Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

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

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

Determinants of worse liver-related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort.

OBJECTIVES: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated. METHODS: People living with HIV (PLWH) from Italian Foundation cohort Naïve antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. PRIMARY END-POINT: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence. RESULTS: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 > 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 < 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5). CONCLUSIONS: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments.

Uncover a microbiota signature of upper respiratory tract in patients with SARS-CoV-2 + .

The outbreak of Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, forced us to face a pandemic with unprecedented social, economic, and public health consequences. Several nations have launched campaigns to immunize millions of people using various vaccines to prevent infections. Meanwhile, therapeutic approaches and discoveries continuously arise; however, identifying infected patients that are going to experience the more severe outcomes of COVID-19 is still a major need, to focus therapeutic efforts, reducing hospitalization and mitigating drug adverse effects. Microbial communities colonizing the respiratory tract exert significant effects on host immune responses, influencing the susceptibility to infectious agents. Through 16S rDNAseq we characterized the upper airways' microbiota of 192 subjects with nasopharyngeal swab positive for SARS-CoV-2. Patients were divided into groups based on the presence of symptoms, pneumonia severity, and need for oxygen therapy or intubation. Indeed, unlike most of the literature, our study focuses on identifying microbial signatures predictive of disease progression rather than on the probability of infection itself, for which a consensus is lacking. Diversity, differential abundance, and network analysis at different taxonomic levels were synergistically adopted, in a robust bioinformatic pipeline, highlighting novel possible taxa correlated with patients' disease progression to intubation.

Trends in chronic hepatitis B virus infection in Italy over a 10-year period: Clues from the nationwide PITER and MASTER cohorts toward elimination.

OBJECTIVES: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy. METHODS: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used. RESULTS: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P <0.0001) and that of anti-hepatitis D virus (HDV) remained stable (9.3% vs 8.3%). In both cohorts, about 25% of the patients had cirrhosis, and those in the PITER cohort were older. HBeAg-positive was 5.0% vs 12.6% (P <0.0001) and anti-HDV positive 24.8% vs 17.5% (P <0.0017). In the logistic model, the variables associated with cirrhosis were anti-HDV-positive (odds ratio = 10.08; confidence interval 7.63-13.43), age, sex, and body mass index; the likelihood of cirrhosis was reduced by 40% in the PITER cohort. Among non-Italians, 12.3% were HBeAg-positive (vs 23.4% in the MASTER cohort; P <0.0001), and 12.3% were anti-HDV-positive (vs 11.1%). Overall, the adherence to the European Association for the Study of the Liver recommendations for antiviral treatment increased over time. CONCLUSION: Chronic hepatitis B virus infection appears to be in the process of becoming under control in Italy; however, HDV infection is still a health concern in patients with cirrhosis and in migrants.

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

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

Hepatitis delta coinfection in persons with HIV: misdiagnosis and disease burden in Italy.

Hepatitis Delta virus (HDV) causes severe liver disease. Due to similarities in transmission routes, persons living with HIV (PLWH) are at risk of HDV infection. This analysis investigates the prevalence and the long-term clinical outcome of people with HDV in a large cohort of PLWH. We retrieved HBsAg ± anti-HDV positive PLWH enrolled from 1997 to 2015 in the multicentre, prospective ICONA study. The primary endpoint was a composite clinical outcome (CCO = having experienced ≥1 of the following: Fib4 score >3.25; diagnosis of cirrhosis; decompensation; hepatocellular carcinoma or liver-related death). Kaplan-Meier curves and unweighted and weighted Cox regression models were used for data analysis. Less than half of HBsAg positive patients had been tested for anti-HDV in clinical practice. After testing stored sera, among 617 HBV/HIV cases, 115 (19%) were anti-HDV positive; 405 (65%) HBV monoinfected; 99 (16%) undeterminate. The prevalence declined over the observation period. HDV patients were more often males, intravenous drug users, HCV coinfected. After a median of 26 months, 55/115 (48%) developed CCO among HDV+; 98/403 (24%) among HBV monoinfected; 18/99 (18%) in HDV unknown (p < 0.001). After controlling for geographical region, alcohol consumption, CD4 count, anti-HCV status and IFN-based therapies, the association with HDV retained statistical significance [HR = 1.67 (1.15, 2.95; p = 0.025)]. HDV infection among PLWH is underdiagnosed, although HDV entails an high risk of liver disease progression. Because effective drugs to treat HDV are now available, it is even more crucial to identify PLWH at an early stage of liver disease.

Impact of antigen test target failure and testing strategies on the transmission of SARS-CoV-2 variants.

Population testing remains central to COVID-19 control and surveillance, with countries increasingly using antigen tests rather than molecular tests. Here we describe a SARS-CoV-2 variant that escapes N antigen tests due to multiple disruptive amino-acid substitutions in the N protein. By fitting a multistrain compartmental model to genomic and epidemiological data, we show that widespread antigen testing in the Italian region of Veneto favored the undetected spread of the antigen-escape variant compared to the rest of Italy. We highlight novel limitations of widespread antigen testing in the absence of molecular testing for diagnostic or confirmatory purposes. Notably, we find that genomic surveillance systems which rely on antigen population testing to identify samples for sequencing will bias detection of escape antigen test variants. Together, these findings highlight the importance of retaining molecular testing for surveillance purposes, including in contexts where the use of antigen tests is widespread.

Recent breakthroughs in the treatment of chronic hepatitis Delta.

Hepatitis Delta virus (HDV) is responsible for the most aggressive form of chronic hepatitis, which may evolve towards cirrhosis, hepatocellular carcinoma and death within few years. During the last 30 years the only available therapy was interferon or peg-IFN, which was characterized by poor tolerability and modest results. The detailed knowledge of the HDV replication cycle and its interaction with HBV allowed the introduction of new drugs which are currently in phase II or III of experimentation. Basically, bulevirtide, to date the only one approved by EMA, inhibits the entry of the virus into the hepatocytes and hence its intrahepatic spread; lonafarnib inhibits the pharnesylation process of the L-HDAg, which is critical for the assembly of the HDV virion; the nucleic acid polymers (NAPs) mainly block the production/release of HBsAg. The available clinical trials with these compounds showed an excellent anti-viral activity against HDV.

A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort.

BACKGROUND AND AIMS: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. APPROACH AND RESULTS: Direct-acting antiviral-treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. CONCLUSION: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Liver function following hepatitis C virus eradication by direct acting antivirals in patients with liver cirrhosis: data from the PITER cohort.

BACKGROUND: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA. METHODS: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication. RESULTS: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8-47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0-44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00-6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18-3.36), platelet count < 100,000/µl (HR = 1.75; 95% CI 1.08-2.85) and increased INR (HR = 2.41; 95% CI 1.51-3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p = 0.83). CONCLUSIONS: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease.

Liver Transplantation for T2 Hepatocellular Carcinoma during the COVID-19 Pandemic: A Novel Model Balancing Individual Benefit against Healthcare Resources.

The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study was to provide a quantitative model to aid decision-making in liver transplantation for T2 HCC. We proposed a novel ethical framework where the individual transplant benefit for a T2 HCC patient should outweigh the harm to others on the waiting list, determining a "net benefit", to define appropriate organ allocation. This ethical framework was then translated into a quantitative Markov model including Italian averages for waiting list characteristics, donor resources, mortality, and transplant rates obtained from a national prospective database (n = 8567 patients). The net benefit of transplantation in a T2 HCC patient in a usual situation varied from 0 life months with a model for end-stage liver disease (MELD) score of 15, to 34 life months with a MELD score of 40, while it progressively decreased with acute organ shortage during a pandemic (i.e., with a 50% decrease in organs, the net benefit varied from 0 life months with MELD 30, to 12 life months with MELD 40). Our study supports the continuation of transplantation for T2 HCC patients during crises such as COVID-19; however, the focus needs to be on those T2 HCC patients with the highest net survival benefit.

Overview of Prognostic Systems for Hepatocellular Carcinoma and ITA.LI.CA External Validation of MESH and CNLC Classifications.

Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described.

An Increase in the Levels of Middle Surface Antigen Characterizes Patients Developing HBV-Driven Liver Cancer Despite Prolonged Virological Suppression.

Hepatitis B virus (HBV) contains three surface glycoproteins-Large-HBs (L-HBs), Middle-HBs (M-HBs), and Small-HBs (S-HBs), known to contribute to HBV-driven pro-oncogenic properties. Here, we examined the kinetics of HBs-isoforms in virologically-suppressed patients who developed or did not develop hepatocellular carcinoma (HCC). This study enrolled 30 chronically HBV-infected cirrhotic patients under fully-suppressive anti-HBV treatment. Among them, 13 patients developed HCC. Serum samples were collected at enrolment (T0) and at HCC diagnosis or at the last control for non-HCC patients (median (range) follow-up: 38 (12-48) months). Ad-hoc ELISAs were designed to quantify L-HBs, M-HBs and S-HBs (Beacle). At T0, median (IQR) levels of S-HBs, M-HBs and L-HBs were 3140 (457-6995), 220 (31-433) and 0.2 (0-1.7) ng/mL. No significant differences in the fraction of the three HBs-isoforms were noticed between patients who developed or did not develop HCC at T0. On treatment, S-HBs showed a >25% decline or remained stable in a similar proportion of HCC and non-HCC patients (58.3% of HCC- vs. 47.1% of non-HCC patients, p = 0.6; 25% of HCC vs. 29.4% of non-HCC, p = 0.8, respectively). Conversely, M-HBs showed a >25% increase in a higher proportion of HCC compared to non-HCC patients (50% vs. 11.8%, p = 0.02), in line with M-HBs pro-oncogenic role reported in in vitro studies. No difference in L-HBs kinetics was observed in HCC and non-HCC patients. In conclusion, an increase in M-HBs levels characterizes a significant fraction of HCC-patients while under prolonged HBV suppression and stable/reduced total-HBs. The role of M-HBs kinetics in identifying patients at higher HCC risk deserves further investigation.

CD8+ T cells specific to apoptosis-associated epitopes are expanded in patients with chronic HBV infection and fibrosis.

BACKGROUND & AIMS: During chronic viral infections, the apoptosis of activated T cell elicits a CD8+ T cell response directed to those cryptic epitopes that emerge from caspase-cleaved structural proteins. Such response directed to apoptosis-associated epitopes (AEs) contributes to the amplification of immunopathology. METHODS: Here, we have analysed through flow cytometry AE-specific CD8+ T cells in patients with chronic hepatitis B virus (HBV) infection, naïve-to-treatment or undergoing nucleos(t)ide-analogue (NUC) therapy. RESULTS: We found that AE-specific CD8+ T cell frequencies were significantly increased only in those NUC-treated patients who also presented advanced hepatic fibrosis. Regulatory T cells were also expanded in those patients, and AE-specific, but not HBV-specific, CD8+ T cell frequency positively correlated with Treg percentages. Through multiparameter flow cytometry, multidimensionality reduction and unsupervised clustering analysis, we could identify novel subpopulations among effector memory (em) and emCD45RA+ T cell (Tem and Temra) subsets. CD8+ T cells with distinct specificities differentially populated the subpopulation map: while HBV-specific were mostly contained in the Tem subset, AE-specific CD8+ T cells encompassed naïve, as well as T central memory, Tem and Temra cells. CONCLUSION: All together, these findings indicate a link between AE-specific CD8+ T cells and advanced liver fibrosis in patients with chronic HBV infection, and suggest that virus-specific and AE-specific CD8+ T cells exhibit distinct differentiation states and contribute in distinct ways to immunopathology.

Changing indications for liver transplant: slow decline of hepatitis viruses in Italy.

Background: The indications to LT are changing rapidly in Europe and the U.S. mainly due to the extensive use of direct-acting antiviral agents (DAA) against HCV. Italy was an endemic area for viral hepatitis.Methods: The study reviewed liver transplant registry of a leading Italian centre from the year 2014 (the year before the extensive use of DAA in Italy) to December 2018, with the scope of recording trends in indications. The indications were categorised as: HCV; HBV ± HDV; alcohol-dependent liver disease (ALD); NASH; mescellaneous. Transplants for decompensation or hepatocellular carcinoma were analysed separately. The data were analysed using standard statistical methods.Results: During the study period 463 LTs were accomplished. For the scope of the present study second transplants and transplant in patients <18 years were eliminated; in all, 397 patients were analysed. Overall, HCV infection was the main aetiological factor leading to transplant (139/397, 35%) followed by alcohol use (20.9%), HBV ± HDV (15.8%) and NASH (12.8%). In the decompensation group HCV decreased from 41.9% in 2014 to 14.3% in 2018 while alcohol increased (p < .001); in the HCC group, HCV decreased from 52.6% to 34% and alcohol and NASH increased; the number and proportion of HBV infections remained stable over time, with a 56% prevalence of HDV among decompensated patients.Conclusion: LT landscape is rapidly evolving; hepatitis virus infections still maintain a remarkable proportion among the indications for LT in an area that reached in the past high endemic levels for hepatitis C and B.

Prophylaxis of Hepatitis B Virus (HBV) Re-Infection in Liver Transplantation: Is the Reappearance of Hepatitis B Surface Antigen (HBsAg) Significant?

The recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) was in the past a primary cause of organ loss or mortality. Currently, post-OLT prophylaxis with anti-HBs immunoglobulins plus a nucleos(t)ide analogue has virtually abolished the risk of re-infection. Some studies have proposed to simplify prophylaxis by discontinuing immunoglobulins while continuing the analogue alone. This review analysed the available studies, focusing on the recurrence of HBsAg in serum and its biological effects. In all, 16 studies were retrieved, mainly observational or retrospective, each enrolling 14 to 80 patients. Our review of the literature found that HBsAg re-appeared in 0% to 24% of the patients, generally with HBV DNA undetectable in plasma. One study measured HBsAg using a new ultra-sensitive method, which could allow a reappraisal of the incidence of recurrence. This review discusses the role of HBV surface proteins in inducing hepatocellular carcinoma, particularly when mutations in the C-terminal occur that induce stop-codons that cause defects of secretion and retention of truncated protein S, resulting in direct cell toxicity and cancer. The data on the suspension of immunoglobulins in the prophylaxis regimes of post-transplant re infection do not appear sufficiently robust for an extensive and safe application in clinical practice.

Real-life use of elbasvir/grazoprevir in adults and elderly patients: a prospective evaluation of comedications used in the PITER cohort.

BACKGROUND: In patients treated for HCV infection, potential drug-drug interactions (DDIs) can occur among direct-acting antiviral drugs (DAAs) and comedications used. The real-life effectiveness and safety of elbasvir/grazoprevir (ELB/GZR) among co-medicated HCV patients was evaluated. METHODS: We prospectively evaluated consecutive patients from 15 clinical centres participating in PITER who were treated with ELB/GZR and had been followed for at least 12 weeks after treatment. Data were prospectively collected on the use of comedications (including discontinuation, dose modification and addition of drugs) and potential DDIs with DAAs. RESULTS: Of the 356 patients with at least 12-week post-treatment follow-up (median age 67, range 50-88 years), 338 (95%) achieved sustained virological response. Of these, 219 (60%) had at least one comorbidity (median 2, range 1-6); information on comedication was available for 212 of them. Of 190 comedications used, 15 (8%) drugs were modified during ELB/GZR therapy, specifically in 9 (4%) patients they were interrupted, in 2 (1%) of whom, the comedication was interrupted before the DAA therapy because of potential DDI (that is, patients treated with carbamazepine); in 12 (6%) patients the comedications were modified in terms of dosage. In 29 (14%) patients, the comedications required monitoring when used with ELB/GZR, as well as with all available DAAs. Of the 190 drugs, 27 (14%) used in 67% of patients were free of DDIs when used with ELB/GZR, whereas they required monitoring if used with other DAA regimens. CONCLUSIONS: The results of this prospective study support findings that ELB/GZR is effective and safe in most treated patients.