Effect of comedication on ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin therapy in chronic hepatitis C - a real-world study.

AIM OF THE STUDY: This multicentre study aimed to examine the actual risk for drug-drug interactions in a cohort of Polish patients, and their impact on antiviral therapy. MATERIAL AND METHODS: Concomitant medications were analyzed in hepatitis C virus (HCV)-infected patients treated with still valuable therapy with OBV/PTV/r ± DSV ± RBV. An established online tool (http://www.hep-druginteractions.org/) was used to assess potential drug interactions. To assess the impact of comedications on virologic outcomes, HCV RNA levels were measured at given time points during and after the treatment. The results were compared between subgroups depending on the number of drugs used. RESULTS: Among the 209 patients included in this multicentre study, concomitant medications were taken by 140 (67.0%) patients. Modification of treatment due to expected interactions was required in 33 (15.8%) patients, of whom nine (4.3%) had at least one comedication replaced or discontinued. Sustained virologic response rates ranged from 95.1% to 100.0%, and were lowest in patients taking one to five comedications who were null-responders to pegylated interferon or cirrhotic. CONCLUSIONS: Although most HCV-infected patients received concomitant medications, only some required treatment modification. OBV/PTV/r ± DSV ± RBV was effective in all subgroups, irrespective of the number of comedications taken. Multimorbidity and polypharmacy in patients with chronic hepatitis C should not discourage the decision to initiate antiviral therapy, although caution should be exercised for potential drug-drug interactions.

Expression of programmed cell death protein 1 and T-cell immunoglobulin- and mucin-domain-containing molecule-3 on peripheral blood CD4+CD8+ double positive T cells in patients with chronic hepatitis C virus infection and in subjects who spontaneously cleared the virus.

Chronic hepatitis C virus (HCV) infection is characterized by increased proportion of CD4+CD8+ double positive (DP) T cells, but their role in this infection is unclear. In chronic hepatitis C, immune responses to HCV become functionally exhausted, which manifests itself by increased expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) on T cells. The aim of our study was to determine PD-1 and Tim-3 phenotype of DP T cells in subjects with naturally resolved and chronic HCV infection. Peripheral blood mononuclear cells from 16 patients with chronic infection and 14 subjects who cleared HCV in the past were stained with anti-CD3, anti-CD4, anti-CD8, anti-PD-1 and anti-Tim-3 antibodies and, in 12 HLA-A*02-positive subjects, MHC class I pentamer with HCV NS31406 epitope. In chronic and past HCV infection, proportions of total DP T cells and PD-1+ DP T cells were similar but significantly higher than in healthy controls. DP T cells were more likely to be PD-1+ than either CD4+ or CD8+ single positive (SP) T cells. HCV-specific cells were present in higher proportions among DP T cells than among CD8+ SP T cells in both patient groups. Furthermore, while the majority of HCV-specific DP T cells were PD-1+, the proportion of HCV-specific CD8+ T cells which were PD-1+ was 4.9 and 1.9 times lower (chronic and past infection, respectively). PD-1 and Tim-3 were predominantly expressed on CD4high CD8low and CD4low CD8high cells, respectively, and co-expression of both markers was uncommon.

Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide.

AIMS: To compare the pharmacokinetics (PK) of a single-dose of liraglutide in subjects with hepatic impairment. METHODS: This parallel group, open label trial involved four groups of six subjects with healthy, mild, moderate and severe hepatic impairment, respectively. Each subject received 0.75 mg of liraglutide (s.c., thigh), and blood samples were taken over 72 h for PK assessment. Standard laboratory and safety data were collected. The primary endpoint was area under the plasma liraglutide concentration-time curve from time zero to infinity (AUC(0,∞)). RESULTS: Exposure to liraglutide was not increased by hepatic impairment. On the contrary, mean AUC(0,∞) was highest for healthy subjects and lowest for subjects with severe hepatic impairment (severe/healthy: 0.56, with 90% CI 0.39, 0.81) and equivalence in this parameter across groups was not demonstrated. C(max) also tended to decrease with hepatic impairment (severe/healthy: 0.71, with 90% CI 0.52, 0.97), but t(max) was similar across groups (11.3-13.2 h). There were no serious adverse events, hypoglycaemic episodes or clinically significant changes in laboratory parameters and liraglutide was considered well tolerated. CONCLUSIONS: This study indicated no safety concerns regarding use of liraglutide in patients with hepatic impairment. Exposure to liraglutide was not increased by impaired liver function; rather, the results suggest a decreased exposure with increasing degree of hepatic impairment. However, data are not conclusive to suggest a dose increase of liraglutide. Thus, the results indicate that patients with type 2 diabetes mellitus and hepatic impairment can use standard treatment regimens of liraglutide. There is, however, currently limited clinical experience with liraglutide in patients with hepatic impairment.

[Pegylated interferon-alfa 2a with ribavirin in chronic viral hepatitis C (final report)]. / Pegylowany interferon alpha-2a z rybawiryna w leczeniu przewleklego wirusowego zapalenia watroby typu C (raport koncowy z badan).

UNLABELLED: We evaluated the efficacy and safety of peginterferon alfa-2a [40KD] (Peg-IFNalpha-2a) plus ribavirin in patients with chronic hepatitis C in an open-label programme in a routine clinical setting in Poland. Patients received Peg-IFNalpha-2a 180mg/week plus ribavirin 800-1200 mg/d for 48 weeks. Sustained virological response (SVR) was defined as undetectable HCV RNA (<50IU/mL) at the end of follow-up (week 72). 466 adults were enrolled. Most patients (87.3%) had genotype 1 infection. 440 subjects (94,4%) completed treatment. The overall SVR rate was 55.7%. A higher SVR rate was obtained in treatment-naïve patients (58.7%) than in relapsers (47.8%; p=0,048). SVR rates in genotype 1 and non-1 patients were 51.1% and 88.5%, respectively (p<0.001). There were significant higher SVR rates in patients with lower baseline fibrosis (p=0,01). There were no differences in SVRs by gender or viral load. Hemoglobin, leukocyte and neutrophil levels decreased significantly during treatment, but returned to baseline after the end of treatment. ALT levels decreased significantly during treatment in patients with and without an SVR. 38.4% of patients experienced adverse events like neutropenia, anemia, thrombocytopenia, and other. There was one death (severe thrombocytopenia). CONCLUSIONS: The overall SVR achieved in this predominantly genotype 1 population was 55.7%. SVR rates were significantly higher in treatment-naïve patients, those with non-1 genotypes, and in patients with lower baseline fibrosis scores.

[Peginterferon alpha-2b in patients with chronic hepatitis C]. / Pegylowany intefeon alpha-62b i rybawiyna w leczen przewlekllego wirusoweg zapalenia watroby typu C.

150 adult patients were assigned pegylated interferon alpha-2b (once weekly 1.5 microg/kg) plus ribavirin (800-1200 mg depending on bodyweight). The treatment lasted 52 weeks and was completed by 139 persons (92.7%). Because of adverse events the treatment was interrupted in 7 persons, 4 other persons resigned. Periodical reduction of pegylated interferon doses was necessary in 19% and the reduction of ribavirin in 21% of patients. Six months after the completion of treatment HCV-RNA was negative in 82 (59%) patients. Neither hepatitis C virus genotype, nor viremia was marked in the study. The negative correlation between the degree of fibrosis in the liver tissue and the results of sustained virological response was stated. Degree of inflammation at liver tissue, sex, age over and less than 40 years did not correlate with the final virological results. The recurrence of infection happened at 7% of the treated persons (negative HCV-RNA directly after the treatment--positive 6 months after the completion). During the treatment period, and comparison with the results obtained before its implementation, statistically significantly decreased: hemoglobin concentration, the number of leukocytes, granulocytes and thrombocytes. They returned to the referential values half a year after the completion of treatment. The activity of enzymes (AIAT, AspAT, GGTP) was decreasing statistically significantly since the first weeks of the treatment till the end and remained significantly lower after 6 months. In both sexes statistically significant reduction of bodyweight was stated, while it increased during the six months after the completion of treatment. Adverse events, which mostly were mild and were not the cause of interruption of treatment, were numerous and occurred at different frequency, in the range from over 50% (flu-like) to 0.7%.

[Lamivudine in patients with chronic HBV infection and therapeutic difficulties]. / Lamiwudyna u chorych z przewleklym zakazeniem HBV i trudnosciami terapeutycznymi.

AIMS: The primary objective of this study was to determine the efficacy and safety of lamivudine (LAM) therapy in patients with chronic HBV infection and contraindications to IFN therapy, nonresponders to IFN and patients with advanced liver fibrosis. PATIENTS AND METHODS: In this open study, 38 patients (25 men and 13 women, age 19-68) with chronic hepatitis B virus infection (HBsAg, HBeAg and p-DNA HBV positive) were treated with LAM (150 mg daily) for 48 weeks. All were negative for HCV or HDV coinfection and had no decompensated liver disease. Fourteen patients (group I) were nonresponders to IFN therapy, 15 patients (group II) had different contraindications for IFN therapy (e.g. depression, low number of neutrophils and/or platelets), and 9 (group III) had advanced liver fibrosis (staging = 3 or 4 [Knodell]). In all cases ALT activity was at least 2 times ULN before the therapy. After discontinuation of therapy all patients were followed-up for another 36 weeks. RESULTS: During first 8-12 weeks of therapy rapid inhibition of HBV replication (p-DNA negativization) was noticed in all cases. At the end of therapy seroconversion to anti-HBe was observed in 24 cases (63%): 9 patients (64%), 10 (67%) and 5 (55.5%) from groups I, II and III, respectively. In one case elimination of HBsAg and appearance of anti-HBs was observed. Sustained normalization of ALT activity was noticed in 22 patients (58%): 9 cases (64%) in group I, 8 (53%) in group II and 5 (55.5%) in III, respectively. During 24 weeks of follow-up in 4 cases (17%) reseroconversion to HBeAg with reapperance of p-DNA activity was observed. ALT activity in these cases was slightly elevated but without clinical signs of exacerbation. In no case serious side effects were observed. CONCLUSIONS: The results indicate that monotherapy with lamivudine (150 mg daily) for 48 weeks induces sustained inhibition of viral replication and normalisation of transminases in majority of patients with chronic HBV infection who did not respond to IFN, had contraindications to IFN therapy, and in those who had advanced liver fibrosis. The absence of side effects during lamivudine therapy is of special importance especially in patients with advanced liver fibrosis.

A multi-center open study to determine the effect of lamivudine on HBV DNA clearance and to assess the safety of the regimen in patients with chronic hepatitis B infection.

BACKGROUND: Patients with on-going HBV viral replication often present with clinical features of active chronic hepatitis. Until the recent introduction of nucleoside analogues, interferon-alpha was the only approved drug for these patients. One of the former drugs, lamivudine, has been shown in clinical trials in the US and Asia to effectively inhibit the viral polymerase of HBV. Our study was undertaken to assess the efficacy and safety of lamivudine therapy in Polish patients with chronic hepatitis B. MATERIAL/METHODS: Forty-five patients with chronic hepatitis B (HBeAg positive, anti-e negative, HBV-DNA positive by hybridization assay) were enrolled in the study. The patients received 100mg of lamivudine orally, once daily for 12 months. They returned for routine clinical and laboratory control every two weeks during the first months of treatment, and later at 3-month intervals while receiving lamivudine. RESULTS: At the end of treatment, serum HBeAg was not detected in 21 patients (48.8%), and anti-HBe appeared in the serum of 19 patients. 37.2% of the patients in the study group showed sustained suppression of serum HBV DNA at the end of treatment. Lamivudine therapy was well tolerated, with the rate of occurrence of adverse events similar to that observed in other clinical studies. CONCLUSIONS: 12-month lamivudine therapy in this Polish population of patients with chronic hepatitis B induced a high rate of HBeAg seroconversion, accompanied by reduction of HBV-DNA and the normalization of alanine aminotransferase activities.