Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy.

BACKGROUND & AIMS: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy. METHODS: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT. RESULTS: A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5-80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival. CONCLUSIONS: In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy.

Prospective comparison of transient, point shear wave, and magnetic resonance elastography for staging liver fibrosis.

OBJECTIVES: To perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE). METHODS: This prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6 weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method. RESULTS: TE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85-0.93), 0.90 (95% CI 0.85-0.94), and 0.94 (95% CI 0.91-0.96). CONCLUSION: MRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis. TRIAL REGISTRATION: NCT02044523 KEY POINTS: • The technical failure rate was similar between MRE and US-based elastography techniques. • Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis. • MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.

Langerhans cell histiocytosis presenting as Crohn's disease: a case report.

PURPOSE: We describe an exceptional case of Langerhans cell histiocytosis (LCH) that presented as Crohn's disease and primary sclerosing cholangitis. METHODS: The patient's clinical, endoscopic, and histologic data from the Centre Hospitalier de l'Universite de Montreal were reviewed, as well as the literature on LCH involving the digestive tract and the liver, with a focus on the similarities with Crohn's disease and primary sclerosing cholangitis. RESULTS: A 39 years-old man first presented with anal fissures and deep punctiform colonic ulcers. Histologic assessment of colon biopsies showed chronic active colitis, consistent with Crohn's disease. Mild cholestasis and endoscopic retrograde cholangiopancreatography (ERCP) showing multiple intra and extrahepatic biliary tract strictures also led to a diagnosis of sclerosing cholangitis. Perianal disease progressed despite conventional treatment with antibiotics and infliximab. Subsequent discovery of non-Langerhans cutaneous xanthogranulomas and panhypopituitarism raised the suspicion of LCH, and a second review of colon biopsies ultimately led to the diagnosis, with the identification of Langerhans cells depicting elongated, irregular nuclei with nuclear grooves as well as immunohistochemical reactivity for S100, CD1a and vimentin. BRAF V600E mutation was detected afterwards by DNA sequencing of a bile duct sample. CONCLUSION: LCH may mimic inflammatory bowel disease (IBD) and must be suspected in the presence of other suggestive clinical signs, or when there is failure of conventional IBD treatment.

Cost-utility analysis of nonalcoholic steatohepatitis screening.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. No studies have examined the cost-effectiveness of screening its advanced form, nonalcoholic steatohepatitis (NASH). METHODS: We performed a cost-utility analysis of annual noninvasive screening strategies using third-party payer perspective in a general population in comparison to screening a high-risk obese or diabetic population. Screening algorithms involved well-studied techniques, including NAFLD fibrosis score, transient elastography (TE), and acoustic radiation force impulse (ARFI) imaging for detecting advanced fibrosis (≥ F3); and plasma cytokeratin (CK)-18 for NASH detection. Liver biopsy and magnetic resonance elastography (MRE) were compared as confirmation methods. Canadian dollar (CAD or C$) costs were adjusted for inflation and discounted at 5%. Incremental cost-effectiveness ratio (ICER) of ≤C$ 50,000 was considered cost-effective. RESULTS: Compared with no screening, screening with NAFLD fibrosis score/TE/CK-18 algorithm with MRE as confirmation for advanced fibrosis had an ICER of C$ 26,143 per quality-adjusted life year (QALY) gained. Screening in high-risk obese or diabetic populations was more cost-effective, with an ICER of C$ 9,051 and C$ 7,991 per quality-adjusted life-year (QALY) gained, respectively. Liver biopsy confirmation was not found to be cost-effective. CONCLUSIONS: Our model suggests that annual NASH screening in high-risk obese or diabetic populations can be cost-effective. KEY POINTS: • This cost-utility analysis suggests that screening for nonalcoholic steatohepatitis may be cost-effective. • In particular, screening of high-risk obese or diabetic populations is more cost-effective. • Magnetic resonance elastography was more cost-effective to confirm disease compared to biopsy. • More studies are needed to determine quality of life in nonalcoholic steatohepatitis. • More management strategies for nonalcoholic steatohepatitis are also needed.

Future treatment of patients with HCV cirrhosis.

Of all hepatitis C virus (HCV) patients, those with cirrhosis are most in need of treatment because of increased morbidity and mortality. Treatment with pegylated-interferon (PEG-IFN) and ribavirin (RBV) (PR) has definitely shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PR are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir was increased by 14% in patients with severe fibrosis or cirrhosis compared with PR. This benefit was lower than that observed in patients with mild or moderate fibrosis (30%). The SVR rate of the triple regimen with telaprevir was increased by 10-30% compared with PR in patients with severe fibrosis or cirrhosis compared with nearly 30% in patients with mild or moderate fibrosis. In treatment-experienced patients, previous relapsers have the highest increase in SVR with the triple regimen compared with PR, whatever the status of fibrosis. Previous partial or non-responder patients with cirrhosis had lower SVR rates than those without cirrhosis. However, the benefits of telaprevir and boceprevir vs PR was maintained. Previous non-responder patients with cirrhosis benefited the least from treatment. The relapse rate was always higher and side effects were more frequent in patients with cirrhosis compared with those without. First generation protease inhibitors plus PR appear to be a new step forward in the management of HCV genotype 1 patients with cirrhosis.

Impact of an Accelerated Pretreatment Evaluation on Linkage-to-Care for Hepatitis C-infected Persons Who Inject Drugs.

Background: Historically, hepatitis C virus (HCV) pretreatment evaluation has required multiple visits, frequently resulting in loss to follow-up and a delayed initiation of treatment. New technologies can accelerate this process. We investigated the feasibility of a single-day evaluation program and its impact on evaluation completion, treatment eligibility awareness, and treatment initiation among people who inject drugs (PWIDs). Methods: HCV-infected PWID who were unaware if they were eligible for treatment were recruited in a prospective evaluation of an accelerated model of care between 2017 and 2019 and compared to a historical cohort. The patients underwent a medical evaluation, rapid HCV viral load testing, and transient elastography during a single visit, at the end of which they were informed whether they were eligible for treatment. A historical cohort of patients fulfilling the same inclusion criteria and evaluated with the usual standard of care spanning several visits who were examined at the addiction medicine clinic from 2014 to 2016 served as the comparison group. Results: The accelerated and historical cohorts included 99 and 76 patients, respectively. The cohorts did not differ significantly by age and gender, but more patients in the historical cohort were undergoing opioid agonist therapy, while more patients in the accelerated cohort injected drugs in the last month. An accelerated evaluation resulted in a higher rate of evaluation completion (100% vs 67.1%; P < .001). Among those eligible for treatment, the proportion of those initiating treatment was similar between the groups (51/64 (79.7%) vs. 26/37 (70.3%); P = .28). The delay in the initiation of treatment was shorter in the accelerated cohort than in the historical cohort (69 (IQR: 49-106) days vs. 219 (IQR: 141-416) days; P < .001). Conclusions: Accelerated evaluation enhanced the awareness of eligibility and reduced the time to initiation among eligible patients. Trial Registration: This study is registered on www.clinicaltrials.gov (NCT02755402).

A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS: We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS: HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p<0.001). At the end of the trial, ALT levels normalized (≤35 IU/L) in 24.5% of patients treated with HD-UDCA and in 4.8% of patients who received placebo (p=0.003). Both results were not accounted for by changes in weight during the trial. HD-UDCA significantly reduced the FibroTest® serum fibrosis marker (p<0.001) compared with placebo. HD-UDCA also significantly improved markers of glycemic control and insulin resistance. There were no safety issues in this population. CONCLUSIONS: Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Studies with histologic end points are warranted.

[Management of hepatitis C among drug user patients]. / Prise en charge de l'hépatite C chez les patients utilisateurs de drogues.

Opiate substitution treatments radically changed the care management of HCV among drug user patients. Thanks to substitution, it is possible to treat HCV among these patients even with ongoing drug abuse. Overall, in terms of response to treatment, observance, adverse side effects and premature interruptions of treatment, the results are comparable with those observed among non drug addict patients. It is advisable nevertheless to create specific conditions which favour this total care management. The non-invasive fibrosis tests largely improve access to care as compared to liver biopsy. A multidisciplinary team is essential in addressing the associated problem of addiction, hepatitis C and psychiatric co-morbidities. HCV prevails strongly among patients in centres for drug users. These structures are particularly adapted to the management of HCV with the assistance of multidisciplinary teams and access to the non-invasive tests.

High dose daily interferon-alpha induction and secondary adjunction of ribavirin in treatment-naive patients with chronic hepatitis C. A multicentric, randomised, controlled trial.

OBJECTIVES: To evaluate in naive patients with chronic hepatitis C 1- the efficacy and safety of one month interferon alpha (IFN-alpha) induction regimen; 2- the potential virological benefit of a secondary adjunction of ribavirin among HCV RNA negative patients after 20 weeks of IFN therapy, with or without an initial 4-week IFN induction. MATERIAL AND METHODS: 151 naive HCV-RNA positive patients presenting with biopsy- proven chronic hepatitis C and elevated ALT were randomised in a 2: 1 ratio in two arms: IFN-alpha 3 MU thrice a week (tiw) for 24 weeks (non-induced patients); IFN-alpha 6 MU daily for two weeks, then 3 MU daily for two weeks then 3 MU tiw for 20 weeks (induced patients). At week 24, HCV-RNA negative patients were randomised to receive in addition or not ribavirin 1-1.2 g daily for 24 additional weeks. Induction efficacy was assessed on the early viral response (EVR) defined as undetectable HCV RNA at week 4 then week 20. Ribavirin efficacy was assessed on the proportion of maintained complete response until the end of follow-up, 24 weeks after discontinuation of treatment. Data were analysed on an intent-to-treat basis. RESULTS: Efficacy of IFN-alpha induction: 104 patients were randomised to the non-induction group, 47 to the induction group. Gender, age, genotype distribution and HCV viral load at baseline did not differ significantly between the two groups. There was one treatment discontinuation because of adverse events in induced patients versus four in non-induced patients (P > 0.05). The 4 week EVR was significantly greater in induced patients in patients with HCV genotype 1, 4 or 5 (47% vs 12%, P=0.0002) only. There was no impact of induction in patients with HCV genotype 2 or 3. Efficacy of ribavirin: at week 24, 28 and 26 HCV-RNA negative patients were randomised to addition of ribavirin or not, respectively. Patients randomised to secondary additive ribavirin were more often HCV-RNA negative at the end of follow-up than patients treated with IFN-alpha alone: 18/28 (64%) vs 10/26 (39%); P=0.06. Among patients randomised to bitherapy, the relapse rate was significantly lower in patients with genotype 2 or 3 (0/12 vs 6/13, P=0.01) and not in those with genotype 1, 4 or 5 (5/11 vs 3/6, P=0.99). CONCLUSION: A 4 week IFN-alpha induction significantly increases the EVR rate in patients with HCV genotype 1, 4 or 5. Late secondary adjunction of ribavirin to IFN-alpha for 6 months in HCV-RNA negative patients after 6 months of IFN-alpha significantly decreases the relapse rate in patients with HCV genotype 2 or 3, but not in patients with genotypes 1, 4 or 5.

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial.

OBJECTIVE: This study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin. RESEARCH DESIGN AND METHODS: Thirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 weeks. The liver proton density fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver volume, and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical analysis. RESULTS: Insulin treatment was associated with a significant improvement in glycated hemoglobin (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver volume (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % ⋅ mL, P = 0.01). Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver volume (P = 0.30), or the total liver fat index (P = 0.39). CONCLUSIONS: The administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group.

How did chronic hepatitis C impact costs related to hospital health care in France in 2009?

AIMS: To evaluate the health care burden of chronic hepatitis C (CHC) in French hospitals. METHODS: All hospital stays with CHC ICD-10 code were extracted from the 2009 French hospital discharge database and classified in five groups: non-complicated CHC, liver cirrhosis (CIR), hepatocarcinoma (HCC), liver transplantation (LT) and unclassified. Hospital costs were calculated according to the French official prices and expressed in 2010 euro. The economic analysis was carried out from the Social Security point of view. RESULTS: Twenty-seven thousand two hundred and fifty-eight of the 68,683 hospital stays with CHC ICD-10 code corresponding to 15,482 patients were considered as directly related to HCV: 52% for non-complicated CHC, 33% for CIR, 11% for HCC, 2% for LT and 2% unclassified. The total cost of hospital stays for CHC and its complications was estimated at 65,956,938 €. Almost half (47%) of total costs were attributable to CIR while HCC and LT contributed to 18% and 19%, respectively. CONCLUSION: This first analysis of the French hospital discharge database focused on CHC brings new and essential information. It shows that 84% of HCV-related hospital costs are attributable to advanced liver diseases. Together with more efficient therapies, enhancing screening and access to treatment policies could substantially relieve the hospital burden of CHC.

Impact of cytolysis following transarterial chemoembolization for hepatocellular carcinoma.

BACKGROUND AIMS: Transarterial chemoembolization (TACE) is increasingly used as a treatment of hepatocellular carcinoma. Cytolysis, which may occur within days following the procedure is due to either necrosis of the tumour or of the non-tumoral parenchyma. Therefore it may influence either tumour response or liver function or both. We evaluated the impact of cytolysis after TACE on tumour response, incidence of hepatobiliary complications and overall survival. METHODS: We conducted a retrospective analysis of 157 patients with liver disease who underwent 271 treatments for hepatocellular carcinoma. Cytolysis was defined as an increase of AST value above 100 IU/L with at least doubling of the baseline value. The associations between cytolysis and radiologic tumor response two months following each treatment and adverse hepatobiliary events were estimated using generalized estimating equations models. Comparison of 18 months survival after a first treatment of chemoembolization between the groups with and without cytolysis was performed using the proportional hazards model. RESULTS: Cytolysis occurred in 198 out of 271 cases and was associated with a favourable radiological response (OR 1.90, 1.03-3.54) at two months compared to non-cytolysis with no difference in the occurrence of adverse hepatobiliary events. The adjusted hazard ratio for overall survival was 1.33 times greater in the group with cytolysis compared to non-cytolysis (0.45-3.90). CONCLUSIONS: The occurrence of cytolysis was associated with a favorable radiological response, but had no impact on short-term adverse events and on survival at 18 months.

Chronic hepatitis C: treatments of the future.

The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance has, up to now, only been applicable to genotype-1 patients. Second-wave and second-generation PIs appear to achieve higher antiviral potency, with pan-genotype activities, fewer side-effects and potential activity against PI-resistant mutation by second-generation PIs, through more convenient daily administration. Other direct-acting antivirals (DAAs) include NS5B inhibitors such as nucleoside/nucleotide inhibitors (NIs) and non-nucleoside inhibitors (NNIs). NIs have similar efficacy across all genotypes and present with the highest barrier to resistance of all DAAs to date. PSI-7977, a pyrimidine nucleotide analogue, also has highly potent antiviral activity across all HCV genotypes. In combination with ribavirin in an interferon-free regimen, it can achieve a 100% sustained viral response (SVR) rate in genotype 2/3 treatment-naïve patients. In association with pegylated interferon and ribavirin (PR), it achieves an SVR of 91% in genotype-1 naïve patients. NNIs in association with PR appear to be less potent, but they may nonetheless play a key role in many of the combination trials including either PIs or NIs. NS5A inhibitors also exhibit highly potent antiviral activity. Evaluation of their activity in combination with PIs demonstrated for the first time that an interferon-free regimen can cure genotype-1b null-responder patients. Furthermore, quadruple therapy with PR can achieve a 100% SVR in genotype-1 null-responder patients. Other players in the field, such as cyclophilin inhibitors and therapeutic vaccines, may have a role in combination with DAAs. The near future of HCV treatment looks promising. However, whether or not DAA combinations will lead to an interferon-free regimen for all patients remains an open question.