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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.Ровно 30 лет назад был идентифицирован вирус гепатита С. За эти годы достигнут огромный успех в лечении гепатита С, который в настоящее время рассматривается как практически полностью излечимое заболевание. В обзоре представлены основные этапы становления противовирусной терапии гепатита С, эффективность различных схем лечения. Наибольший прогресс в лечении отмечен в течение последних 5 лет, когда появились и стали широко применяться, в том числе и в России, препараты с прямым противовирусным действием, которые обеспечивают элиминацию вируса в 90-95% случаев.

Hepatitis C virus (HCV) is a global population problem due to its high prevalence, usually late diagnosis, the difficulties of treatment. In the prognosis of patients with HCV not only hepatic, but increasingly frequent of extrahepatic HCV manifestations, such as mixed cryoglobulinemia (CG), are important. Mixed CG is currently considered as a B-cell benign lymphoproliferative disorders. The role of HCV virus in the pathogenesis of lymphoproliferative diseases is confirmed by a large number of epidemiological studies, as well as by the effectiveness of antiviral therapy in patients with non-Hodgkin’s lymphoma (NHL). The purpose of the review was to provide an overview of recent literature data and the meta-analysis of epidemiological data explaining the role of HCV in the development of NHL. The review also discusses the treatment for HCV-associated NHL by antiviral therapy or other therapeutic options, such as chemotherapy.

Aim of the study was to explore the role of the FGF-23/sKlotho/sclerostin ratio disturbance in the determining of cardiovascular risk in end stage renal disease (ESRD) patients, receiving treatment with regular hemodialysis (НD) or hemodiafiltration (НDF) online in Russia.42 patients with ESRD, at the age of 18-55 years, treated with HD or HDF on line for at least 6 months, were examined. 22 (52.3%) patients received traditional HD, the remaining 20 (47.7%) - HDF online. In all the patients, in addition to a general examination, the serum levels of FGF-23, sKlotho, sclerostine (by ELISA), their associations with cardiovascular risk factors (left ventricular hypertrophy (LVH), acute coronary syndrome (ACS), serum troponin I levels) with the numbers of techniques (ECG; Eho-CGF (with calculation of left ventricular myocardium mass index (LVMMI), as well as the relative thickness of the walls of the left ventricle (RWT); sphygmography (central (aortal) blood pressure (CBP), subendocardial blood flow (SBF) - by «Sphygmocor»), and the effect of regular HD and HDF on serum levels of the studied markers, were assessed.An independent effect of FGF-23 on the risk of LVH, as well as on the increase of serum troponin I in the studied ESRD patients [β=3.576 plt;0.01, and β=1.115, plt;0.05, respectively] was found. Serum Klotho was the factor most associated with the CBP [β=-0.023; plt;0.001]. The increased serum sclerostin was correlated with a lower incidence of both reduced SBF [r=0.492; plt;0.05], symptoms of coronary heart disease [r=-0.449; plt;0.05] and rhythm disturbances [r=-0.446; plt;0.05]. In addition, in HD patients higher FGF-23 and lower Klotho and sclerostine serum levels were associated with: inadequate dialysis syndrome (Kt/Vlt;1.1; r=0.463; plt;0.05), chronic inflammation (C-reactive proteingt;10 mg/L; r=0.612; plt;0.01), and with a decrease in serum albumin level (lt;35 g/l; r=0.459; plt;0.05). The FGF-23/sKlotho/sclerostin ratio disturbance was more pronounced in patients treated with traditional HD then HDF online. A direct correlation (r=0.445; plt;0.05) was established between FGF-23 serum levels and serum phosphorus, which was more pronounced in HD patients (r=0.545; plt;0.01).In HD and HDF ESRD patients, higher serum FGF-23 and lower sKlotho and sclerostin levels were associated with a chronic inflammation, malnutrition, secondary hyperparathyroidism, and may considered as predictors of cardiovascular complications such as LVH, ACS, rhythm disturbances, persisting of subincreased serum troponin I.

The study demonstrated the results of the comparative analysis of various types of renal replacement therapy effects on the quality of life patients with terminal stage of chronic kidney disease on the basis of standardized questionnaires. It has been shown that the quality of life is significantly improved after a kidney transplantation. At the same time, it has also been found that the introduction of home dialysis, epoetins, active metabolites of vitamin D, calcimimetics in the clinic care expanded the opportunities for the labor rehabilitation of the dialysis patients and made their quality of life comparable with the same of the kidney transplant recipients.

Aim. To investigate the impact of anemia correction with erythropoiesis stimulants on the serum level of the circulating morphogenetic protein α-Klotho in patients with Stages 3B—4 chronic kidney disease (CKD). Subjects and methods. 64 patients aged 42±8 years with Stages 3B—4 nondiabetic CKD were examined and divided into 2 groups: 1) 32 patients with anemia (the target hemoglobin levels could be achieved and kept with erythropoietin and iron saccharate in 20 patients (Group A) and those could not be done in 12 patients (Group 1B). A control group (Group 2) consisted of 32 non-anemic patients matched for gender, age, and degree of a glomerular filtration rate (GFR) reduction. Along with iron exchange indicators, the time course of changes in serum Klotho levels were examined in all the 64 patients during screening and one year after the end of the study. For correction of anemia, 32 patients with this condition (Groups 1A and 1B) took short-acting epoetin (hypodermic recormon 2,000 IU thrice per week + iron (intravenous venofer 5 ml of 100 mg once per week)) under control of hemoglobin levels and serum transferrin iron and ferritin saturation. After achieving the target hemoglobin level of 110-120 g/l, for its keeping, all the patients received, instead of short-acting epoetin, long-acting hypodermic darbepoetin-α 1.5 µg once every 2 months and intravenous iron saccharate 100 mg once every 2 weeks. Results. Among the 32 anemic patients in Group 1, 20 (63%) (Group 1 A) could achieve the target hemoglobin level (110—120 g/l) and maintain it within this range, by performing therapy with epoitin-β + iron saccharate; anemia (the hemoglobin level of

The paper presents the steps for studying cryoglobulinemia from essential to cryoglobulinemic vasculitis associated with hepatitis C virus. It shows advances in the study of the etiology of cryoglobulinemia, diagnosis, specific features of renal injury, and current approaches to treating HCV infection-related cryoglobulinemic vasculitis with renal involvement, by using 3 clinical cases (with a difference of a few decades during a follow-up).

Aim. To analyze changes in the serum concentrations of the morphogenetic proteins fibroblast growth factor 23 (FGF-23) and Klotho, as well as sclerostin, an osteocyte-secreted glycoprotein, in relation to the degree of hypertension, left ventricular (LV) hypertrophy, and arterial stiffness in patients with chronic kidney disease (CKD) at its different stages. Subjects and methods: Sixty-five patients (33 men and 32 women) aged 20—65 years, including 25 with chronic glomerulonephritis, 15 with tubulointerstitial nephritis, and 25 with hypertensive nephrosclerosis, were examined. A control group consisted of 15 healthy volunteers matched to the study group patients for age and gender. Serum FGF-23 concentrations and blood pressure (BP) were measured in the all subjects. Patients with BPs >140/80 mm Hg underwent echocardiography, followed by determination of LV mass (LVM) and calculation of LVM index. Vascular circulation, pulse wave velocity, cardiac and vascular calcifications, and vascular functional properties were estimated. Results. There was a strong direct correlation between the serum concentration of FGF-23 and the stage of CKD and an inverse correlation between the levels of Klotho and sclerostin and the stage of CKD. As the glomerular filtration rate became lower, the concentration of FGF-23 increased and that of Klotho and sclerostin decreased just in Stage III CKD while hyperphosphatemia and elevated parathyroid hormone levels were noted in Stages IV-V CKD. As CKD progressed, the serum concentrations of Klotho and sclerostin were inversely correlated with the levels of phosphorus and parathyroid hormone. The degree of blood pressure elevation correlated positively with serum FGF-23 concentrations and inversely with Klotho levels. There was no significant correlation of the level of sclerostin with the degree of BP increase. The direct correlation between higher FGF-23 level and higher VLM is most pronounced in hypertensive patients. There was a strong direct relationship between FGF-23 and Klotho levels and a strong inverse relationship between sclerostin levels and pulse wave velocity. Lower Klotho concentrations were associated with the detection rate of calcifications in the heart valves and large arteries (the abdominal aorta). The reduced serum levels of Klotho and sclerostin were also correlated with concentric LV remodeling. Conclusion. It was demonstrated that there was a clear link between increased serum FGF-23 and decreased Klotho concentration as CKD progressed, and that between arterial stiffness and calcification and myocardial remodelling regardless of traditional risk factors. More experimental and clinical studies are required to clarify the role of sclerostin in CKD.

To summarize the experience of a multidisciplinary therapy hospital in treating patients with hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis (CV).Seventy-two patients (mean age, 49.4±10.3 years) with HCV-associated CV were examined and followed up for an average period of 2.8±3.6 years. The efficiency of traditional (corticosteroids ± cyclophosphamide) and selective (rituximab) immunosuppressive therapy (IST) was estimated in 31 and 15 observations, respectively, and that of antiviral therapy (AVT) in 25. Vasculitis activity was assessed using the Birmingham vasculitis activity score (BVAS). The patients' survival was studied; multivariate logistic regression analysis was carried out.24 (33.4%) of the 72 patients had a stage of liver cirrhosis (LC). The pretreatment mean BVAS was 11.9±7.2 (range 2 to 36). Severe CV (BVAS ≥15) was present in 30.6% of the patients. AVT was accompanied by achievement of sustained virologic response in 48% of the patients, clinical remission in 68% and had an advantage over IST in relation to long-term treatment results. Rituximab was significantly more effective than traditional immunosuppressants (remission rates of 73 and 13%, respectively). Combined therapy (rituximab and AVT) was most effective in patients with severe forms of vasculitis. Sixteen patients died from complications of vasculitis (37.5%), infection (37.5%), and LC (25%). The factors adversely affecting prognosis were age55 years (odds ratio (OR), 4.49), the presence of LC (OR, 3.68), renal failure (OR, 4.66) and the use of glucocorticosteroids (OR, 3.91).HCV-associated CV can determine the prognosis of chronic HСV infection. AVT is the treatment of choice in all patients with HСV-associated CV. AVT must be combined with rituximab therapy in patients with severe forms of vasculitis.Цель исследования. Обобщить опыт многопрофильного терапевтического стационара в лечении больных криоглобулинемическим васкулитом (КВ), ассоциированным с вирусом гепатита С (HСV). Материалы и методы. Обследовали и наблюдали в среднем 2,8±3,6 года 72 больных хроническим гепатитом С (ХГС) с ассоциированным с HСV КВ (средний возраст 49,4±10,3 года). Эффективность традиционной (глюкокортикостероиды ± циклофосфамид) и селективной (ритуксимаб) иммуносупрессивной терапии (ИСТ) оценена в 31 и 15 наблюдениях соответственно, противовирусной терапии (ПВТ) - в 25. Активность васкулита оценивали с помощью BVAS (Birmingham vasculitis activity score). Изучали выживаемость больных, проводили многофакторный логистический регрессионный анализ. Результаты. У 24 (33,4%) из 72 больных имелась стадия цирроза печени (ЦП). Средняя оценка по BVAS до лечения составила 11,9±7,2 балла (от 2 до 36 баллов). Тяжелая форма КВ (BVAS ≥15 баллов) имелась у 30,6% больных. ПВТ сопровождалась достижением устойчивого вирусологического ответа у 48%, клинической ремиссии - у 68% больных и имела преимущество перед ИСТ в отношении отдаленных результатов лечения. Ритуксимаб оказался статистически значимо эффективнее традиционных иммуносупрессоров (ремиссия 73 и 13% соответственно). У больных с тяжелыми формами васкулита наиболее эффективна сочетанная терапия (ритуксимаб и ПВТ). Умерли 16 больных: от осложнений васкулита 37,5%, инфекции 37,5%, осложнений ЦП 25%. Факторами, негативно влияющими на прогноз, явились возраст55 лет (отношение шансов - ОШ 4,49), наличие ЦП (ОШ 3,68), почечной недостаточности (ОШ 4,66) и применение глюкокортикостероидов (ОШ 3,91). Заключение. КВ, ассоциированный с HСV, может определять прогноз хронической инфекции HСV. ПВТ является терапией выбора у всех больных HСV КВ. У больных с тяжелыми формами васкулита ПВТ должна сочетаться с терапией ритуксимабом.

Aim. To reveal clinical and morphological characteristics of renal damage in patients with cryoglobulinemia (CGE) associated with chronic viral hepatitis C (CVH-C) for upgrading diagnosis, prognosis and optimization of the treatment methods. Material and methods.Њ Two groups of CVH-C patients were studied: with CGE (group 1, n = 64) and free of CGE (group 2, n = 62) matched for gender, age and duration of the disease. Biopsy of the liver for assessment of the histological activity index and histological sclerosis index by METAVIR scale was conducted in 63 patients. Of patients with CGE-related damage to the kidneys, 48 were examined for clinical picture with morphological investigation of renal tissue in 15 of them including semiquantitative evaluation of fibrosis degree and activity. Results. Patients with CVH-C and CGE had a wider spectrum of systemic lesions than CVH-C patients without CGE. Only CGE patients demonstrated more severe affection of the skin, joints, kidneys and the nervous system. Therefore, CGE can be considered as a marker of poor prognosis. Liver biopsy showed that CGE patients had more pronounced fibrosis (3-6 points) versus 0-2 points in 80% patients from group 2. Duration of CVH-C from probable infection to renal damage in 48 patients with CGE glomerulonephritis (GN) averaged 197.05±18.5 months. Renal biopsy diagnosed CGE mesangiocapillary GN in 13 patients and membranoproliferative GN in 2 patients. Patients with HCV infection had a more severe proliferative form of nephritis - mesangiocapillary GN. In 48 GN patients with HCV-infection and CGE, GN ran latently with moderate urinary syndrome in 29 (60.4%) patients, with nephrotic syndrome - in 9 (18.6%), with acute nephritic syndrome - in 10 (21.0%) patients. Most of the patients had arterial hypertension, 13 patients had creatinemia (3.02±0.55 mg/dl), rapidly progressive GN was diagnosed in 4 patients. Conclusion. Persistent CGE marks poor prognosis in CHC patients and is an indication for antiviral treatment to prevent severe organ lesions, first of all of the kidneys. Development of CGE vasculitis with severe damage to the kidneys demands immunosuppressive therapy in combination with plasmapheresis or cryapheresis followed by antiviral drugs. As shown by pilot results, a new approach with rituximab is perspective but further evidence is needed for final conclusions.

A report is presented of a rare case of B-cell non-Hodgkin"s lymphoma and severe exacerbation of cryoglobulinic vasculitis which developed in a female patient with chronic hepatitis C four years after achievement of a persistent virusological response to antivirus treatment. Causes of a specific course of the disease and development of the tumor in the absence of HCV in blood serum are discussed: latent HCV-infection in immune cells with persistent antigenic stimulation of B-lymphocytes, possibility of HCV-independent lymphoproliferation.