Factors associated with high costs of patients with metabolic dysfunction-associated steatotic liver disease: an observational study using the French CONSTANCES cohort.

BACKGROUND & AIMS: Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France. METHODS: The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS). Study participants were identified by the fatty liver index (FLI) over the period 2015-2019. MASLD individuals were classified according as "high-cost" (above 90th percentile) or "non-high cost" (below 90th percentile). Factors significantly associated with high costs were identified using a multivariate logistic regression model. RESULTS: A total of 14,437 predominantly male (69%) participants with an average age of 53 ± SD 12 years were included. They mainly belonged to socially deprived population groups with co-morbidities such as diabetes, high blood pressure, mental health disorders and cardiovascular complications. The average expenditure was €1860 ± SD 4634 per year. High-cost MASLD cost €10,863 ± SD 10,859 per year. Conditions associated with high-cost were mental health disorders OR 1.79 (1.44-2.22), cardiovascular diseases OR 1.54 (1.21-1.95), metabolic comorbidities OR 1.50 (1.25-1.81), and respiratory disease OR 1.50 (1.11-2.00). The 10% high-cost participants accounted for 58% of the total national health care expenditures for MASLD. CONCLUSION: Our results emphasize the need for comprehensive management of the comorbid conditions which were the major cost drivers of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in European countries, affecting 4­50% of the European population. Confirmation of diagnosis requires liver biopsy which is an invasive procedure. We studied the healthcare costs of patients with MASLD in order to identify cost predictors and cost drivers. We found that patients cost on average €1860 per year. Conditions associated with high-cost were mental health disorders, cardiovascular diseases, metabolic comorbidities, and respiratory disease.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

BACKGROUND: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in type 2 diabetes (T2DM) patients are lacking. The aim of this multicenter prospective study was to compare head-to-head FAST (FibroScan-aspartate aminotransferase [AST]), MAST (magnetic resonance imaging [MRI]-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in T2DM patients. METHODS: 330 T2DM outpatients with biopsy-proven metabolic dysfunction associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-PDFF and MRE at the time of liver biopsy (LB) were studied. The main outcome was fibrotic MASH, defined as NAS ≥ 4 (with at least one point each) and fibrosis stage ≥ 2 (centrally reviewed). RESULTS: 245 patients (median age 59 years, male 65%, BMI 31 kg/m2; fibrotic MASH 39%) had all data available for scores comparison. FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p < 0.0001). When using original cutoffs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom LB would be avoided (69% vs. 48%, 46%, 39%, respectively; p < 0.001). When using cutoffs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p < 0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify T2DM patients with fibrotic MASH in secondary/tertiary diabetes clinics. Cutoffs adapted to T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold.

OBJECTIVE: Most people with type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH) or advanced fibrosis (AF) remain undiagnosed, resulting in missed opportunities for early intervention. This multicenter, prospective study assessed the yield of using routinely available data to identify these patients. RESEARCH DESIGN AND METHODS: A total of 713 outpatients with T2DM, screened in four diabetology clinics for nonalcoholic fatty liver disease according to American Diabetes Association criteria, were referred to hepatologists for further work-up (Fibrosis-4 and vibration-controlled transient elastography [VCTE]). A liver biopsy was proposed when ALT levels were persistently >20 IU/L in female patients or >30 IU/L in male patients, in the absence of other liver disease. RESULTS: Liver biopsies were performed in 360 patients and considered adequate for reading after central review for 330 specimens (median patient age, 59 years; male patients, 63%; median BMI and HbA1c values, 32 and 7.5%, respectively). Prevalence of NASH, AF, and cirrhosis were 58%, 38%, and 10%, respectively. Liver lesions were independently associated with the components of metabolic syndrome but not with the micro- and macrovascular complications of T2DM. Models based on routinely available data with or without VCTE had good accuracy to predict AF (respectively: area under the receiver operating characteristic curve [AUROC], 0.84 and 0.77; and correctly classified 59% and 45%) and NASH (respectively: AUROC, 0.82 and 0.81; 44% and 42%). CONCLUSIONS: Despite the use of a low ALT threshold, prevalence of NASH (58%) or AF (38%) was high. Routinely available data had a high yield in identifying patients with T2DM with AF and/or NASH requiring further liver assessment.

Validation of a screening algorithm for hepatic fibrosis by Doppler ultrasound and elastography in a general population.

BACKGROUND: Early detection can prevent the initial stages of fibrosis from progressing to cirrhosis. PURPOSE: To evaluate an algorithm combining three echographic indicators and elastographic measurements to screen for hepatic fibrosis in an unselected population. MATERIAL AND METHODS: From May 2017 to June 2018, all patients with no history and no known chronic liver disease who were referred for an ultrasound (US) were prospectively included in eight hospitals. The indicators being sought were liver surface irregularity, demodulation of hepatic veins, and spleen length >110 mm. Patients presenting at least one of these underwent elastography measurements with virtual touch quantification (VTQ) or supersonic shear imaging (SSI). If elastography was positive, patients were referred to hepatologist for fibrosis evaluation. Reference standard was obtained by FibroMeterVCTE or biopsy. A FibroMeterVCTE result >0.384 indicated a "necessary referral" to a hepatologist. RESULTS: Of the 1501 patients included, 504 (33.6%) were positive for at least one US indicator. All of them underwent US elastography, with 85 being positive. Of the patients, 58 (3.6%) had a consultation with a liver specialist: 21 had positive FibroMeterVCTE and nine had an indication of biopsy for suspicion of fibrosis. This screening algorithm made it possible to diagnose 1.6% of patients in our population with unknown fibrosis. Of the patients, 50% referred to the liver specialist were "necessary referrals." CONCLUSION: Our study suggests that three simple US indicators with no systematic elastographic measurement could be applied in day-to-day practice to look for hepatic fibrosis in an unsuspected population allowing relevant referrals to a hepatologist.

Patients Treated for HCV Infection and Listed for Liver Transplantation in a French Multicenter Study: What Happens at Five Years?

BACKGROUND: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up. METHODS: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals. RESULTS: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child-Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed. CONCLUSIONS: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective.

Prospective external validation of a new non-invasive test for the diagnosis of non-alcoholic steatohepatitis in patients with type 2 diabetes.

BACKGROUND: One of the unmet needs in patients with type 2 diabetes mellitus (T2DM) is the prediction of non-alcoholic liver disease by non-invasive blood tests, for each of the three main histological features, fibrosis, non-alcoholic steatohepatitis (NASH) and steatosis. AIMS: To validate externally the performances of a recent panel, Nash-FibroTest, for the assessment of the severity of fibrosis stages, NASH grades and steatosis grades. METHODS: We prospectively analysed 272 patients with T2DM. Standard definitions of stages and grades were used, and analyses were centralised and blinded. The performances of the FibroTest, NashTest-2 and SteatoTest-2 were assessed using the Obuchowski measure (OM), the main outcome recommended as a summary measure of accuracy includeing all pairwise stages and grades comparisons, which is not provided par the extensively used binary area under the ROC curve. RESULTS: The diagnostic performance of each component of the panel was significant. OM (SE; significance) of the FibroTest, the NashTest-2 and the SteatoTest-2 was 0.862 (0.012; P < 0.001), 0.827 (0.015; P < 0.001) and 0.794 (0.020; P < 0.01), respectively. For ballooning and lobular inflammation, OM was 0.794 (0.021; P < 0.001) and 0.821 (0.017; P < 0.001), respectively. In a post hoc analysis the FibroTest outperformed VCTE by 4.1% (2.5-6.5; P < 0.001) for reliability, with a non-significant difference for OM for fibrosis staging, 0.859 (0.012) for FibroTest vs 0.870 (0.009) for VCTE. CONCLUSIONS: From a single blood sample, the panel provides non-invasive diagnosis of the stages of fibrosis, and the grades of NASH and steatosis in patients with T2DM. TRIAL REGISTRATION NUMBER: NCT03634098.

Is elimination of HCV realistic by 2030: France.

The World Health Organization (WHO) has proposed a plan for the elimination of viral hepatitis with a goal of reducing new hepatitis infections by 30% and 90% in 2020 and 2030, and associated mortality by 10% and 65% respectively. Actions and targets to reach these goals include improving hepatitis B virus (HBV) vaccination programs, the prevention of mother-to-child transmission of HBV, improving the safety of blood products and injections, risk reduction policies and optimizing the diagnosis and treatment of hepatitis. The goal of eliminating hepatitis C virus (HCV) by 2030 is based on three main actions: increased screening, strengthening access to care and the prevention of infections and re-infections. But, can this goal be reached? The answer to this question is yes in some countries, perhaps in others and no in most countries. Success will be limited by a "diagnosis burn-out" with 5 times more new viral infections than diagnoses in 2016 and a "treatment burn-out" with cure rates that are 5 times lower than the number of new infections. Nevertheless, France, like 10 other countries, is on track to achieve the WHO elimination plan by 2030. In France, the prioritization of oral antivirals in 2013-2014 which was extended to high-risk populations in 2015 (HIV-infected patients) and 2016 (men who have sex with men, dialyzed or kidney transplant recipients), then in 2017 to universal treatment with full coverage by French national healthcare (10 to 15 000 treatments per year) has resulted in half of the 120 000 patients needed to be treated by 2022 have been treated. Renewed efforts should make it possible to reach the target announced by the French Minister of Health in May 2018 by 2025.

Review article: immunisation against hepatitis B virus infection and the prevention of hepatocellular carcinoma.

BACKGROUND: Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications: cirrhosis decompensation, hepatocellular carcinoma (HCC, the fourth most common cause of cancer-related mortality worldwide), liver transplantation and death. It is now 40 years since development of the first plasmatic vaccine which has been proven to prevent (liver) cancer. AIMS: To update firstly the molecular and epidemiological aspects of HBV-related HCC and its natural history together with the benefits associated with viral suppression and secondly the safety, immunogenicity and efficacy of HBV vaccination. METHODS: Analysis of recent published data regarding HBV replication, anti-viral treatments and vaccination. RESULTS: The nuclear HBV replication cycle in the hepatocyte combines two limiting steps to achievement of HBV cure during chronic infection: the formation of a minichromosome, the supercoiled cccDNA, and host-genome integration of HBV DNA which triggers direct viral hepatocarcinogenesis. Even if specific anti-viral treatments significantly reduce viral replication, they decrease but do not cancel the risk of liver-related events in contrast with the prevention of HBV through HBV vaccination. CONCLUSIONS: To achieve the 2030 viral hepatitis elimination plan, the HBV vaccine is a priority tool for achieving the sustainable development goals of the World Health Organization.

Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

Absence of impact of direct acting antivirals for hepatitis C virus on recurrent hepatocellular carcinoma tumor growth in the AFEF/ANRS CO22 Hepather cohort.

BACKGROUND: Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment. BASIC PROCEDURES: Thirty-nine HCV-infected patients from the AFEF/ANRS CO22 Hepather cohort who experienced HCC recurrence after so-called curative treatment were evaluated. Contrast-enhanced CT and/or MR images were read blindly 6 months before HCC recurrence and during the follow-up period. Seventeen patients who received DAA (DAA+) before HCC recurrence were compared to the 22 who did not receive (DAA-), according to the LiRads and mRECIST criteria. MAIN FINDINGS: There were 28 men and 11 women, median age 62 years old, 37 (95%) with cirrhosis. DAA+ patients had a lower median MELD score (8±2 vs. 10±4, P=0.0286) than DAA- patients. The median time to HCC recurrence (time from the date of curative treatment to the diagnosis of recurrence) was not different (20 vs. 18 months) (P=0.73) between the two groups. There was no difference between the 2 groups in the overall survival and/or transplantation-free survival (P=0.71) and for the mRECIST time to progression (P=0.25). CONCLUSION: This blinded analysis of HCC recurrence after HCC treatment does not support any negative impact of DAA therapy on the severity or progression of recurrent HCC.

Can we differentiate HIV-associated obliterative portopathy from liver cirrhosis using MRI?

AIM: To describe the magnetic resonance imaging (MRI) features of HIV-associated obliterative portopathy (HIV-OP) and determine the most indicative appearance of this condition on MRI by using a retrospective case-control study. METHODS: MRI examinations of 24 patients with HIV-OP (16 men, 8 women; mean age = 48 ± 6.6 [SD] years; age range, 35-71 years) were analyzed by two blinded observers and compared with those obtained in 18 HIV-infected patients with hepatic cirrhosis (14 men, 4 women; mean age = 51 ± 3.4 [SD] years; age range, 35-60 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. Comparisons were performed using uni- and multivariate analyses. RESULTS: Regular liver contours had the highest accuracy for the diagnosis of HIV-OP (83%, 35 of 42; 95% confidence interval [CI], 69-93%) and was the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio, 51; 95%CI, 4.96-1272%) (p < 0.0001). At multivariate analysis, the width of segment 4 in millimeters (OR = 1.23 [95%CI, 1.05-1.44%]; p = 0.011) and the presence of regular liver contours (OR = 7.69 [95%CI, 1.48-39.92%]; p = 0.015) were the variables independently associated with the diagnosis of HIV-OP. CONCLUSIONS: Regular liver contours are the most discriminating independent variable for the diagnosis of HIV-OP but have limited accuracy. Familiarity with this finding may help differentiate HIV-OP from cirrhosis in HIV-infected patients. KEY POINTS: • Regular liver contour is the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio = 51) with 83% accuracy. • At multivariate analysis, the width of segment 4 in millimeters and the presence of regular liver contours are the variables independently associated with the diagnosis of HIV-OP. • MRI helps diagnose HIV-OP in the presence of several categorical findings, which are more frequently observed in HIV-OP patients than in HIV patients with cirrhosis.

[Epidemiology of non-alcoholic steatohepatitis. Extent/burden of the problem and its impact on public health]. / Épidémiologie de la stéato-hépatite non alcoolique. Étendue du problème et son impact sur la santé publique.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, the most common cause of chronic liver function augmentation and it will be the most common indication for liver transplantation in 2020. The prevalence of NAFLD has increased over time in line with the increase of obesity and type 2 diabetes. There is a discrepancy between the studies concerning the prevalence of NAFLD because of the different diagnostic methods used (ultrasound or magnetic resonance, fibroscan, controlled attenuation parameter (CAP), histology). Because of its high prevalence the impact of NAFLD in public health is real. Therapeutic advances must be made to better understand the natural history of NAFLD and improve the management of this emerging liver disease.

[FIB-4 index to rule-out advanced liver fibrosis in NAFLD patients]. / L'index FIB-4 pour faire le diagnostic de fibrose hépatique avancée au cours de la stéatose hépatique.

The FIB-4 index is a biomarker of advanced hepatic fibrosis in a context of fatty liver disease. The calculation of the FIB-4 index requires of age, serum ALT and AST transaminase levels and platelet count. A FIB-4 index<1.45 in a context of fatty liver disease excludes clinically significant hepatic fibrosis. Additional explorations are mandatory to excluded hepatic fibrosis for a a FIB-4 index>1.45 in a context of fatty liver disease. A complete hepatological workup is mandatory for a FIB-4 index>3.25 in a context of fatty liver disease.

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

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

Direct-acting antivirals and hepatitis B virus (HBV) reactivation in co-infected HBV/HCV kidney-transplant recipients.

Direct-acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg-positive and HBsAg-negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA-associated sustained virological response in 3 kidney-transplant recipients initially HBsAg-negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti-HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation.

Transmission of Hepatitis E Virus With Plasma Exchange in Kidney Transplant Recipients: A Retrospective Cohort Study.

BACKGROUND: After observing a case of plasma exchange-mediated hepatitis E virus (HEV) infection in a kidney transplant recipient, we investigated the relationship between plasma exchange and HEV infection after kidney transplantation. METHODS: A cohort of 263 patients who underwent kidney transplantation from January 1, 2011, through December 31, 2012, was screened for HEV markers, including anti-HEV IgG and IgM antibodies and HEV ribonucleic acid (RNA), on 3 consecutive blood samples: 1 before, 1 with a mean (standard deviation) of 9.5 (9) months, and 1 with a mean (standard deviation) of 18.2 (6.6) months after transplantation, respectively. Transfusional investigation was performed in patients with detectable HEV RNA. We explored the relationships between plasma exchange, posttransplantation transaminase elevation and HEV markers acquisition. RESULTS: Overall, 24 (9.1%) patients had acquired HEV markers on the first posttransplantation sample, including 2 patients with detectable HEV RNA, and 7 (2.3%) patients had long-term persistent HEV markers on the second posttransplantation sample, including 3 patients with detectable HEV RNA without detectable anti-HEV antibodies. Plasma exchange was an independent risk factor for the acquisition of posttransplantation and long-term persistent HEV markers. Pathogen-reduced plasma-borne transmission of HEV was demonstrated. Plasma exchange and long-term persistent HEV markers were risk factors of posttransplantation transaminase elevation. CONCLUSIONS: Plasma exchange, including with pathogen-reduced plasma, is a risk factor for posttransplantation HEV infection and transaminase elevation. Screening for HEV RNA should be carried out in kidney transplant recipients treated with plasma exchange.

Extrahepatic cancers and chronic HCV infection.

Infectious agents, such as HCV, account for ∼15% of human cancers. HCV infects not only hepatocytes but also extrahepatic cells. Chronic HCV infection can induce chronic inflammation with qualitative and quantitative alterations of the immune repertoire and tissue microenvironment, which could induce various neoplasias. Epidemiological studies and meta-analyses suggest an increased rate of extrahepatic cancers in patients with chronic HCV infection along with a higher risk of intrahepatic cholangiocarcinoma, pancreatic cancer and non-Hodgkin lymphoma (NHL), highlighting the need to screen for HCV infection in patients with these cancers. Development of B cell NHL has been associated with HCV infection, with a relative risk of ∼1.5. Direct transformation related to the presence of the virus and chronic antigenic stimulation are the two major non-exclusive mechanisms involved in HCV-related lymphomagenesis. HCV infection alters survival of patients with lymphoma, and sustained virologic response (SVR) substantially improves prognosis. Antiviral treatments might induce remission of indolent lymphoma when SVR is achieved even without chemotherapy, emphasizing the role of HCV in lymphomagenesis in this context. However, studies are needed to provide prospective evidence of a causal relationship between chronic HCV infection and other extrahepatic cancers and to determine whether the risk of extrahepatic cancers is reduced with SVR. In this Review, we report on recent studies analysing the risk of extrahepatic cancers associated with chronic HCV infection. Although there is no doubt regarding the direct and indirect causality between HCV and NHL, an increased risk of other cancers is less clear, with the exception of cholangiocarcinoma.