NS5A replication complex inhibitor daclatasvir in the basis of chronic hepatitis C interferon-free therapy

The aim of review. To analyze antiviral activity of a new NS5A replication complex inhibitor daclatasvir in patients with chronic HCV-infection in relation to different genotypes, including patients with failure of previous antiviral therapy, with liver cirrhosis, within different modes of treatment.Summary. Daclatasvir is NS5A inhibitor which has proven high antiviral activity in relation to all hepatitis C virus genotypes. Prescription of the drug in combination to pegilated interferon and ribavirin for treatment-naive patients made possible to reduce treatment duration from 48 to 24 weeks and to increase frequency of sustained virologic response (SVR) to 87% in 1b genotypeand to 100% — in 4-th genotype. Daclatasvir is no less effective within treatment modes that include other direct-acting antiviral agents as well. In combination to asunaprevir (second waveprotease inhibitor) it demonstrated high rate of SVR both in untreated patients (91%), and in «difficult to treat» groups patients — with liver cirrhosis and nonresponders to the previous therapy (up to 83%). Quadrotherapy including pegilated interferon, ribavirin and asunaprevir has allowed to increase treatment efficacy in nonresponders with 1b genotype even more (up to 98,9% of SVR). Combination of daclatasvir and sofosbuvir is considered to be effective as well, demonstrating 96% rate of SVR in patients with the 3-rd genotype without liver cirrhosis, irrespective of treatment experience. A safety profile and tolerability of daclatasvir is good, comparable to placebo group. The drug is not registered in Russia yet, its approval in combination to asunaprevir is expected soon.Conclusion. Clinical trials have demonstrated that combination of daclatasvir with other medications possessing direct antiviral action, in particular with asunaprevir, and with pegilated interferon and ribavirin significantly increases treatment response rate at different categories of patients with chronic HCV-infection; that allows to reduce treatment duration of these patientsgroups. The drug possesses favorable safety profile, including at treatment of liver cirrhosis

Budesonide in treatment of alcohol-induced severe hepatitis: results of randomized trial

Aim of investigation. To determine efficacy and safety of budesonide and prednisolone at alcoholinduced hepatitis (AH) of severe course on development of inflammation and results of the functional hepatic tests, to estimate treatment response and short-term survival rate of patients.Material and methods. Original study included 37 patients with acute AH, that have been selected from 3 medical centers and randomized in two groups. The first group included 17 patients (7 men, 10 women, mean age 46,53±11,01 years). Median of daily alcohol dose was 77 g; 25th and 75th percentiles were 55 and 96 g; duration of intake 13,41±8,55 years. Mean Maddrey index (MI) was 65,22 (37,2 to 145,4). The second group included 20 patients (16 men, 4 women, mean age was 46,5±11,89 years). A median of used alcohol consumption was 70,55 g/day (25th 75th percentiles were 37 and 88 g), duration of intake — 16,85±13,32 years. Mean MI – 58,11 (32,1 to 121,7). Groups were comparable for main clinical and laboratory features. In the first group oral budesonide 9 mg/day per os was applied, in the second – oral prednisolone 40 mg/day. Lille index was used as treatment response criterion. Following statistical criteria were used for data processing: χ2, Wilcoxon, Mann-Whitney, Kaplan – Mayer method.Results. At comparison of treatment efficacy (р=0,810) and short-term survival rate (р=0,857) no significant differences were obtained. At treatment safety analysis in the first group adverse events (AE) were registered in 23,5% of cases (in 4 of 17 patients), in the second group – in 70% (in 14 of 20 patients, р=0,011). Hepatorenal syndrome was significantly more frequent in the second group (р=0,033).Conclusions. Short-time survival in budesonide and prednisolone group does not differ significantly. At application of prednisolone frequency of AE is higher as a whole, particularly – hepatorenal syndrome

Triple antiviral therapy in patient with liver cirrhosis: complications and options of pharmacological treatment

The aim of review. To discuss options of telaprevir application and risk of adverse events at triple antiviral therapy (AVT) in patients with the 1-st genotype of chronic hepatitis C and compensated liver cirrhosis (LC), and options of pharmacological treatment of hematological complications by original clinical case example.Key points. Introduction of NS3/4A protease inhibitor — telaprevir — to treatment mode for patients infected by the 1-st genotype of chronic hepatitis C, has allowed to increase treatment response rate considerably. Patients with LC who represent heterogenic group require the special approach. AVT with good efficacy and sufficient safety profile in patients with compensated cirrhosis, is as well as for patients in the Waiting list for liver transplantation currently possible. The most common complication of triple AVT are hematological adverse events — development of anemia, neutropenia and thrombocytopenia (or aggravation of severity of the latter in patients with severe fibrosis and LC). Nowadays thrombopoietin receptors agonist (eltrombopag) which allows to provide interferon-based AVT to patients with thrombocytopenia and to optimize it, is developed and approved for clinical application. Assessment of indications to thrombocytopoiesis stimulation, correction of dozes of drug and regular monitoring of peripheral blood parameters are important points.Conclusion. Introduction of direct antiviral agents — viral proteases inhibitors (telaprevir) to practice has allowed to increase AVT efficacy in patients with CHC G1 and liver cirrhosis providing comprehensible safety profile of AVT. Pharmacological stimulation of thrombocytopoiesis by thrombopoietin receptors agonists (eltrombopag) prior or during AVT has allowed not only to take into account patients with initially severe thrombocytopenia as candidates for AVT, but also to carry out sufficient treatment without decrease or with lower frequency of interferon doze reduction, achieving higher rate of sustained virologic response

Chronic hepatitis B and risk of kidney involvement

The aim of review. To present data on causes, pathogenesis, clinical manifestations and prognosis of renal disease at chronic hepatitis B (CHB).Key points. Renal disease at chronic hepatitis B can be assessed from several points of view. First of all, it is HBV-associated glomerulonephritis developed as systemic manifestation of infection and presented, as a rule, by membranous nephropathy in children and mesangiocapillary glomerulonephritis in adults, resulting in chronic renal failure (CRF) in 30% of cases, while program hemodialysis is required in 10% of patients. Moreover, renal disease may be caused by medications used for CHB treatment, e.g. direct nephrotoxicity of adefovir or tenofovir, alpha interferon-induced glomerulonephritis, etc. Relation of HBV-infection to periarteritis nodosa - necrotizing vasculitis, ischemic nephropathy is known. Issue of CHB is important in patients who are undergoing substitution treatment: hemodialysis or post kidney transplantation. Antiviral therapy is indicated to the most of these patients which potential, at the same time, is limited by initially decreased renal function, nephrotoxicity of some drugs or simultaneous prescription of immunosuppressants after organ transplantation. At development of liver cirrhosis (LC) and its decompensation one more aspect of renal disease at CHB arises i.e. risk of hepatorenal syndrome (HRS) of the 1st or 2nd type that is a poor prognostic marker and requires individual therapeutic approach.Conclusion. HBV-associated renal disease can develop as glomerulonephritis within systemic CHB manifestation or as complication of interferon-therapy due to nephrotoxicity of some antiviral agents, or as infection during replacement renal therapy (hemodialysis, transplantation of kidneys, etc.), as well as acute damage of kidneys or CRF (HRS of the 1st or 2nd type) in patients with decompensated LC at CHB outcome. Telbivudine is a drug of choice among new anti-HBV agents for treatment of patients, having high risk of renal disease, which demonstrates not only absence of nephrotoxicity, but also the proved predictable improvement of renal function

Principles of effective out-patient diagnostics of diffuse liver diseases

Aim of investigation. To study prevalence of diffuse liver diseases in the Russian Federation by the example of large industrial city with application of screening tests. Material and methods. Overall 5000 Moscow inhabitants age 18 to 75 years, chosen randomly within the «the liver check up» project, have been included in prospective population study. All patients underwent following investigation: physical examination, filling of nutrition diary, CAGE and AUDIT questionnaires, taking occupational history, anthopometrical examination, US of abdominal organs, clinical and biochemical blood tests, assessment of HCVAb and HBsAg. In the case of abnormal liver tests preliminary diagnosis was determined according to certain algorithm and these patients were recruited for further investigation and specifications of diagnosis in department of hepatology, University clinical hospital N 2, State educational government-financed institution of higher professional education «Sechenov First Moscow state medical university». Results. Abnormal liver functional tests were revealed in 30,6% of industrial city inhabitants — in 1461 of 4768 cases (232 patients were excluded from the study due to partial data loss), significantly more frequently in men in comparison to women, i.e. 49,7 and 25,5% respectively (p<0,001). Prevalence of diffuse liver diseases in the studied sample (n=4768) was following: non-alcoholic fatty liver disease —7,4% (n=352), alcohol-induced liver disease — 6,9% (n=329), hepatitis C — 6,7% (n=322), hepatitis B — 1,9% (n=91), drug-induced liver disease — 0,82% (n=39), cholestatic liver diseases — 0,69 % (n=33), autoimmune hepatitis — 0,78% (n=37), others — 5,4% (n=258). Conclusion. Risk factors for diseases, defined by one-way ANOVA test, were: male gender (p<0,001), excessive body weight and obesity (body mass index >25 kg/m2 (p<0,001)), hyperglycemia (p<0,001), hypertriglyceridemia (p<0,001). By more strict estimation at multifactorial analysis major risk factors were determined: age 30 to 59 years (p<0,001), intake of alcoholic beverages in harmful dozes (over 16 points of AUDIT questionnaire, p=0,04), hypercholesterolemia (p=0,016). Relative weight of those, requiring etiological and pathogenic treatment after specification of preliminary diagnosis, of patients with abnormal liver tests, revealed at screening stage, was 80,3%

Polymorphism of genes and drug-induced liver injury

The aim of review. To analyze publications in the world scientific literature on relation between druginduced liver injury and genetic polymorphism of enzymes and transport systems, xenobiotics involved in metabolism.Key points. Drug-induced liver injury can be accompanied by wide spectrum of clinical symptoms, ranging from asymptomatic elevation of aminotransaminases activity to development of fulminant liver failure. The most cases are related to idiosyncrasy phenomenon which is based on genetic predisposition for production of reactive metabolites at xenobiotic transformation reactions in the liver. Types of genetic polymorphism known for today to be associated with the risk of druginduced liver injury are presented in this article. The perspective trends in diagnostics based on application of molecular genetic methods are taken into account as well.Conclusion. Studies of genetic polymorphism of enzymes and transporters involved in xenobiotic metabolism in the liver, looks to be perspective. Data of investigations allow to expand the concept of pathogenetic mechanisms of drug-induced liver disease, that, in turn, promotes development of the test systems providing diagnostics at molecular genetic level

Rules for investigation of patients with asymptomatic elevation of serum aminotransferase activity

Publication is intended for clinicians dealing with patients who have abnormal blood biochemical tests. Nowadays investigation of blood biochemistry scores, which reflect functional state of body organs and systems, deeply settled in medical practice. Correct understanding of these results helps to diagnose, stage the disease, prescribe treatment and control its efficacy. Features of differential diagnosis and medical approach in patients without any clinical symptoms is actual and common issue faced by many general practitioners every day. As a rule, elevation of activity of alanine and-or aspartate aminotransferases (ALT, AST) is considered as highly significant marker of hepatocyte damage. However, it is necessary to remember, that far from all patients with raised level of aminotransferases have serious liver diseases. More often doctor should interpret elevation of level of ALT and-or AST in patients with obesity, diabetes mellitus, disorder of lipid metabolism or in the case of absence of clinical symptoms of any disease. In presented article issues of patient management with asymptomatic elevation of ALT and AST activity are covered both general-theoretical, and practical points of view. Screening markers and specifying diagnostic tests are necessary to diagnose correct the majority of liver diseases – viral hepatites, alcoholic (ALD) and non-alcoholic fatty liver diseases (NAFLD), autoimmune hepatitis (AIH), Wilson diseases, primary hemochromatosis etc. States at which in absence of primary liver disease levels of ALT and AST can raise are described

Critical evaluation of pathogenic factors of primary biliary cirrhosis

The aim of review. Primary biliary cirrhosis (PBC) is related to the group of autoimmune cholestasisassociated liver diseases. In the last years prevalence of PBC increased considerably, especially – in Northern European countries. Despite of sufficient progress in studying of main pathophysiological mechanisms of PBC, etiology of disease remains obscure. There was a task to fill these gaps to some extent.Key points. Etiological factors increasing risk of PBC development include genetic factors, immunologic disorders, and environmental features. Thus the contribution of each of the mentioned groups of factors, at least, partly is determined by demographic, ethnic and geographical features.Conclusion. Detection of risk factors and the possible PBC causes allows to develop additional treatment approaches, and define new PBC markers, increase rate of early stage diagnostics

Structure and Functions of Human Serum Albumin in Normal Conditions and in Patients with Liver Cirrhosis

The aim: to highlight the main points of albumin synthesis, posttranslational modifications and functions in normal conditions and in patients with liver cirrhosis.Key points. Albumin is the most abundant protein in blood plasma. Along with oncotic properties, albumin performs transport, antioxidant, immunomodulatory and endothelioprotective functions. Serum albumin in patient with liver cirrhosis undergoes modifications, leading to functional impairment. Human serum albumin is a compaund of human mercaptalbumin with cysteine residues having a reducing ability, and oxidized human non-mercaptalbumin. The proportion of irreversibly oxidized non-mercaptalbumin-2 with impaired functional activity increases in liver cirrhosis.Conclusion. The conformational structure of the albumin molecule plays an important role in maintaining its non-oncotic functions. Non-oncotic functions depend on albumin conformation. Further investigation of albumin conformation and albumin functions in patients with hepatic insufficiency can serve as an additional criterion for assessing the severity of cirrhosis and predictor of complications may become an additional criterion to new clinical applications and treatment strategies of liver failure

Modern modes of chronic hepatitis B treatment in daily clinical practice

The aim of review and clinical case. To bring modern standards of antiviral therapy (AVT) of chronic hepatitis B (CHB) and possible mistakes at assessment of medical tactics to focus of general practitioners.Summary. Chronic hepatitis B still remains one of the most actual problems in hepatology. The main aim of treatment is improvement of patients quality of life and prognosis of disease that can be achieved at permanent suppression of virus replication. The modern modes of AVT have several variants: treatment for the limited term by interferon-alpha or nucleotides/ nucleosides analogues and long-term treatment by nucleotides/nucleosides analogues. The major factor decreasing nucleotides/nucleosides AVT efficacy is virus resistance development. At application of pegilated interferon (PEG-IFN) resistance does not develop, however frequency of adverse events is high. The low level of virologic response at of PEG-IFN treatment should be mentioned as well. Nowadays detailed international and Russian guidelines on with chronic hepatitis B patient management are developed. Despite of them general practitioners quite often experience difficulties at choice of medical approach. This article reviews in brief up-to-date modes of CHB treatment, clinical case demonstrating the basic AVT stages is presented: decision-making on its onset, monitoring of the patient during treatment, rules of choice and substitution of antiviral agents, criteria of treatment response assessment and indications for its termination.Conclusion. The adequate choice of drug at definition of antiviral treatment approach allows to suppress virus replication effectively, reduces risk of resistance development and rate of side effects while violation of international standards can result in fatal outcome. The presented clinical case evidently shows possible mistakes at chronic hepatitis B patient management and their consequences