Sd Ryder

Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers

The detection of fibrosis within nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis and the stratification of patients for emerging therapeutic intervention. We validated the Original European Liver Fibrosis panel (OELF) and a simplified algorithm not containing age, the Enhanced Liver fibrosis panel (ELF), in an independent cohort of patients with NAFLD. Furthermore, we explored whether the addition of simple markers to the existing panel test could improve diagnostic performance. One hundred ninety‐six consecutively recruited patients from 2 centers were included in the validation study. The diagnostic accuracy of the discriminant scores of the ELF panel, simple markers, and a combined panel were compared using receiver operator curves, predictive values, and a clinical utility model. The ELF panel had an area under the curve (AUC) of 0.90 for distinguishing severe fibrosis, 0.82 for moderate fibrosis, and 0.76 for no fibrosis. Simplification of the algorithm by removing age did not alter diagnostic performance. Addition of simple markers to the panel improved diagnostic performance with AUCs of 0.98, 0.93, and 0.84 for the detection of severe fibrosis, moderate fibrosis, and no fibrosis, respectively. The clinical utility model showed that 82% and 88% of liver biopsies could be potentially avoided for the diagnosis of severe fibrosis using ELF and the combined panel, respectively. The ELF panel has good diagnostic accuracy in an independent validation cohort of patients with NAFLD. The addition of established simple markers augments the diagnostic performance across different stages of fibrosis, which will potentially allow superior stratification of patients with NAFLD for emerging therapeutic strategies. (HEPATOLOGY 2007.)

UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients

The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment‐naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side‐effects and costs.

Surveillance of cirrhosis for hepatocellular carcinoma: a cost–utility analysis

Using a decision-analytic model, we evaluated the effectiveness and cost-effectiveness of surveillance for hepatocellular carcinoma (HCC) in individuals with cirrhosis. Separate cohorts with cirrhosis due to alcoholic liver disease, hepatitis B and hepatitis C were simulated. Results were also combined to approximate a mixed aetiology population. Comparisons were made between a variety of surveillance algorithms using α-foetoprotein (AFP) assay and/or ultrasound at 6- and 12-monthly intervals. Parameter estimates were obtained from comprehensive literature reviews. Uncertainty was explored using one-way and probabilistic sensitivity analyses. In the mixed aetiology cohort, 6-monthly AFP+ultrasound was predicted to be the most effective strategy. The model estimates that, compared with no surveillance, this strategy may triple the number of people with operable tumours at diagnosis and almost halve the number of people who die from HCC. The cheapest strategy employed triage with annual AFP (incremental cost-effectiveness ratio (ICER): £20 700 per quality-adjusted life-year (QALY) gained). At a willingness-to-pay threshold of £30 000 per QALY the most cost-effective strategy used triage with 6-monthly AFP (ICER: £27 600 per QALY gained). The addition of ultrasound to this strategy increased the ICER to £60 100 per QALY gained. Surveillance appears most cost-effective in individuals with hepatitis B-related cirrhosis, potentially due to younger age at diagnosis of cirrhosis. Our results suggest that, in a UK NHS context, surveillance of individuals with cirrhosis for HCC should be considered effective and cost-effective. The economic efficiency of different surveillance strategies is predicted to vary markedly according to cirrhosis aetiology.

HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact.

Hepatitis C virus (HCV) antiviral treatment for people who inject drugs (PWID) could prevent onwards transmission and reduce chronic prevalence. We assessed current PWID treatment rates in seven UK settings and projected the potential impact of current and scaled‐up treatment on HCV chronic prevalence. Data on number of PWID treated and sustained viral response rates (SVR) were collected from seven UK settings: Bristol (37–48% HCV chronic prevalence among PWID), East London (37–48%), Manchester (48–56%), Nottingham (37–44%), Plymouth (30–37%), Dundee (20–27%) and North Wales (27–33%). A model of HCV transmission among PWID projected the 10‐year impact of (i) current treatment rates and SVR (ii) scale‐up with interferon‐free direct acting antivirals (IFN‐free DAAs) with 90% SVR. Treatment rates varied from <5 to over 25 per 1000 PWID. Pooled intention‐to‐treat SVR for PWID were 45% genotypes 1/4 [95%CI 33–57%] and 61% genotypes 2/3 [95%CI 47–76%]. Projections of chronic HCV prevalence among PWID after 10 years of current levels of treatment overlapped substantially with current HCV prevalence estimates. Scaling‐up treatment to 26/1000 PWID annually (achieved already in two sites) with IFN‐free DAAs could achieve an observable absolute reduction in HCV chronic prevalence of at least 15% among PWID in all sites and greater than a halving in chronic HCV in Plymouth, Dundee and North Wales within a decade. Current treatment rates among PWID are unlikely to achieve observable reductions in HCV chronic prevalence over the next 10 years. Achievable scale‐up, however, could lead to substantial reductions in HCV chronic prevalence.

Review article: 2014 UK consensus guidelines – hepatitis C management and direct‐acting anti‐viral therapy

Therapeutic options for the management of hepatitis C virus (HCV) infection have evolved rapidly over the past two decades, with a consequent improvement in cure rates. Novel therapeutic agents are an area of great interest in the research community, with a number of these agents showing promise in the clinical setting.

Prediction of liver disease in patients whose liver function tests have been checked in primary care: model development and validation using population-based observational cohorts

Objective To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. Design Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. Setting Primary care, Tayside, Scotland. Participants Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. Primary and secondary outcome measures Diagnosis of a liver condition within 2 years. Results From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20–30% for high-risk patients. Conclusions This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk.

Prevention of progression to cirrhosis in hepatitis C with fibrosis: effectiveness and cost effectiveness of sequential therapy with new direct‐acting anti‐virals

The new direct‐acting anti‐virals (DAAs) for hepatitis C virus (HCV) infection offer higher cure rates, but at a much higher cost than the standard interferon‐based treatments.

P790 REDUCING THE DISEASE BURDEN OF CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IN ENGLAND

Background and Aims: Several miRNAs have been described to finely regulate lipid metabolism including, miR-33, miR-122. miR33a represents one of the most interesting and attractive targets for metabolic-related. The identification of ABCA1 and NPC1 as miR-33 target genes leads to the hypothesis that miR-33 may be regulating high-density lipoproteins (HDL) levels in vivo. The hepatitis C virus (HCV) requires elements of host lipid metabolism to replicate. Our purpose was measure hepatic levels of miR-33a, miR-122 and miR33a target genes in HCV infection. Methods: Liver biopsies from 62 treatment-naive patients with chronic Hepatitis C were included (48 infected by HCV-1 and 14 infected by HCV-3). After isolation of total RNA, a miRNA expression assay was performed to detect expression. At the same time, a gene expression assays were performed to investigate mRNA expression changes in miRNA target genes (NPC1, ABCA-1 and CPT1). Results: In patients infected by HCV-3, a positive correlation was found between hepatic miR-33a expression and serum cholesterol (p = 0.0306; r = 0.5548). In addition, miR-33a expression also was correlated to NPC1 gene expression (p =0.0439; r = 0.5134). A significant negative correlation between hepatic NPC1 and CPT1 expression and the levels of serum APO-E was observed in HCV-1 infection (p =0.0076; r = −0.3805 and p=0.0242; r = −0.3250, respectively). Conclusions: HCV infection leads to the expression of genes involved in biosynthesis and transport of lipids, creating a favorable environment for virus replication. A better understanding of the mechanisms that underlie miR-33-mediated coupled with improvements in drug delivery technology, will definitely enable miR-33-mediated therapy to open a new area.

1076 DIRECT SERUM MARKERS ARE MORE ACCURATE THAN SIMPLE MARKER PANELS FOR THE DETECTION OF FIBROSIS IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Introduction The identification of fibrosis in patients with NAFLD is important for ascertaining prognosis and stratifying patients for emerging therapeutic interventions. Use of both direct marker panels (liver matrix components) and indirect marker panels (simple biochemical tests) have been described for the detection of fibrosis in NAFLD. The aim of this study was to compare the performance of direct and indirect serum marker panels in the detection of fibrosis in NAFLD as compared with liver biopsy. Methods From two centres, 177 patients were recruited and underwent percutaneous liver biopsy. Fibrosis staging was assessed using Kleiner criteria by two senior liver-histopathologists. Serum at the time of biopsy was used to calculate six indirect marker panels of fibrosis (APRI, BAAT, BARD, Cirrhosis discriminate score, NAFLD fibrosis index and Fib4). These panels were compared with the ELF Test (HA, TIMP1, PIIINP) and HA alone. Diagnostic accuracy was assessed using receiver operating characteristic curves which were compared using the method of DeLong. Results The distribution of fibrosis stages in the cohort were as follows: F0 39.5% (n=70), F1 19.2% (n=34), F2 17.5% (n=31), F3 13.6% (n=24), F4 10.2% (n=18). While ELF and HA alone had the best performance overall, the ELF test was better than HA in its ability to discriminate minimal fibrosis (p=0.02) and cirrhosis (p=0.06). All indirect serum markers tested had significantly worse performance than ELF in the detection of cirrhosis (p Conclusion In patients with NAFLD, direct serum marker panels have superior performance compared to indirect marker panels allowing superior stratification and prognostication. The performance of HA alone is enhanced by the addition of PIIINP and TIMP1. Competing interests None declared.