Real-World Effectiveness and Safety of Direct-Acting Antivirals in Patients with Chronic Hepatitis C and Epilepsy: An Epi-Ter-2 Study in Poland.

INTRODUCTION: In Poland, active HCV infection affects between 0.4 and 0.5% of the population, i.e., about 150,000 people, while the number of patients with epilepsy is estimated to be 350,000-400,000. Currently available antiviral therapies show little interaction with neurological drugs. The aim of our study was to evaluate the effectiveness and safety of the treatment of chronic HCV infection in patients with coexisting epilepsy. METHODS: A total of 184 epilepsy patients were selected from the group of 10,152 HCV-infected patients treated for HCV infection within the Epiter-2 database from 2015 to 2018. Comparing the effectiveness and safety of anti-HCV regimens between the patients with comorbid epilepsy and 3573 patients without comorbidities was our study's objective. RESULTS: The effectiveness of anti-HCV treatment was high in both the sample and the control group. No statistically significant SVR difference was observed between the sample group, with ITT = 93.5% and mITT = 95.5%, and the control group, with ITT = 95.2% and mITT = 97.5%, regardless of the genotype and the stage of liver disease at the start of therapy. The treatment was safe in patients with epilepsy. CONCLUSIONS: The effectiveness and safety of HCV treatment in patients with epilepsy are comparable to those of patients with no significant comorbidities.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Impact of SARS CoV-2 /COVID-19 infection on the course of advanced chronic liver disease and hepatocellular carcinoma.

BACKGROUND: About 20% of patients infected with SARS-CoV-2 develop COVID-19-the disease that has dominated health care in the last two years. The course of COVID-19 in patients with advanced liver disease tends to be severe, patients also suffer from a higher risk of complications and death. The primary object of this study was to assess the risk and causes of death in patients with cirrhosis and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From a group of 4,314 patients hospitalized at Jerzy Gromkowski Regional Specialist Hospital in Wroclaw (Poland) due to SARS-CoV-2/COVID-19 infection between March 15, 2020, and January 31, 2022, we selected a cohort of 31 patients with liver cirrhosis (12 women and 19 men) and 7 patients with HCC developed on the cirrhotic liver (1 woman, 6 men). The control group included 123 patients without liver disease. In the entire cohort, we analyzed the course of COVID-19 infection, baseline oxygen demand, liver function (assessed using the CTP-Child-Turoctte-Pugh score and MELD-Model of End-Stage Liver Disease scales), length of hospitalization, development of acute-on-chronic liver failure, and deaths. RESULTS: The mean age of the patients was 56.6 years in the liver cirrhosis group, 63.3 years for patients with (HCC) hepatocellular carcinoma, and 64 years in the control group. Time of hospitalization averaged 15.52 days and 11.14 days for patients with liver cirrhosis and liver cancer, respectively. For the control group, the average duration of the hospital stay was 11.61 days. With respect to baseline liver function assessed using the CTP score, in the cirrhosis group 10 patients were CTP class A, 19 patients were class B and 9 patients were class C. The cancer group included 3 patients with class A, 2 patients with class B, and 2 patients with class C. In the studied cohort, 22 patients had a baseline MELD score < 12 points, and in 15 patients was > 12. In the HCC group, it was, respectively, CTP A:3, B: 2, C: 2, and MELD < 12: 3, ≥12: 4 people. Most of these patients presented with a progression of liver disease. Fifteen patients died, including 12 with cirrhosis and 3 with HCC, accounting for 39.47% in the entire cohort, 39% in the cirrhotic group and 43% in the HCC group, and 13 in the control group (10.6%), There was a clear statistical difference between the mortality rate in the group with liver disease and in the control group. CONCLUSIONS: Infection with SARS-CoV-2/COVID-19 in patients with cirrhosis and HCC tends to have a more severe course and leads to exacerbation of the liver disease. The most common cause of death in the analyzed cohort infected with SARS-CoV-2/COVID-19 was the progression of liver disease, complicated by liver failure.

Severe Breakthrough COVID-19 Cases during Six Months of Delta Variant (B.1.617.2) Domination in Poland.

The emergence of a highly transmissible and a more pathogenic B.1.617.2 (delta) variant of SARS-CoV-2 has brought concern over COVID-19 vaccine efficacy and the increased risk of severe breakthrough infections. The objective of this study was to assess the frequency and the clinical characteristics of severe breakthrough COVID-19 cases recorded in 10 Polish healthcare units between 1 June and 31 December 2021, a period during which a rapid surge in the share of B.1.617.2 infections was seen, while a significant number of populations were already fully vaccinated. Overall, 723 individuals who completed the initial vaccination regime (fully vaccinated group) and an additional 18 who received a booster dose were identified­together, they represented 20.8% of all the COVID-19 patients hospitalized during the same period in the same healthcare institutions (0.5% in the case of a group that received a booster dose). Although laboratory and clinical parameters did not differ between both groups, patients who received a booster tended to have lower CRP, IL-6, PCT, and d-dimer levels and they required oxygen therapy less frequently. The most common early COVID-19 symptoms in the studied group were fatigue, cough, fever (>38 °C), and dyspnea. Individuals with no detectable anti-spike IgG antibodies constituted 13%; the odds of being a humoral non-responder to the vaccine were increased in patients aged >70 years. Fully vaccinated patients hospitalized after more than 180 days from the last vaccine dose were significantly older and they were predominantly represented by individuals over 70 years and with comorbidities, particularly cardiovascular disease. Contrary to mRNA vaccines, most patients vaccinated with adenoviral vector vaccines were infected within six months. A total of 102 fatal cases (14% of all deaths among vaccinated individuals; 0.7% in the case of a group that received a booster dose) were recorded, representing 17.6% of all the COVID-19 fatalities recorded in June−December 2021 in the considered healthcare units. The odds of death were significantly increased in men, individuals aged >70 years, patients with comorbidities, and those identified as humoral non-responders to vaccination; in fully vaccinated patients the odds were also increased when the second vaccine dose was given >180 days before the first COVID-19 symptoms. The mortality rate in immunocompromised subjects was 19%. The results indicate that compared to vaccinated individuals, severe COVID-19 and deaths in the unvaccinated group were significantly more prevalent during the B.1.617.2-dominated wave in Poland; and, it highlight the protective role of a booster dose, particularly for more vulnerable individuals.

Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study.

Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child−Turcotte−Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity.

Liver Injury in Patients with COVID-19 without Underlying Liver Disease.

SARS-CoV-2 shows a high affinity for the ACE-2 receptor, present on the epithelial cells of the upper and lower respiratory tract, within the intestine, kidneys, heart, testes, biliary epithelium, and-where it is particularly challenging-on vascular endothelial cells. Liver involvement is a rare manifestation of COVID-19. MATERIAL AND METHODS: We reviewed 450 patients admitted due to the fact of SARS-CoV-2 infection (COVID-19) including 88 with liver injury. Based on medical history and previous laboratory test results, we excluded cases of underlying liver disease. The analysis involved a clinical course of COVID-19 in patients without underlying liver disease as well as the type and course of liver injury. RESULTS: Signs and symptoms of liver injury were present in 20% of patients, mostly presenting as a mixed-type pattern of injury with less common cases of standalone hepatocellular (parenchymal) or cholestatic injury. The liver injury symptoms resolved at the end of inpatient treatment in 20% of cases. Sixteen patients died with no cases where liver injury would be deemed a cause of death. CONCLUSIONS: (1) Liver injury secondary to COVID-19 was mild, and in in 20%, the signs and symptoms of liver injury resolved by the end of hospitalization. (2) It seems that liver injury in patients with COVID-19 was not associated with a higher risk of mortality. (3) The underlying mechanism of liver injury as well as its sequelae are not fully known. Therefore, caution and further monitoring are advised, especially in patients whose liver function tests have not returned to normal values.

Simple demographic characteristics and laboratory findings on admission may predict in-hospital mortality in patients with SARS-CoV-2 infection: development and validation of the covid-19 score.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a major health burden worldwide due to high mortality rates and hospital bed shortages. SARS-CoV-2 infection is associated with several laboratory abnormalities. We aimed to develop and validate a risk score based on simple demographic and laboratory data that could be used on admission in patients with SARS-CoV-2 infection to predict in-hospital mortality. METHODS: Three cohorts of patients from different hospitals were studied consecutively (developing, validation, and prospective cohorts). The following demographic and laboratory data were obtained from medical records: sex, age, hemoglobin, mean corpuscular volume (MCV), platelets, leukocytes, sodium, potassium, creatinine, and C-reactive protein (CRP). For each variable, classification and regression tree analysis were used to establish the cut-off point(s) associated with in-hospital mortality outcome based on data from developing cohort and before they were used for analysis in the validation and prospective cohort. The covid-19 score was calculated as a sum of cut-off points associated with mortality outcome. RESULTS: The developing, validation, and prospective cohorts included 129, 239, and 497 patients, respectively (median age, 71, 67, and 70 years, respectively). The following cut of points associated with in-hospital mortality: age > 56 years, male sex, hemoglobin < 10.55 g/dL, MCV > 92.9 fL, leukocyte count > 9.635 or < 2.64 103/µL, platelet count, < 81.49 or > 315.5 103/µL, CRP > 51.14 mg/dL, creatinine > 1.115 mg/dL, sodium < 134.7 or > 145.4 mEq/L, and potassium < 3.65 or > 6.255 mEq/L. The AUC of the covid-19 score for predicting in-hospital mortality was 0.89 (0.84-0.95), 0.850 (0.75-0.88), and 0.773 (0.731-0.816) in the developing, validation, and prospective cohorts, respectively (P < 0.001The mortality of the prospective cohort stratified on the basis of the covid-19 score was as follows: 0-2 points,4.2%; 3 points, 15%; 4 points, 29%; 5 points, 38.2%; 6 and more points, 60%. CONCLUSION: The covid-19 score based on simple demographic and laboratory parameters may become an easy-to-use, widely accessible, and objective tool for predicting mortality in hospitalized patients with SARS-CoV-2 infection.

Clinical Characteristics of Hospitalized COVID-19 Patients Who Received at Least One Dose of COVID-19 Vaccine.

The clinical trials of the COVID-19 vaccines that are authorized in the European Union have revealed high efficacy in preventing symptomatic infections. However, during vaccination campaigns, some vaccine recipients, including those partially and fully vaccinated, will experience severe COVID-19, requiring hospitalization. This may particularly concern patients with a diminished immune response to the vaccine, as well as non-responders. This work has retrospectively analyzed the 92 cases of patients who were hospitalized between 27 December 2020 and 31 May 2021 in four Polish healthcare units due to COVID-19, and who have previously received the COVID-19 vaccine (54.3% ≤ 14 days after the first dose, 26.1% > 14 days after the first dose, 7.6% ≤ 14 days after the second dose, and 12% > 14 days after the second dose). These patients represented a minute fraction (1.2%) of all the COVID-19 patients who were hospitalized during the same period in the same healthcare institutions. No significant differences in white blood count, absolute lymphocyte count nadir, C-reactive protein, interleukin-6, procalcitonin, oxygen saturation, lung involvement, and fever frequency were found between the recipients of the first and second vaccine dose. A total of 15 deaths were noted (1.1% of all fatal COVID-19 cases in the considered period and healthcare units), including six in patients who received the second dose (five > 14 days after the second dose)-three of these subjects were using immunosuppressive medicines, and two were confirmed to be vaccine non-responders. The study reassures that severe COVID-19 and deaths are not common in vaccinated individuals, highlights that the clinical course in such patients may not reveal any distinctive features, and advocates for close monitoring of those at a higher risk of vaccine failure.

Five-Year Follow-Up of Cured HCV Patients under Real-World Interferon-Free Therapy.

(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2-3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver.

Real-world effectiveness and safety of direct-acting antivirals in patients with cirrhosis and history of hepatic decompensation: Epi-Ter2 Study.

BACKGROUND AND AIMS: The aim of this study was to assess the real-life effectiveness and safety of direct acting antivirals (DAAs) in patients with cirrhosis and history of hepatic decompensation compared to those with compensated cirrhosis. METHOD: Data of patients treated with DAAs and included in the EpiTer-2 database (N = 10 152) were collected retrospectively. The primary endpoint was sustained viral response (SVR) at 12 weeks posttreatment. Patients were also evaluated in terms of liver-related adverse events and treatment modification/discontinuation. RESULTS: The overall SVR rate was 91.4% in the intent to treat (ITT) analysis and 95.2% in the per-protocol (PP) analysis (P < .001). Patients with decompensated cirrhosis had lower SVR rates compared to those with compensated cirrhosis in ITT analysis (86.4% vs 92.0%, P < .001), while not in PP analysis (92.9% vs 95.5%, P > .05). Adverse events (AE) occurred 45.6% and 29.3% of patients with decompensated and compensated cirrhosis (P < .001). Patients with decompensated cirrhosis were at higher risk of death (5.4% vs 0.9%; P < .0001) or liver decompensation (21.5% vs 1.3%; P < .0001). Treatment with protease inhibitors was not associated with hepatic decompensation (P = .3). Only 82.6% of patients with decompensated cirrhosis completed DAA treatment (vs 92.8% in compensated cirrhotics; P < .0001). CONCLUSION: Despite higher frequency of AE and treatment modifications, once completed, DAAs yield comparable results for patients with decompensated and compensated cirrhosis. High rate of serious adverse events in patients with advanced liver disease treated with PI may not be related to the detrimental effect of the medications, but rather to the disease itself.

Serum concentrations of selected adipokines in virus-related liver cirrhosis and hepatocellular carcinoma.

AIM OF THE STUDY: Hepatotropic viruses cause metabolic disturbances such as insulin resistance and hepatosteatosis. Moreover, metabolic factors, such as insulin resistance, obesity, and type 2 diabetes mellitus, increase the risk for hepatocellular carcinoma (HCC) in patients with virus-related liver cirrhosis. Cytokines secreted by the adipose tissue (adipokines) may be implicated in these metabolic disturbances, but there is little evidence regarding the role of adipokines in virus-related cirrhosis and HCC. Thus, we studied whether serum concentrations of selected adipokines were altered in patients with virus-related liver cirrhosis, including patients with HCC. MATERIAL AND METHODS: We included 43 patients with liver cirrhosis due to chronic hepatitis B or chronic hepatitis C. Of these patients, 36 had HCC and 7 did not have any malignant lesions. In addition to routine clinical and laboratory variables, we analyzed serum concentrations of betatrophin, insulin, vaspin, visfatin, and irisin. RESULTS: Compared with healthy controls, patients with HCC had significantly increased vaspin concentrations and significantly reduced irisin concentrations. Compared with controls, patients with virus-related cirrhosis, with or without HCC, had significantly increased concentrations of insulin and betatrophin. The serum visfatin concentration was non-significantly higher in patients with virus-related cirrhosis than in controls. None of the studied adipokines was a significant predictor of HCC. Serum concentrations of the studied adipokines were not related to cirrhosis severity or HCC stage. CONCLUSIONS: Metabolic parameters, including serum adipokine concentrations, are altered in patients with virus-related liver cirrhosis. Adipokines might be related to the HCC risk in these patients.

COVID-19, MERS and SARS with Concomitant Liver Injury-Systematic Review of the Existing Literature.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection has been predominantly linked to respiratory distress syndrome, but gastrointestinal symptoms and hepatic injury have also been reported. The mechanism of liver injury is poorly understood and may result as a consequence of viral hepatitis, systemic inflammatory response, gut barrier and microbiome alterations, intensive care treatment or drug toxicity. The incidence of hepatopathy among patients with coronavirus disease 2019 (COVID-19) is unclear, but studies have reported liver injury in patients with SARS and Middle East respiratory syndrome (MERS). We aimed to systematically review data on the prevalence of hepatic impairments and their clinical course in SARS and MERS Coronaviridae infections. A systematic literature search (PubMed/Embase/Cinahl/Web of Science) according to preferred reporting items for systematic review and meta-analysis protocols (PRISMA) was conducted from database inception until 17/03/2020 for studies that evaluated the incidence of hepatic abnormalities in SARS CoV-1, SARS CoV-2 and MERS infected patients with reported liver-related parameters. A total of forty-three studies were included. Liver anomalies were predominantly mild to moderately elevated transaminases, hypoalbuminemia and prolongation of prothrombin time. Histopathology varied between non-specific inflammation, mild steatosis, congestion and massive necrosis. More studies to elucidate the mechanism and importance of liver injury on the clinical course and prognosis in patients with novel SARS-CoV-2 infection are warranted.

Serum visfatin and vaspin levels in hepatocellular carcinoma (HCC).

Hepatocellular carcinoma (HCC) is the most common liver cancer, accountable for 90% cases. Visfatin and vaspin are adipocytokines with various suggested functions and proven significant correlations between BMI and percentage of body fat. The aim was to assess visfatin and vaspin serum levels in HCC patients and controls, compare their levels in patients with different cancer etiology and grade assessed according to the Barcelona-Clinic Liver Cancer (BCLC) staging system. The additional aim was to analyze relationship between analyzed adipokines and metabolic abnormalities and liver disfunction severity. The study was performed on 69 cirrhotic patients (54 males/15 females) with HCC, aged 59.0 ± 12.1 years, and with BMI 29.0 ± 4.5 kg/m2 compared to 20 healthy volunteers. Serum visfatin and vaspin concentrations were significantly increased in HCC patients compared to controls (p = 0.01 and p = 0.02, respectively). Serum vaspin was significantly higher in HCC patients with viral compared to those with non-viral etiology (p = 0.02), with more evident increase in chronic hepatitis C patients (CHC). Serum visfatin levels were significantly higher in patients with higher insulin resistance (p = 0.04) and with platelets count > 100 000/mm3 (p<0.001). Patients with BMI >30 kg/m2 had markedly up-regulated vaspin levels (p = 0.04). There was no difference in vaspin and visfatin serum levels with respect to liver dysfunction and BCLC classification. In conclusion, our study revealed serum vaspin and visfatin to be significantly increased in HCC patients independently of cancer etiology compared to controls. Additionally, serum vaspin was elevated in viral disease, especially in CHC. Vaspin up-regulation can be a compensatory mechanism against IR in HCC patients. Serum visfatin and vaspin, although up-regulated, seem not to be associated with cancer grade and cirrhosis severity.

Accurate prediction of significant liver fibrosis using the Pentra score model in patients with chronic hepatitis C.

INTRODUCTION: Noninvasive methods are increasingly used in the clinical assessment of patients with chronic hepatitis C (CHC). OBJECTIVES: We aimed to develop a predictive model for the evaluation of significant fibrosis in patients with CHC, based on serum biomarkers. We compared the accuracy of our model in detecting significant fibrosis with currently known markers / models of fibrosis (such as the aspartate aminotransferase to platelet ratio index [APRI], the Fibrosis­4 [FIB-4] score, and the Forns index). PATIENTS AND METHODS: A total of 242 patients with CHC not receiving antiviral treatment were divided into 2 groups: training group (n = 150) and validation group (n = 92). Significant fibrosis was defined as F2 or higher on the Meta­analysis of Histological Data in Viral Hepatitis (METAVIR) scale. RESULTS: Multivariable analysis revealed that age (P <0.001), pentraxin 3 (PTX3) levels (P = 0.009), γ­glutamyl transpeptidase (GGT) to platelet count (PLT) ratio (P = 0.08), and hyaluronic acid levels (HA) (P = 0.07) were independent predictors of significant fibrosis. Based on that, we developed a model for predicting significant fibrosis: Pentra score = 0.176 × PTX3 (ng/ml) + 0.522 × HA (ng/ml) + 0.29 × GGT (IU/l) to PLT (×109/l) ratio + 0.14 × age (years) - 3.9346. Then, we compared our model with the biomarkers and models currently used to predict liver fibrosis. The Pentra score yielded the largest area under the receiver operating characteristic curve for predicting significant fibrosis in the training and validation groups (0.894 and 0.867, respectively). It also had the highest diagnostic accuracy in both groups (90.6% and 87.0%, respectively). CONCLUSIONS: Our model for detecting significant fibrosis in patients with CHC using pentraxin 3 and other serum biomarkers compares well with the existing and previously published indices. However, further validation in larger cohorts is needed.

Pentraxin 3 Detects Clinically Significant Fibrosis in Patients with Chronic Viral Hepatitis C.

Pentraxin 3 (PTX3) plays a pathogenic role in experimental models of chronic liver injury and contributes to the progression of fibrosis. The detection of advanced fibrosis (METAVIR F≥3) is important to identify patients who are in urgent need of antiviral treatments versus those whose treatment could be deferred (F≥2). The aim was to assess the diagnostic value of PTX3 as a potential biomarker for clinically significant and advanced fibrosis. PTX3 associations with biochemical and histological parameters of inflammatory activity and fibrosis were investigated in 138 patients with chronic viral hepatitis C (HCV) before antiviral treatment. METAVIR histological scores of activity and fibrosis were obtained. PTX3 was measured by enzyme-linked immunosorbent assay. The diagnostic accuracy of serum PTX3 levels was compared to that of other fibrosis markers, including transforming growth factor-ß 1 (TGF-ß 1), hyaluronic acid (HA), aspartate transaminase to platelet ratio index (APRI), fibrosis score based on four factors (FIB4), gamma-glutamyltranspeptidase to platelet ratio (GPR), and the liver stiffness measurement (LSM) by transient elastography (FibroScan®). In HCV patients the PTX3 level increased in parallel with the METAVIR histological score of activity, being independently associated with the METAVIR fibrosis score (P < 0.001). Using the receiver operating characteristics analysis, the best marker for detecting F≥2 and F≥3 was PTX3 with AUC = 0.802 and AUC = 0.867, respectively. The area under the curve of PTX3 for predicting significant fibrosis (F≥2) was significantly greater than those for the GPR ratio (AUC = 0.648) and FIB-4 score (AUC = 0.770) and similar to that for APRI index (AUC = 0.831). PTX3 provided clinically relevant diagnostic accuracy as a single marker of significant fibrosis.

Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.