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To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

High alcohol intake leads to an inadequate diet and impaired absorption, transport, and utilization of nutrients in the body, which results in malnutrition. Micronutrient supplementation, such as vitamins A, E, group B vitamins, folic acid zinc, and selenium may have a positive effect on those patients. In this article, the actual supplementation recommendations for vitamins and microelements in ethanol-induced liver disease patients are presented.

Hepatitis C infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, more and more is being heard about extrahepatic manifestations of the hepatitis C infection including its possible influence on the development of hypertension and cardiovascular diseases. In the given work, the frequency analysis of the incidence of hypertension and cardiovascular diseases among 2898 HCV-infected patients treated in Poland and the assessment of their relevance to the HCV genotype and the progression of liver fibrosis can be found. The prevalence of hypertension in the group of analyzed patients was 39% and was significantly associated with old age (OR = 1.08 (1.07–1.08)) and female sex, as well as the progression of liver fibrosis (OR = 1.54 (1.29–1.85)). Hypertension was found in 47.6% of patients with F4 fibrosis, 42.1% of patients with F3 fibrosis, and 25% of patients with F1 fibrosis. The incidence of cardiovascular disease in the studied group of patients was as follows: all incidents, 131 (4.52%); including ischemic heart disease 104, (3.95%); stroke, 2 (0.07%); atherosclerosis, 21 (0.72%); and aneurysms, 4 (0.14%). The obtained results prove that the prevalence of cardiovascular diseases is significantly associated with the advanced age of patients and the progression of liver fibrosis. The relevance of sex and the HCV genotype to the prevalence frequency of cardiovascular diseases in the study group has not been proven. This being the case, no differences in the frequency of their incidence depending on the HCV genotype, including genotype 3, was found. Hepatitis C infection as a non-classical risk factor for cardiovascular disease and hypertension does require further studying.

Background: The quantification of hepatitis B surface antigen (qHBsAg) was proposed as a helpful tool to monitor treatment efficacy with nucleos(t)ide analogs (NA) in HB e antigen-negative chronic HB. Objectives: The present study aimed to assess the effect of entecavir (ETV) and tenofovir dipivoxil (TDF) on qHBsAg kinetics and estimate the time necessary to achieve HBsAg clearance with each of these drugs. Methods: The study was conducted on 93 patients, 54 and 39 of whom were treated with ETV and TDF for a median time of 42 months, respectively. The qHBsAg was measured in 6-month intervals with the Elecsys HBsAg II Quantitative assay. The estimated time to undetectable HBsAg was calculated using the best-fitted curve analysis. Results: There was a significant decrease in qHBsAg titers in 79 (84.9%) patients with no difference between ETV and TDF groups (P = 0.754). The median quantitative HBsAg drop was 2003 IU/mL (interquartile range: 638.1 - 5010). The HBsAg levels decreased by 40.3 ± 25.9% on average. The expected time required for HBsAg clearance was comparable in both groups, equaling 104 and 114 months for TDF and ETV, respectively. Conclusions: The HBsAg clearance can be achieved in a substantial proportion of patients after additional 5 years of treatment with NA. The potency of TDF and ETV in qHBsAg reduction is similar.

Ulcerative colitis is a chronic inflammatory bowel disease of the colon. The most frequent symptoms include bloody diarrhoea with rectal urgency and tenesmus. It is often complicated by the presence of primary sclerosing cholangitis, a chronic, cholestatic liver disease, characterised by the inflammation and fibrosis of bile ducts. The presence of primary sclerosing cholangitis seems to alter the course of ulcerative colitis, changing its natural course.

BACKGROUND: Liver transplantation (LT) is at high-risk for cardiovascular events. Therefore, candidates have pre-operative cardiological diagnostics to reduce risk of complications after surgery. The purpose of the study was to analyze a cohort of liver recipients from one transplant centre in Poland and to evaluate the accuracy of pretransplant cardiac assessment in the prediction of short and long-term outcomes and to investigate correlation of cardiovascular events with the patient’s characteristics. MATERIAL AND METHODS: This retrospective study was conducted among 141 consecutive patients evaluated for LT in 2017-1018. Recipients under 40 were excluded. All candidates had ECG, echocardiography and their functional capacity was assessed. Patients with MET < 4 or clinical indications were subjected to stress echocardiography. After transplantation, patients were re-screened for cardiovascular complications by December 2019. RESULTS: In 2017-2018 141 patients were evaluated, 116 patients were finally listed, 4 recipients were disqualificated for cardiological reasons, the remaining 21 were rejected for non-cardiological reasons. There were no early cardiovascular complications in 30-day follow-up. Late cardiovascular complications were observed in 4 transplanted patients. Diabetes increases cardiovascular complications (p=0,001). CONCLUSION: The applied cardiological diagnostics allowed to avoid early cardiovascular events. Very careful post-transplant monitoring is indicated, particularly in diabetes patients, due to the greater risk of long-term complications. Post-transplant immunosuppression and liver function recovery may contribute to this.

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1normal " (N = 129), T cell-mediated rejection (TCMR) "R2TCMR " (N = 37), early injury "R3injury " (N = 61), and fibrosis "R4late " (N = 8). Groups differed in median time posttransplant, for example, R3injury 99 days vs R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR , R3injury , and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.

The following elaboration presents positions of experts from various, mainly European scientific societies regarding utility of postprandial hypertriglyceridemia (HTG) in predicting cardiovascular (CV) risk. New studies and different categories of patients have been included. The following text has been based mainly on 2019 European Society of Cardiology and European Atherosclerosis Society guidelines regarding the management of dyslipidemia, as well as the 2019 international expert panel document. The position of Polish experts on using oral fat tolerance test in clinical practice has also been presented. Remaining problem is to assess potential usefulness of postprandial HTG in estimation of CV risk and to determine whether performing the oral fat tolerance test, that involves consumption of a standard high-fat preparation followed by blood collection at indicated time intervals, can improve CV risk assessment. Although importance of postprandial HTG in the assessment of atherogenic risk is increasingly well documented, there is still need for further research.

HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.

Hepatitis delta (HDV) virus still poses a serious health problem worldwide. Being a satellite particle, it may complete its life cycle only in the presence of HBs antigen produced by hepatitis B virus (HBV). According to epidemiological data, about 5% of HBs antigen carriers are infected with this virus, which equates to approximately 15-20 million individuals worldwide. Although the infection with both HBV and HDV viruses is considered to be the worst form of viral hepatitis, the only approved treatment, with pegylated interferon α, is not satisfactory. Thus effective and safe therapy is still lacking, which stands in contrast to the latest development in therapeutic areas of HBV and hepatitis C virus (HCV) infections. As the exact data on prevalence of this infection in some countries as well as natural history of this disease are still incomplete, further studies are warranted. Polish investigations on this field are very scarce and at most dating from the 1990s. This publication makes another attempt to broaden our knowledge of this temporarily forgotten but still ongoing and complex problem.

BACKGROUND There is a worldwide increase in use of liver transplantation (LT) for treatment of hepatocellular carcinoma (HCC). We analyzed our experience with LT for HCC to determine long-term and recurrence-free survival, accuracy of imaging diagnosis of HCC compared to the explant pathology, recurrence rate of HCC, and predictors of recurrence. MATERIAL AND METHODS The whole explant was examined by the same pathologist and compared with the baseline diagnosis established according to clinical, laboratory, and radiological data. A group of patients with pathologically confirmed HCC was characterized, with special attention to etiology, survival, recurrence, and diagnostic accuracy of imaging techniques. RESULTS Among 718 patients transplanted from 2000 to 2018 in our center, HCC was found in 166 explanted livers. In 42 cases the clinical diagnosis of HCC was not accurate, being either false positive or negative; however, the specificity and sensitivity of CT/MRI in HCC recognition was 97.87% and 88.24%, respectively. Five- and 10-year survival was 81.27% and 66.57%, respectively, and it was inferior to the overall survival. The recurrence rate was 9.6% with a median time to recurrence of 14 months and a median survival time of 9 months. Poor differentiation of HCC and HCV etiology of the baseline disease, but not previous DAA treatment, were the risk factors of HCC recurrence. CONCLUSIONS Adherence to strictly defined selection criteria for LT in HCC patients guarantees the success of LT in HCC treatment.

Case series Patient: Female, 31-year-old • Female, 40-year-old Final Diagnosis: Alcohol liver disease • COVID-19 Symptoms: Ascites • cough • dyspnea • jaundice Medication: — Clinical Procedure: CT scan Specialty: Anesthesiology • Gastroenterology and Hepatology • Infectious Diseases • General and Internal Medicine Objective: Rare co-existance of disease or pathology Background: COVID-19 is an infectious disease caused by SARS-CoV-2. It has spread rapidly through the world, endangering human life. The main target of COVID-19 is the lungs; however, it can involve other organs, including the liver. Patients with severe COVID-19 have an increased incidence of abnormal liver function, and patients with liver disorders are considered to be at a higher risk of severe COVID-19 infection. The mechanism of liver injury reported in 14% to 53% of COVID-19 patients is poorly recognized and several possibilities need to be considered (cytokine storm, direct viral action, hypoxia). The incidence of underlying liver comorbidities in patients with a COVID-19 infection ranges from 1% to 11%. Case Reports: This is a report of 2 nosocomial COVID-19 infections and severe COVID-19 pneumonia in 2 patients who were hospitalized during treatment for alcoholic liver disease (ALD). Case 1 and case 2 were a 31-year-old woman and a 40-year-old woman, respectively, with decompensated ALD and symptoms of the COVID-19 infection. Both patients were transferred from another hospital to our hospital after confirmation of COVID-19 during their hospitalization. The course of the infection progressed rapidly in both patients with the development of multiple-organ failure and death over a short period. Conclusions: There are no clear recommendations on the management of ALD in the COVID-19 pandemic. Alcoholic hepatitis may be a risk factor for severe COVID-19 and a poor outcome. A high percentage of nosocomial COVID-19 infections are observed; therefore, special precautions should be taken to minimize the risk of COVID-19 exposure.

The aim of the study is to analyze treatments available for patients infected with genotype (G) 3 hepatitis C virus (HCV) in Poland at the beginning of the interferon (IFN)-free era and evaluate the efficacy and safety of different therapeutic options administered in a real-world setting. We analyzed data of 198 patients who started antiviral therapy after July 1, 2015, and completed it before December 31, 2016; 57.6% of them had liver cirrhosis and 46% were treatment experienced. Fifty percent of patients were assigned to sofosbuvir (SOF)+pegylated IFN alfa (PegIFNa)+ribavirin (RBV), 9% to PegIFNa+RBV, 36% received SOF+RBV, and 5% SOF+daclatasvir (DCV)±RBV. Cirrhotic patients were assigned more frequently to IFN-free regimens. Overall, a sustained virological response was achieved by 84.3% of patients in intent-to-treat (ITT) analysis and 87% in modified ITT analysis. For SOF+PegIFNa+RBV and SOF+DCV±RBV regimens, the sustained virologic response (SVR) rate reached at least 90%, whereas the two other therapeutic options demonstrated efficacy

Background This study analysed the NS3 and NS5A mutation frequencies, persistence and drug susceptibility in a cohort of real-life patients, with failed hepatitis C virus (HCV) therapy following directly acting antiviral (DAA) treatment. Methods NS3/NS5A Sanger sequences from 105 patients infected with HCV genotype (G) 1a (6,5.7%), G1b (94,89.5%), G3a (4,3.8%), and G4 (1,1.0%) post DAA treatment failure were analysed. NS3 and NS5A resistance-associated substitutions (RASs) were identified using the geno2pheno algorithm and associated with clinical variables. Time trends were examined using logistic regression. Results NS5A RAS were found in 87.9% of sequences derived from patients exposed to this class of agents, whereas NS3 RAS was found in 59.1% of HCV protease-exposed subjects. The frequency of the NS3 RAS increased with fibrosis stage, from 40.0% among F0/F1 individuals to 81.8% among patients with liver cirrhosis (F4, p = 0.094). NS5A mutation frequencies were 7.6% for 28A/V/M, 10.6% for 30 K/Q/R, 42.4% for 31I/F/M/V, and 75.8% for 93H. For NS3, the most common RASs were 56F–23.7%, 168A/E/I/Y/T/V–14.0%, and 117H–5.4%. Susceptibility to glecaprevir/pibrentasvir, velpatasvir/voxlaprevir, and elbasvir/grazoprevir was retained in 92.9%, 43.4%, and, 25.3% of patients, respectively. The frequency of NS3 RAS decreased with time elapsed from failure to sampling (p = 0.034 for trend). NS5A RAS frequency remained stable over the 24-months. Conclusions Following DAA treatment failure, NS5A and NS3 RASs were common with increasing frequency among patients with advanced liver disease. In most cases, despite the presence of RASs, susceptibility to DAA combinations with higher genetic barrier was retained.

Liver injury—expressed as elevated liver enzymes—is common in patients with COVID-19. Little is known about the potential mechanisms of liver damage by SARS-CoV-2. A direct cytopathic effect on hepatocytes as well as injury related to hypoxia or hepatotoxicity are being considered. The aim of the study was to compare the clinical characteristic of COVID-19 disease in patients with normal and abnormal liver enzymes activity. A group of 150 patients with COVID-19, hospitalized in our center, was analyzed. Patients with the known liver comorbidities were excluded (n = 15). Clinical features and laboratory parameters were compared between patients with normal and abnormal aminotransferase values. Liver injury expressed as any alanine aminotransferase (ALT) elevation was noted in 45.6% of patients hospitalized due to COVID-19. The frequencies of aspartate aminotransferase (AST) elevation were lower. It was noted that elevated ALT/AST unfavorably affected other parameters related to liver function such as albumin level, gamma-glutamyl transpeptidase (GGTP), and partly, ALP activity and influenced inflammation-related parameters. The most probable cause of mild hepatitis during COVID-19 was anoxia and immune-mediated damage due to the inflammatory response following SARS-CoV-2 infection. A direct cytopathic effect of SARS-CoV-2 on hepatocytes, albeit less probable, can be considered as well. The use of potentially hepatotoxic drugs may contribute to liver damage.

Background Alcoholic cirrhosis is an indication for 40% of liver transplantations (LT) in Europe. In most centers, 6 months of abstinence is required before listing. However, alcohol recidivism is quite high after LT, and approximately 20–25% of recipients with ALD resume harmful drinking, resulting in liver insufficiency, which casts doubt on the 6-months rule as a reliable marker of abstinence maintenance after LT. Material/Methods We analyzed data on patients who underwent orthotopic LT in Marie Curie Hospital, Szczecin, Poland, from 2000 to 2015 due to alcoholic or cryptogenic cirrhosis. Every ALD patient met the 6-month abstinence requirement. Alcohol recidivism has been studied based on a history of alcohol abuse taken from the patients or from their relatives, and in case of denial, on laboratory tests for alcohol abuse. Five patterns of recidivism were distinguished: death, constant heavy drinking, heavy drinking with abstinence attempts, occasional laps, and a single episode of alcohol intake. The analysis of survival was performed according to the Kaplan-Meier method. Patient survival rates in ALD recipients vs. non-ALD recipients were compared using the log-rank test. Results Alcohol recidivism was finally evaluated in 109 patients: 81 males and 28 females, with a median age of 53.3 years (range 30–66). Harmful drinking was discovered in 16 patients (14.7%), including seven deaths due to alcoholic hepatitis. Sporadic or episodic drinking was found in 29 patients (27%). In heavy drinkers, the abstinence period after transplantation was significantly shorter and patients were younger than the average (median age 43.8 years). Women break abstinence faster than men and are at greater risk of liver insufficiency. Five, 10 and 15-year survival in the ALD group was superior in comparison with non-ALD group, but differences did not reach statistical significance (p=0.066, p=0.063, p=0.075, respectively). Conclusions The prognostic value of a 6-month abstinence period before transplantation is rather low as it does not predict sobriety after transplantation. However, only a minority of such patients drink harmfully. Survival in ALD recipients tends to be better in comparison with survival in the other etiologies. Younger women dependent on alcohol shortly before LT are at greatest risk of recidivism.

The therapeutic goal which is currently unfrequent but realistic in HBV infected patients is sustained HBsAg clearance. It is preceded by the loss or significant suppression of HBV replication and leads to inhibition of the progression of liver fibrosis, normalization of biochemical indicators of liver damage, reduction in the risk of hepatocellular carcinoma, prolongation of survival, prevention of HBV infection in the transplanted organ in post-transplant patients, enhancement of the quality of life, inhibition or reversal of extrahepatic changes associated with HBV infection, and halting of the spread of HBV infections. Recommendations of Polish Group of Experts for HBV for 2017 provide guidelines to assess treatment eligibility, choice of the first-line drug, monitoring and duration of treatment, management of treatment failure as well as therapy of HBV associated cirrhosis or hepatocellular carcinoma. Moreover it contains advice for treatment of HBV infection in children, females planning pregnancy or pregnant. We also included recommendations for pre- and post-exposure prophylaxis, prevention of HBV transmission from mother to infant, after liver transplantation, on immunosuppressive therapy and during HCV treatment.

BACKGROUND Despite excellent transplantation results, there is a vulnerable period of time in the post-transplant management of pediatric liver recipients, which is the time when a child becomes an adolescent. This period of psychological distress influences compliance and may result in premature transplant failure and graft loss. We performed a retrospective review of pediatric liver transplant recipients, transferred to our service for adults, in order to identify key issues associated with transition into the adult care. MATERIAL AND METHODS We analyzed medical files of 20 liver recipients transferred from pediatric post-transplant outpatient clinic to the post-transplant service for adults, since year 2000 until December 2015. For survival analyses, Kaplan-Meier model with log-rank test and Cox proportional hazards regression model, to calculate hazard ratio (HR), were used. RESULTS Survival rate exceeds 90% in the study population. The major complication was late acute rejection, in most instances due to non-compliance. There were single cases of recurrent liver disease and de novo graft disorders. CONCLUSIONS Dedicated service for young people may be needed to optimize outcomes.

SummaryBackground Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies. Aim To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions. Methods Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT. Results A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child–Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients. Conclusions The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting.

Introduction Hepatitis C (HCV) infection adversely affects survival among people living with HIV, increasing mortality risk due to liver-related causes. In Poland HCV is found among ~30% of HIV infected individuals, with only a small percentage successfully treated for this coinfection. This study aimed to analyze the HCV-associated influence on the life expectancy among HIV/HCV coinfected patients from northwestern Poland. Material and methods Longitudinal data of 701 (368 HIV monoinfected and 368 HIV/HCV coinfected) patients were investigated to assess the life expectancy and survival after HIV diagnosis. Kaplan-Meier and Cox analyses were used to assess the mortality risk in both unadjusted and multivariate models. Effect plots indicate the adjusted hazard ratio for HCV-associated survival. Results Overall mortality was significantly higher among HCV coinfected (22.52%) compared to HIV monoinfected (10.32%) cases (p < 0.001, OR = 2.52 (95% CI: 1.65-3.85)), with shorter life expectancy among HIV/HCV infected patients (median: 55.4 (IQR: 42.8-59.1) years) compared to HIV monoinfection (median 72.7 (IQR: 60.4-76.8) years, univariate HR = 4.15 (95% CI: 2.7-6.38), p < 0.0001, adjusted HR = 2.32 (95% CI: 1.47-3.65), p < 0.0001). After HIV diagnosis, HCV adversely influenced the survival after 15 years of follow-up, with a strengthened impact in the subsequent 5 years (univariate HR = 1.57 (95% CI: 1.05-2.34) p = 0.026 for the 20-year survival time point, adjusted HR = 2.21 (95% CI: 1.18-4.13), p = 0.013). Conclusions Among patients living with HIV, HCV coinfection is associated with a median life expectancy decrease of 17.3 years and low probability of surviving until the age of 65 years. In the era of directly acting anti-HCV drugs, treatment scale-up and immediacy of treatment are advisable in this cohort.

Aim of the study This multicentre study aimed to examine the actual risk for drug-drug interactions in a cohort of Polish patients, and their impact on antiviral therapy. Material and methods Concomitant medications were analyzed in hepatitis C virus (HCV)-infected patients treated with still valuable therapy with OBV/PTV/r ± DSV ± RBV. An established online tool (http://www.hep-druginteractions.org/) was used to assess potential drug interactions. To assess the impact of comedications on virologic outcomes, HCV RNA levels were measured at given time points during and after the treatment. The results were compared between subgroups depending on the number of drugs used. Results Among the 209 patients included in this multicentre study, concomitant medications were taken by 140 (67.0%) patients. Modification of treatment due to expected interactions was required in 33 (15.8%) patients, of whom nine (4.3%) had at least one comedication replaced or discontinued. Sustained virologic response rates ranged from 95.1% to 100.0%, and were lowest in patients taking one to five comedications who were null-responders to pegylated interferon or cirrhotic. Conclusions Although most HCV-infected patients received concomitant medications, only some required treatment modification. OBV/PTV/r ± DSV ± RBV was effective in all subgroups, irrespective of the number of comedications taken. Multimorbidity and polypharmacy in patients with chronic hepatitis C should not discourage the decision to initiate antiviral therapy, although caution should be exercised for potential drug-drug interactions.

Objectives The aim of the study was to characterize the differences in the frequencies of NS3 and NS5A resistance-associated variants (RAVs) among Polish therapy-naive genotype 1 (G1) hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients including clustering patterns and association of RAV frequency with liver fibrosis. Methods NS3/NS5A RAVs were identified by population sequencing in 387 directly acting antiviral treatment-naive G1-infected individuals (54 with genotype 1a (G1a) and 333 with genotype 1b (G1b)). Liver fibrosis was assessed based on histopathology or ultrasound elastography. Phylogenetic clusters were identified using maximum likelihood models. For statistics, chi-squared or two-sided Fisher's exact tests and multivariate logistic regression models were used, as appropriate. Results NS3 RAVs were found in 33.33% (18/54) for G1a and 2.62% (8/297) for G1b whereas NS5A variants were present in 5.55% (3/54) G1a and 9.31% (31/333) G1b sequences. Variations in NS5A 31 and 93 codon positions were found only in G1b (4.2% (14/333) for L31I/F/M and 5.39% (17/333) for Y93H). NS5A RAVs were more frequent among patients with advanced liver fibrosis (17.17% (17/99) for F3–F4 versus 6.94% (17/245) for F0–F2; p 0.004) or liver cirrhosis (20.34% (12/59) for F4 versus 7.72% (22/285) for F0–F3; p 0.003). Liver cirrhosis (F4) was associated with higher odds ratio of the NS5A RAVs among HCV-infected patients (odds ratio 2.34, 95% CI 1.004–5.291; p 0.049). NS5A RAVs were less frequent among sequences forming clusters and pairs (5.16% (8/155) versus 11.21% (26/232); p 0.039). Conclusions Presence of NS5A RAVs correlated with progression of liver fibrosis and represents de novo selection of variants rather than transmission of drug resistance. Hence, the presence of NS5A RAVs may be a predictor for a long-lasting HCV infection.

Background: In the interferon era, patients with HCV-related cirrhosis were considered hard to treat due to contraindications to therapy, safety issues, and poor response. Objectives: We investigated interferon-free regimens in cirrhotic patients in real-world practice. Methods: We analyzed data of HCV infected patients with liver cirrhosis conducted in 22 Polish hepatology centers. They were assigned to a treatment schedule based on physician decision. Data were collected retrospectively by an online questionnaire. Results: In total, 1113 patients infected with genotype 1 HCV were enrolled to the analysis, 96.6% presented GT1b infection. A total of 56% were treatment-experienced, mostly with PegIFN + RBV, 77.2% of group presented comorbidities with the most frequent hypertension and diabetes,73.2% patients were treated with concomitant medications, and 31% of cohort was assigned to RBV-free regimen, majority of them to OBV/PTV/r + DSV. Overall, 94.7% patients achieved the sustained virological response in intent-to-treat analysis, with comparable rate for RBV-free and RBV-containing options (94.2% vs. 94.9%). Treatment course was more often modified in RBV-containing group, whereas rate of discontinuation was the same for both cohorts. Adverse events were observed in 41% with the most common weakness/fatigue; more frequently in RBV-containing regimens (43% vs. 36.6%). Serious adverse events were reported in 4.1% patients. A total of 16 deaths not related to study drugs were documented, mostly in RBV-containing group. Conclusions: We confirmed effectiveness of the interferon-free regimens without ribavirin in real-world cohort of cirrhotic patients with chronic HCV infection genotype 1. Therapy was well tolerated with infrequent adverse events.

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections.

Background According to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir±ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir±RBV (LSR) in PI-experienced patients in real-life setting. Methods Our analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database. Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR). Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively). Subjects were assigned to IFN-free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR. Results SVR rates were comparable for particular groups: BOC → PrODR- 100%; BOC → LSR - 98%; TVR → PrODR - 97%; TVR → LSR - 96% (intent-to treat analysis-ITT) and BOC → PrODR→100%; BOC → LSR - 99%; TVR → PrODR - 99%; TVR → LSR - 98% (modified intent-to treat analysis-mITT). Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR). Conclusion Efficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients.

Aim of the study To identify distribution of HBV genotypes in particular regions of Poland. Material and methods The study included 270 treatment-naive, HBV-infected individuals, enrolled in 7 centers of Poland. HBV genotyping was performed in 243 of them with the INNO-LiPA HBV Genotyping assay (Innogenetics). Results Genotype A present in 2/3 patients was demonstrated as the most predominant in Poland. It was followed by D (20%), H (5%) and mixed A + D (5%). Remaining patients were infected with genotype F, mixed D + G, A + C or D + F. Analysis of distribution demonstrated regional differences, with a higher rate of genotype D prevalence (about 30%) in the eastern (Bialystok and Lublin) and south-western (Wroclaw) parts compared to other regions, where the prevalence rate was below 15%. The highest prevalence of genotype A (exceeding 80%) was observed in central Poland (Bydgoszcz, Łodź). Conclusions The presented data reveal the current distribution of HBV genotypes across Poland, which is the first and the largest such epidemiological analysis.

BACKGROUND The introduction of direct-acting antivirals (DAAs) has considerably improved therapeutic outcomes for patients with chronic hepatitis C virus (HCV) infections. The AMBER-CEE study aimed to assess real-world efficacy and safety of ombitasvir/paritaprevir/ritonavir/+ dasabuvir ±ribavirin (OBV/PTV/r/ +DSV±RBV) in the treatment of post-transplant recurrence of HCV infection. MATERIAL AND METHODS Liver transplant recipients with recurrent HCV genotype 1 infection, scheduled for OBV/PTV/r/+DSV±RBV according to therapeutic guidelines, were eligible. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks after the end of treatment (FU12). Clinical and laboratory adverse events (AEs) were recorded from baseline to FU12. RESULTS A total of 35 patients were included: 91.4% genotype 1b-infected, 94.3% treatment-experienced, and 77.1% at fibrosis stage ≥F2. SVR12 was achieved by all patients (35/35, 100%) including one patient with genotype 1a, one patient with detectable HCV RNA at the end of treatment, two patients with a history of first-generation DAA therapy, and two patients who prematurely discontinued the regimen. AEs were experienced by 22 patients (62.9%) and were mostly mild. No death, graft loss, or acute graft rejections were reported during the therapy. On-treatment hepatic decompensation occurred in three patients (8.6%). Anemia was observed in 29 patients (83.9%), with 21 (60%) requiring RBV dose reduction or discontinuation. CONCLUSIONS OBV/PTV/r/+DSV±RBV has excellent efficacy in post-transplant recurrence of HCV genotype 1-infection treated under real-world conditions. Excellent virologic outcomes were observed irrespective of prior treatment history or the degree of fibrosis, and AEs were mostly mild and transient.

BACKGROUND Recurrence of hepatitis C virus (HCV) infection after liver transplantation is inevitable and decreases survival. Graft loss due to recurrent HCV occurs in 25% to 30% of patients. The recommended AASLD treatment is PEG-IFN, with or without ribavirin, but some patients might be not eligible for this treatment. An alternative antiviral agent is silibinin (SIL). In vitro silibinin stops replication, probably by inhibiting HCV RNA polymerase. CASE REPORT We present the cases of 2 patients with severe recurrent HCV infection who received intravenous silibinin (IV SIL) as a "rescue therapy". In the first patient with cholestatic fibrosing hepatitis, HCV RNA became undetectable. We also noted significant viremia reduction, and improvement in laboratory results and clinical presentation in the second patient. CONCLUSIONS Administration of IV SIL resulted in a rapid decrease of HCV viremia. In post-transplant patients with HCV recurrence who are not eligible for standard antiviral treatment, IV SIL can be considered as an alternative, but further investigations are necessary to establish treatment protocols.

Background To evaluate the effectiveness and safety of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) regimen in a real-world setting. Methods Patients received a fixed-dose combination tablet containing LDV and SOF with or without RBV, for 8, 12 or 24 weeks. Patients were assessed at baseline, end of treatment, and 12 weeks after the end of treatment. The primary effectiveness endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Results Of the 86 patients, aged 20–80 years, 82.6% were HCV genotype 1b-infected and 50.0% were cirrhotic. More than half (52.3%) had previously followed pegylated interferon-containing (PEG-IFN) treatment regimens, and 38.5% were null-responders. SVR12 was achieved by 94.2% of patients. All non-responders were cirrhotic: two demonstrated virologic breakthrough and the remaining three relapsed. All patients treated with an 8-week regimen achieved SVR12 despite having high viral load at baseline (HCV RNA of >1 million IU/mL in 8/10 patients, including one with a viral load of >6 million IU/mL). Adverse events were generally mild and transient. Most frequently, fatigue (22.1%), headache (15.1%), and arthralgia (7.0%) were observed. Laboratory abnormalities included anemia and hyperbilirubinemia. Conclusions Treatment with LDV/SOF ± RBV is an effective and safe option for patients with HCV, including those with advanced liver disease or a history of non-response to PEG-IFN-based therapy.

Attempt to create simple practical algorithm for prospective assessment of PEG interferon/ribavirin related treatment response in individuals with chronic hepatitis C (CHC) basing on the risk factors defined prior to the treatment initiation.Retrospective assessment of 45 female and 39 male previously untreated CHC patients aged 20 to 73 years, with genotype 1, undergoing standard treatment with PEG-IFNa2b+RBV was performed. For the final analysis 78 patients were included (38 effectively treated and 40 treatment failures). Thirty-six sustained virological response (SVR) related factors, which were routinely measured before treatment initiation were compared (including physical, biochemical, serologic and histopathologic). From this group the risk factors of the highest predictive value for treatment failure were selected. Cut-off values for statistical significance were defined for each parameter, with risk score (RS) calculated and compared in the group with and without SVR.Seven factors related to treatment failure were identified: HCV600000 IU/L, blood platelet count150000/ul, GGTP45 IU/ml, total serum protein7.8 g/dl, glycaemia105 mg/dl, detectable HBc IgG antibodies and cirrhosis. In the group with RS 1 the likelihood of SVR was 70% (p0.028), while in patients with RS 3 the response was reduced to 23.8% (p0.016), with no SVR achieved among patients with RS3.Low risk score (0-2) is associated with high probability of treatment success with scores3 predictive for treatment failure. The presented model is a simple tool for prediction of treatment success for clinical use before PegIFN/RBV treatment initiation among genotype 1 CHC patients.

Introduction: Osteoporosis poses significant risk for HIV infected subjects in the era of the long-term antiretroviral treatment. For this study frequency of the selected 11 single nucleotide polymorphisms (SNP single nucleotide polymorphism) previously associated with osteoporosis risk in HIV infected and uninfected cohorts was analysed. Association with the SNP variation and the risk of osteoporosis in the entire study and in HIV-infected cases was investigated. Material and methods: The study included 568 patients (226 women and 342 men): 315 HIV-infected patients and 253 anti-HIV negative cases. Osteoporosis was confirmed using dual energy absorptiometry ionizing radiation (DXA) in eight HIV infected patients and three controls [odds ratio (OR): 7.66, 95% CI: 1.98–29.6; p = 0.001; relative risk (RR): 7.04, 95% CI: 1.98–25.97, p = 0.0019]. SNP assays performed for collagen type 1 (COL1A1) rs1800012, parathyroid hormone (PTH) rs9630182, estrogen receptor gene (ER1) rs2077647, rs3020314 and rs1884051, Vitamin D receptor (VDR) rs1544410 and rs731236, Osteoprotegerin rs4355801, LDL receptor protein (LRP5) rs3736228, RANK rs3018362 and CYP19A1 (aromatase) rs700518 using TaqMan SNP Genotyping Assay (Applied Biosystems) according to the manufacturer’s protocol. For statistics Statistica 12 software was used. Results: Majority of allele frequencies for the studied polymorphisms were consistent with the Hardy-Weinberg equilibrium. CC homozygotes for ER1 rs2077647 were notably more common in HIV (+) cases compared to controls [OR: 2.29, 95%CI: 1.25–4.19, p = 0.003; RR: 2.11, 1.22–3.68, p = 0.0072]. Also GG homozygotes for ER1 rs1884051 were more common both in HIV(+) [OR: 2.57, 1.33–4.94, p = 0.0016; RR: 2.37, 1.29–4.36, p = 0.002] and in all patients with osteoporosis [OR 5.04, 1.24–20.4, p = 0.025; RR 3.94, 1.38–11.24, p = 0.043] . Additionally, in HIV (+) patients parathyroid hormone rs9630182 T allele was notably more common [OR: 1.4, 1.0–1.97, p = 0.024; RR: 1.15, 0.99–1.33, p = 0.029]. Conclusions: Genetic variability for the osteoporosis-associated SNPs was similar in HIV-infected patients and uninfected persons. ER1rs1884051 variants may be associated with the increased osteoporosis risk, but increased incidence of osteoporosis in HIV-infected compared to uninfected people seems to be weakly associated with investigated single nucleotide polymorphisms. Variation in the gene for the estrogen receptor ER1rs1884051 was significantly more frequent in patients with osteoporosis and more common in HIV infection.

The study describes four cases of tularaemia – one developed after contact with rabbits and three developed after an arthropod bite. Due to non-specific clinical symptoms, accurate diagnosis of tularaemia may be difficult. The increasing contribution of the arthropod vectors in the transmission of the disease indicates that special effort should be made to apply sensitive and specific diagnostic methods for tularaemia, and to remind health-care workers about this route of [i]Francisella tularensis[/i] infections. The advantages and disadvantages of various diagnostic methods – molecular, serological and microbiological culture – are discussed. The PCR as a rapid and proper diagnostic method for ulceroglandular tularaemia is presented.

Background/Aims: Though there is a consensus that the HLA DQB1*0301 allele is important in untreated HCV clearance, this association is not universal and a number of genes outside the major histocompatibility complex may also play a role in host responses to HCV infection. Prime candidates, at present, are the genes encoding pro-inflammatory and immuno-regulatory cytokines. The aim of this study was to investigate the relationship between a number of these candidate genes and both spontaneous and treatment related clearance of hepatitis C virus infection. Methods: Three members of the interleukin-1 gene family: IL-1A, IL-1B and IL-1RN, three polymorphic sites in the interleukin-10 gene promoter (− 1082, − 819, − 592) and two in the tumour necrosis factor-alpha promoter (− 308, − 238) were studied in two independent DNA banks, each with appropriate controls. Standard PCR-based genotyping techniques were used. Results: No significant difference in the distribution of any of the polymorphisms was found in either study set. Conclusions: These findings in two large groups suggest that future investigations should focus on other candidate genes and may support the view that MHC-encoded susceptibility to chronic HCV infection may be determined by MHC class II rather than MHC class III genes.

BACKGROUND Sequels of chronic HCV infection are currently one of the most common indications for liver transplantation (LTx). Because HCV reinfection and allograft injury are inevitable, it may influence survival. Earlier studies have not reported higher mortality among HCV-infected patients, but cumulative data seem to contradict these findings. The aim of the study was to analyze post-LTx survival in HCV-positive patients in comparison with non-HCV-positive recipients and impact of antiviral treatment on survival in patients with recurrent HCV hepatitis. MATERIAL AND METHODS Using data from the Polish national transplant registry, a retrospective cohort study of 327 patients who underwent LTx between 2000 and 2012 was performed. Cumulative 5-year mortality for HCV-positive patients vs. HCV-negative recipients and HCV-positive recipients treated with pegylated interferon/ribavirin vs. non-treated subjects was calculated using Kaplan-Meyer methodology. Mortality hazard rates were estimated using univariate proportional Cox models. RESULTS Liver transplantation in HCV-positive vs. HCV-negative recipients was associated with significantly lower survival rate (cumulative 5-year survival 89.8 vs. 80.26%, respectively, p=0.04276) with a 5-year mortality HR of 1.99. Antiviral treatment improved survival irrespective of virological response (84.06% treated vs. 51.22% non-treated, p=0.00003). Univariate Cox HR for HCV treated vs. untreated patients is 0.18. Further improvement of survival was significantly associated with sustained virological response (100% vs. 77.67%, p=0.042). CONCLUSIONS Our study confirms higher mortality risk among HCV-infected transplant recipients, improved survival related to the HCV treatment following graft reinfection, and positive association between the HCV treatment success and better survival.

AIMS/BACKGROUND Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.