Introduction. As a result of portal hypertension (sequestration of platelets in an enlarged spleen) and liver failure (decreased production of thrombopoietin in the liver) in liver cirrhosis, thrombocytopenia develops, which is associated with the risk of periprocedural/perioperative bleeding complications. There are still unresolved questions regarding risk stratification of bleeding complications, the prognostic role of thrombocytopenia, as well as the need for treatment of thrombocytopenia and its methods.Materials and methods. The Russian Scientific Liver Society selected a panel of experts in the field of therapeutic and surgical hepatology, hematology, transfusion medicine to make reasoned statements and recommendations on the issue of treatment of thrombocytopenia before elective surgery / invasive procedures in patients with liver cirrhosis.Results. Relevant clinical issues were determined based on the PICO principle (patient or population, intervention, comparison, outcome). The Delphi panel made five questions and gave reasoned answers, framed as ‘clinical practice recommendations and statements’ with evidence-based comments. The questions and statements were based on the results of search and critical analysis of medical literature using keywords in English- and Russian-language databases. The formulated questions could be combined into four categories: bleeding risk stratification, the prognostic value of thrombocytopenia, the necessity and methods of thrombocytopenia drug correction, and bleeding risk reduction.Conclusions. The results of experts' work are directly related to high-quality management of patients with liver cirrhosis and thrombocytopenia, who have scheduled invasive procedures/surgery. Thus, this recommendations and statements can be used in clinical practice.

Seven of the country’s leading experts in the field of therapeutic and surgical hepatology answer questions on this issue: how relevant is thrombocytopenia in patients with CLD for clinical practice, what is the average proportion of patients who need correction of thrombocytopenia before scheduled and emergency surgical/invasive interventions and how is thrombocytopenia correction performed. All experts are unanimous in the opinion that thrombocytopenia is most common at the stage of cirrhosis. Further, the experts discussed the issues of the total number of patients with CLD, the proportion of patients with thrombocytopenia at all, the proportion of patients with thrombocytopenia in need of surgical interventions, the experts were asked to provide schemes for correcting thrombocytopenia, which they use in their clinical practice. The focus of the experts’ attention was on the discussion of patients who have a platelet level of less than 50 000/µl and need scheduled surgical interventions / invasive procedures. All experts unanimously stratify these interventions according to the risk of hemorrhagic complications: high – more than 1.5%, low – less than 1.5%. The most common and available method for the correction of thrombocytopenia at present is platelet transfusion. Details of all this information, as well as statistical data, can be found in this article.

Background: Glecaprevir/pibrentasvir (GLE/PIB) is the first pangenotypic ribavirin-free regimen allowing for treatment duration as short as 8 weeks for the majority of patients with chronic hepatitis C (CHC) genotypes (GT) 1 to 6. The results of clinical trials showed good tolerability of GLE/PIB and high virologic response rate (mostly >95%) among different patient populations. The main objective of this study was to determine how the efficacy and safety of GLE/PIB translates into real-world clinical settings in Russia. Materials and Methods: This was a prospective, multicenter observational study in patients with CHC who received the GLE/PIB regimen. The treatment regimen was prescribed by a physician in accordance with all applicable requirements before the enrollment in the study. Patients were observed for the duration of GLE/PIB therapy and at least for up to 12 weeks after the treatment completion. Real-world data were collected in patient records. Follow-up visits, procedures, and diagnostic methods followed physicians’ routine clinical practice. Results: Overall 161 patients were enrolled in the study in 11 study sites of them 128 patients had sufficient follow-up data to assess sustained virological response 12 weeks [i.e. ≥70 days] after the end of treatment with GLE/PIB (SVR12). Overall, 127 out of 128 patients (99.2%) achieved SVR12. Depending on treatment duration the following SVR12 rates were achieved: 98.7% in 8-week group (75/76), 100% in 12-week group (49/49) and 100% in 16-week group (3/3). One patient failed to achieve SVR, the exact reasons of failure couldn’t be established by the Investigator. Since only one patient didn’t achieve primary endpoint the following SVR12 rates were achieved in different subpopulations: 91.7% in patients with GT2 (11/12); 98.9% in non-cirrhotic patients (88/89); 99.1% in treatment-naïve patients (113/114); 99.1% in patients without HIV co-infection (116/117); 99.2% in patients younger than 65 years (120/121). On the other hand, SVR12 was achieved by all patients (100%) in the following subpopulations: patients with GT3 (n=76), GT1a (n=5), GT1b (n=29) and other GTs (n=6); cirrhotic patients (n=36) and those with unknown cirrhosis status (n=3); treatment-experienced patients (n=14); HIV/HCV co-infected patients (n=11); patients older than 65 years (n=7); and drug users (n=10). No clinically significant abnormalities in the key laboratory parameters were noted during the study. On contrary, the overall improvement of the liver enzymes was observed at SVR12 Visit. There were 3 patients with 3 adverse events (AEs): 2 cases were mild (cough and rash), and 1 case was severe and evaluated as a serious AE (hepatic decompensation). Hepatic decompensation led to the patient withdrawal from the study; this serious AE was preceded by 2 months of daily alcohol consumption and in the investigator’s opinion was not related to GLE/PIB intake. Of all AEs only rash was related to GLE/PIB administration according to investigator’s opinion. Conclusion: GLE/PIB has proven to be a highly effective treatment regimen in the routine clinical practice in patients with all hepatitis C virus genotypes, including those with GT3 and compensated liver cirrhosis. SVR12 rates demonstrated in this study are fully consistent with the previously published data. The regimen was well tolerated by patients.

Hemostasis disorders in cirrhosis / severe liver disease are complex, as they affect both pro- and anticoagulant factors, as well as pro- and antifibrinolytic components. Most of the tests that are used in clinical practice to assess coagulation do not take into account the compensatory capabilities of this system as a whole. This document provides guidance for the optimal application and interpretation of global screening tests in the assessment of hemostasis in cirrhosis/severe liver disease, analysis of risk factor of spontaneous and perioperative hemorrhagic complications in these patients, and possible ways to correct them. Thrombocytopenia is one of the most common hematological abnormalities in cirrhosis/ severe liver disease. The frequency of thrombocytopenia in such patients at the stage of liver cirrhosis is 70%, at the pre-cirrhotic stage – 6%. The latest scientific data on the use of thrombopoietin receptor agonists in chronic liver diseases are presented: which patients are the best candidates for a such of therapy. The rationality and limitations in prescribing blood components to patients with liver cirrhosis/severe liver diseases are described. Emphasis is placed on the fact that a number of hemorrhagic complications develop for other non-coagulopathic reasons: decompensated portal hypertension, traumatization of a varicose vein with trophic wall disorders, etc. Data are presented on the use of viscoelastic tests to optimize the management of patients with liver cirrhosis, which simultaneously assess the four main known components of the hemostasis system: the coagulation cascade, platelets, anticoagulant mechanisms and the fibrinolysis system. These tests allow optimization of transfusion of blood components in such patients and should be further studied. Research in this very complex area of hepatology is ongoing and must continue.

Aim of investigation. To estimate efficacy and safety of narlaprevir (NVR) with ritonavir (RTV), pegilated interferon (peg-IFN) and ribavirin (RBV) at treatmentnaïve and earlier treated noncirrhotic patients with chronic hepatitis C caused by the 1st virus genotype in double blind placebo-controlled 3rd phase study (PIONEER). Material and methods. The main group received NVR (200 mg od orally) in combination to RTV (100 mg) and pegIFN/RBV for 12 weeks that was followed by peg-IFN/ RBV for 12 weeks. Comparison group received pegIFN/ RBV for 48 weeks, for the first 12 weeks in combination to placebo. Results. The sustained virologic response in 24 weeks after treatment termination (SVR24) in the main group (NVR/RTV, PEG IFN/RBV)) was achieved in 89.1% (163/183) of treatment-naïve and 69.7% (69/99) of earlier treated patients. SVR24 was achieved in 86.5% (32/37) of patients with relapse after previous peg-IFN/ RBV treatment course. The viral load decreased for the mean of 5.3 log10 in 2 weeks and 5.9 log10 in 4 weeks of treatment in the main group vs 1.5 log10 in 2 weeks and 2.5 log10 in 4 weeks in comparison group. In treatment-naïve patients from the main group SVR24 was achieved in 90.8% at initial METAVIR F0-F2 liver fibrosis stage and in 75% at F3 liver fibrosis stage. In those who were previously treated by peg-IFN/RBV, in the main group SVR-24 was attained in 72.6% at liver fibrosis stage F0-F2 and in 53.3% with F3 liver fibrosis stage. NVR/RTV addition to peg-IFN/RBV treatment did not alter safety profile as compared to peg-IFN/RBV therapy. Conclusions. In PIONEER study the narlaprevir combination therapy was characterized by high efficacy, convenience of administration and favorable safety profile.

Aim. Study of efficacy and safety of ribavirin in combination to pegylated interferon α-2a (PegIFN- α-2a) within combined mode of treatment of patients with chronic hepatitis C (CHC) including patients with compensated cirrhosis and and HIV coinfection were conducted. Material and methods. Two open prospective multicenter, non-comparative clinical trials ML16709 NCT00922779 and ML27851 «Standart» (NCT01609049) were conducted. 6661 and 1496 patients with CHC were included accordingly. All were administrated combined therapy: ribavirin and PegIFN- α-2a. Patients with HCV genotype 1 received prescribing treatment for at least 12 but not more than 48 weeks, patients with HCV genotypes 2 and 3 – for at least 12 but not more than 24 weeks. The efficacy analysis included determining the frequency of achieving a rapid virologic response (BVO), an early virologic response (RVO), a virologic response at the end of therapy, and a sustained virologic response (SVR). The safety endpoints were assessed on data of all adverse events (AEs), serious adverse events (SNP), and clinical laboratory findings. Results. At 24 weeks SVR frequency was 43.4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 72,0% in the ML27851 study; 58,9% and 89,3% in the subgroup of patients with HCV genotypes 2 and 3 accordingly. In the ML27851 study proportion of patients with BVO was 46,8% in patients with HCV genotype 1 and 86,0% in patients with a different HCV genotype. RVO frequency was 37,4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 90,1% in the ML27851 study; 79,7% and 97,4% in a subgroup of patients with HCV genotypes 2 and 3 accordingly. The proportion of patients with virologic response at the end of therapy was 44,6% in the ML16709 study and 86.7% in the ML27851 study; in a subgroup of patients with genotypes 2 and 3, 73.8% and 97.6%, accordingly. In the ML16709 study 5887 AEs were registered, including 5812 (99%) of non-serious AEs and 75 serious AEs. In the ML27851 study 2557 non-serious AEs occurred in 822 (54.95%) patients. 49 serious AEs were registered in 39 patients (2.6%). Conclusion. The results of studies ML16709 and ML27851 confirm the efficacy and safety of treatment with ribavirin plus peginterferon alfa-2a in patients with chronic hepatitis C. The registered AEs profile is representative of pegylated interferons and ribavirin combination.

Aim of investigation. Nowadays the question, whether pegylated interferon should be completely abandoned in the treatment of chronic hepatitis C (CHC) is still open. Beneficial interferon properties include: absence of mutagenic capacity for hepatitis C virus and drug interaction, stimulation of host immune response. These qualities formed the basis for development of the Russian pegilated interferon-alpha 2b (Pegaltevir®, LLC «FARMAPARK», Russia) and carrying out doublestaged randomized open clinical trial: study of safety, tolerability and pharmacokinetics of Pegaltevir® at single injection of increasing doses in various groups of healthy volunteers - the I stage; studying of efficacy and safety of Pegaltevir® in comparison to PegIntron® (Schering-Plough, USA) at CHC as a part of double antiviral therapy with ribavirin (Rebetol®, Schering-Plough, USA) - the II stage. This article presents results of the II phase of investigation. Material and methods. Original study included 140 adult antiviral treatment-naive patients with CHC and compensated liver function. Patients (aged 18 to 70 years) were distributed into four groups. Group 1 (main group, Pegaltevir®/Rebetol® treatment) - 55 patients, HCV genotype 1; group 2 (comparison group, PegIntron®/Rebetol® treatment) - 20 patients, HCV genotype 1; group 3 (main group, Pegaltevir®/Rebetol® treatment) - 47 patients, non-genotype 1 (2 and 3); group 4 (comparison group, PegIntron®/ Rebetol ® treatment) with non-genotype 1 (2 and 3). Assessment of Pegaltevir® efficacy was carried out in 4 weeks (rapid virologic response, RVR) and 12 weeks of treatment (early virologic response, EVR) in groups 1 and 3 in comparison to corresponding scores in groups 2 and 4 (primary criteria of efficacy were estimated in all 140 patients enrolled in original study. The response rate at the moment of secession of antiviral therapy, the sustained virologic response (SVR), histologic response (comparison of paired liver biopsies) served as secondary efficacy criteria and were estimated in 129 patients who completed treatment. The safety analysis was carried out for each patients included in the protocol who received at least one Pegaltevir® dose in comparison to patients who received at least one dose of PegIntron®, - respectively 102 and 38 patients. Results. RVR was comparable in the Pegaltevir® and PegIntron® groups: 65,6 and 82,4% respectively (p>0,05). RVR frequency genotype one patients was 45,3% in Pegaltevir® treatment group and 66,7% in PegIntron® treatment group (p>0,1). At patients with non-genotype 1 (2 and 3): 92,5 and 100% respectively (p>0,05). RVO did not significantly differ in the studied groups: 91,6 and 97,1% for all genotypes respectively (р>0,1). RVO rate for genotype 1 patients in Pegaltevir® group was 86,8%, in PegIntron® treatment group - 94,4% (р>0,1), in non-genotype 1 patients (2 and 3) it reached 97,6 and 100% in the specified patient groups (р>0,1). Response rate at the moment of treatment secession for Pegaltevir® and PegIntron® was 87,4 and 97,1% respectively for all genotypes (р>0,05). In patients with HCV genotype 1 this score Pegaltevir® treatment group reached 79,3%, in PegIntron® group - 94,4% (р> 0,05), in non-genotype 1 patients (2 and 3) - 97,6 and 100% respectively (р>0,1). SVR rate at Pegaltevir® treatment was 82,1% (for all genotypes), PegIntron® - 82,4% (for all genotypes, p>0,1). In HCV genotype 1 patients in Pegaltevir® treatment group SVR made 73,6%, in PegIntron® treatment group - 83,3%, p>0,1, for non-genotype 1 (2 and 3) - 92,9 and 81,3%, p>0,1. No significant differences between basic and control groups at analysis of paired liver biopsies for fibrosis stage reduction rate, absence of negative changes for fibrosis severity and proportion of patients with fibrosis progression were found. Pegaltevir® and PegIntron® treatment groups were comparable safety profile, adverse events were expected, mainly of mild and moderate severity. Conclusion. The hypothesis of identical efficacy of the Russian drug Pegaltevir® tested in the protocol in comparison to PegIntron® was correct and proved. Safety of Pegaltevir® was comparable to safety of PegIntron® as well.

Introduction. The options of antiviral therapy (AVT) in the stages of severe liver fibrosis and cirrhosis (LC) as well as in the patients with comorbidities for the long time were limited to the standard therapy by pegilated interferon (peg-IFN) in combination to ribavirin (RBV). Before official registration of interferon-free treatment modes in 2015 experience of the application was limited to clinical trials or treatment within early approach programs. Aim of investigation. To analyze the efficacy of PTV for chronic hepatitis C within the named patient program of expanded access to daclatasvir. Material and methods. Approval of Ministry of Healthcare of the Russian Federation to import of drugs was received for the treatment of 101 HCV-infected patients with compensated LC, who, been untreated had an urgent need for effective therapy, with estimated life expectancy less than 12 months, in 12 centers of the Russian Federation. The patients with 1b HCV genotype received treatment by combination of daclatasvir and asunaprevir 100 mg, patients with 2 and 3 HCV genotypes, and those with 1b HCV genotype after the liver transplantation received daclatasvir to sofosbuvir combination. Results. Sustained virologic response for 24 wks (SVR24) in early approach program was 89% (83 of 93) of patients with severe liver disease who urgently needed effective treatment with estimated life expectancy of less than 12 months if been untreated. In group of the patients receiving treatment mode of daclatasvir + asunaprevir the frequency of SVR24 achievement was 90%. Of 93 patients who underwent complete treatment course no severe adverse effects were registered. During treatment infrequent nonspecific adverse events, such as a headache and fatigue were observed. No significant elevation of alanine transaminase and aspartate aminotransferase activity, or bilirubin level were detected. Conclusions. Daclatasvir combination to asunaprevir or sofosbuvir demonstrated high efficacy, including that at treatment of patients with poor prognostic signs.

Material and methods. The original study included overall 120 patients with ALD, who were randomized in two identical groups. The patients of the main group (group A) received 2 courses of therapy: the first - Phosphogliv 5 mg/day as intravenous bolus injection for 2 wks, followed by the oral intake of 2 capsules t.i.d. for 10 wks (the total treatment duration was 24 wks). Patients of the control group (group B) received placebo in the same regimen. The dynamics of serum alanine transaminase (ALT), aspartate transaminase (AST), liver scores by noninvasive FibroMax test was applied to assess the treatment efficacy and safety, along with change in quality of life of patients. Results. In 24 wks in group A in comparison to the group B significantly lower mean ALT level was found: 35,2±29,4 U/l vs 48,4±36,1 U/l (р =0,044), AST level became normal in higher rate of patients: 69,4% vs 47,7% (р =0,034), that had more prominent decrease in gamma-glutamyltranspeptidase (GGT) level - 47,4±36,5% vs 25,1±63,9% (р =0,039), the rate of patients with Aktitest A2-A3 range decreased - 8,5% vs 21,4% (p

Material and methods. The original study included overall 120 patients with ALD, who were randomized in two identical groups. The patients of the main group (group A) received 2 courses of therapy: the first - Phosphogliv 5 mg/day as intravenous bolus injection for 2 wks, followed by the oral intake of 2 capsules t.i.d. for 10 wks (the total treatment duration was 24 wks). Patients of the control group (group B) received placebo in the same regimen. The dynamics of serum alanine transaminase (ALT), aspartate transaminase (AST), liver scores by noninvasive FibroMax test was applied to assess the treatment efficacy and safety, along with change in quality of life of patients. Results. In 24 wks in group A in comparison to the group B significantly lower mean ALT level was found: 35,2±29,4 U/l vs 48,4±36,1 U/l (р =0,044), AST level became normal in higher rate of patients: 69,4% vs 47,7% (р =0,034), that had more prominent decrease in gamma-glutamyltranspeptidase (GGT) level - 47,4±36,5% vs 25,1±63,9% (р =0,039), the rate of patients with Aktitest A2-A3 range decreased - 8,5% vs 21,4% (p<0,05) with no patients remained in FibroTest F3-F4 range; significantly more pronounced improvement by the vitality and social functioning scales of «SF-36» questionnaire was registered. The safety profile was comparable in both groups. Conclusions. Expected effects of the drug include reduction of inflammatory activity in the liver, improvement of cholestasis at longer follow-up period, decrease in fibrosis severity, improvement of quality of life at favorable safety profile.

Aim of investigation. Comparative assessment of efficacy and safety of Pegaltevir and PegIntron in within pattern of combined antiviral therapy in previously untreated patients with chronic hepatitis C.Material and methods. Overall 140 patients with chronic hepatitis C, who received no antiviral therapy previously were included in original study. Patients were randomized in 4 groups. Groups differed in relation to received drug and hepatitis C virus genotype. All patients received 1,5 mkg per 1 kg body weight per week of Pegaltevir or PegIntron and 800–1400 mg of ribavirin per day. Preliminary estimation of drug efficacy was based on rates of rapid and early virologic response (RVR and EVR) achievement, dynamics of biochemical tests, dynamics of blood level of peginterferon alpha and neopterin. Safety features were estimated as well.Results. Comparative analysis has demonstrated absence of statistically significant distinctions of RVR and РВО rates at application of two peginterferon alpha-2b drugs. There were no differences in frequency of achievement of serologic response, as well as safety in Pegaltevir and PegIntron groups. Dynamics of blood concentration of peginterferon alpha correlated to neopterin concentration both in Pegaltevir group and in PegIntron group.Conclusions. Study results have shown high rates of RVR and РВО achievement, and acceptable safety profile of Pegaltevir, comparable with that of PegIntron at chronic hepatitis C in previously untreated patients.

Aim of investigation. HEP3002 is the international early access program of efficacy and safety estimation of telaprevir in combination to peginterferon alpha and ribavirin for patients with severe fibrosis or liver cirrhosis caused by hepatitis C virus (HCV) genotype 1. Efficacy and safety of this therapeutic mode were evaluated in intermediate analysis on 16-th week of treatment in 153 patients from Russia who have already reached the 16-th week of treatment or potentially can do so.Material and methods. The study has prospectively included 153 HCV infected patients (genotype 1), with bridging fibrosis or compensated liver cirrhosis who received treatment by telaprevir in combination to peginterferon-alpha and ribavirin for 12 wks with subsequent 12-or 36-week rate of antiviral therapy (AVT) by peginterferon alpha and ribavirin in relation to virologic response and fibrosis severity. Analysis has been carried out for intention to treat (ITT) populations with application of 16-th week AVT data.Results. Total of 153 patients have completed 12-week course of triple therapy and 4-week course of peginterferon-alpha and ribavirin treatment (48% cirrhotic patients, 97% – HCV-1b). The level of HCV RNA was undetectable both at the 4-th week, and at the 12-th week (extended rapid virologic response) in 42 (75%) of 56 previously untreated patients, in 34 (89%) of 38 with relapses after previous treatment, in 4 (57%) of 7 with previous incomplete response, in 22 (52%) of 42 with the previous zero response and in 7 (70%) of 10 with previous virologic breakthrough. Sustained virologic response was achieved in 73 (80%) of patients available for analysis (n=91). Most frequent adverse events of the 2-4 degrees, related to telaprevir, were anemia (63 patients, 41%), thrombocytopenia (15 patients, 10%) and skin rash (7 patients, 5%). For anemia treatment in 50 (33%) patients the doze of ribavirin has been reduced, erythropoietin was prescribed to 12 (8%) to patients and no blood transfusion was required; 10 (7%) patients have ahead of schedule stopped course of treatment by telaprevir in connection with development of anemia (6), thrombocytopenia (2) and occurrence of skin rash (2).Conclusion. In 153 patients with severe liver fibrosis caused by hepatitis C virus (genotype 1), on background of triple AVT with telaprevir high level of immediate virologic response and low level of the preterm treatment discontinuation was marked.