further clinical evaluation or antiviral treatment, and are unlikely to benefit from secondary prevention recommendations to limit disease progression and mortality.

Uptake of hepatitis C screening, characteristics of patients tested, and intervention costs in the BEST-C study.

From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert [BPA], and patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard‐of‐care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity‐based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth‐Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945‐1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard‐of‐care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 [95% confidence interval (CI), 9.7–38.2] for repeated mailing, 13.2 [95% CI, 3.6–48.6] for BPA, and 32.9 [95% CI, 19.3–56.1] for patient solicitation). The BPA intervention had the lowest incremental cost per completed test (

Hepatitis C virus testing perspectives among primary care physicians in four large primary care settings.

24 with fixed startup costs,

Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization.

3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs (

Hepatitis C virus testing for case identification in persons born during 1945‐1965: Results from three randomized controlled trials

1691). Conclusion: HCV testing interventions resulted in an increase in BC testing compared with standard‐of‐care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44‐53).