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Despite the overall excellent efficacy of pangenotypic direct-acting antiviral (DAA) options, there is still a small percentage of patients with hepatitis C virus (HCV) infection who do not respond to therapy.This analysis was designed to evaluate the effectiveness of pangenotypic retreatment in pangenotypic failures.The study included patients treated with the pangenotypic regimen selected from the EpiTer-2 database, real-world project evaluating DAA-based treatment in Poland.Among 15,123 patients, 4,345 received one course of pangenotypic treatment (PAN-group) and 48 patients were retreated with pangenotypic regimens after pangenotypic failure (PAP-group). Patients from PAP-group were more often males (79% vs 53%, P0.001), had higher BMI (27.5 IQR:25.7-30.1 vs 25.7 IQR: 22.9-28.7 kg/m2, P0.001), were more often infected with genotype (GT) 3 (58% vs 27%, P0.001) and more frequently had liver cirrhosis (46% vs 21%, P0.001) compared with the PAN-group. Importantly, no significant difference in treatment effectiveness was found between PAP and PAN-groups with sustained virologic response (SVR) rate of 89.6% vs 93.7% (P=0.39) in intent-to-treat and 91.5% vs 97.6% (P=0.17) in per protocol analysis. The selection of a specific retherapy regimen did not affect SVR.Our study demonstrated the excellent effectiveness of pangenotypic regimens and that most DAA non-responders could be successfully retreated with next pangenotypic regimen. The best retreatment strategy is a triple pangenotypic regimen, especially in patients with unfavorable response factors such as GT3 infection, cirrhosis, and male sex.

Background The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C, making it highly effective and safe for patients. However, few researchers have analyzed the factors causing therapy failure in some patients. Aim To analyze factors influencing the failure of direct antiviral drugs in the large, multicenter EpiTer-2 cohort in a real-world setting. Methods The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020. Data collected from the online EpiTer-2 database included the following: hepatitis C virus (HCV) genotype, stage of fibrosis, hematology and liver function parameters, Child-Turcotte-Pugh and Model for End-stage Liver Disease scores, prior antiviral therapy, concomitant diseases, and drugs used in relation to hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) coinfections. Adverse events observed during the treatment and follow-up period were reported. Both standard and machine learning methods were used for statistical analysis. Results During analysis, 12614 patients with chronic hepatitis C were registered, of which 11938 (mean age: 52 years) had available sustained virologic response (SVR) data [11629 (97%) achieved SVR and 309 (3%) did not]. Most patients (78.1%) were infected with HCV genotype 1b. Liver cirrhosis was diagnosed in 2974 patients, while advanced fibrosis (F3) was diagnosed in 1717 patients. We included patients with features of hepatic failure at baseline [ascites in 142 (1.2%) and encephalopathy in 68 (0.6%) patients]. The most important host factors negatively influencing treatment efficacy were liver cirrhosis, clinical and laboratory features of liver failure, history of hepatocellular carcinoma, and higher body mass index. Among viral factors, genotype 3 and viral load also exerted an influence on treatment efficacy. Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex, which was not confirmed by the multivariate analysis using the machine learning algorithm (random forest). Coinfection with HBV (including patients with on-treatment reactivation of HBV infection) or HIV, extrahepatic manifestations, and renal failure did not significantly affect the treatment efficacy. Conclusion In patients with advanced liver disease, individualized therapy (testing for resistance-associated variants and response-guided treatment) should be considered to maximize the chance of achieving SVR.

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.

Introduction Cardiovascular diseases are ranked as the third cause of mortality among people infected with hepatitis C virus (HCV), but the relationship of infection with cardiovascular risk remains disputable. We have focused on the comprehensive use of parameters obtainable during long-term electrocardiographic (ECG) Holter monitoring. Material and methods Heart rate variability and turbulence (HRV and HRT), deceleration/acceleration capacity (DC/AC), corrected QT interval (QTc) and late potential (LP) were used. 36 persons were included, and 30 healthy subjects formed a control group. All were submitted to 24-hour Holter ECG-monitoring. Results The studied groups were not statistically significantly different with regards to basic anthropometric parameters. Statistically significantly higher medium and maximum heart rhythm and aminotransferase activities were recorded in patients with hepatitis C. The HRV parameters r-MSSD, p50NN, HF, and absolute DC/AC values were significantly lower in the subjects with hepatitis C than those in the control group. The QTc interval, measured for nocturnal hours, was also significantly longer in that group. There were no differences in the albumin level or basic echocardiographic parameters, including left ventricle ejection fraction. Nor was there any difference in the HRT parameters, or LP. The most interesting observation was the positive correlation among the number of viral RNA copies and DC, and LF. Conclusions We confirmed the presence of autonomic disorders with prevalence of sympathetic system activity and prolonged QTc interval in patients with chronic hepatitis C. Those parameters significantly correlated with infection intensity. Our results suggest that HCV infection could be an independent cardiovascular risk factor, not associated with the lipid profile. Further prospective studies are needed.

The aim of the study was to analyze the prevalence and clinical characteristics of HCV/HBV coinfection and to evaluate the rate of HBV-reactivation during anti-HCV therapy in a large real-world study.Analyzed population consisted of 10,152 chronic hepatitis C patients treated with DAA between 2015 and 2019 in a nationwide study. Prior to the DAA all subjects had HBsAg and 60% anti-HBc testing.111 of 10,152 patients (1.1%) had detectable HBsAg and 1239 of 6139 (20.2%) anti-HBcAb. The prevalence of occult hepatitis B was 0.48%. HCV/HBV patients were younger with a higher proportion of males, HIV-coinfected, and advanced fibrosis. They were less often diagnosed with diabetes but more often with chronic kidney disease. In HBsAg(+) subjects with baseline HBV-DNA available 6/102 (5.9%) HBV-reactivations during or after DAA therapy were observed, and in two (1.9%) significant hepatic flares were noted. In HBsAg(-)/anti-HBc(+) group 2 (0.16%) reactivations were observed only in patients undergoing immunosuppressive therapy.Data from a large European cohort suggest a relatively low risk of HBV-reactivation during DAA-therapy for HCV infection in HBsAg(+) patients. In HBsAg(-)/anti-HBc(+) HBV-reactivation seems to be limited to subjects with immunodeficiency. Importantly, previous exposure to HBV and occult hepatitis B is present in a significant proportion of HCV-infected.

Purpose Since 2017 treatment-naive patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting. Materials and methods We analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0–F2). Results A total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0–F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response. Conclusions This real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin.

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.

There is still limited data available from real-world experience studies on the pangenotypic regimens in patients with genotype (GT) 3 hepatitis C virus (HCV) infection and liver cirrhosis. The current study aimed to evaluate the efficacy and safety of pangenotypic regimens in this difficult-to-treat population. A total of 236 patients with mean age 52.3 ± 11.3 years and male predominance (72%) selected from EpiTer-2 database were included in the analysis, 72% of them were treatment-naïve. The majority of patients (55%) received the combination of sofosbuvir/velpatasvir (SOF/VEL), 71 without and 58 with ribavirin (RBV), whereas the remaining 107 individuals were assigned to glecaprevir/pibrentasvir (GLE/PIB). The effectiveness of the treatment following GLE/PIB and SOF/VEL regimens (96% and 93%) was higher compared to SOF/VEL + RBV option (79%). The univariate analysis demonstrated the significantly lower sustained virologic response in males, in patients with baseline HCV RNA ≥ 1,000,000 IU/mL, and among those who failed previous DAA-based therapy. The multivariate logistic regression analysis recognized only the male gender and presence of ascites at baseline as the independent factors of non-response to treatment. It should be emphasized that despite the availability of pangenotypic, strong therapeutic options, GT3 infected patients with cirrhosis still remain difficult-to-treat, especially those with hepatic impairment and DAA-experienced.

(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.

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.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.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).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.

Background Patients who undergo hemodialysis (HD) or kidney transplantation (KTx) previously had limited possibilities for treatment of hepatitis C virus (HCV) infection. Direct-acting antivirals (DAA) give these patients a chance of virus eradication and safe transplantation. The aim of this study was to evaluate the effectiveness and safety of DAA in KTx and HD patients in real-world settings. Methods Sustained virologic response (SVR) and treatment safety were analyzed in KTx and HD patients from the EpiTer-2 database, which included HCV-infected subjects treated with DAA between 2015 and 2019. Additionally, for KTx patients, changes in creatinine concentration, estimated glomerular filtration rate (eGFR), proteinuria within a year after treatment, and changes in the need for calcineurin inhibitors were assessed. Results Among 10,152 patients from the EpiTer-2 database 148 were selected, 85 after KTx and 63 undergoing HD. The most common genotype, 1b HCV, was found in 73% and 86% of patients, respectively. Cirrhosis was noted in 10% and 19%, respectively. The most common DAA regimen after KTx was sofosbuvir/ledipasvir (54%), whereas in HD patients it was ombitasvir/paritaprevir/ritonavir +/- dasabuvir (56%). All patients with available follow-up results achieved SVR. No deaths, kidney loss or acute rejection episodes were noted. The most common adverse effects in both groups were anemia and weakness. One year after treatment, creatinine concentration, eGFR and proteinuria remained stable in the majority of patients. Conclusion DAA treatment of HCV infection demonstrated high effectiveness and safety in hemodialyzed patients and patients who had undergone KTx in this real-world study.

BACKGROUND AND AIMS The revolution of the antiviral treatment of hepatitis C virus (HCV) infection resulting in higher effectiveness came with the introduction of direct-acting antivirals with pangenotypic regimens as a final touch. Among them, the combination of glecaprevir (GLE) and pibrentasvir (PIB) provides the opportunity for shortening therapy to 8 weeks in the majority of patients. Because of still insufficient evaluation of this regimen in the real-world experience, our study aimed to assess the efficacy and safety of 8-week GLE/PIB in chronic hepatitis C patients depending on liver fibrosis and genotype (GT). METHODS The analysis included patients who received GLE/PIB for 8 weeks selected from the EpiTer-2 database, large retrospective national real-world study evaluating antiviral treatment in 12 584 individuals in 22 Polish hepatology centers. RESULTS A total of 1034 patients with female predominance (52%) were enrolled in the analysis. The majority of them were treatment naive (94%), presented liver fibrosis (F) of F0-F3 (92%), with the most common GT1b, followed by GT3. The overall sustained virologic response after exclusion of nonvirologic failures was achieved in 95.8% and 98%, respectively (P = 0.19). In multivariate logistic regression HCV GT-3 (beta = 0.07, P = 0.02) and HIV infection (beta = -0.14, P

Every year, 3-4 million people become infected with HCV, most of them are asymptomatic. In more than 20-30 years from infection, it leads to 10-20% of patients with cirrhosis, followed by hepatocellular carcinoma. Cardiological complications of the antiviral treatment are relatively rare, but force us to take additional diagnostic or discontinuation of therapy.The aim of study was to assess the cardiovascular safety of chronic hepatitis C treatment of genotype 1 in a triple regimen containing pegylated interferon-α in combination with ribavirin and boceprevir based on analysis of 24-hour ECG Holer monitoring, as well as changes in the concentration of cardiac fraction of fatty acid binding proteins (h-FABP).14 hepatitis C patients and 15 healthy people were included. The participants had an ambulatory 24-hour ECG-Holter recording at home condition and the determined level of h-FABP at baseline, after 4 and 12-16 weeks of treatment and 2 weeks after the end of therapy. The HRV parameters, AC/DC and QTc was calculated.At baseline there were no statistically significant differences in the HRV parameters, DC/AC, and QTc-interval. Absolute DC/AC values, HRV parameters: SDNN-ix, rMSDD, TP, HF, VLF and ULF were significantly lower in the treated group. LF/HF ratio was higher in this group (p=0.047). These changes persisted during the follow-up and disappeared after treatment. QTc was the shortest in the 4th week and withdrew during further follow-up. H-FABP levels did not differ statistically significantly between any subsequent determinations.At baseline there were no statistically significant differences in the HRV parameters, DC/AC, and QTc-interval. Absolute DC/AC values, HRV parameters: SDNN-ix, rMSDD, TP, HF, VLF and ULF were significantly lower in the treated group. LF/HF ratio was higher in this group (p=0.047). These changes persisted during the follow-up and disappeared after treatment. QTc was the shortest in the 4th week and withdrew during further follow-up. H-FABP levels did not differ statistically significantly between any subsequent determinations.

Aim of the study The aim of this overview was to evaluate the efficacy of sofosbuvir/velpatasvir (SOF/VEL) combination in a real-life setting, with particular regard to treatment-experienced individuals. Material and methods Seventy-five consecutive patients who were treated with SOF/VEL, completed the 12-week follow-up and had sustained virologic response (SVR) evaluated were included in the analysis. Out of them, 60 (80%) patients were treatment-naïve and 15 (20%) were treatment-experienced. Results SVR rates reached 89.4% (66/75) in the whole study group and were comparable irrespective of the fibrosis stage or HCV genotype. However, a significant difference in treatment efficacy between treatment-naïve and treatment-experienced individuals was observed, with SVR rates of 98.3% (59/60) and 46.7% (7/15), respectively (p < 0.0001). Conclusions Further studies including large real-life cohorts of treatment-experienced patients treated with SOF/VEL are warranted to elucidate the real efficacy of this regimen as a retreatment option.

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 AND AIM Grazoprevir/elbasvir (GZR/EBR) was approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infected patients with or without compensated liver cirrhosis. The aim of this study was to assess GZR/EBR regimen in the real-world experience, particularly in previously "difficult-to-treat" patients with chronic kidney diseases, human immunodeficiency virus-coinfected, cirrhotics, and treatment-experienced. METHODS The analysis included patients treated with GZR/EBR selected from 10 152 individuals from the EpiTer-2 database, large national real-world study evaluating antiviral treatment in 22 Polish hepatology centers between 2015 and 2018. Data were completed retrospectively and submitted online. RESULTS A total of 1615 patients who started GZR/EBR therapy in 2017 and 2018 with a female predominance (54%) and median age of 54 years were analyzed. The majority were infected with GT1b (89%) and treatment naive (81%). Liver cirrhosis was diagnosed in 19%, and 70% of patients had comorbidities, of which chronic renal disease was present in 7% and HIV-coinfection in 4%. Overall, a sustained virologic response (SVR) was achieved by 95% according to intent-to-treat (ITT) and 98% after exclusion of lost to follow up (modified ITT). No differences were found in cure rate between all included patients and subpopulations previously considered as difficult-to-treat. Majority of patients completed the treatment course as scheduled, adverse events were mostly mild and did not lead to therapy discontinuation. CONCLUSIONS GZR/EBR treatment carried-out in patients infected with HCV genotype 1 and 4 demonstrated good tolerability and an excellent SVR rate with no effectiveness reduction in so called difficult-to-treat populations.

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.

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.

Imatinib revolutionized the therapy of chronic myeloid leukemia (CML), but the resistance to it became an emerging problem. We reported previously that CML cells expressing the BCR/ABL1 fusion gene, accumulated a high level of reactive oxygen species (ROS) due to deregulated mitochondrial electron transport chain, which in turn led to genomic instability, resulting in imatinib resistance. In the present work, we hypothesize that imatinib-resistant cells may show higher instability of mitochondrial DNA (mtDNA) than their sensitive counterparts. To verify this hypothesis, we checked the ROS level and mtDNA damage and repair in model CML cells sensitive and resistant to imatinib and exposed to doxorubicin (DOX), a DNA-damaging agent. The extent of endogenous ROS in imatinib-resistant cells was higher than in their sensitive counterparts and DOX potentiated this relationship. ROS level in cells with primary resistance, which resulted from the T315I mutation in BCR/ABL1, was higher than in cells with acquired resistance. DOX-induced mtDNA damage in T315I imatinib-resistant cells was more pronounced than in imatinib-sensitive cells. All kinds of cells were repairing mtDNA damage with similar kinetics. In conclusion, imatinib-resistant cells can show increased instability of mtDNA, which can result from increased ROS production.

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.

We followed for 2 years patients treated with direct-acting agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction in liver stiffness (LS) and risk of hepatocellular carcinoma (HCC). The study included patients from 16 hepatologic centres involved in the AMBER, investigator-initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. A total of 204 patients among 209 from the primary study were enrolled, 200 with available testing at 2-year follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 nonresponders retreated). During 2yFU, 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post-treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses were lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, 2-year follow-up confirmed durability of virologic response after treatment of HCV infection with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics that support the need for longer than 2-year monitoring for possible disease progression.

DNA methylation, an epigenetic modification plays a role in the pathogenesis of colorectal cancer (CRC). CRC cases, both sporadic and familial, are often characterized by abnormal pattern of the cytosine methylation in CpG dinucleotides in regulatory regions of genes important for cancer transformation. Also genes mutated in CRC can have their epigenetic pattern altered and we suggest that changes in DNA methylation array can be important for CRC metastatic potential ‒ the main reason of CRC-associated mortality. These genes are: KRAS, genes of the Rho family of GTPases, MACC1, Met, MTA1 and RASSF1A. In addition, genes encoding miRNA important for epithelial mesenchymal transition and other metastasis-related effects, such as mir-9, miR-34 and miR-210 can be good candidates for associating their DNA methylation profiles with CRC metastasis. Analysis of DNA methylation profile in various stages of CRC along with other genetic/epigenetic changes specific for all main stages of CRC transformation could help in anti-metastatic therapy immediately after CRC diagnosis. However, targeting DNA methylation pattern in CRC therapy is a conception, which requires further work to precisely change DNA methylation array, without affecting genes, whose expression should not be changed.

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.

Introduction: Cirrhosis is associated with many disorders of the cardiovascular system defined "cirrhotic cardiomyopathy". They concern, among others autonomic imbalance. One of the ways to evaluate these disorders is to study the heart rate variability (HRV). Abnormal HRV values occur in hypertension, ischemic heart disease, post myocardial infarction and heart failure. Are one of the prognostic factors. Aim: Evaluation of parameters of HRV in 24-hour Holter monitoring in patients with decompensated cirrhosis. Material and methods: The study included 18 patients with decompensated cirrhosis and the control group consisted of 16 healthy subjects. Enrolled were performed 24-hour Holter ECG. Heart rate variability parameters, were estimated during whole recording period, separately for night resting and morning activity hours. Results: There have been significant differences in almost all, both time and frequency HRV parameters between the two groups for follow-up clock. Similar results were obtained by comparing the HRV separately for the night and morning with a control group. The control group achieved statistically significant differences between all the time parameters of HRV at night compared with morning. Frequency parameters showed no significant differences. In patients with cirrhosis demonstrated such differences for the average time NN, SDNN, SDANN, Tr-I, Tinn and ULF. In a 24-hour observation of HRV parameters did not differ significantly depending on the grade in Child-Pugh classification. Conclusions: Patients with decompensated cirrhosis showed significantly lower HRV parameters than healthy volunteers. In addition, disturbances of circadian distribution showed Streszczenie Wstep: Marskośc wątroby wiąze sie z wieloma zaburzeniami ukladu sercowo-naczyniowego określanymi jako cirrhotic cardio myopathy. Dotyczą one m.in. ukladu autonomicznego i rownowagi wspolczulno-przywspolczulnej. Jednym ze sposobow oceny tych zaburzen jest badanie dobowej zmienności rytmu serca (heart rate variability – HRV). Nieprawidlowe wartości HRV wystepują w nadciśnieniu tetniczym, chorobie niedokrwiennej serca, po przebytym zawale i niewydolności serca. Stanowią jeden z czynnikow rokowniczych. Cel: Ocena parametrow HRV w 24-godzinnym badaniu elektrokardiograficznym (EKG) metodą Holtera u osob z niewyrownaną (zdekompensowaną) marskością wątroby. Material i metody: Do badania wlączono 18 chorych z niewyrownaną (zdekompensowaną) marskością wątroby. Grupe kontrolną stanowilo 16 zdrowych ochotnikow. Zakwalifikowanym pacjentom wykonano 24-godzinne EKG metodą Holtera. Parametry HRV szacowano dla obserwacji calodobowej oraz dla godzin nocnych (24.00–4.00) i porannych (8.00–12.00). Wyniki: Odnotowano statystycznie istotne roznice w prawie wszystkich, zarowno czasowych, jak i czestotliwościowych, parametrach HRV pomiedzy badanymi grupami dla obserwacji calodobowej. Podobne wyniki uzyskano, porownując odrebnie HRV dla godzin nocnych i porannych z grupą kontrolną. U osob z grupy kontrolnej stwierdzono znamienne statystycznie roznice pomiedzy wszystkimi parametrami czasowymi HRV z godzin nocnych w porownaniu z godzinami porannymi. Parametry czestotliwościowe nie wykazywaly znamiennych roznic. U osob z marskością wątroby roznice takie wykazano dla średniego czasu NN, SDNN, SDANN, Tr-I, TINN oraz ULF. W 24-go dzinnej obserwacji parametry HRV nie roznily sie znamiennie w zalezności od stopnia w skali Childa-Pugha.

Autoimmune polyglandular syndrome, type 1 (APS-1) is a rare syndrome. Here we present a case report of a 24-year-old female patient who complained of progressive weakness. While autoimmune hepatitis was diagnosed, no improvement of biochemical parameters was obtained after immunosuppressive treatment. Hypoparathyroidism and adrenocortical failure were identified. Her health status clearly improved once proper control of the calcium-phosphate metabolism was obtained and after the administration of substitution hydrocortisone doses, leading to full normalization of biochemical liver tests. The reported case illustrates a rare form of APS-1 failure, in which the diagnosed autoimmune hepatitis was only the first symptom.

Summary Background Heart rhythm turbulence (HRT) is a novel tool for evaluation of cardiovascular mortality. Liver cirrhosis is associated with hemodynamic and myocardial disturbances termed cirrhotic cardiomyopathy. In the stable stage of liver cirrhosis, systolic and myocardial dysfunction is correlated with brain natriuretic peptide (BNP). The aim was to evaluate HRT and its correlation with NT-proBNP, echocardiographic and biochemical parameters in patients with decompensation of liver cirrhosis. Material/Methods The study included 18 patients with decompensated liver cirrhosis and 18 healthy volunteers. Participants underwent echocardiography and 24-hour ECG monitoring. Serum NT-proBNP and other biochemical parameters were measured. Turbulence onset (TO) and turbulence slope (TS) were used to indicate HRT. Results Mean HR (87/min vs. 75/min), TO (−0.385% vs. −0.92%), NT-proBNP (304.85 pg/ml vs. 83.2 pg/ml), LAd (42.5 mm vs. 34.5 mm), RVdd (29.5 mm vs. 25 mm), SPAP (36.5 mmHg vs. 22.5 mmHg) were significantly (p

INTRODUCTION Pharmacological treatment options for nonalcoholic fatty liver disease (NAFLD) are limited. It has been suggested that thiazolidinediones may be useful in NAFLD treatment. OBJECTIVES An open-label prospective study was conducted to assess the efficacy and safety of rosiglitazone treatment in nondiabetic subjects with NAFLD. PATIENTS AND METHODS A total of 27 subjects (mean age 44 ± 11 years, body mass index 29.2 ± 3.1 kg/m2), with biopsy-confirmed NAFLD and no other complaints, were treated with rosiglitazone 4 mg daily for 6 months. RESULTS No adverse events were observed during a 6-month treatment with rosiglitazone. Liver enzymes gradually decreased (alanine transaminase from 101 ± 59 to 58 ± 39 IU/l, aspartate transaminase from 52 ± 24 to 37 ± 15 IU/l; P

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML) with the expression of the BCR-ABL1 tyrosine kinase, but imatinib resistance is an emerging problem. Imatinib can hinder the inhibitory effects of BCR-ABL1 on mitochondrial apoptotic pathway, so mitochondrial mutagenesis can be important for its action. To explore the mechanisms of imatinib resistance we created a mouse-derived CML model cells consisting of parental 32D cells (P) and cells transfected with the BCR-ABL1 gene (S cells) or its variants with the Y253H or T315I mutations (253 and 315 cells, respectively), conferring resistance to imatinib. A fraction of the S cells was cultured in increasing concentrations of imatinib, acquiring resistance to this drug (AR cells). The 253, 315 and AR cells, in contrast to S cells, displayed resistance to imatinib. We observed that the T315I cells displayed greater extent of H2O2-induced mtDNA damage than their imatinib-sensitive counterparts. No difference in the sensitivity to UV radiation was observed among all the cell lines. A decrease in the extent of H2O2-induced mtDNA damage was observed during a 120-min repair incubation in all cell lines, but it was significant only in imatinib-sensitive and T315I cells. No difference in the copy number of mtDNA and frequency of the 3,867-bp deletion was observed and genotoxic stress induced by H2O2 or UV did not change this relationship. In conclusion, some aspects of mtDNA mutagenesis, including sensitivity to oxidative stress and DNA repair can contribute to imatinib resistance in BCR-ABL1-expressing cells.

International audience; BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen. METHODS: In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks. RESULTS: At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received \\textgreater/=1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA \\textless50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed. CONCLUSIONS: In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent

Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML). Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX), a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3) and cytochromeb(MT-CYB) in model CML cells showing imatinib resistance caused by Y253H mutation in theBCR-ABL1gene (253) or culturing imatinib-sensitive (S) cells in increasing concentrations of imatinib (AR). The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 μM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 μM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance.