[The long-term prospective study of patients with liver cirrhosis after elimination of the hepatitis C virus].

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.

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018).

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.

Efficacy and safety of long-term therapy with nucleos(t)ide analogues in chronic hepatitis B.

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: 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<0.0001) and reduction in the number of patients with advanced fibrosis (from 48.1% to 13.8%, р<0.0001). Entecavir and tenofovir were safe and well tolerated, while treatment with telbivudine was associated with development of myopathy in 13% of cases. CONCLUSION: Entecavir and tenofovir might be recommended for the treatment of chronic hepatitis B because of having potent antiviral effect, high genetic barriers against resistance and good safety.

[Antiviral therapy of chronic hepatitis C: 30 years success story].

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.

[Cryoglobulinemic vasculitis in chronic hepatitis C: Genetic aspects]. / Geneticheskie aspekty krioglobulinemicheskogo vaskulita pri khronicheskom gepatite S.

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.

[NODULAR POLYARTERITIS ASSOCIATED WITH HEPATITIS B VIRUS (A CASE STUDY)].

This study is focused on a case of nodular polyarteritis associated with hepatitis B virus successfully treated by immunosuppressive and antiviral agents.

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

[Alcoholic liver disease: current state of the problem].

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.

Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C.

BACKGROUND AND AIM: Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). METHODS: 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. RESULTS: 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). CONCLUSIONS: In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

[Entecavir in the treatment of chronic hepatitis B: multicenter randomized trials and real clinical practice].

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.

[Current concepts of pathogenesis, clinical course and treatment of hepatitis delta (35 years since its discovery)].

Chronic HDV infection is a most serious and rapidly progressing hepatic disease with high risk of liver cirrhosis and hepato cellular carcinoma (HCC). Many aspects of its pathogenesis, virus biology and treatment remain unknown 35 years after the discovery of the disease. HDV is significantly different from HCV and HBV despite common route of infection. HDV as a satellite pathogen realizes its pathological action in an organism with compromised immune system that proved unable to eliminate HBEV. Hepatic lesions induced by HBV create favourable conditions for HDV propagation that causes rapid development of cirrhosis and its complications. The low efficacy of IFN-alpha therapy is due to the properties of HDV that inhibits the immune response. In most cases, decompensation and hepatic insufficiency determine prognosis of and mortality from HDV infection rather than HCC as in HBV and HCV.

[Antiviral therapy and risk for hepatocellular carcinoma in chronic viral hepatitis].

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.

[Possibilities provided by personalized therapy of chronic hepatitis C (case conference at E.M.Tareev Clinic of Nephrology, Internal and Occupational Diseases)].

The presented clinical case gave rise to discussion of the main mechanisms and factors behind the progress of chronic hepatitis C. Special emphasis is laid on the currently available possibilities of antiviral therapy and its future prospects. The efficacy of personalized treatment and approaches to its improvement are considered based on the proper preventive measures and correction of factors responsible for poor responsiveness to the treatment, in the first place metabolic disorders (obesity, hepatic steatosis).

[Metabolic syndrome in patients with chronic hepatitis C genotype 1].

The aim of this prospective study was too asses the frequency and clinical significance of metabolic syndrome (MS), insulin resistance (IR) and hepatic steatosis in 114 patients with chronic hepatitis C (HCV) genotype 1. MS was found in 47% and IR in 50% of the cases. Diagnosis of IR in patients without MC and marked fibrosis supported the role of HCV in the development of metabolic abnormalities. Hepatic steatosis was found in 38% of the patients and the degree of steatosis significantly correlated with that of fibrosis. Obesity, IR, steatosis and liver cirrhosis were independent negative predictors of the response to the treatment with peginterferon alpha and ribavirin.

[Vascular purpura associated with chronic diffusive hepatic pathologies]. / Sosudistaia purpura, assotsiirovannaia s khronicheskimi diffuznymi zabolevaniiami pecheni.

The study results related with the rate of vascular purpura in 660 patients with different-type chronic diffusive hepatic pathologies both of the viral and other natures are described in the paper. The main regularities characterizing the phenomenon (spread and possible cause of purpura development) are defined. According to an analysis of actual materials, dermal vasculitis is not an exclusive feature of virus-associated hepatitis or liver cirrhosis. Vascular purpura can be regarded, on the basis of the obtained data, as a universal sign typical of any liver pathologies.

[Clinico-morphological characteristics of chronic HbcAg-negative HBV infection with a normal level of aminotransferases]. / Kliniko-morfologicheskaia kharakteristika khronicheskoi Hbc-Ag-negativnoi HBV-infektsii s normal'nym urovnem aminotransferaz.

To study clinicomorphological characteristics and a course of chronic HbeAg-negative HBV-infection with a normal level of aminotransferases, 38 patients whose blood contained HbsAg, HBVDNA and anti-Hbe were divided into 2 groups: with normal (20 patients, test group) and elevated (18 patients, control group) level is of aminotransferases. All the patients' livers were studied morphologically and semiquantitative test for viremia was made. Compared to the controls, the test group patients had low morphological activity (3.4 +/- 1.1 and 8.7 +/- 3.2, respectively, p < 0.005), a fibrosis degree (1.1 +/- 0.4 and 2.3 +/- 1.4 score, respectively p < 0.01) and viremia (log 10 - 3.7 +/- 1.2 vs 6.1 +/- 2.4, p < 0.05). The monofactor analysis has established that viremia 10(5) cop/ml maximum significantly associates with a normal level of aminotransferases (chi-square = 7.89, p = 0.005) while viremia higher than 10(7) cop/ml strongly correlates with a high level of aminotransferases (chi-square = 4.11, p = 0.043). Follow-up of patients with a normal level of aminotransferases for 28 +/- 24 months (6-72 months) showed neither deterioration of the clinical status nor laboratory changes. Thus, patients having anti-HBe and no HbeAg with a normal level of ALT and low viremia (under 10(5) cop/ml) can be considered inactive carriers of HbsAg. In spite of a relatively favourable prognosis, these patients should be followed up for a long time.

[Efficacy of lamivudine in HBeAg-negative chronic hepatitis B]. / Effektivnost' lamibudina pri HBeAg-hegativnom khronocheskom gepatite B.

The necessity of the search for new drugs to treat chronic hepatitis B (CHB) is explained by the necessity to prevent hepatic cirrhosis (HC) and hepatocellular carcinoma. Treatment of HBeAg-negative CHB rests on the same principles as of HBeAg-positive one. Efficacy of nucleoside analogue lamivudin is well studied in HBeAg-positive CHB. The aim of this study was to evaluate lamivudine efficacy in therapy of HBeAg-negative CHB. Lamivudine (epivir--150 mg/day or zeffix--100 mg/day) was given for 1 year to 10 patients (5 males, 5 females, mean age 49.5 +/- 13.5). Their blood serum contained no HBeAg but contained HBeAb and HBVDNA. Chronic hepatitis was verified morphologically in 9 patients of whom 2 had HC and 2 developing HC. Moderate activity of the disease was in 4 patients, low--in 5. All the patients had a high ALT level (150 +/- 140 U/l, 60-528 U/l, high normal value 40 U/l). ALT and HBV DNA in the serum were examined by polymerase chain reaction in the course of treatment and for 6 months after its end. To the end of the treatment a complete response (absence of HBVDNA and normalization of ALT) was achieved in 8 (80%) patients. 5 (63%) of them 2-4 months after the end of the treatment had the exacerbation with appearance of HBVDNA in the serum and elevation of ALT level. A persistent response (6 months after lamivudin treatment) was in 3 (30%) patients, in 2 of them HBsAg was not detected. Lamivudin therapy is effective in HBeAg-negative CHB. In this study a high baseline level of ALT was the factor predisposing to a lasting response to treatment.