ANTIVIRAL THERAPY IN LIVER CIRRHOSIS

Management of patients with liver cirrhosis due to viral hepatitis is complicated; nevertheless, effective treatment is possible in the majority of diagnosed cases. Etiotropic treatment should be initiated as soon as liver cirrhosis is diagnosed. Antiviral therapy is the only evidence-based and justified treatment approach in such patients. Use of hepatoprotectors with doubtful efficacy significantly reduces chances of recovery and increases likelihood of poor outcomes. During the choice of antiviral regimen, considerations must be given to disease etiology and stage as well as liver functional status. Generally accepted scales for staging of liver cirrhosis (e.g. Child-Turcotte-Pugh and MELD) are helpful in the choice of up-to-date therapy regimen, assessment of the disease prognosis and planning of radical interventions

Результаты трансплантации печени в эпоху современной противовирусной терапии гепатита С

The emergence of direct-acting antivirals (DAAs) has become the basis for a new potential treatment for chronic hepatitis C (CHC) in patients with decompensated cirrhosis, who previously had no other alternative than liver transplantation (LT). However, optimal timing of antiviral therapy (AVT) remains an issue. Objective: to present a spectrum of clinical outcomes in LT waitlisted patients with HCV-related cirrhosis, who received and did not receive DAA therapy. Materials and methods. Enrolled for the study were 49 waitlisted patients with HCV-related end-stage liver diseases. The patients were divided into 2 groups: Group 1 included 40 patients who received DAA therapy before LT, while Group 2 consisted of 9 patients who did not receive antiviral treatment while on the LT waiting list. Results. The sample was represented in most cases by patients who had MELD/Na score <20. Only six had MELD/Na score >20, but <25. At the time of analysis, 38 patients had reached 12 weeks post AVT. Of these, 35 (92.1%) had sustained virologic response (SVR). Of these, 51.4% (n = 18) of cases showed decreased MELD/Na. There were no changes in 22.9% (n = 8). Increased MELD/Na was noted in 25.7% (n = 9). In 42.8% (n = 15) of cases, sustained elimination of HCV infection led to delisting. Among patients without SVR, increased MELD/Na was observed in all cases (n = 3). In the non-AVT group, one patient showed improved liver function (11.1%); in the rest, MELD/Na either remained stable or continued to increase - 44.5% (n = 4). A comparison of the frequency of deaths depending on AVT showed statistically significant differences (p < 0.001, V = 0.728). Among the non-AVT patients, the likelihood of waitlist death increased 66.5 times (95% CI: 7.99-554). Conclusion: DAA therapy carries significant advantages for waitlisted patients with MELD/Na score <25.Появление препаратов прямого противовирусного действия (ПППД) стало основой для формирования нового потенциала для лечения хронического гепатита С (ХГС) у больных с декомпенсированным циррозом печени, которые ранее не имели иной альтернативы, как трансплантация печени (ТП). Однако открытым остается вопрос оптимальных сроков проведения противовирусной терапии (ПВТ). Цель: представить спектр клинических исходов у пациентов с циррозом печени HCV-этиологии, получавших ПВТ ПППД и без нее, в листе ожидания ТП. Материалы и методы. Для исследования было отобрано 49 пациентов из листа ожидания с терминальной стадией заболевания печени в исходе ХГС. Данные были разделены на 2 группы: 1-я включала 40 пациентов, получавших ПВТ ПППД до ТП, 2-я - 9 пациентов без противовирусного лечения в листе ожидания ТП. Результаты. Выборка представлена в большинстве случаев пациентами с MELD-Na <20 баллов, и лишь у шести MELD-Na был больше 20 баллов, но не превышал 25 баллов. На момент анализа 38 пациентов достигли срока 12 недель после ПВТ. Из них у 35 (92,1%) зарегистрирован устойчивый вирусологический ответ (УВО). Из них в 51,4% (n = 18) случаев наблюдалось снижение MELD-Na. Изменения отсутствовали в 22,9% (n = 8), в то время как у 25,7% (n = 9) отмечено нарастание MELD-Na. В 42,8% (n = 15) случаев стойкая элиминация HCV-инфекции привела к делистингу. Среди пациентов без УВО во всех случаях (n = 3) зарегистрировано увеличение показателя MELD-Na. В группе без ПВТ у одного пациента наблюдалось улучшение функции печени (11,1%), у остальных MELD-Na либо оставался стабильным, либо продолжал расти: такие случаи составили равные доли по 44,5% (n = 4). При сравнении частоты летального исхода в зависимости от проведения ПВТ были получены статистически значимые различия (p < 0,001, V = 0,728). При отсутствии ПВТ шансы погибнуть в листе ожидания увеличивались в 66,5 раза (95% ДИ: 7 ,99-554). Заключение. Результаты нашего исследования продемонстрировали значимые преимущества проведения ПВТ ПППД для пациентов в листе ожидания с уровнем MELD-Na <25 баллов

EXPRESSION OF TLR2, TLR3, TLR4 AND PROINFLAMMATORY TNF AND IL-6 CYTOKINES IN LIVER BIOPSIES OF NONALCOHOLIC FATTY LIVER DISEASE PATIENTS

Non-alcoholic fatty liver disease (NAFLD) is a group of conditions closely associated with obesity that are among the most common and socially significant liver diseases in the modern Western world. The emergence and progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis with the subsequent development of fibrosis are the leading factors in the pathogenesis of a significant proportion of the most severe liver pathologies, such as cirrhosis and hepatocellular carcinoma, as well as extrahepatic metabolic complications of NAFLD, such as insulin resistance and type 2 diabetes mellitus. The inflammatory component is one of the most important factors in the pathogenesis of NAFLD, particularly in the context of the progression of simple steatosis to non-alcoholic steatohepatitis. At the same time, the role of the most important mediators of the inflammatory response, innate immunity receptors and the Toll-like receptors in particular, in the pathogenesis of NAFLD has been poorly studied. In the present work, we first used the bioinformatics analysis of the publicly available gene expression databases to demonstrate that only TLR1, TLR2, TLR3 and TLR4 were significantly expressed in the healthy human liver. We then used the reverse transcription PCR to measure the mRNA expression levels of TLR2, TLR3, and TLR4, as well as those of the important pro-inflammatory mediators tumor necrosis factor (TNF) and interleukin-6 (IL-6), in the liver biopsy specimens obtained from 20 patients with NAFLD (simple steatosis, n = 10; non-alcoholic steatohepatitis, n = 10), as well as from 4 obese patients with clinical suspicion for NAFLD but no histological signs of NAFLD in their liver biopsies. We found a significant increase in the expression of TLR2, TLR3 and TLR4 mRNA in liver biopsy samples obtained from patients with non-alcoholic steatohepatitis as compared to those obtained from controls without histological signs of NAFLD. We were also able to demonstrate the association between the hepatic levels of TLR2, TLR3 and TLR4 mRNAs with the histological degree of liver damage as evidenced by the degree of steatosis and balloon dystrophy of hepatocytes, as well as with the plasma levels of uric acid, the important endogenous stimulator of innate immunity. Our data indicate the possible involvement of innate immunity, particularly the Toll-like receptors, in the pathogenesis of NAFLD

Severe Clostridium diffi cile infection after liver and kidney transplantation

Recent statistics have shown increased rates of morbidity and mortality from Clostridium difficile infection worldwide. This problem is mainly typical for surgical patients and is associated with an antibiotic therapy and a prolonged hospital stay. Recipients of solid organs are at a high risk of developing severe forms of C. difficile infection due to immunosupression. Existing recommendations for the treatment of C. difficile infection are based on the severity of the disease and do not consider patients after liver transplantation. The aim of this work is to determine an actual tactics for the diagnosis and treatment of C. difficile in organ recipients in clinical practice

Liver cirrhosis in the Moscow Region: figures and facts

The majority of deaths related to complications of liver cirrhosis would have been preventable with timely diagnosis and proper treatment. However, absence of the population-based screening programs for hepatitis, an asymptomatic course of the majority of liver disorders, failures in the registration of etiologically confirmed cases of liver cirrhosis, low population awareness of its risks and of current diagnostic and management opportunities do impede the collection of reliable epidemiological data on the incidence and prevalence of liver disorders including their end-stages, and on the related mortality of the population; as a consequence, all these factors hinder a comprehensive assessment of the medical and social burden of hepatic disorders. Medical registries are the single system for their registration and follow-up. Analysis of data from the Moscow Regional Registry of patients with liver disease has shown that the leading cause of liver cirrhosis is HCV infection (66%), with alcoholic liver cirrhosis ranking second (16.1%). There is a trend towards higher proportions of liver cirrhosis as an outcome of HCV hepatitis among newly referred patients (7.2% in 2012 and 10.6% in 2016). HCV genotype characteristics determine the rates of the disease progression: in those with genotype 3, liver cirrhosis would occur at an earlier age (51.8% of patients aged from 26 to 45) than with genotype 1 (58.7% of patients aged from 46 to 65). In older patients, various comorbidities can contribute to the development of liver cirrhosis. Among patients with HBV infection, 4.9% have liver cirrhosis, and most of patients receive antiviral treatment with nucleoside/nucleotide analogues. The highest percentage of liver cirrhosis has been found in the patients with chronic D hepatitis (46/116, 39.7%). In 10.3% of the patients with chronic D hepatitis, the aggressive course of the disease leads to primary liver cancer. Thus, the necessity of the development of prevention measures and early detection of liver disorders, as well as modernization of the public healthcare system at all stages of medical care should be recognized as the short-term goals, in addition to the search for highly effective etiologic treatment and making it available within the state-financed programs

CHRONIC HEPATITIS B VIRUS INFECTION IN PREGNANCY: STRATEGIES OF ANTIVIRAL THERAPY

Treatment of chronic hepatitis B during pregnancy is an extremely complicated issue. Despite  implementation of immune prophylaxis, a significant proportion of babies born by mothers with  high viral load are infected by hepatitis B virus.  Cumulative data suggest that antiviral therapy in  the 3  trimester of pregnancy is an effective intervention in the event of unsuccessful immune prord phylaxis. To minimize fetal effects of nucleoside  and nucleotide analogues, antiviral therapy during  pregnancy should be administered to mothers with high risk of disease progression and/or uncontrolled hepatitis B virus infection. The safety  data obtained indicate that telbivudine and tenofovir can be used during pregnancy. Nevertheless,  antiviral therapy requires a  thorough assessment of the risk to benefit ratio

Clinical Traits of SARS-CoV-2 Infection

Aim. Analysis of clinical manifestations, laboratory and instrumental examination data in SARS-CoV-2 patients with taking into account the disease severity and outcome.Materials and methods. The study included 92 patients with confirmed coronavirus infection, including 15 lethal cases, hospitalised at the Vasilenko Clinic of Internal Disease Propaedeutics, Gastroenterology and Hepatology of the Sechenov University in April 2020. The analysis included demographic data, the presence of concomitant diseases, chest computed tomography (CT) results, laboratory tests (including SARS-CoV-2-diagnostic PCR, general and metabolic blood panels, coagulogram) and the duration of disease.Results. Patients infected with SARS-CoV-2 usually exhibit lymphopenia (p ≤ 0.001), leucocytosis, the elevated neutrophils (p ≤ 0.05), neutrophil-lymphocyte ratio (p ≤0,05), C-reactive protein (p ≤ 0.05), ferritin (p ≤ 0.05), D-dimer (p ≤ 0.05) and fibrinogen (p ≤ 0.05), altered prothrombin time (p ≤ 0.05) and INR (p ≤ 0.05). In a critical coronavirus infection, the pulmonary lesion exceeds 50% (corresponds to CT3 — CT4). The risk of critical SARS-CoV-2 infection increases with elder age (p ≤ 0.001), associates with the male gender and presence of concomitant diseases, such as obesity (p < 0.01), diabetes mellitus (p < 0.001), hypertension (p ≤ 0.001), CHD (p ≤ 0.001) and atrial fibrillation (p <0.05).Conclusion. The risk of severe and adverse coronavirus infection is significantly higher in elder comorbid patients

Epidemiology of hepatitis C in the Moscow Region: data from the Moscow Regional Registry and screening for HCV antibodies

Background: Epidemiological characteristics of chronic hepatitis C virus (HCV) infection presented in the literature are not representative for the real situation with its incidence and prevalence in the Russian Federation. In the Moscow Region, which is the second largest population in the Russian Federation (7.2 million people), the Moscow Regional Registry of patients with hepatic disorders has been continuously maintained since 2010, as well as screening programs for anti-HCV positive individuals. Analysis of this data allows for generalization of the results obtain to the general population and for description of the prevalence of the infection among adult population of the Russian Federation. Aim: To analyze the epidemiological situation with chronic hepatitis C in the Moscow Region. Materials and methods: We analyzed data from the Moscow Regional Registry of patients with hepatic disorders as per April 2016, as well as the results of large scale screening of the population of the Moscow Region with oral express test for anti-HCV antibodies (OraQuick HСV Rapid Antibody Test). Based on the registry, we assessed the following parameters of the patient cohort with chronic HCV infection (n = 17 182): age, gender, HCV genotype, grade of liver fibrosis, allele variants of interleukin 28В. Within the large scale screening program among the population of the Moscow Region, 1447 individuals from 6 districts of the region were screened for anti-HCV antibodies. Results: As per April 2016, the proportion of patients with chronic viral hepatitis in the Registry was 75.3% (n = 12 938 of 17 182). The vast majority of them (80.3%, or n = 10 393) had chronic hepatitis C, with 84% (n = 8726) of referrals were patients of productive age (from 20 to 50 years). 8.4% (n = 873) of all HCV infected patients had liver cirrhosis. Although the proportion of patients with cirrhosis was negligibly low (< 1.5%) in patients below 30 years of age, it was progressively increasing with age, with a maximum of 23.8% in those above their 50-es. As far as the HCV genotype distribution is concerned, it was as follows: genotype 1, 54.1% (n = 5622) of patients, genotype 2, 7.2% (n = 747), genotype 3, 38.4% (n = 3990). According to the results of assessment of IL28B genetic polymorphisms (n = 3212), СС rs12979860, which is associated with the most favorable sensitivity to interferon α, was found in 27.5% (n = 883), СТ allele, in 58.4% (n = 1876), and ТТ in 14,1% (n = 453). Prevalence of HCV infection in the Moscow Region, assessed by the screening program, is 1.38% of adults, or 77 200 anti-HCV positive persons, whereas estimated number of patients with chronic hepatitis C may amount to 54 000 to 61 700. Conclusion: HCV infection is the most prevalent among other viral hepatites in the Moscow Region (80.3%), and the largest numbers of infected individuals are of productive age. Almost three quarters of these patients are referred for medical care at the stage of minimal liver injury, and antiviral therapy can be used on an elective basis. Knowing the proportion of patients with liver cirrhosis (8.4%) allows for planning of the need in emergency treatments. The true prevalence of HCV infection estimated from the results of the screening program is at least 5-fold higher than that in the Registry. This indicates the necessity to upgrade the system of primary assessments. In particular, it seems reasonable to include detection of anti-HCV antibodies into the list of obligatory screening laboratory tests

Efficacy and safety of 3D-therapy at HCV-related subcompensated liver cirrhosis (genotype 1b)

Aim of the study. To estimate efficacy and safety of 3D mode of interferon­free therapy in patients with subcompensated liver cirrhosis (LC) of HCV etiology (genotype 1b). Material and methods. Original study included the data of 66 patients (26 men and 40 women) with subcompensated LC of HCV etiology (genotype 1b) who underwent interferon­free therapy by ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin for 12 weeks (the latter was cancelled at receiving the new data on treatment efficacy after 4 weeks of therapy) in September, 2015, before the drug instruction was updated. Mean age of patients was 56.4±10.0 years. At onset of etiological therapy 21 patients (31.8%) had Child­Pugh score of 9, eleven patients (16.7%) had Child­Pugh 8, 34 patients (51.5%) had Child­Pugh 7. The causes of inefficacy of previous modes of combined antiviral therapy (CAT) included absence of virologic response in 43.9% of the cases, recurrence of HCV replication - in 30.3%, virological breakthrough - in 16.7%, development of serious adverse effects - in 9.1%. Taking into account the change of the group quantity during the course of therapy because of treatment cancellation for safety reasons and the subsequent assessment of its efficacy in patients with early treatment cancellation, the modified «intent­to­treat» (ITT) analysis was the basic method of results evaluation. Along with that «per protocol» (PP) analysis was carried out as well. Results. During the treatment course aviremia in 14 days was achieved in 53.8% of patients (in 35 patients of 65), prompt virologic response - at 79.7% (in 51 of 64 patients). All patients underwent complete 12 week course of CAT (n=60) and those for whom treatment was canceled for safety reasons (n=3) - in terms from 14 to 30 days - sustained virologic response (SVR) in 12 weeks and SVR in 24 weeks was registered. The assessment of liver function compensation degree in 6 months after CAT termination demonstrated 3 to 4 points reduction of the Child-Pugh Score in 21 patients (33.9 %), 1 to 2 points in 35 patients (56.5 %). According to the MELD score the clinical improvement was achieved in 66.1% of patients. The early treatment termination was caused by progression of hepatic encephalopathy symptoms and/or jaundice development (4 cases). Most cases of the progression­related treatment termination due to liver failure were reversible after CAT interruption. Three lethal outcomes after the early treatment termination and 1 patients death in follow­up period were registered. Conclusion. Antiviral therapy in 3D mode for subcompensated LC is highly effective not only in those patients who received complete treatment course, but also in those with early treatment secession. Profiling of 3D therapy safety demonstrated that development of serious adverse effects during the treatment is comparable to outcomes at natural course of subcompensated LC in the absence of etiological therapy