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).