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Exactly 30 years ago, hepatitis C virus was identified. Over the years, tremendous success has been achieved in the treatment of hepatitis C, which is currently considered to be an almost completely curable disease. The review presents the main stages in the development of hepatitis C antiviral therapy, the efficacy of various treatment regimens. The greatest progress in treatment was noted over the past 5 years when drugs with direct antiviral action appeared and began to be widely used, including in Russia, which ensure the elimination of the virus in 90-95% of cases.

Nucleos(t)ide analogues are first-line therapies for the treatment of chronic hepatitis B. However, the efficacy and safety of long-term treatment and the necessary duration of therapy remains the subject of discussion. Aim. To assess the efficacy and safety of long-term treatment with nucleos(t)ide analogues in patients with chronic hepatitis B. Materials and methods. We conducted an observational study in 101 chronic hepatitis B (HBeAg-negative and HBeAg-positive) patients treated (≥3 years) with entecavir, tenofovir or telbivudine. Results and discussion. Treatment with entecavir and tenofovir was associated with high rate of virologic and biochemical response (>95%) and HBeAg seroconversion (93% and 67%, respectively). Cumulative rate of virologic resistance was 0; 3.1% and 43.5% for tenofovir, entecavir and telbivudine, respectively. Long-term nucleos(t)ide analogues treatment resulted in a regress of liver fibrosis (from 8.92 to 7.18 kPa, р

The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications

Cryoglobulinemia (CG) is detected in more than 50% of patients with chronic hepatitis C (CHC); however, only 15—25% of them develop cryoglobulinemic vasculitis (CV) that is a systemic vasculitis due to the formation of immune deposits, which affects small (less than medium-sized) vessels and which is frequently fatal for the patient. The causes of CG only in some patients with CHC and the pathogenesis of CV remain unstudied; however, the accumulated data allow one to identify the special contribution of the patient’s genetic factors to the development of the disease. The paper considers the genetic aspects of the development of CG and CV in CHC.

The goal of treatment for chronic hepatitis B (CHB) is now to improve quality of life and to prevent the poor outcomes of the disease rather than to eliminate the virus from the body. This goal may be achieved via the long-term maintenance of aviremia. According to the International and Russian clinical guidelines, entecavir is the first-line drug of choice to treat patients with CHB. For almost 10 years of world clinical practice there has been evidence that entecavir has a high efficacy and a favorable safety profile in a number of randomized clinical trials and in real medical practice worldwide, in Russia in particular. For instance, the BRAVR (Baraclude Russian Analysis of Virological Response) trial of 147 CHB patients from 10 Russian cities indicated that the rate of aviremia was 85.8% (n=147), 89.9% (n=138), 89.4% (n=97), and 93.5% (n=81) at 1, 2, 3, and 4 years, respectively. In addition to its virological, immunological, and biochemical efficacies, entecavir also proved to be effective in achieving the regression of histological changes and in preventing the decompensation of cirrhosis and the development of carcinoma. The given data permit the use of entecavir for the long-term therapy of CHB with confidence.

The literature review gives the present views of the diagnosis and treatment of alcoholic liver disease (ALD) and data on the genetic markers associated with the development of ALD and alcohol addiction. It discusses in detail the mechanisms of liver damage within the disease in question and substantiates indications for the use of prednisolone and pentoxifylline in alcoholic hepatitis. Therapeutic approaches to treating different forms of ALD are considered.

Hepatocellular carcinoma (HCC) is one of the most common human malignancies in incidence and mortality, which develops in the majority of patients in the stage of cirrhosis. Because of the major etiological role of hepatitis viruses, the prevention of HCC is vaccination against hepatitis B virus and successful antiviral therapy for chronic hepatitis B and C.

Objective – to evaluate the long-term outcomes of HCV eradication with direct-acting antivirals (DAAs) in patients with hepatitis C-associated cryoglobulinemic vasculitis (HCV-CV)Materials and methods. We retrospectively assessed 48 patients with HCV-CV treated with DAAs. The activity of HCV-CV was assessed by using Birmingham Vasculitis Activity Score version 3 (BVAS v. 3). In patients with HCV-CV the rate of sustained virologic (defined as undetectable HCV-RNA levels 12 weeks after treatment cessation) and immunological (defined as absence of circulating cryoglobulins, rheumatoid factor and normal C4 level) response; and the rate of complete (defined by a BVAS v. 3 score of 0) and partial (defined as BVAS v. 3 score

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.

Aim. To estimate efficacy and safety of direct antiviral drugs for hepatitis C treatment in donor lung recipients. Key points. The first cases in Russian literature and one of the first-ever cases of hepatitis C treatment by direct antiviral agents in lung transplant recipients are presented. Combined therapy by asunaprevir and daclatasvir for 24 weeks resulted in sustained virologic response. No significant adverse effects on drug to drug interactions, except for mild and controllable alteration of tacrolimus blood level, were noted. Conclusion. Daclatasvir and asunaprevir combination is effective and safe treatment mode for hepatitis C in donor lung recipients

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 of investigation. To estimate frequency of late relapses and clinical outcomes in patients with chronic hepatitis C (CHC) with sustained virologic response (SVO) achievement at antiviral therapy (AVT).Material and methods. Overall 208 patients with CHC, including 12 at the stage of liver cirrhosis (LC), who achieved SVO were investigated. Mean duration of the follow-up was 56,1±35,4 months. Standard clinical and laboratory investigation and evaluation of RNA HCV was carried out. In 114 patients RNA HCV and DNA HBV in blood serum and peripheral mononuclear blood cells were studied by polymerase chain reaction (PCR) with fluorescent hybridization detection in «real time» mode (sensitivity of 10 IU/ml for HCV and 5 IU/ml for HBV).Results. In 3 (1,5%) patients late (i.e. over 6 months after AVT) relapses of HCV-infection were observed. Application of ultraresponsive PCR method allowed to reveal relapse half a year prior to its clinical and laboratory manifestation in 2 cases. No data on latent HCVinfection was obtained not in a single case, including patients with relapse of cryoglobulinemia syndrome. A principal cause of elevation of alanine transaminase activity was non-alcoholic steatohepatitis. In one LC patient development of esophageal varicose veins was detected. There were no cases of decompensation of LC, hepatocellular carcinoma and death due to liver disease.Conclusion. At patients who have achieved SVO as a result of AVT, late relapses of HCV-infection are rare and in the majority no disease progression was found. Relapses of cryoglobulinemia syndrome were observed, but data on presence of latent HCV-infection were not received. Highly sensitive PCR methods are rational for assessment of SVO.

Aim of investigation. To estimate risk of development of liver function decompensation, hepatocellular carcinoma (HCC) development and prognostic factors of liver-related mortality in patients with chronic viral mixed-hepatitis.Material and methods. 82 patients with hepatitis D, 56 – with hepatitis B+C and 20 – with hepatitis B+C+D, followed-up from Jan 2002 to Dec 2011, were included in the study. Results. During follow-up, decompensation occurred in 45.1, 8.9 and 62.5% of patients with compensated liver cirrhosis in groups D, BC and BCD, respectively. The 5-year risk of decompensation was 62%, 27% and 60%. HCC developed in 5.7% of patients, high AFP being the only predictor of HCC. The 5-year risk of HCC was 3.8%, 3.5% and 0%, respectively. 17.1%, 1.8% and 20% of patients died in groups D, BC and BCD, respectively, 5-year survival rate was 90%, 97% and 82%.Conclusions. In patients with chronic viral mixed hepatitis it is decompensation with liver failure development that determines prognosis and is principal cause of liver-related mortality in the most cases, not HCC development.

Aim of investigation. To study the functional changes of cardio-vascular system in patients with viral liver diseases.Material and methods. Overall 150 patients with hepatitis virus C-associated liver diseases, including 80 patients with chronic hepatitis and 70 – with liver cirrhosis (LC) have been included in original study. All patient underwent electro- and echocardiography, and Reberg test with calculation of sodium filtration fraction. At ECG analysis corrected Q-T (Q-Tс) interval was calculated by Bazett's formula.Results. In LC patients elongation of Q–Tc interval (432±21 ms) was revealed in comparison to patients with hepatitis (412±20 ms, р

The aim of review. Studying of effect of antiviral therapy on regression of fibrosis in chronic hepatitis B.Original positions. Article presents analysis of the largest investigations estimating effect of interferon α and nucleoside/nucleotide analogues on development of liver fibrosis. Decrease of severity of fibrosis (for prophylaxis of liver cirrhosis and hepatocellular carcinoma development) is one of the basic criteria of efficacy of treatment of chronic liver diseases. Now various strategies of influence on fibrosis are discussed, including elimination of etiological factor, suppression of inflammation and specific antifibrotic therapy.Conclusion. Successful antiviral therapy at chronic hepatitis B (continuous suppression of replication of virus and activity of inflammation in the liver) results in regression of fibrosis, including cirrhotic stage, and is associated with improvement of patients’ survival rate.

The aim of review. To analyze efficacy of antiviral therapy of various duration in patients with chronic hepatitis C (CHC).Original positions of the report. According to published data viremia dynamics has important prognostic value during treatment, which allows to consider it as one of important factors determining duration and efficacy of treatment along with virus genotype. Poor efficacy of the latter, especially at patients with the 1-st HCV genotype, high cost and risk of the serious undesirable effects cause necessity to individualize antiviral therapy at CHC, improve risk/benefit ratio.Conclusion. At CHC patients with the rapid virologic response (absence of viremia at the 4-th week) it is possible to limit duration of treatment by pegilated interferon and ribavirin in the case of the 1-st HCV genotype to 24 wks, in the case of the 2 and 3-rd genotypes to 12–16 wk. In patients with the 3-rd HCV genotype without rapid virologic response and in patients with the 1-st HCV genotype and slow virologic response treatment probably should be prolonged to 48 and 72 wks respectively.

Hepatitis B virus (HBV) is often found and associated with immune-mediated inflammatory rheumatic diseases (IMIRDs), necessitating the modification of both antiviral and antirheumatic therapies. The review provides basic information about the structure of HBV, the course of chronic HBV infection, and the prevention of HBV reactivation in patients with IMIRDs who receive immunosuppressive therapy.

Direct-acting antivirals (DAAs) therapy is associated with fibrosis regression in patients with hepatitis C virus liver cirrhosis.Aim. To study the dynamic of liver fibrosis in cirrhotic patients with a DAAs-induced sustained virological response (SVR).Materials and methods. The retrospective cohort study included 80 cirrhotic patients (male — 43%, median age 54 years). Liver stiffness (LS) was measured by transient elastography before treatment and after SVR. Patients with LS improvement ≥30% were included in group 1, other patients — in group 2. Clinical, laboratory and instrumental parameters were assessed. Independent risk factors for the absence of LS improvement ≥30% were determined by binary logistic regression with the definition of odds ration (OR) and 95% confidence interval (CI).Results. LS reduced from 21.35 (15.2; 27.7) to 13.5 [10.1; 20.0] kPa (p < 0.001), the median reduction was 5.1 [2.6; 11.0] kPa. Regression of fibrosis from F4 to F2 and F3 stages was observed in 16 (20%) and 19 (24%) of cases, respectively. Overall, 36 patients were included in group 1, 44 patients — in group 2. Platelet counts increased in group 1 compared to group 2 by 24.5% vs 5.2% (p = 0.014), a disappearance or reducing the size of esophageal varices were observed in 72% vs. 35% of cases (p = 0.035). Significant differences in ALT, AST, albumin, prothrombin time dynamics were not observed. Baseline albumin level ≤35 g/l is an independent risk factor for the absence of significant improvement of LS: OR 6.7 (95% CI 1.7–25.9, p = 0.006).Conclusion. SVR leads to fibrosis regression to F2-F3 stages in 44% of patients. Baseline albumin level ≤35 g/l is an independent risk factor for the absence of significant improvement of LS.

Aim.To study liver function and portal hypertension, incidence and risk factors of liver-related complications, including hepatocellular carcinoma (HCC), in patients with HCV-related liver cirrhosis achieved sustained virologic response (SVR) after direct-acting antiviral therapy. Materials and methods.Patients with HCV-related liver cirrhosis were followed up after achievement SVR with assessment of liver function parameters, portal hypertension, Model for End-stage Liver Disease (MELD) and Сhild Pugh (CP) scores, complications development, including HCC, every 36 months. The median follow-up duration was 24 [18; 30] months after end of treatment. Results.At last observation, a number of cirrhotic patients with CP class A increased from 72% to 85%, with CP class B reduced from 23.5% to 12.5%, with CP class C from 4.5% to 2.5%. In 89% patients were identified a regress of liver fibrosis (from 23.5 [16.9; 28] to 15.0 [10.2; 21.3] kPa,p0.005), each third patient reduction of fibrosis stage to F2/F3. In 19 (9.5%) patients were occurred liver-related complications, including HCC (in 9 patients). Baseline high total bilirubin level (34 mol/l) (Hazard ratio (HR) 11.5, 95% confidence interval (CI) 2.357.8,р0.005) and ascites (HR=17.6, 95% CI 2.1144.8,p=0.008) were independent risk factors associated with HCC development. Conclusion.The risk of HCC development remains in patients with HCV-related liver cirrhosis, despite on eradication of hepatitis C virus. Therefore, these patients should continue to undergo more intensive examination (ultrasound examination and determination of alfa-fetoprotein level each 36 months), including contrast-enhanced methods of imaging, the frequency of which should be determined.