Liver-related Events Research Articles

Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial

Background & aimsImmunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation.MethodsWe enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival.ResultsAdverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects.ConclusionsThe adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC.Clinical trials registrationThis study was registered at ClinicalTrials.gov (NCT03899415).

Health-related quality of life improves after entecavir treatment in patients with compensated HBV cirrhosis.

Antiviral therapy is effective in decreasing disease progression in HBV cirrhosis. However, the long-term effect of antiviral therapy on health-related quality of life (HRQoL) in patients with compensated HBV cirrhosis is unknown. The patients with compensated HBV cirrhosis enrolled in a randomized controlled trial of entecavir-based therapy were recruited in the present study, if they had HRQoL score at 5-year follow-up or who developed liver-related events (LRE) during follow-up were included. HRQoL was measured with 36-Item Short-Form Health Survey (SF-36) and EuroQol-5D (EQ-5D) at baseline and yearly during follow-up. LRE was defined as the development of decompensation, HCC, or death. A total of 161 patients were included in the present study, with a median age of 48.0 (41.0, 53.0) years, 77.6% being male and 37.2% being HBeAg-positive. During 5years, 45 patients developed LRE. All eight dimensions of SF-36 were significantly improved after 5years of antiviral therapy (all p < 0.001), with all dimensions improved more than five points except for physical functioning. Proportion of patients reporting no problems in all five dimensions in EQ-5D increased from 57.8 to 72.0%; visual analogue scale (VAS) and utility index (UI) increased significantly (VAS 79.8 ± 16.4 to 84.4 ± 13.2, UI 0.91 ± 0.13 to 0.95 ± 0.10, both p < 0.001). HRQoL improved or kept stable in the majority of patients who had LRE during follow-up, even stratified by Baveno VI criteria for clinically significant portal hypertension. After 5years of ETV treatment, HRQoL significantly improved in patients with compensated HBV cirrhosis. (NCT01943617, NCT02849132).

PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese patients with histopathologically-confirmed NAFLD

BackgroundReliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined.MethodsWe retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors.ResultsA score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%.ConclusionsOur results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients.

Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study)

Functional cure, defined based on hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes after NA cessation in a large, international, multicenter, multiethnic cohort of patients with chronic hepatitis B (CHB). This cohort study included patients with virally suppressed CHB who were hepatitis B e antigen (HBeAg)-negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virologic, biochemical, and clinical relapse, alanine aminotransferase flare, retreatment, and liver-related events after NA cessation. Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; 95% confidence interval, 2.7-16.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; 95% confidence interval, 13.1-38.7; P < .001). At 48 months of follow-up, Whites with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate ofhepatic decompensation and hepatocellular carcinoma was0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with hepatocellular carcinoma. The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whiteswith <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.

A Cholestatic Pattern Predicts Liver-Related Events in Patients with Nonalcoholic Fatty Liver Disease

Background & Aims: Liver test alteration patterns can be categorized as: predominantly hepatocellular(H), with an ALT/ALP ratio>5; predominantly cholestatic pattern(C) with a ratio < 2; mixed(M), with a ratio between 2 and 5. NAFLD usually has an H pattern, but a C pattern can also be observed. We aimed to assess in subjects with NAFLD the impact of the C pattern on the likelihood of developing of liver-related events(LRE). Methods: 582 consecutive patients with biopsy-proven NAFLD or a clinical diagnosis of NAFLD-related compensated cirrhosis were classified as H, C are M patterns, by using the formula (ALT/ALT Upper Limit of Normal-ULN)/(ALP/ALP ULN). LRE were recorded during follow-up. An external cohort of 1281 biopsy-proven NAFLD patients was enrolled as validation set. Results: H, M and C patterns were found in 153(26.3%), 272(46.7%) and 157(27%) patients, respectively. During a median follow-up of 78 months, only 1(0.6%) patient with H pattern experienced LRE, while 15(5.5%) and 38(24.2%) patients in M and C group had LRE. At multivariate Cox regression analysis, age>55 years(HR2.55,95%C.I.1.17-5.54;p=0.01), platelets<150,000/mmc(HR0.14,95%C.I.0.06-0.32;p<0.001), albumin<4g/L(HR0.62,95%C.I.0.35-1.08;p=0.09), C vs M pattern(HR7.86,95%C.I.1.03-60.1;p=0.04), C vs H pattern(HR12.1,95% C.I.1.61-90.9;p=0.01) and fibrosis F3-F4(HR35.8,95%C.I.4.65-275.2;p<0.001) were independent risk factors for LRE occurrence. C vs M pattern(HR14.3,95%C.I.1.90-105.6;p=0.008) and C vs H pattern(HR15.6,95%C.I. 2.10-115.1;p=0.0068) were confirmed independently associated with LRE occurrence in the validation set. Immunohistochemical analysis found a significant higher prevalence of moderate-high grade ductular metaplasia combined with low grade ductular proliferation in C pattern when compared with biochemical H pattern. Gene expression analysis showed a lower expression of NR1H3, RXRα, VCAM1 in patients with the C pattern. Conclusions: The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of LRE independently from other features of liver disease. Funding: GS is supported by a Senior Salary Award from Fonds de la Recherche en Sante du Quebec (FRQS) (#296306). Declaration of Interest: GS has acted as speaker for Pfizer, Merck, Novonordisk, Novartis, Gilead, and AbbVie, served as an advisory board member for Merck, Gilead, Pfizer, Allergan, Novonordisk, Intercept and Novartis and has received research funding from Merck and Theratec. All others have nothing to declare. Ethical Approval: Approval was obtained by the Ethical Committee of the University Hospital “Paolo Giaccone” in Palermo.

From the Editor’s desk…

From the Editor’s desk…

OC-06A cholestatic pattern predicts liver-related events in patients with nonalcoholic fatty liver disease

Background&Aims: Liver tests alteration patterns can be categorized as: predominantly hepatocellular(H), with an ALT/ALP ratio>5; predominantly cholestatic pattern (C) with a ratio < 2; mixed(M), with a ratio between 2 and 5. NAFLD has usually an H pattern, but a C pattern can also be observed. We aimed to assess in subjects with NAFLD the impact of the C pattern on the likelihood of developing of liver-related events(LRE).

OC-10Liver-related and extrahepatic events occurrence in patients with nonalcoholic fatty liver disease: a competing risk analysis

Background&Aim: Nonalcoholic fatty liver disease(NAFLD) is associated with a high risk of liver-related events(LRE) and also extrahepatic events(EHE). We evaluated the competive risk occurrence of LRE and EHE in a large cohort of biopsy-proven NAFLD stratified according to baseline severity of fibrosis.

Evolution of Nonmalignant Portal Vein Thrombosis in Liver Cirrhosis: A Pictorial Review.

Portal vein thrombosis (PVT) is a common complication in liver cirrhosis, especially in advanced cirrhosis. It may be related to a higher risk of liver-related events and liver function deterioration. Imaging examinations can not only provide an accurate diagnosis of PVT, such as the extent of thrombus involvement and the degree of lumen occupied, but also identify the nature of thrombus (i.e., benign/malignant and acute/chronic). Evolution of PVT, mainly including development, recanalization, progression, stability, and recurrence, could also be assessed based on the imaging examinations. This article briefly reviews the pathophysiology, diagnosis, classification, and evolution of PVT with an emphasis on their computed tomography imaging features.

Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR

As the long-term benefits of a sustained virological response (SVR) in HCV-related cirrhosis following direct-acting antiviral (DAA) treatment remain undefined, we assessed the incidence and predictors of liver-related events (LREs), non-liver-related events (NLREs) and mortality in DAA-treated patients with cirrhosis. Consecutive patients with cirrhosis and SVR were enrolled in a longitudinal, single-center study, and divided into 3 cohorts: Cohort A (Child-Pugh A without a previous LRE), Cohort B (Child-Pugh B or Child-Pugh A with prior non-hepatocellular carcinoma [HCC] LREs), Cohort C (previous HCC). A total of 636 patients with cirrhosis (median 65 years-old, 58% males, 89% Child-Pugh A) were followed for 51 (8-68) months (Cohort A n= 480, Cohort B n= 89, Cohort C n= 67). The 5-year estimated cumulative incidences of LREs were 10.4% in Cohort A vs. 32.0% in Cohort B (HCC 7.7% vs. 19.7%; ascites 1.4% vs. 8.6%; variceal bleeding 1.3% vs. 7.8%; encephalopathy 0 vs. 2.5%) vs. 71% in Cohort C (HCC only) (p <0.0001). The corresponding figures for NLREs were 11.7% in Cohort A vs. 17.9% in Cohort B vs. 17.5% in Cohort C (p= 0.32). The 5-year estimated probabilities of liver-related vs. non-liver-related deaths were 0.5% vs. 4.5% in Cohort A, 16.2% vs. 8.8% in Cohort B and 12.1% vs. 7.7% in Cohort C. The all-cause mortality rate in Cohort A was similar to the rate expected for the general population stratified by age, sex and calendar year according to the Human Mortality Database, while it was significantly higher in Cohort B. Patients with cirrhosis and an SVR on DAAs face risks of liver-related and non-liver-related events and mortality; however, their incidence is strongly influenced by pre-DAA patient history. In this large single-center study enrolling patients with hepatitis C virus (HCV)-related cirrhosis cured by direct-acting antivirals, pre-treatment liver disease history strongly influenced long-term outcomes. In patients with HCV-related cirrhosis, hepatocellular carcinoma was the most frequent liver-related complication after viral cure. Due to improved long-term outcomes, patients with cirrhosis after HCV cure are exposed to a significant proportion of non-liver-related events.

Non-invasive tests for predicting liver outcomes in chronic hepatitis C patients: A systematic review and meta-analysis.

BACKGROUNDLiver fibrosis leads to liver-related events in patients with chronic hepatitis C (CHC) infection. Although non-invasive tests (NITs) are critical to early detection of the development of liver fibrosis, the prognostic role of NITs remains unclear due to the limited types of NITs and liver outcomes explored in previous studies.AIMTo determine the prognostic value of NITs for risk stratification in CHC patients.METHODSThe protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42019128176). The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search was performed using MEDLINE and EMBASE databases under a timeframe from the inception of the databases through February 25, 2020. We restricted our search to CHC cohort studies reporting an association between liver fibrosis assessed by NITs and the development of hepatocellular carcinoma, decompensation, or mortality. Pooled hazard ratios (HR) and area under the receiver operating characteristic (AUROC) for each NIT were estimated using a random effects model. Subgroup analyses were performed for NITs assessed at pre-treatment or post-treatment with sustained virologic response (SVR), treatment with either pegylated interferon and ribavirin or direct acting antiviral, Eastern or Western countries, and different cutoff points.RESULTSThe present meta-analysis included 29 cohort studies, enrolling 69339 CHC patients. Fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio (APRI) score, and liver stiffness measurement (LSM) were found to have hepatocellular carcinoma predictive potential with pooled adjusted HRs of 2.48 [95% confidence interval (CI): 1.91-3.23, I2 = 96%], 4.24 (95%CI: 2.15-8.38, I2 = 20%) and 7.90 (95%CI: 3.98-15.68, I2 = 52%) and AUROCs of 0.81 (95%CI: 0.73-0.89, I2 = 77%), 0.81 (95%CI: 0.75-0.87, I2 = 68%), and 0.79 (95%CI: 0.63-0.96, I2 = 90%), respectively. Pooled adjusted HR with a pre-treatment FIB-4 cutoff of 3.25 was 3.22 (95%CI: 2.32-4.47, I2 = 80%). Pooled adjusted HRs for post-treatment with SVR FIB-4, APRI, and LSM were 3.01 (95%CI: 0.32-28.61, I2 = 89%), 9.88 (95%CI: 2.21-44.17, I2 = 24%), and 6.33 (95%CI: 2.57-15.59, I2 = 17%), respectively. Pooled adjusted HRs for LSM in patients with SVR following direct acting antiviral therapy was 5.55 (95%CI: 1.47-21.02, I2 = 36%). Pooled AUROCs for post-treatment with SVR FIB-4 and LSM were 0.75 (95%CI: 0.55-0.95, I2 = 88%) and 0.84 (95%CI: 0.66-1.03, I2 = 88%), respectively. Additionally, FIB-4 and LSM were associated with overall mortality, with pooled adjusted HRs of 2.07 (95%CI: 1.49-2.88, I2 = 27%) and 4.04 (95%CI: 2.40-6.80, I2 = 63%), respectively. CONCLUSIONFIB-4, APRI, and LSM showed potential for risk stratification in CHC patients. Cutoff levels need further validation.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n=5474, 58.9%) with a mean age of 47.5years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n=1595) and 13.2% (n=1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n=1740). During follow-up (median: 60.0months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p<.001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B

Background & AimsA recent consensus document has defined metabolic dysfunction-associated fatty liver disease (MAFLD) as hepatic steatosis together with overweight, diabetes, and/or a combination of other metabolic risk factors. The clinical relevance of this novel diagnosis is unknown among patients with chronic hepatitis B (CHB). We studied the association between MAFLD (with or without steatohepatitis) and adverse clinical outcomes in patients with CHB.MethodsWe performed a retrospective long-term follow-up cohort study at 2 tertiary hospitals in patients with CHB who underwent liver biopsy. Biopsies were reassessed for steatosis, degree of fibrosis, and presence of steatohepatitis. Associations with event-free hepatocellular carcinoma (HCC)-free and transplant-free survival were explored.ResultsIn our cohort, 1076 patients were included, median follow-up was 9.8 years (25th–75th percentile: 6.6−14.0), and 107 events occurred in 78 patients, comprising death (n = 43), HCC (n = 36), liver decompensation (n = 21), and/or liver transplantation (n = 7). MAFLD was present in 296 (27.5%) patients and was associated with reduced event-free (adjusted hazard ratio [aHR] 2.00, 95% CI 1.26–3.19), HCC-free (aHR 1.93, 95% CI 1.17–3.21), and transplant-free survival (aHR 1.80, 95% CI 0.98–3.29) in multivariable analysis. Among patients with MAFLD, the presence of steatohepatitis (p = 0.95, log-rank test) was not associated with adverse outcomes.ConclusionsThe presence of MAFLD in patients with CHB was associated with an increased risk for liver-related clinical events and death. Among patients with MAFLD, steatohepatitis did not increase the risk of adverse outcomes. Our findings highlight the importance of metabolic dysfunction in patients with CHB.Lay summaryRecently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been defined as fatty liver disease with signs of metabolic dysfunction. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death. Metabolic health assessment should be encouraged among patients with chronic hepatitis B, especially in those with fatty liver disease.

Risk Factors for Liver Decompensation and HCC in HCV-Cirrhotic Patients after DAAs: A Multicenter Prospective Study.

Simple SummaryThe present study explored the predictors of the development of liver-related events in HCV cirrhotic subjects achieving SVR following antiviral therapy with direct-acting antiviral agents (DAAs) during a follow-up of 24 months after SVR confirmation. Patients had a liver stiffness measurement (LSM) of ≥14 kPa at baseline. We found that baseline liver stiffness ≥ 20 kPa and HCV genotype different from 1 were both independent predictors of liver decompensation, while only LSM ≥ 20 kPa was an independent predictor of HCC.Background: Prospective studies on predictors of liver-related events in cirrhotic subjects achieving SVR after DAAs are lacking. Methods: We prospectively enrolled HCV cirrhotic patients in four Italian centers between November 2015 and October 2017. SVR and no-SVR cases were compared according to the presence or absence of liver-related events during a 24-month follow-up. Independent predictors of liver-related events were evaluated by Cox regression analysis. Results: A total of 706 subjects started DAAs therapy. SVR was confirmed in 687 (97.3%). A total of 61 subjects (8.9%) in the SVR group and 5 (26.3%) in the no-SVR group had liver-related events (p < 0.03). The incidence rate x 100 p/y was 1.6 for HCC, 1.7 for any liver decompensation, and 0.5 for hepatic death. Baseline liver stiffness (LSM) ≥ 20 kPa (HR 4.0; 95% CI 1.1–14.1) and genotype different from 1 (HR 7.5; 95% CI 2.1–27.3) were both independent predictors of liver decompensation. Baseline LSM > 20 KPa (HR 7.2; 95% CI 1.9–26.7) was the sole independent predictor of HCC. A decrease in liver stiffness (Delta LSM) by at least 20% at the end of follow-up was not associated with a decreased risk of liver-related events. Conclusion: Baseline LSM ≥ 20 kPa identifies HCV cirrhotic subjects at higher risk of liver-related events after SVR.

Transjugular intrahepatic portosystemic shunt (TIPS) placement at index portal hypertensive decompensation (anticipant TIPS) in cirrhosis and the role of early intervention in variceal bleeding and ascites.

Transjugular intrahepatic portosystemic shunt (TIPS) placement improves survival in patients with refractory/recurrent acute variceal bleeding (RAVB) and refractory ascites/hydrothorax. Recently, early TIPS was shown to reduce rebleeding and improve survival compared to the conventional TIPS. We aimed to study outcomes in patients with cirrhosis undergoing TIPS at first significant portal hypertensive (PHT) decompensation (termed anticipant TIPS) compared to those undergoing TIPS for recurrent or persistent PHT complications (conventional) and compared the former to matched controls on standard medical management (SMT). We retrospectively analyzed the clinical, biochemical, and liver disease severity parameters and survival at baseline and post-intervention in cirrhosis patients at two major hepatobiliary intervention centers undergoing anticipant (n = 27) or conventional TIPS (n = 30) and compared the former group to matched historical controls on SMT (n = 35). Baseline parameters were comparable between both the groups, including the Child-Pugh class and model for end-stage liver disease (MELD) scores. Length of stay in the intensive care unit, post-procedure admission rates, and sepsis events were higher among patients undergoing conventional TIPS (p < 0.05). Post-TIPS, at 1 year, overall and sub-grouped survivals were better in patients undergoing anticipant TIPS. On further sub-group analysis, based on the PHT events and stratified based on Child-Pugh and MELD scores, a higher proportion of patients survived after anticipant TIPS at 1 year. Compared to SMT, patients undergoing anticipant TIPS had significantly lesser hospitalizations, recurrence of varices, and ascites at 1 year, reducing hospital visits and financial burden. Anticipant TIPS at the first significant PHT event could improve liver-related events and survival compared to standard medical management and conventional TIPS, respectively.

The Disease-Modifying Therapies of Relapsing-Remitting Multiple Sclerosis and Liver Injury: A Narrative Review.

In this narrative review, we analyze pre-registration and post-marketing data concerning hepatotoxicity of all disease-modifying therapies (DMTs) available for the treatment of relapsing-remitting multiple sclerosis, including beta interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, cladribine, natalizumab, alemtuzumab, and ocrelizumab. We review the proposed causal mechanisms described in the literature and we also address issues like use of DMTs in patients with viral hepatitis or liver cirrhosis. Most data emerged in the post-marketing phase by reports to national pharmacovigilance agencies and published case reports or case series. Serious liver adverse events are rare, but exact incidence is largely unknown, as are predictive factors. Unfortunately, none of the DMTs currently available for the treatment of multiple sclerosis is free of potential hepatic toxic effects. Cases of acute liver failure have been reported for beta-interferon, fingolimod, natalizumab, alemtuzumab, and ocrelizumab by different mechanisms (idiosyncratic reaction, autoimmune hepatitis, or viral reactivation). Patients with multiple sclerosis should be informed about possible hepatic side effects of their treatment. Most cases of liver injury are idiosyncratic and unpredictable. The specific monitoring schedule for each DMT has been reviewed and the clinician should be ready to recognize clinical symptoms suggestive for liver injury. Not all DMTs are indicated in cirrhotic patients. For some DMTs, screening for hepatitis B virus and hepatitis C virus is required before starting treatment and a monitoring or antiviral prophylaxis schedule has been established. Beta interferon, glatiramer acetate, natalizumab, and alemtuzumab are relatively contraindicated in autoimmune hepatitis due to the risk of disease exacerbation.

Risk Difference of Liver-Related and Cardiovascular Events by Liver Fibrosis Status in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has affected more than one-fourth of the global population, thus emerging as a worldwide health and economic burden.1 The common causes of death in patients with NAFLD include cardiovascular disease (CVD), decompensation, and hepatocellular carcinoma (HCC). However, identifying the risk of these complications in patients with NAFLD remains an unmet need in clinical practice.

Long-term clinical outcomes in sustained responders with chronic hepatitis C after treatment with direct-acting antivirals.

Little is known about how the achievement of sustained virological response (SVR) after treatment with direct-antiviral agents (DAAs) affects fibrosis and clinical outcomes in the long term. Our study aimed to evaluate the impact of achieving SVR on long-term changes in fibrosis and clinical outcomes in CHC patients treated with different DAAs-based regimens. a prospective, 3-year follow-up study of 113 CHC patients who had achieved SVR after treatment with different DAAs-based regimens between January and June 2015 was conducted. The clinical outcomes of SVR on the biochemical profile, changes in fibrosis, ALBI score and grade and occurrence of liver-related events were analyzed. Overall, liver function parameters and serum alpha-fetoprotein level showed improvement from baseline to SVR12 and remained steady thereafter. Moreover, the ALBI score showed nonsignificant change at baseline to SVR12 (P = 0.2) but it was significantly better at 3-years follow-up than at SVR12 (P = 0.001). Regarding liver stiffness (LS) by transient elastography, a significant decrease in TE values was observed between baseline to SVR12 (P ≤ 0.0001) as well as between SVR12 to 3-years follow-up (P = 0.0005). Stratified by fibrosis stage, patients with advanced fibrosis and cirrhosis showed a more pronounced and significant improvement of LS during follow-up after SVR compared to patients with less advanced fibrosis stage. During the follow-up period, 3 (5.2%) cirrhotic patients developed liver-related events, including 2 (3.4%) patients with de novo HCC and one (1.7%) patient experienced ascites for the first time. This 3-year follow-up study provides evidence for the durability of SVR, improvement of liver function parameters and ALBI score and grade in patients with an advanced stage of fibrosis, in particular, and reduction of the clinical events after successful treatment with DAAs.

Risk for hepatic and extra-hepatic outcomes in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is defined by presence of steatosis in more than 5% of liver cells. The gold standard for diagnosis is liver biopsy, but this is seldom achieved due to costs and risk for side effects, and that is why the diagnosis is mostly made based on a combination of radiology and exclusion of other liver diseases. Disease severity staging can be noninvasively achieved with radiological exams such as elastography or blood-based markers that usually have lower sensitivity and specificity. NAFLD is today the most common chronic liver disease globally with a prevalence estimated to be 25%. Fortunately, for many persons NAFLD is an incidental finding with a good prognosis. Whilst a major focus has been on liver-related outcomes in NAFLD, there has recently been an increased interest in extrahepatic consequences of NAFLD. The most commonly studied outcomes include cardiovascular disease and cancer. The risk of adverse outcomes generally differs according to the baseline fibrosis stage. There is a five-time higher risk of liver-related events in NAFLD patients with fibrosis stage 3 as compared to those with no or little fibrosis. Meanwhile, the presence of nonalcoholic steatohepatitis (NASH) does not seem to influence prognosis in addition to fibrosis stage. Patients with NAFLD clearly have a higher risk for cardiovascular outcomes compared to the general population, with a recent meta-analysis indicating a 37% increased hazard for cardiovascular events as opposed to individuals without NAFLD. The risk of liver cancer is increased, which is mostly driven by presence of cirrhosis, but the increased risk is present also in patients without cirrhosis, and to a greater extent than for other chronic liver disease. Around one-third of patients with NAFLD and liver cancer do not have cirrhosis. Additionally, the risk of extrahepatic malignancies is thought to be moderately increased, with most evidence for a link between NAFLD and colorectal cancer where the risk is approximately 50% higher compared to patients without NAFLD. A particularly salient point is if NAFLD can be considered an independent risk factor for outcomes. Many studies have not been able to adjust for key confounders, or suffer from different forms of bias. The clinical problem is nevertheless to identify persons with an increased risk for adverse hepatic and extrahepatic outcomes. We here discuss the evidence linking NAFLD to severe hepatic and extrahepatic outcomes.

Risk of severe clinical events after sustained virological response following direct-acting antiviral therapy in HIV and hepatitis C virus coinfected participants.

Sustained virological response (SVR) decreases the risk of hepatitis C virus (HCV)-related events. Nevertheless, a substantial risk of events persists. We estimated incidences and identified factors associated with severe clinical events after SVR following treatment with a direct-acting antiviral (DAA) in HIV/HCV-coinfected patients. Participants from the ANRS CO13 HEPAVIH were included if they reached SVR. Incidence rates of overall mortality, liver-related events, AIDS-defining events, ischaemic events and non-liver non-AIDS-defining cancers (NLNA) were estimated. Factors associated with the risk of those events were identified using Poisson models adjusted on age at SVR and sex. In all, 775 participants were included. Incidence rates (95% confidence interval) of liver-related events, overall mortality, AIDS-defining events, ischaemic events and NLNA cancers per 1000 person-years were 5.9 (3.3-10.3), 22.2 (16.8-29.5), 0.6 (0.1-4.5), 7.3 (4.4-12.2) and 13.7 (9.4-20.0), respectively. For all events, incidence rates were higher in cirrhotic than in non-cirrhotic participants. Cirrhosis, liver stiffness and CD4 count were associated with liver-related events. Factors associated with overall mortality were age, cirrhosis, liver stiffness and gamma-glutamyl transferase (GGT). For ischaemic events and NLNA cancers, associated factors were total cholesterol and CD4 count, respectively. After SVR following a DAA treatment, liver-related and AIDS-defining events were observed less frequently than NLNA cancers. Severity of liver disease was associated with the risk of liver-related events and of overall mortality but not with ischaemic events and NLNA cancers. Factors reflecting HIV infection were associated with NLNA cancers and liver-related events.