Quantitative Evaluation by Digital Pathology of Immunohistochemical Expression of CK7, CK19, and EpCAM in Advanced Stages of NASH.

(1) Background: Nonalcoholic Steatohepatitis/Nonalcoholic Fatty Liver Disease (NASH/NAFLD) is the most recurrent chronic liver disease. NASH could present with a cholestatic (C) or hepatic (H) pattern of damage. Recently, we observed that increased Epithelial Cell Adhesion Molecule (EpCAM) expression was the main immunohistochemical feature to distinguish C from H pattern in NASH. (2) Methods: In the present study, we used digital pathology to compare the quantitative results of digital image analysis by QuPath software (Q-results), with the semi-quantitative results of observer assessment (S-results) for cytokeratin 7 and 19, (CK7, CK19) as well as EpCAM expression. Patients were classified into H or C group on the basis of the ratio between alanine transaminase (ALT) and alkaline phosphatase (ALP) values, using the "R-ratio formula". (3) Results: Q- and S-results showed a significant correlation for all markers (p < 0.05). Q-EpCAM expression was significantly higher in the C group than in the H group (p < 0.05). Importantly ALP, an indicator of hepatobiliary disorder, was the only biochemical parameter significantly correlated with Q-EpCAM. Instead, Q-CK7, but not Q-CK19, correlated only with γGlutamyl-Transferase (γGT). Of note, Stage 4 fibrosis correlated with Q-EpCAM, Q-CK19, and ALP but not with γGT or ALT. Conclusions: Image analysis confirms the relation between cholestatic-like pattern, associated with a worse prognosis, with increased ALP values, EpCAM positive biliary metaplasia, and advanced fibrosis. These preliminary data could be useful for the implementation of AI algorithms for the assessment of cholestatic NASH.

Depth effect on point shear wave velocity elastography: Evidence in a chronic hepatitis C patient cohort.

Background and Aims: This study investigated the depth-related bias and the influence of scan plane angle on performance of point-shear-wave elastometry in a chronic hepatitis C patient cohort. Materials and Methods: We included 104 patients affected by chronic liver disease related to the hepatitis C virus. Liver surface nodularity was the reference to diagnose cirrhosis. The ultrasound platform was the Siemens S2000, equipped with point-shear-wave elastometry software. Measurements were obtained in left lateral decubitus from the liver surface to the maximum depth of 8 cm in two orthogonal scan planes according to a standard sampling plane. Scatterplot and box plots explored the depth-related bias graphically. The area under the receiver operating characteristic was used to determine the point-shear-wave elastometry diagnostic performance at progressive depths according to liver surface nodularity. Results: Of the 104 patients, 68 were cirrhotics. Depth-related bias equally modified point-shear-wave elastometry in the two orthogonal scan planes. A better point-shear-wave elastometry diagnostic performance was observed between depths of 4 and 5 cm. The frontal scan plane assured better discrimination between cirrhotic patients and non-cirrhotic patients. Conclusion: Depth is crucial for point-shear-wave elastometry performance. Excellent diagnostic performance at a depth between 4 and 5 cm can also be obtained with a smaller number of measurements than previously recommended.

Predicting de-novo portal vein thrombosis after HCV eradication: A long-term competing risk analysis in the ongoing PITER cohort.

BACKGROUND & AIMS: Sustained virological response (SVR) by direct-acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non-tumoral PVT in patients with cirrhosis after HCV eradication. METHODS: Patients with HCV-related cirrhosis, consecutively enrolled in the multi-center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan-Meier and competing risk regression analyses were performed. RESULTS: During a median time of 38.3 months (IQR: 25.1-48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count ≤120,000/µL, albumin levels ≤3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB-4, and RESIST scores were significantly different (p < 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33-24.99) and pre-treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36-13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p < 0.001) versus pre-treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p > 0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16-27.53 and subHR: 5.50; CI 95% 1.67-18.13, respectively). CONCLUSIONS: In patients with HCV-related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

Oesophageal varices predict complications in compensated advanced non-alcoholic fatty liver disease.

Background & Aims: We aimed to evaluate the impact of oesophageal varices (OV) and their evolution on the risk of complications of compensated advanced chronic liver disease (cACLD) caused by non-alcoholic fatty liver disease (NAFLD). We also assessed the accuracy of non-invasive scores for predicting the development of complications and for identifying patients at low risk of high-risk OV. Methods: We performed a retrospective assessment of 629 patients with NAFLD-related cACLD who had baseline and follow-up oesophagogastroduodenoscopy and clinical follow-up to record decompensation, portal vein thrombosis (PVT), and hepatocellular carcinoma. Results: Small and large OV were observed at baseline in 30 and 15.9% of patients, respectively. The 4-year incidence of OV from absence at baseline, and that of progression from small to large OV were 16.3 and 22.4%, respectively. Diabetes and a ≥5% increase in BMI were associated with OV progression. Multivariate Cox regression revealed that small (hazard ratio [HR] 2.24, 95% CI 1.47-3.41) and large (HR 3.86, 95% CI 2.34-6.39) OV were independently associated with decompensation. When considering OV status and trajectories, small (HR 2.65, 95% CI 1.39-5.05) and large (HR 4.90, 95% CI 2.49-9.63) OV at baseline and/or follow-up were independently associated with decompensation compared with the absence of OV at baseline and/or follow-up. The presence of either small (HR 2.8, 95% CI 1.16-6.74) or large (HR 5.29, 95% CI 1.96-14.2) OV was also independently associated with incident PVT. Conclusion: In NAFLD-related cACLD, the presence, severity, and evolution of OV stratify the risk of developing decompensation and PVT. Impact and implications: Portal hypertension is the main driver of liver decompensation in chronic liver diseases, and its non-invasive markers can help risk prediction. The presence, severity, and progression of oesophageal varices stratify the risk of complications of non-alcoholic fatty liver disease. Easily obtainable laboratory values and liver stiffness measurement can identify patients at low risk for whom endoscopy may be withheld, and can also stratify the risk of liver-related complications.

Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study.

Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01-1.06), HE (HR 1.67, 95% CI 1.08-2.56), ascites (HR 2.56, 95% CI 1.55-4.23), and sodium levels (HR 0.94, 95% CI 0.90-0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39-18.49) and BMI (HR 0.86, 95% CI 0.75-0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Child-Pugh Class and Not Thrombocytopenia Impacts the Risk of Complications of Endoscopic Band Ligation in Patients with Cirrhosis and High Risk Varices.

Background and Aims: Endoscopic band legation (EBL) is an effective method for the prophylaxis of acute variceal bleeding (AVB). This procedure may be associated with several complications, particularly bleeding. Our analysis aimed to evaluate the risk of complications due to EBL in a cohort of patients who underwent EBL for the prophylaxis of variceal bleeding and the eventual presence of risk predictors. Patients and Methods: We retrospectively analysed data from consecutive patients who underwent EBL in a primary prophylaxis regimen. For all patients, simultaneously with EBL, we recorded the Child-Pugh and MELD score, platelet count and US features of portal hypertension. Results: We collected data from 431 patients who performed a total of 1028 EBLs. We recorded 86 events (8.4% of all procedures). Bleeding after EBL occurred 64 times (6.2% of all procedures), with the following distribution: intraprocedural bleeding in 4%; hematocystis formation in 17 cases (1.7%); 6 events (0.6%) of AVB due to post-EBL ulcers. None of these events presented a correlation with platelet count (84,235 ± 54,175 × 103/mL vs. 77,804 ± 75,949 × 103/mL; p = 0.70) or with the condition of severe thrombocitopenia established at PLT < 50,000/mmc (22.7% with PLT ≤ 50,000/mmc vs. 15.9% with PLT ≥ 50,000/mmc; p = 0.39). Our results showed a relationship between cumulative complications of EBL and Child-Pugh score (6.9 ± 1.6 vs. 6.5 ± 1.3; p = 0.043). Conclusions: EBL in cirrhotic patients is a safe procedure. The risk of adverse events depends on the severity of liver disease, without a relationship with platelet count.

Glecaprevir/Pibrentasvir is safe and effective in Italian patients with chronic hepatitis C aged 75 years or older: A multicentre study.

BACKGROUND: Glecaprevir and Pibrentasvir (G/P) determine high rates of sustained virological response (SVR) with optimal safety profile in patients with chronic hepatitis C virus (HCV) infection. The efficacy and safety of G/P in Caucasian patients aged 75 years and older have not been widely analysed. METHODS: This is a retrospective multicentre real-world study enrolling all consecutive patients 75 years and older who received G/P between October 2017 and January 2022 at five referral centres in Italy. SVR was analysed by intention-to-treat (ITT) and per-protocol analyses (PP). RESULTS: A total of 570 patients met the inclusion criteria and were analysed: mean age was 80 (75-97) years, 356 (62%) were females, 52% (298/570) had HCV-1, 44% (252/570) had HCV-2 and 137 (24%) patients had liver cirrhosis. Four hundred and sixty-three (81%) patients were taking at least one concomitant drug, with 144 (25%) taking ≥5 concomitant drugs. G/P was given for 8 weeks in 488 patients (86%). During treatment, 48 patients (8%) reported side effects, with 10 (2%) patients discontinuing treatment prematurely. Two patients developed treatment-unrelated serious adverse events. Overall, the SVR rate was 97.9% (558/570) by ITT analysis and 99.6% (558/560) by PP analysis. SVR rates remained consistently high among subgroup analysis stratified by genotype, treatment duration, fibrosis stage and concomitant medications. CONCLUSIONS: Treatment with G/P achieved 97.9% SVR rates in HCV patients older than 75 years of age. Safety was optimal with only 2% of patients discontinuing early.

Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort.

BACKGROUND AND AIMS: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. METHODS: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. RESULTS: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. CONCLUSIONS: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.

Heart rate variability is associated with disease severity and portal hypertension in cirrhosis.

INTRODUCTION: Autonomic nervous system activity in cirrhotic portal hypertension is linked to hyperdynamic circulation. Heart rate variability (HRV) is a validated noninvasive method to assess the sympathovagal balance. To investigate the correlation between HRV parameters and degree of portal hypertension, we studied a cohort of patients with cirrhosis accounting for etiology and treatments. PATIENTS AND METHODS: In this cross-sectional, observational cohort study, 157 outpatients of both sex with nonalcoholic cirrhosis were assessed by upper gastrointestinal endoscopy to search for esophagogastric varices. Twenty-four-hour electrocardiogram Holter monitoring with 3 HRV parameters measurement [SD of the NN intervals, root mean square successive difference of NN intervals, and SD of the averages of NN intervals (SDANN)] according to time-domain analysis were performed in all patients. Sixteen patients with large esophagogastric varices underwent measurements of the HVPG and assessment of HRV parameters at baseline and after 45 days on carvedilol. RESULTS: The liver dysfunction, expressed by Child-Pugh class or MELD score, was directly related to root mean square successive difference of NN intervals and inversely related to SDANN. Presence of ascites was inversely related to SDANN and to SD of the NN intervals. Treatment with carvedilol had an inverse relation with SDANN. Presence and size of esophagogastric varices had an inverse relation to SDANN and SD of the NN intervals. Upon multivariate analysis the associations between SDANN and Child-Pugh class, size of varices and ascites were confirmed. In the subgroup of 16 patients undergoing HVPG measurement, pressure gradient was unrelated to heart rate and HRV parameters. CONCLUSIONS: Time-domain HRV parameters in patients with cirrhosis, confirm the autonomic nervous system alteration, and their correlation to the degree of portal hypertension suggesting a role of the ANS in hepatic decompensation.

The unhealthy lifestyle in primary biliary cholangitis: An enemy to fight.

BACKGROUND AND AIM: Metabolic dysfunctions, particularly hyperlipidemia, are a common finding in Primary Biliary Cholangitis (PBC). In presence of metabolic components of fatty-liver-disease (MAFLD), the liver fibrosis progression risk is higher. The aim of this study was to evaluate lifestyle of PBC patients compared to controls. METHODS: In a prospective, multicenter study 107 PBC patients were enrolled; among these, 54 subjects were age-and sex-matched with 54 controls with a propensity-score-matching-analysis. Eating habits and physical activity were evaluated, respectively, with a food-frequency-questionnaire and with a short pre-validated-questionnaire. The adherence to Mediterranean diet was assessed with the alternate Mediterranean diet score. RESULTS: The total fat intake was higher in controls than in PBC (p=0.004), unless above the national recommendations in both groups. Moreover, in PBC monounsaturated-fat and polyunsaturated-fatty-acid intakes and the adherence to Mediterranean diet were significantly lower than in controls (p<0.001, p=0.005 and p<0.001 respectively). Regarding physical activity, PBC subjects had a sedentary behavior as well as controls. CONCLUSIONS: The lifestyle of both PBC and controls is at high risk of developing MAFLD. Therefore, hepatologists should regularly evaluate eating habits and physical activity in PBC patients and promote a lifestyle change to reduce liver disease progression risk.

Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model.

BACKGROUND AND AIMS: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. APPROACH AND RESULTS: We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. CONCLUSIONS: After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.

Mer Tyrosine Kinase (MERTK) modulates liver fibrosis progression and hepatocellular carcinoma development.

MerTK is a tyrosine kinase receptor that belongs to the TAM (Tyro3/Axl/Mer) receptor family. It is involved in different processes including cellular proliferation/survival, cellular adhesion/migration, and release of the inflammatory/anti-inflammatory cytokines. Although it is reported that MERTK polymorphisms affect the severity of viral and metabolic liver diseases, being able to influence fibrosis progression and hepatocellular carcinoma development, the mechanisms remain unknown. METHODS: using a microarray approach, we evaluated the liver expression of genes involved in fibrogenesis and hepatocarcinogenesis in patient with chronic hepatitis C (CHC), stratified for MERTK genotype and MERTK expression. RESULTS: we found that the rs 4374383 AA homozygosity is associated with lower MERTK expression in CHC patients and that, depending on MERTK genotype, Matrix Metallopeptidase 9 (MMP9), Matrix Metallopeptidase 7 (MMP7), Secreted Frizzled Related Protein 1 (SFRP1) and WNT gene family 11(WNT11) show differential expression in patients with CHC with or without neoplastic progression. CONCLUSIONS: our results confirm that MERTK represents a genetic biomarker for progression of liver disease and are suggestive of translational relevance for the study of downstream pathways involved in fibrogenesis and hepatocarcinogenesis.

RESIST-HCV Criteria to Monitor Progression of Low-Risk Esophageal Varices in Patients With Compensated Cirrhosis After HCV Eradication: The SIMPLE Study: SIMPLE: Scoring Index to Monitor Progression of Low-risk Esophageal varices.

INTRODUCTION: Noninvasive criteria to predict the progression of low-risk esophageal varices (EV) in patients with compensated hepatitis C virus (HCV) cirrhosis after sustained virological response (SVR) by direct-acting antivirals (DAAs) are lacking. Our aim was to assess the diagnostic performance of Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) criteria for EV progression compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII-HCV criteria). METHODS: All consecutive patients observed at 3 referral centers with compensated HCV cirrhosis with or without F1 EV who achieved sustained virological response by DAAs were classified at last esophagogastroduodenoscopy (EGDS) as RESIST-HCV low risk (i.e., low probability of high-risk varices [HRV]) if platelets were >120 × 10 9 /L and serum albumin >3.6 g/dL or RESIST-HCV high risk (i.e., high probability of HRV) if platelets were <120 × 10 9 /L or serum albumin <3.6 g/dL. The primary outcome was the progression to HRV. The area under the receiver operating characteristic curve and decision curve analysis of noninvasive criteria were calculated. RESULTS: The cohort consisted of 353 patients in Child-Pugh class A (mean age 67.2 years, 53.8% males). During a mean follow-up of 44.2 months, 34 patients (9.6%, 95% CI 6.7%-13.5%) developed HRV. At the last EGDS, 178 patients (50.4%) were RESIST-low risk, and 175 (49.6%) were RESIST-high risk. RESIST-HCV criteria showed the highest area under the receiver operating characteristic curve (0.70, 95% confidence interval 0.65-0.75), correctly sparing the highest number of EGDS (54.3%), with the lowest false-positive rate (45.7%), compared with elastography-based criteria. Decision curve analysis showed that RESIST-HCV had higher clinical utility than elastography-based criteria. DISCUSSION: Biochemical-based RESIST-HCV criteria are useful to easily predict HRV development after HCV eradication by DAAs in patients with compensated cirrhosis and low-risk EV.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Primary biliary cholangitis: perception and expectation of illness.

An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. AIM: To assess the perception of illness in a cohort of Italian patients with PBC. METHODS: Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. RESULTS: Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. CONCLUSIONS: The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients.

First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials.

INTRODUCTION: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. METHODS: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. RESULTS: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. CONCLUSION: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.

Efficacy of 8 weeks elbasvir/grazoprevir regimen for naïve-genotype 1b, HCV infected patients with or without glucose abnormalities: Results of the EGG18 study.

BACKGROUND AND AIM: Direct Acting Antivirals(DAAs) achieve the highest rate of sustained viral response(SVR) in patients with genotype-1b(G1b) Hepatitis C virus(HCV) infection. Reducing treatment duration can simplify the management and improve adherence of therapy. PATIENTS AND METHODS: The study evaluates the efficacy of 8 weeks of elbasvir/grazoprevir regimen in 75 treatment-naïve(TN), G1b patients with mild-moderate fibrosis(Liver Stiffness by Fibroscan® <9.0 kPa). Viral load(VL) has been evaluated by Roche TaqMan RT-PCR(LLOQ<15 IU/ml). RESULTS: Mean age was 61.0 ± 14.2 years, 44% were male, mean LS by Fibroscan® was 6.1 ± 1.8 kPa. Twenty-eight patients(37.3%) had an HOMA>2.5. Two patients were excluded from analysis(one dropped out and the other one had diagnosed genotype 2c at genotyping by sequencing performed after relapse). At 8 weeks(EOT), 71 out of 73 patients(97.3%) had undetectable HCV-RNA, while in two cases HCV-RNA was detectable but with VL<15 IU/ml. Both of them achieved SVR. Two G1b patients relapsed at 12 weeks of follow-up, both with baseline VL>800,000 IU/ml and HOMA score 1.3 and 3.8 respectively. Both had undetectable HCV VL at 4th week and at the EOT. Modified intention-to-treat SVR12 for G1b patients was 71/73(97.3%). CONCLUSION: In naïve, genotype-1b HCV-infected patients with mild/moderate liver fibrosis, short course of 8 weeks of EBR/GZR appears to achieve high efficacy regardless of features of insulin resistance.

Liver and cardiovascular mortality after hepatitis C virus eradication by DAA: Data from RESIST-HCV cohort.

Real-world evidence on the course of Hepatitis C Virus (HCV) chronic liver disease after Sustained Virologic Response (SVR) obtained with direct-acting antiviral drugs (DAAs) are still limited, and the effects on mortality remain unclear. We evaluated the post-treatment survival of 4307 patients in the RESIST-HCV cohort (mean age 66.3 ± 11.6 years, 56.9% males, 24.7% chronic hepatitis, 66.9% Child-Pugh A cirrhosis and 8.4% Child-Pugh B cirrhosis) treated with DAAs between March 2015 and December 2016 and followed for a median of 73 weeks (range 16-152). Proportional cause-specific hazard regression for competing risks was used to evaluate the survival and to assess the predictors of liver and cardiovascular death. Overall, 94.7% of patients achieved SVR while 5.3% were HCV RNA-positive at last follow-up. Sixty-three patients (1.4%) died during the observation period. SVR was associated with a decreased risk of liver mortality (hazard ratio,HR0.09, beta -2.37, p < .001). Also, platelet count (HR 0.99, beta-0.01, p = .007) and albumin value (HR 0.26, beta -1.36 p = .001) were associated with liver mortality by competing risk analysis. SVR was associated with a reduced risk of cardiovascular mortality regardless of presence of cirrhosis (HR 0.07, beta-2.67, p < .001). Presence of diabetes (HR 3.45, beta 1.24, p = .014) and chronic kidney disease class ≥3 (HR 3.60, beta 1.28, p = 0.016) were two factors independently associated with higher risk of cardiovascular mortality. Patients with SVR to a DAA therapy have a better liver and cardiovascular survival, and the effects of HCV eradication are most evident in patients with compensated liver disease.

Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b.

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7-82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4-6.2) log IU/mL vs. 5.3 (4.4-5.6) log IU/mL, p = 0.02) and lower ALT (35 (30-71) vs. 83 (48-108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and ß-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

Long-term evolution of LI-RADS observations in HCV-related cirrhosis treated with direct-acting antivirals.

BACKGROUND & AIMS: The risk of progression of indeterminate observations to hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA) is still undetermined. To assess whether DAA therapy changes the risk of progression of observations with low (LR-2), intermediate (LR-3) and high (LR-4) probability for HCC in cirrhotic patients and to identify predictors of progression. METHODS: This retrospective study included cirrhotic patients treated with DAA who achieved sustained virological response between 2015 and 2019. A total of 68 patients had pre-DAA indeterminate observations and at least six months CT/MRI follow-up before and after DAA. Two radiologists reviewed CT/MRI studies to categorize observations according to the LI-RADSv2018 and assess the evolution on subsequent follow-ups. Predictors of evolutions were evaluated by using the Cox proportional hazard model, Kaplan-Meier method and log-rank test. RESULTS: A total of 109 untreated observations were evaluated, including 31 (28.4%) LR-2, 67 (61.5%) LR-3 and 11 (10.1%) LR-4. During a median follow-up of 41 months, 17.4% and 13.3% of observations evolved to LR-5 or LR-M and LR-5, before and after DAA respectively (P = .428). There was no difference in rate of progression of neither LR-2 (P = 1.000), LR-3 (P = .833) or LR-4 (P = .505). At multivariate analysis, only initial LI-RADS category was an independent predictor of progression to LR-5 or LR-M for all observations (hazard ratio 6.75, P < .001), and of progression to LR-5 after DAA (hazard ratio 4.34, P = .047). CONCLUSIONS: DAA therapy does not increase progression of indeterminate observations to malignant categories. The initial LI-RADS category is an independent predictor of observations upgrade.