Low alcohol consumption influences outcomes in individuals with alcohol-related compensated cirrhosis in a French multicenter cohort.

BACKGROUND & AIMS: The harmful impact of heavy alcohol consumption and recurrence in patients with alcohol-related cirrhosis is long-established, although this is based on old studies. However, the drivers of long-term outcome still need to be clearly investigated. METHOD: All patients with biopsy-proven compensated alcohol-related cirrhosis included in the CIRRAL cohort (22 centers) were prospectively studied. Prognostic variables of survival and liver event-free survival were assessed using multivariable Cox models with stepwise selection. The prognostic impact of alcohol recurrence during follow-up (computed in glass-years in the same way as pack-years for tobacco) was assessed using a time-dependent covariable. RESULTS: From 2010 to 2016, 650 patients were included. The median age at baseline was 58.4 years, 67.4% were men and the median BMI was 27.8 kg/m2, 63.8% had a history of liver decompensation, and 70.2% had discontinued alcohol. At 5 years, recurrence occurred in 30.9% of abstinent patients and this risk was higher in patients with a history of drug abuse and in those with shorter alcohol discontinuation times. Median survival was 97 months. Age, alcohol consumption at baseline, platelet count and Child-Pugh score >5 were associated with overall and liver event-free survival on multivariate analysis. Alcohol consumption of more than 25 glass-years during follow-up was independently associated with lower survival and with a trend toward lower liver event-free survival, with the risk increasing from 1 glass-year, though not significantly. Simon & Makuch plots confirm the benefit of no alcohol consumption (<1 glass/week) on both outcomes and the dose-dependent impact of alcohol over time. CONCLUSION: This prospective study in patients with compensated alcohol-related cirrhosis identifies factors predictive of alcohol recurrence during follow-up and shows that moderate alcohol consumption during follow-up negatively impacts outcomes. Patients with alcohol-related cirrhosis should be advised to completely stop drinking alcohol. REGISTRATION: CIRRAL (NCT01213927) cohort was registered at ClinicalTrials.gov and the full protocol is available at the following link: https://clinicaltrials.gov/ct2/show/NCT01213927. IMPACT AND IMPLICATIONS: In patients with alcohol-related cirrhosis, data are lacking about the impact of the amount of alcohol consumed on both survival and liver-related events. The present study based on the CIRRAL cohort demonstrates that alcohol recurrence occurs in more than 30% of patients with compensated cirrhosis and that even a moderate recurrence strongly influences outcomes. Patients with compensated alcohol-related cirrhosis should be advised to completely discontinue alcohol consumption, even in small amounts, as the present study shows that no alcohol consumption can be regarded as safe when cirrhosis has developed.

Phase 3, Multicenter Open-Label study to investigate the efficacy of elbasvir and grazoprevir fixed-dose combination for 8 weeks in treatment-naïve, HCV GT1b-infected patients, with non-severe fibrosis.

BACKGROUND: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis. METHODS: HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan® <9.5 kPa and Fibrotest®  < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12). FINDINGS: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan® , 100 had F0-1 fibrosis score. FIB-4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance-associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24. INTERPRETATION: Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks.

Direct comparison of the specialised blood fibrosis tests FibroMeterV2G and Enhanced Liver Fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres.

BACKGROUND: The Enhanced Liver Fibrosis score (ELF) and the FibroMeterV2G are two specialized blood fibrosis tests which include direct markers of liver fibrosis. They have been shown to be more accurate than the simple blood fibrosis tests FIB4 and the non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). AIMS: To directly compare the accuracies of ELF and FibroMeterV2G for the non-invasive diagnosis of liver fibrosis in NAFLD. METHODS: Four hundred and seventeen patients with biopsy-proven NAFLD were enrolled from two tertiary care centres. Four blood fibrosis tests were calculated: ELF, FibroMeterV2G , NFS, and FIB4. Advanced fibrosis F3/4 on liver biopsy (NASH CRN scoring) was the primary endpoint. RESULTS: Areas under the receiver operating characteristic (AUROC) curve for advanced fibrosis were not significantly different between the direct markers of liver fibrosis (hyaluronate, PIIINP, TIMP-1, alpha2-macroglobulin) and the simple blood fibrosis tests NFS and FIB4. ELF (0.793 ± 0.022) and FibroMeterV2G (0.804 ± 0.021) had significantly higher AUROC than NFS (0.722 ± 0.025, P < .010) and FIB4 (0.739 ± 0.024, P < .020). AUROC for advanced fibrosis and Obuchowski index were not significantly different between ELF and FibroMeterV2G . Algorithms using first ELF or FibroMeterV2G and then liver biopsy in case of undetermined diagnosis provided high diagnostic accuracy for advanced fibrosis: 90% sensitivity, 90% specificity, 93% negative predictive value, 85% positive predictive value, and 90% correct classification. In these algorithms, the rate of liver biopsy was 45.3% with ELF versus 39.3% with FibroMeterV2G (P = .065). CONCLUSIONS: ELF and FibroMeterV2G have equal accuracy and perform better than the simple FIB4 and NFS tests for the non-invasive diagnosis of advanced liver fibrosis in patients with NAFLD from tertiary care centres.

Liver Stiffness Measurement With FibroScan: Use the Right Probe in the Right Conditions!

INTRODUCTION: FibroScan's M and XL probes give significantly different results, which could lead to misevaluation of liver fibrosis if the correct probe is not chosen. According to the manufacturer, the M probe should be used when the skin-liver capsule distance (SCD) is <25 mm, and the XL probe should be used when SCD is ≥25 mm. We aimed at validating this recommendation and defining the conditions of use for FibroScan probes in clinical practice. METHODS: Four hundred thirty-nine patients with biopsy-proven chronic liver disease were included. Of them, 382 had successful examinations with both M and XL probes. Advanced fibrosis was defined as Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) F ≥3 or Metavir F ≥2. RESULTS: In a same patient, XL probe results were significantly lower than M probe results: 7.9 (5.6-11.7) vs 9.5 (6.7-14.6) kPa, respectively (P < 0.001). After matching for age, sex, liver fibrosis, and serum transaminases, M probe results in patients with SCD <25 mm and XL probe results in those with SCD ≥25 mm did not significantly differ: 8.8 (6.0-12.0) vs 9.1 (6.7-12.8) kPa, respectively (P = 0.175). Of note, 81.4% of patients with body mass index (BMI) <32 kg/m had SCD <25 mm, and 77.7% of patients with BMI ≥32 kg/m had SCD ≥25 mm. A practical algorithm using BMI first and then the FibroScan Automatic Probe Selection tool was proposed to help physicians accurately choose which probe to use in clinical practice. CONCLUSIONS: There is no significant difference in results between M and XL probes when they are used in the right conditions. In clinical practice, the probe should be selected according to the BMI and the Automatic Probe Selection tool.

Criteria to Determine Reliability of Noninvasive Assessment of Liver Fibrosis With Virtual Touch Quantification.

BACKGROUND & AIMS: Virtual Touch Quantification (VTQ) evaluates liver fibrosis in patients with chronic liver diseases by measuring shear wave speed in the liver. We aimed to determine the reliability criteria of VTQ examination. METHODS: We performed a prospective study of 1094 patients with chronic liver disease from November 2009 through October 2016 at Angers University Hospital, and between April 2010 and May 2015 at Bordeaux University Hospital, in France. All patients underwent liver biopsy analysis (reference standard), and VTQ examination was made by experienced operators on the same day, or no more than 3 months before or afterward. Advanced liver fibrosis was defined as fibrosis stage F ≥ 3 according to the scoring system of the Nonalcoholic Steatohepatitis Clinical Research Network, or fibrosis stage F ≥ 2 according to the Metavir scoring system. The diagnostic accuracy of VTQ in detection of advanced fibrosis or cirrhosis was assessed using the area under the receiver operating characteristic (AUROC) and the rate of correctly classified patients. Reliability criteria were defined from the intrinsic characteristics of VTQ examination, which were shown to influence the diagnostic accuracy. RESULTS: VTQ identified patients with advanced fibrosis with an AUROC of 0.773 ± 0.014 and correctly classified 72.0% of patients using a diagnostic cut-off value of 1.37 m/s. VTQ identified patients with cirrhosis with an AUROC value of 0.839 ± 0.014 and correctly classified 78.4% of patients using a cut-off value of 1.87 m/s. The reliability of VTQ decreased with an increasing ratio of interquartile range/median (IQR/M) in patients with intermediate-high VTQ results. We defined 3 reliability categories for VTQ: unreliable (IQR/M ≥0.35 with VTQ result ≥1.37 m/s), reliable (IQR/M ≥0.35 with VTQ result <1.37 m/s or IQR/M 0.15-0.34), and very reliable (IQR/M <0.15). For advanced fibrosis, VTQ correctly classified 57.8% of patients in the unreliable group, 73.7% of patients in the reliable group, and 80.9% of patients in the very reliable group (P < .001); for cirrhosis, these values were 50.0%, 83.4%, and 92.6%, respectively (P < .001). Of the VTQ examinations made, 21.4% were unreliable, 55.0% were reliable, and 23.6% were very reliable. The skin-liver capsule distance was independently associated with an unreliable VTQ examination, which occurred in 52.7% of patients with a distance of 30 mm or more. CONCLUSIONS: In a study to determine the reliability of VTQ findings, compared with results from biopsy analysis, we assigned VTQ examinations to 3 categories (unreliable, reliable, and very reliable). VTQ examinations with IQR/M ≥0.35 and ≥1.37 m/s had very low diagnostic accuracy. Our reliability criteria for liver fibrosis assessment with VTQ will help physicians to accurately evaluate the severity of chronic liver diseases and monitor their progression.

Doppler ultrasonography devices, including elastography, allow for accurate diagnosis of severe liver fibrosis.

OBJECTIVES: Advanced chronic liver disease is frequent yet largely underdiagnosed. Doppler-US is a common examination and we recently identified three simple Doppler-US signs associated with severe liver fibrosis. Recent Doppler-US devices include elastography modules, allowing for liver stiffness measurement (LSM). Our aim was to assess whether the use of elastography following positive simple Doppler-US signs improves the detection of severe liver fibrosis in a single Doppler-US examination. METHODS: 514 patients with chronic liver disease who consecutively underwent percutaneous liver biopsy were included in the study. All patients had a Doppler-US examination and LSM with Virtual Touch Quantification (VTQ) on the same day as a liver biopsy. A subset of 326 patients also had LSM with 2D shear wave elastography (SSI). Severe fibrosis was defined as Metavir F ≥ 3 on liver biopsy. RESULTS: Multivariate analysis confirmed our three simple Doppler-US signs (liver surface irregularity, splenomegaly ≥110 mm, and demodulation of hepatic veins) as independently associated with severe fibrosis. The presence of at least one of these three signs showed 85.6% sensitivity and 36.1% specificity for the diagnosis of severe liver fibrosis. Using VTQ (≥1.59 m/s) where there was a positive Doppler-US sign increased the specificity to 80.8%, at the cost of a decrease in sensitivity (73.7%). Similar results were obtained with SSI (≥9.5 kPa), with 73.3% specificity and 81.5% sensitivity. CONCLUSION: Elastography improves the accuracy of Doppler-US in the detection of severe fibrosis. This two-step procedure will help radiologists to accurately identify patients who need to be referred to specialist hepatologists during routine Doppler-US examinations.

Grazoprevir plus elbasvir in HCV genotype-1 or -4 infected patients with stage 4/5 severe chronic kidney disease is safe and effective.

Patients with advanced chronic kidney disease who receive direct-acting antiviral drugs require special consideration regarding comorbid conditions. Here we assessed the efficacy and safety of grazoprevir plus elbasvir in 93 patients infected with HCV genotype 1 or 4 and with advanced chronic kidney disease in a non-randomized, multicenter, nationwide observational survey. Twenty patients with HCV genotype 1a, 51 patients with 1b, four unclassified genotype 1, 17 with genotype 4 and one with genotype 6 received grazoprevir plus elbasvir (100/50 mg) once daily. All patients had severe chronic kidney disease with 70 patients stage G5, including patients on hemodialysis (74.2%), and 23 were stage G4 chronic kidney disease. Severe liver disease (Metavir F3/F4) was found in 33 patients. A sustained virologic response 12 weeks after the end of therapy was achieved in 87 of 90 patients. Two patients had a virologic breakthrough and one had a relapse after treatment withdrawal. Most patients received many concomitant medications (mean 7.7) related to comorbid conditions. Serious adverse events occurred in six patients, including three deaths while on grazoprevir plus elbasvir, not related to this therapy. Thus, once-daily grazoprevir plus elbasvir was highly effective with a low rate of adverse events in this advanced chronic kidney disease difficult-to-treat population with an HCV genotype 1 or 4 infection.

A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis.

Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis-stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi-FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeterV2G) with those of a test targeted for cirrhosis (CirrhoMeterV2G). In the derivation CHC population, we first compared Multi-FibroMeterV2G to FibroMeterV2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis-stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeterV2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi-FibroMeterV2G and FibroMeterV2G were the following: cirrhosis AUROC, 0.906 versus 0.878 (P < 0.001; versus CirroMeterV2G, 0.897, P = 0.014); Obuchowski index, 0.795 versus 0.791 (P = 0.059); classification, 86.0% versus 82.1% (P < 0.001); significant fibrosis AUROC, 0.833 versus 0.832 (P = 0.366). Multi-FibroMeterV2G had the highest correlation with the area of portoseptal fibrosis and the highest reproducibility over time. Correct classification rates of Multi-FibroMeter with hyaluronate (V2G, 86.0%) or without (V3G, 86.1%) did not differ (P = 0.938). Conclusion: Multitargeting biomarkers significantly improves fibrosis staging and especially cirrhosis diagnosis compared to classical single-targeted blood tests. (Hepatology Communications 2018;2:455-466).

Fibrosis assessment using FibroMeter combined to first generation tests in hepatitis C.

AIM: To evaluate the performance of FibroMeterVirus3G combined to the first generation tests aspartate aminotransferase-to-platelet ratio index (APRI) or Forns index to assess significant fibrosis in chronic hepatitis C (CHC). METHODS: First generation tests APRI or Forns were initially applied in a derivation population from Rio de Janeiro in Brazil considering cut-offs previously reported in the literature to evaluate significant fibrosis. FibroMeterVirus3G was sequentially applied to unclassified cases from APRI or Forns. Accuracy of non-invasive combination of tests, APRI plus FibroMeterVirus3G and Forns plus FibroMeterVirus3G was evaluated in the Brazilian derivation population. APRI plus FibroMeterVirus3G combination was validated in a population of CHC patients from Angers in France. All patients were submitted to liver biopsy staged according to METAVIR score by experienced hepatopathologists. Significant fibrosis was considered as METAVIR F ≥ 2. The fibrosis stage classification was used as the reference for accuracy evaluation of non-invasive combination of tests. Blood samples for the calculation of serum tests were collected on the same day of biopsy procedure or within a maximum 3 mo interval and stored at -70 °C. RESULTS: Seven hundred and sixty CHC patients were included (222 in the derivation population and 538 in the validation group). In the derivation population, the FibroMeterVirus3G AUROC was similar to APRI AUROC (0.855 vs 0.815, P = 0.06) but higher than Forns AUROC (0.769, P < 0.001). The best FibroMeterVirus3G cut-off to discriminate significant fibrosis was 0.61 (80% diagnostic accuracy; 75% in the validation population, P = 0.134). The sequential combination of APRI or Forns with FibroMeterVirus3G in derivation population presented similar performance compared to FibroMeterVirus3G used alone (79% vs 78% vs 80%, respectively, P = 0.791). Unclassified cases of significant fibrosis after applying APRI and Forns corresponded to 49% and 54%, respectively, of the total sample. However, the combination of APRI or Forns with FibroMeterVirus3G allowed 73% and 77%, respectively, of these unclassified cases to be correctly evaluated. Moreover, this combination resulted in a reduction of FibroMeterVirus3G requirement in approximately 50% of the entire sample. The stepwise combination of APRI and FibroMeterVirus3G applied to the validation population correctly identified 74% of patients with severe fibrosis (F ≥ 3). CONCLUSION: The stepwise combination of APRI or Forns with FibroMeterVirus3G may represent an accurate lower cost alternative when evaluating significant fibrosis, with no need for liver biopsy.

A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis.

BACKGROUND & AIMS: Chronic liver diseases (CLD) are common, and are therefore mainly managed by non-hepatologists. These physicians lack access to the best non-invasive tests of liver fibrosis, and consequently cannot accurately determine the disease severity. Referral to a hepatologist is then needed. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. METHODS: Diagnostic study: 3754 CLD patients with liver biopsy were 2:1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1275 CLD patients with baseline fibrosis tests. RESULTS: Diagnostic study: the easy liver fibrosis test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gamma-glutamyl transferase, aspartate aminotransferase (AST), platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and fibrosis-4 (FIB4) had the same sensitivity (78.0% vs. 76.6%, p=0.470) but eLIFT gave fewer false positive results, especially in patients ≥60years old (53.8% vs. 82.0%, p<0.001), and was thus more suitable as screening test. FibroMeter with vibration controlled transient elastography (VCTE) was the most accurate among the eight fibrosis tests evaluated. The sensitivity of the eLIFT-FMVCTE algorithm (first-line eLIFT, second-line FibroMeterVCTE) was 76.1% for advanced fibrosis and 92.1% for cirrhosis. Prognostic study: patients diagnosed as having "no/mild fibrosis" by the algorithm had excellent liver-related prognosis with thus no need for referral to a hepatologist. CONCLUSION: The eLIFT-FMVCTE algorithm extends the detection of advanced liver fibrosis to all CLD patients and reduces unnecessary referrals of patients without significant CLD to hepatologists. LAY SUMMARY: Blood fibrosis tests and transient elastography accurately diagnose advanced liver fibrosis in the large population of patients having chronic liver disease, but these non-invasive tests are only currently available in specialized centers. We have developed an algorithm including the easy liver fibrosis test (eLIFT), a new simple and widely available blood test. It is used as a first-line procedure that selects at-risk patients who need further evaluation with the FibroMeterVCTE, an accurate fibrosis test combining blood markers and transient elastography result. This new algorithm, called the eLIFT-FMVCTE, accurately identifies the patients with advanced chronic liver disease who need referral to a specialist, and those with no or mild liver lesions who can remain under the care of their usual physician. CLINICAL TRIAL REGISTRATION: No registration (analysis of pooled data from previously published diagnostic studies).

Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients.

BACKGROUND & AIMS: We report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. METHODS: The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER "Therapeutic options for hepatitis B and C: A French cohort" is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18). RESULTS: A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054). CONCLUSION: The sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. LAY SUMMARY: The sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.

Prognostic durability of liver fibrosis tests and improvement in predictive performance for mortality by combining tests.

BACKGROUND AND AIM: There is currently no recommended time interval between noninvasive fibrosis measurements for monitoring chronic liver diseases. We determined how long a single liver fibrosis evaluation may accurately predict mortality, and assessed whether combining tests improves prognostic performance. METHODS: We included 1559 patients with chronic liver disease and available baseline liver stiffness measurement (LSM) by Fibroscan, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, Hepascore, and FibroMeterV2G . RESULTS: Median follow-up was 2.8 years during which 262 (16.8%) patients died, with 115 liver-related deaths. All fibrosis tests were able to predict mortality, although APRI (and FIB-4 for liver-related mortality) showed lower overall discriminative ability than the other tests (differences in Harrell's C-index: P < 0.050). According to time-dependent AUROCs, the time period with optimal predictive performance was 2-3 years in patients with no/mild fibrosis, 1 year in patients with significant fibrosis, and <6 months in cirrhotic patients even in those with a model of end-stage liver disease (MELD) score <15. Patients were then randomly split in training/testing sets. In the training set, blood tests and LSM were independent predictors of all-cause mortality. The best-fit multivariate model included age, sex, LSM, and FibroMeterV2G with C-index = 0.834 (95% confidence interval, 0.803-0.862). The prognostic model for liver-related mortality included the same covariates with C-index = 0.868 (0.831-0.902). In the testing set, the multivariate models had higher prognostic accuracy than FibroMeterV2G or LSM alone for all-cause mortality and FibroMeterV2G alone for liver-related mortality. CONCLUSIONS: The prognostic durability of a single baseline fibrosis evaluation depends on the liver fibrosis level. Combining LSM with a blood fibrosis test improves mortality risk assessment.

Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: NAFLD is highly prevalent but only a small subset of patients develop advanced liver fibrosis with impaired liver-related prognosis. We aimed to compare blood fibrosis tests and liver stiffness measurement (LSM) by FibroScan for the diagnosis of liver fibrosis and the evaluation of prognosis in NAFLD. METHODS: Diagnostic accuracy was evaluated in a cross-sectional study including 452 NAFLD patients with liver biopsy (NASH-CRN fibrosis stage), LSM, and eight blood fibrosis tests (BARD, NAFLD fibrosis score, FibroMeter(NAFLD), aspartate aminotransferase to platelet ratio index (APRI), FIB4, FibroTest, Hepascore, FibroMeter(V2G)). Prognostic accuracy was evaluated in a longitudinal study including 360 NAFLD patients. RESULTS: LSM and FibroMeter(V2G) were the two best-performing tests in the cross-sectional study: AUROCs for advanced fibrosis (F3/4) were, respectively, 0.831±0.019 and 0.817±0.020 (p⩽0.041 vs. other tests); rates of patients with ⩾90% negative/positive predictive values for F3/4 were 56.4% and 46.7% (p<0.001 vs. other tests); Obuchowski indexes were 0.834±0.014 and 0.798±0.016 (p⩽0.036 vs. other tests). Two fibrosis classifications were developed to precisely estimate the histological fibrosis stage from LSM or FibroMeter(V2G) results without liver biopsy (diagnostic accuracy, respectively: 80.8% vs. 77.4%, p=0.190). Kaplan-Meier curves in the longitudinal study showed that both classifications categorised NAFLD patients into subgroups with significantly different prognoses (p<0.001): the higher was the class of the fibrosis classification, the worse was the prognosis. CONCLUSIONS: LSM and FibroMeter(V2G) were the most accurate of nine evaluated tests for the non-invasive diagnosis of liver fibrosis in NAFLD. LSM and FibroMeter(V2G) fibrosis classifications help physicians estimate both fibrosis stage and patient prognosis in clinical practice. LAY SUMMARY: The amount of liver fibrosis is the main determinant of the liver-related prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated eight blood tests and FibroScan in a cross-sectional diagnostic study and found that FibroScan and the blood test FibroMeter(V2G) were the two most accurate tests for the non-invasive evaluation of liver fibrosis in NAFLD. A longitudinal prognostic study showed these two tests initially developed for the diagnosis are also prognostic markers as they allow for the stratification of NAFLD patients in several subgroups with significantly different prognosis.

Radiofrequency ablation of hepatocellular carcinoma: Mono or multipolar?

BACKGROUND AND AIMS: Thermo-ablation by radiofrequency is recognized as a curative treatment for early-stage hepatocellular carcinoma. However, local recurrence may occur because of incomplete peripheral tumor destruction. Multipolar radiofrequency has been developed to increase the size of the maximal ablation zone. We aimed to compare the efficacy of monopolar and multipolar radiofrequency for the treatment of hepatocellular carcinoma and determine factors predicting failure. METHODS: A total of 171 consecutive patients with 214 hepatocellular carcinomas were retrospectively included. One hundred fifty-eight tumors were treated with an expandable monopolar electrode and 56 with a multipolar technique using several linear bipolar electrodes. Imaging studies at 6 weeks after treatment, then every 3 months, assessed local effectiveness. Radiofrequency failure was defined as persistent residual tumor after two sessions (primary radiofrequency failure) or local tumor recurrence during follow-up. This study received institutional review board approval (number 2014/77). RESULTS: Imaging showed complete tumor ablation in 207 of 214 lesions after the first session of radiofrequency. After a second session, only two cases of residual viable tumor were observed. During follow-up, there were 46 local tumor recurrences. Thus, radiofrequency failure occurred in 48/214 (22.4%) cases. By multivariate analysis, technique (P < 0.001) and tumor size (P = 0.023) were independent predictors of radiofrequency failure. Failure rate was lower with the multipolar technique for tumors < 25 mm (P = 0.023) and for tumors between 25 and 45 mm (P = 0.082). There was no difference for tumors ≥ 45 mm (P = 0.552). CONCLUSIONS: Compared to monopolar radiofrequency, multipolar radiofrequency improves tumor ablation with a subsequent lower rate of local tumor recurrence.

Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis (≥F2) (P = 0.004). Clinical factors related to obesity such as body mass index ≥ 30 kg/m(2) , waist circumference ≥102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R = 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4. CONCLUSION: Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (Hepatology 2016;63:1817-1827).

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon α-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.

Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C.

BACKGROUND: Liver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology. METHODS: 650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis. RESULTS: The relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area ≥4.0 % induced a 50 % increase in LSE result in patients with fibrosis area <9 %. In patients with IQR/LSE median ≤0.30, the rate of F0/1 patients misclassified as F ≥ 2 by Fibroscan was, respectively for steatosis area <4.0 and ≥4.0 %: 12.6 vs 32.4 % (p = 0.003). Steatosis level did not influence LSE median when fibrosis area was ≥9 %, and consequently did not increase the rate of F ≤ 3 patients misclassified as cirrhotic. CONCLUSION: A precise evaluation of liver histology by computerized morphometry shows that liver stiffness measured by Fibroscan is linked to liver fibrosis, activity, and also steatosis. High level of steatosis induces misevaluation of liver fibrosis by Fibroscan.

Determination of reliability criteria for liver stiffness evaluation by transient elastography.

UNLABELLED: Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% versus 81.5% well-classified patients for the diagnosis of cirrhosis (P = 0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of ≥10 valid measurements or LSE success rate. These two reliability criteria determined three LSE groups: "very reliable" (IQR/M ≤0.10), "reliable" (0.10< IQR/M ≤0.30, or IQR/M >0.30 with LSE median <7.1 kPa), and "poorly reliable" (IQR/M >0.30 with LSE median ≥7.1 kPa). The rates of well-classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (P < 10(-3) ). According to these new reliability criteria, 9.1% of LSE were poorly reliable (versus 24.3% unreliable LSE with the usual definition, P < 10(-3) ), 74.3% were reliable, and 16.6% were very reliable. CONCLUSION: The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: very reliable, reliable, and poorly reliable LSE. (HEPATOLOGY 2013).

Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive.

UNLABELLED: The sequential algorithm for fibrosis evaluation (SAFE) and the Bordeaux algorithm (BA), which cross-check FibroTest with the aspartate aminotransferase-to-platelet ratio index (APRI) or FibroScan, are very accurate but provide only a binary diagnosis of significant fibrosis (SAFE or BA for Metavir F ≥ 2) or cirrhosis (SAFE or BA for F4). Therefore, in clinical practice, physicians have to apply the algorithm for F ≥ 2, and then, when needed, the algorithm for F4 ("successive algorithms"). We aimed to evaluate successive SAFE, successive BA, and a new, noninvasive, detailed classification of fibrosis. The study included 1785 patients with chronic hepatitis C, liver biopsy, blood fibrosis tests, and FibroScan (the latter in 729 patients). The most accurate synchronous combination of FibroScan with a blood test (FibroMeter) provided a new detailed (six classes) classification (FM+FS). Successive SAFE had a significantly (P < 10(-3) ) lower diagnostic accuracy (87.3%) than individual SAFE for F ≥ 2 (94.6%) or SAFE for F4 (89.5%), and required significantly more biopsies (70.8% versus 64.0% or 6.4%, respectively, P < 10(-3) ). Similarly, successive BA had significantly (P ≤ 10(-3) ) lower diagnostic accuracy (84.7%) than individual BA for F ≥ 2 (88.3%) or BA for F4 (94.2%), and required significantly more biopsies (49.8% versus 34.6% or 24.6%, respectively, P < 10(-3) ). The diagnostic accuracy of the FM+FS classification (86.7%) was not significantly different from those of successive SAFE or BA. However, this new classification required no biopsy. CONCLUSION: SAFE and BA for significant fibrosis or cirrhosis are very accurate. However, their successive use induces a significant decrease in diagnostic accuracy and a significant increase in required liver biopsy. A new fibrosis classification that synchronously combines two fibrosis tests was as accurate as successive SAFE or BA, while providing an entirely noninvasive (0% liver biopsy) and more precise (six versus two or three fibrosis classes) fibrosis diagnosis.

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.

BACKGROUND & AIMS: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.