Experience of therapy of chronic viral hepatitis c patients with unfavourable response predictors

Introduction in practice of therapeutic establishments in the RF of antiviral therapy of chronic viral hepatitis in the form of interferon-free schemes led to considerable increase of the frequency of the stable virologic response. Study objective: determination of virologic response predictors in CVHC patients when various therapeutic schemes are used. Materials and methods: Group 1 of CVHC 52 patients with genotype 1 of HCV received standard anti-viral therapy, Group 2 (21 subject) – interferon-free scheme (Viekira Pak+ Ribavirin). Genetic polymorphisms IL-28В rs12979860 (С>Т) and rs8099917 (Т>G) and blood interferon-γ induced protein – IP-10 were determined. Results: standard anti-viral therapy in Group 1 resulted in SVR (sustained viral response) in 29 patients (55.7%). In Group 2 that received Viekira Pak 100% SVR was achieved in spite of more frequent F3 and 4 stage of fibrosis, unsuccessful anti-viral therapy (9 persons), contraindications to IFN-α drugs (6 persons). Unfavorable genotypes IL-28B ТТ (rs12979860) and GG (rs8099917) were associated in Group 1 with lack of SVR, level of IP-10 in patients with SVR was lower than the one in non-respondents. The therapy by Viekira Pak was well tolerated and resulted in SVR despite presence of grave hepatic fibrosis/ cirrhosis, concomitant pathology, unfavourable options of IL-28B, high IP-10 protein levels. Conclusion: choice of optimal anti-viral therapy schemes for each patient with CVHC must be done taken into account all possible predictors, which allows optimizing the therapy and preventing the necessity of repeated therapy

The use of telaprevir for the treatment of hepatitis C in patients undergoing liver transplantation (Literature review and clinical experience)

Authors reviewed published data concerning antiviral treatment of liver transplant recipients with 1st generation HCV protease inhibitors (telaprevir and boceprevir). Efficacy and adverse events have been analyzed with peculiar attention to drug-drug interactions between calcineurin inhibitors and HCV protease inhibitors. The article is illustrated with clinical cases

Pegilated interferon alpha 2b «Pegaltevir» chronic hepatitis C treatment (randomized clinical trial)

Aim of investigation. Nowadays the question, whether pegylated interferon should be completely abandoned in the treatment of chronic hepatitis C (CHC) is still open. Beneficial interferon properties include: absence of mutagenic capacity for hepatitis C virus and drug interaction, stimulation of host immune response. These qualities formed the basis for development of the Russian pegilated interferon-alpha 2b (Pegaltevir®, LLC «FARMAPARK», Russia) and carrying out doublestaged randomized open clinical trial: study of safety, tolerability and pharmacokinetics of Pegaltevir® at single injection of increasing doses in various groups of healthy volunteers - the I stage; studying of efficacy and safety of Pegaltevir® in comparison to PegIntron® (Schering-Plough, USA) at CHC as a part of double antiviral therapy with ribavirin (Rebetol®, Schering-Plough, USA) - the II stage. This article presents results of the II phase of investigation. Material and methods. Original study included 140 adult antiviral treatment-naive patients with CHC and compensated liver function. Patients (aged 18 to 70 years) were distributed into four groups. Group 1 (main group, Pegaltevir®/Rebetol® treatment) - 55 patients, HCV genotype 1; group 2 (comparison group, PegIntron®/Rebetol® treatment) - 20 patients, HCV genotype 1; group 3 (main group, Pegaltevir®/Rebetol® treatment) - 47 patients, non-genotype 1 (2 and 3); group 4 (comparison group, PegIntron®/ Rebetol ® treatment) with non-genotype 1 (2 and 3). Assessment of Pegaltevir® efficacy was carried out in 4 weeks (rapid virologic response, RVR) and 12 weeks of treatment (early virologic response, EVR) in groups 1 and 3 in comparison to corresponding scores in groups 2 and 4 (primary criteria of efficacy were estimated in all 140 patients enrolled in original study. The response rate at the moment of secession of antiviral therapy, the sustained virologic response (SVR), histologic response (comparison of paired liver biopsies) served as secondary efficacy criteria and were estimated in 129 patients who completed treatment. The safety analysis was carried out for each patients included in the protocol who received at least one Pegaltevir® dose in comparison to patients who received at least one dose of PegIntron®, - respectively 102 and 38 patients. Results. RVR was comparable in the Pegaltevir® and PegIntron® groups: 65,6 and 82,4% respectively (p>0,05). RVR frequency genotype one patients was 45,3% in Pegaltevir® treatment group and 66,7% in PegIntron® treatment group (p>0,1). At patients with non-genotype 1 (2 and 3): 92,5 and 100% respectively (p>0,05). RVO did not significantly differ in the studied groups: 91,6 and 97,1% for all genotypes respectively (р>0,1). RVO rate for genotype 1 patients in Pegaltevir® group was 86,8%, in PegIntron® treatment group - 94,4% (р>0,1), in non-genotype 1 patients (2 and 3) it reached 97,6 and 100% in the specified patient groups (р>0,1). Response rate at the moment of treatment secession for Pegaltevir® and PegIntron® was 87,4 and 97,1% respectively for all genotypes (р>0,05). In patients with HCV genotype 1 this score Pegaltevir® treatment group reached 79,3%, in PegIntron® group - 94,4% (р> 0,05), in non-genotype 1 patients (2 and 3) - 97,6 and 100% respectively (р>0,1). SVR rate at Pegaltevir® treatment was 82,1% (for all genotypes), PegIntron® - 82,4% (for all genotypes, p>0,1). In HCV genotype 1 patients in Pegaltevir® treatment group SVR made 73,6%, in PegIntron® treatment group - 83,3%, p>0,1, for non-genotype 1 (2 and 3) - 92,9 and 81,3%, p>0,1. No significant differences between basic and control groups at analysis of paired liver biopsies for fibrosis stage reduction rate, absence of negative changes for fibrosis severity and proportion of patients with fibrosis progression were found. Pegaltevir® and PegIntron® treatment groups were comparable safety profile, adverse events were expected, mainly of mild and moderate severity. Conclusion. The hypothesis of identical efficacy of the Russian drug Pegaltevir® tested in the protocol in comparison to PegIntron® was correct and proved. Safety of Pegaltevir® was comparable to safety of PegIntron® as well

Bicyclol in the treatment of patients with chronic diffuse liver diseases

Introduction. The increase in serum transaminases (ALT and AST) and the persistence of their high values is associated with morbidity and mortality from liver diseases. Bicyclol has anti-inflammatory and antioxidant effects, which formed the basis for this study.Materials and methods. The study enrolled 51 patients (MELD < 19); hepatitis stage – 84.4%, cirrhosis – 15.6%. Treatment: Bicyclol 75 mg/day for 12 weeks. Criteria of efficacy: dynamics of ALT, AST, CRP; general well-being (D-FIS scale).Results. After 4 weeks of treatment the share of patients with ALT normalization was 50,9% (p < 0,001); with AST normalization – 62.7% (p < 0.001); after 12 weeks - 79,5% and 89,7% respectively (p < 0,001). CRP decreased statistically significantly after 2 and 4 weeks from the beginning of treatment. The D-FIS questionnaire was filled in by 36 patients at the beginning of the study, in 4 weeks - by 35 patients, in 12 weeks – by 32 patients. Median D-FIS decreased from 12 (8.2; 32.2) to 8 (5; 29) points (p < 0,001) after 4 weeks of treatment, after 12 weeks – to 6.5 (3; 28.5) points (p < 0.001). The CRP was positively correlated with the D-FIS value. Fibrosis (“Fibromax”, “Fibroscan”) was studied in 10 additional patients, the dose of Bicyclol was 150/75 mg/day during 6 months, the result was statistically significant (p < 0.001).Conclusion. Application of Bicyclol leads to reduction of fatigue, local and systemic inflammation, fibrosis in chronic diffuse liver diseases regardless of etiology

The modern options of chronic hepatitis C antiviral therapy with daclatasvir: results of named patient program

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

Efficacy and safety of the Russian protease inhibitor narlaprevir at treatment-naive and earlier treated noncirrhotic patients with the 1st genotype chronic hepatitis C (PIONEER study)

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

Efficacy and safety of glycyrrhizic acid combined to essential phospholipids (Phosphogliv) at non-alcoholic fatty liver disease: results of multicenter double blind randomized placebo-controlled post-registration clinical study (IV phase) «Gepard» (PHG-M2/P02-12)

Aim of investigation. To estimate efficacy and safety of two pharmacological forms of «Phosphogliv» (lyophilizate for intravenous administration and capsules) for the treatment of fatty liver degeneration of non-alcoholic etiology. Material and methods. Original study included overall 180 patients with nonalcoholic fatty liver disease that were randomized to the basic and control groups in the ratio of 2:1. The basic group patients received Phosphogliv 5 mg/day as intravenous bolus injection for 2 weeks, followed by oral intake of 2 capsules t.i.d. for 10 weeks (the total treatment duration was 12 weeks), control group patients received placebo in the same mode. Serum levels of inflammatory marker adiponectin, NAFLD fibrosis score, treatment effect on quality of life and safety of patients were monitored. Results. In 12 wks in patients with more significant cytolysis (threefold and higher serum alanine transaminase activity) and the rate of adiponectin level improvement on the background of Phosphogliv was 57.9% versus only 10.0% (p=0.019) in the placebo group. The mean NAFLD fibrosis score in the basic group remained almost unchanged, while in the control group negative dynamics was revealed, that resulted in statistically significant differences between groups (2.5±1.2 units versus 2.0±1.3 units respectively; р=0.009). At Phosphogliv injection already during the first 2 wks more pronounced improvement of subjective perception of dyspeptic symptoms was observed (mean score was 5.6±1.3 versus 5.1±1.4; р=0.021). When the treatment course was completed the basic group patients had higher mean score by «level of energy» scale (5.9±1.0 versus 5.6±1.0; р=0.034). Only sporadic adverse effects were found to the background of treatment, no statistically significant differences in their rate in were recorded. Dynamics of the basic physical parameters and laboratory tests was comparable as well. Conclusions. Treatment of non-alcoholic fatty liver disease that includes Phosphogliv provides reduction of steatohepatitis activity, retardation of fibrosis progression, improvement of overall disease prognosis and high satisfaction of patients at a favorable safety profile

Efficacy and safety of glycyrrhizic acid and essential phospholipids (Phosphogliv) combination for alcoholic liver disease: results of the double-blind randomized placebo-controlled multicenter post-registration (phase IV) clinical trial «Jaguar» (PHG-M2/P03-12)

Material and methods. The original study included overall 120 patients with ALD, who were randomized in two identical groups. The patients of the main group (group A) received 2 courses of therapy: the first - Phosphogliv 5 mg/day as intravenous bolus injection for 2 wks, followed by the oral intake of 2 capsules t.i.d. for 10 wks (the total treatment duration was 24 wks). Patients of the control group (group B) received placebo in the same regimen. The dynamics of serum alanine transaminase (ALT), aspartate transaminase (AST), liver scores by noninvasive FibroMax test was applied to assess the treatment efficacy and safety, along with change in quality of life of patients. Results. In 24 wks in group A in comparison to the group B significantly lower mean ALT level was found: 35,2±29,4 U/l vs 48,4±36,1 U/l (р =0,044), AST level became normal in higher rate of patients: 69,4% vs 47,7% (р =0,034), that had more prominent decrease in gamma-glutamyltranspeptidase (GGT) level - 47,4±36,5% vs 25,1±63,9% (р =0,039), the rate of patients with Aktitest A2-A3 range decreased - 8,5% vs 21,4% (