Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

EASL position paper on clinical follow-up after HCV cure.

Following the advent of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection can be cured in almost all infected patients. This has led to a number of clinical questions regarding the optimal management of the millions of patients cured of HCV. This position statement provides specific guidance on the appropriate follow-up after a sustained virological response in patients without advanced fibrosis, those with compensated advanced chronic liver disease, and those with decompensated cirrhosis. Guidance on hepatocellular carcinoma risk assessment and the management of extrahepatic manifestations of HCV is also provided. Finally, guidance is provided on the monitoring and treatment of reinfection in at-risk patients. The recommendations are based on the best available evidence and are intended to help healthcare professionals involved in the management of patients after treatment for HCV.

Post-treatment LSM rather than change during treatment predicts decompensation in patients with cACLD after HCV cure.

BACKGROUND & AIMS: Baveno VII has defined a clinically significant (i.e., prognostically meaningful) decrease in liver stiffness measurement (LSM) in cACLD as a decrease of ≥20% associated with a final LSM <20 kPa or any decrease to <10 kPa. However, these rules have not yet been validated against direct clinical endpoints. METHODS: We retrospectively analysed patients with cACLD (LSM ≥10 kPa) with paired liver stiffness measurement (LSM) before (BL) and after (FU) HCV cure by interferon-free therapies from 15 European centres. The cumulative incidence of hepatic decompensation was compared according to these criteria, considering hepatocellular carcinoma and non-liver-related death as competing risks. RESULTS: A total of 2,335 patients followed for a median of 6 years were analysed. Median BL-LSM was 16.6 kPa with 37.1% having ≥20 kPa. After HCV cure, FU-LSM decreased to a median of 10.9 kPa (<10 kPa: 1,002 [42.9%], ≥20 kPa: 465 [19.9%]) translating into a median LSM change of -5.3 (-8.8 to -2.4) kPa corresponding to -33.9 (-48.0 to -15.9) %. Patients achieving a clinically significant decrease (65.4%) had a significantly lower risk of hepatic decompensation (subdistribution hazard ratio: 0.12, 95% CI 0.04-0.35, p <0.001). However, these risk differences were primarily driven by a negligible risk in patients with FU-LSM <10 kPa (5-year cumulative incidence: 0.3%) compared to a high risk in patients with FU-LSM ≥20 kPa (16.6%). Patients with FU-LSM 10-19.9 kPa (37.4%) also had a low risk of hepatic decompensation (5-year cumulative incidence: 1.7%), and importantly, the risk of hepatic decompensation did not differ between those with/without an LSM decrease of ≥20% (p = 0.550). CONCLUSIONS: FU-LSM is key for risk stratification after HCV cure and should guide clinical decision making. LSM dynamics do not hold significant prognostic information in patients with FU-LSM 10-19.9 kPa, and thus, their consideration is not of sufficient incremental value in the specific context of HCV cure. IMPACT AND IMPLICATIONS: Liver stiffness measurement (LSM) is increasingly applied as a prognostic biomarker and commonly decreases in patients with compensated advanced chronic liver disease achieving HCV cure. Although Baveno VII proposed criteria for a clinically significant decrease, little is known about the prognostic utility of LSM dynamics (changes through antiviral therapy). Interestingly, in those with a post-treatment LSM of 10-19.9 kPa, LSM dynamics did not provide incremental information, arguing against the consideration of LSM dynamics as prognostic criteria. Thus, post-treatment LSM should guide the management of patients with compensated advanced chronic liver disease achieving HCV cure.

Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

INTRODUCTION: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN. RESULTS: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

Anticancer drugs are the first cause of drug-induced liver injury in a reference hospital.

Drug-induced liver injury (DILI) is a challenging liver disorder for hepatologists. We aimed to assess the pattern and causes of DILI in a tertiary hospital. We registered prospectively all patients referred with suspicion of DILI from 2018 to 2023. A total of 106 patients fulfilled the diagnostic criteria (30 caused by paracetamol were excluded; total number 76). The pattern of liver injury was hepatocellular in 55 (72%). Drugs causing DILI were antineoplastic (26%), antibiotics (24%), analgesics (12%), and recreational drugs (9%). Regarding clinical outcomes, 39 (51%) required hospitalization and 7 (9%) underwent a liver transplantation or died from acute liver injury. We identified 126 additional patients with DILI due to immune check-point inhibitors who were not referred to a liver disease specialist. Antineoplastic drugs have become the first cause of DILI in hospitals. A multidisciplinary approach and specific educational tools to increase DILI awareness are needed among different specialists.

The role of HBIG in real life for patients undergoing liver transplantation due to HDV-related cirrhosis.

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.

Characterizing Hepatitis Delta in Spain and the gaps in its management.

BACKGROUND AND AIMS: Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated HDV prevalence in Spain is around 5% of patients with hepatitis B. Reimbursement of new antiviral therapies (Bulevirtide, BLV) was delayed in our country until February 2024. We aimed to characterize the clinical profile of patients with HDV/HBV infection in Spain and current barriers in their management at the time of BLV approval. METHOD: Multicenter registry including patients with positive anti-HDV serology actively monitored in 30 Spanish centers. Epidemiological, clinical and virological variables were recorded at the start of follow-up and at the last visit. RESULTS: We identified 329 anti-HDV patients, 41% were female with median age 51 years. The most common geographical origin was Spain (53%) and East Europe (24%). Patients from Spain were older and had HCV and HIV coinfection probably associated to past drug injection (p<0.01). HDV-RNA was positive in 138 of 221 assessed (62%). Liver cirrhosis was present at diagnosis in 33% and it was more frequent among viremic patients (58% vs 25%, p<0.01). After a median follow-up of 6 (3-12) years, 44 (16%) resolved infection (18 spontaneously and 26 after Peg-INF). An additional 10% of patients developed cirrhosis (n=137) during follow-up (45% had portal hypertension and 14% liver decompensation). Liver disease progression was associated to persisting viremia. CONCLUSION: One-third of the patients with CHD already have cirrhosis at diagnosis. Persistence of positive viremia is associated to rapid liver disease progression. Importantly, barriers to locally determine/quantify HDV-RNA were present.

Differential Relapse Patterns After Discontinuation of Entecavir vs Tenofovir Disoproxil Fumarate in Chronic Hepatitis B.

BACKGROUND AND AIMS: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. METHODS: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. RESULTS: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. CONCLUSIONS: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.

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

BACKGROUND & AIMS: 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). METHODS: 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. RESULTS: 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 of hepatic decompensation and hepatocellular carcinoma was 0.48 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. CONCLUSIONS: The best candidates for NA withdrawal are virally suppressed, HBeAg- negative, noncirrhotic patients with CHB with low HBsAg levels, particularly Whites with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.

Incidence of Hepatic Decompensation After Nucleos(t)ide Analog Withdrawal: Results From a Large, International, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study).

INTRODUCTION: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS: This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS: Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION: Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.

Usefulness of dried blood spot samples for monitoring hepatitis C treatment outcome and reinfection among people who inject drugs in a test-and-treat program.

Dried blood spots (DBS) are a reliable tool to diagnose viremic hepatitis C virus (HCV) infection. We evaluated the clinical performance of a DBS-based molecular assay for the assessment of cure and reinfection after on-site treatment at a harm reduction center (HRC). Genotyping from DBS samples was also assessed to discriminate reinfection from treatment failure. People who inject drugs (PWID) from an ongoing test-and-treat pilot at the largest HRC in Barcelona were included in the study. HCV-RNA detection from DBS collected after treatment (with follow-up at 12, 36, and 60 weeks) was compared with a molecular point-of-care test using finger-stick blood (GeneXpert). Baseline and follow-up DBS samples were genotyped by NS5B sequencing or commercial real-time PCR. Among treated patients, 193 follow-up DBS samples were tested. The DBS-based assay showed 100% specificity (129/129), and sensitivity ranged from 84.4% to 96.1% according to different viral load cut-offs (from detectable to 3000 IU/mL). Sensitivity as test of cure (follow-up 12) ranged from 85.1% to 97.4%. Among the 64 patients with recurrent viremia, 10.9% had low viral loads (≤1000 IU/mL); HCV genotyping allowed us to classify 73.5% of viremic cases either as reinfection or as treatment failure. DBS samples are useful to assess cure and differentiate reinfection from relapse after HCV antiviral treatment in the real world, facilitating decentralization of treatment and posttreatment follow-up in PWID. However, a fraction of patients presented with low viral loads, limiting viremia detection and genotyping in DBS and, therefore, repeat testing is recommended.

Low risk of viral hepatitis amongst patients with severe mental disorders.

BACKGROUND AND AIMS: Patients with severe mental disorders (SMD) have been classically considered as a particularly high-risk population for bloodborne virus infections. We performed a systematic screening of hepatitis B and C virus among the population with SMD in the area of influence of Hospital Clínic (Barcelona) in order to evaluate the real prevalence of these infections and achieve HCV microelimination in this subpopulation. METHODS: We screened two cohorts for anti-HCV and HBsAg: Cohort A (hospitalized patients with SMD, done systematically) and Cohort B (outpatients, mental health centre-CSMA, done voluntarily). Risk factors and socio-demographic variables were collected. In positive cases, telematic review was activated by Hepatology, calculation of FIB-4 and prescription of direct-acting agents (DAA) in HCV or follow-up in HBV. RESULTS: In Cohort A, 404 patients were screened. 3 HBV patients were detected (0.7%). In all of them, there was a history of drug use. 12 anti-HCV positive patients were detected (3%); 8 of them had a history of drug use. Among the HCV positive, only 2 patients were viraemic (received DAA, both achieving SVR) as most of them (n = 6) had already been cured with DAA. In cohort B, 305 patients were screened, after 542 (64% of the target population) declined to participate. No cases of HCV or HBV were detected. CONCLUSIONS: HCV/HBV prevalence among SMD population with no history of drug use does not seem to be different from the general population. These data may be of interest for defining health policies.

Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

BACKGROUND AND AIMS: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR). METHODS: The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package). RESULTS: Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%. CONCLUSIONS: A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR.

Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Oportunistic diagnosis based on age and hepatitis C virus clearance: an essential step to improve the overall health of the liver.

Back in January 2022, an EASL-Lancet Commission on the impact of liver disorders in the European region commissioned by the WHO demonstrated that this condition is, actually, the second leading cause of loss of labor years in Europe after ischemic heart disease (1). This is a very relevant piece of information since this is something that is going to impact the new generations of Europeans unless a significant change is made in public health policies. Despite the advances made over the last few years in hepatitis C virus clearance-understood as a significant reduction of morbidity and mortality associated with Hepatitis B and C viruses-there are still challenges ahead to improve liver health due to the high use of alcohol, and the inseparable triad obesity / diabetes mellitus / metabolic associated fatty liver disease. Also, access to healthcare for several population groups at risk of presenting higher rates of liver disease has become a problem.

Recommendations for the integral diagnosis of chronic viral hepatitis in a single analytical extraction. / Recomendaciones para el diagnóstico integral de las hepatitis virales crónicas en una única extracción analítica.

The Spanish Society of Digestive Pathology (SEPD), the Spanish Association for the Study of the Liver (AEEH), the Spanish Society of Infections and Clinical Microbiology (SEIMC) and its Viral Hepatitis Study Group (GEHEP), and with the endorsement of the Alliance for the Elimination of Viral Hepatitis in Spain (AEHVE), have agreed on a document to carry out a comprehensive diagnosis of viral hepatitis (B, C and D), from a single blood sample; that is, a comprehensive diagnosis, in the hospital and/or at the point of care of the patient. We propose an algorithm, so that the positive result in a viral hepatitis serology (B, C and D), as well as human immunodeficiency virus (HIV), would trigger the analysis of the rest of the virus, including the viral load when necessary, in the same blood draw. In addition, we make two additional recommendations. First, the need to rule out a previous hepatitis A virus (VHA) infection, to proceed with its vaccination in cases where IgG-type studies against this virus are negative and the vaccine is indicated. Second, the determination of the HIV serology. Finally, in case of a positive result for any of the viruses analyzed, there must be an automated alerts and initiate epidemiological monitoring.

mTOR inhibitors a potential predisposing factor for chronic hepatitis E: Results from the prospective collaborative CHES study (Chronic Hepatitis EScreening in patients with immune impairment and increased transaminases levels).

BACKGROUND: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. PATIENTS AND METHODS: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. RESULTS: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. CONCLUSIONS: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E.

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort. METHODS: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers. RESULTS: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance. CONCLUSIONS: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound.

Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules.

BACKGROUND & AIMS: Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population. METHODS: We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months. RESULTS: A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified. CONCLUSIONS: Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs. LAY SUMMARY: Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients.

Non-invasive tests for clinically significant portal hypertension after HCV cure.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting. METHODS: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort). RESULTS: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%). CONCLUSIONS: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment. LAY SUMMARY: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden.