Interferon Combination Treatment Research Articles

Cell cycle arrest in mitosis promotes interferon-induced necroptosis.

Resistance to apoptosis is a hallmark of cancer and deregulation of apoptosis often leads to chemoresistance. Therefore, new approaches to target apoptosis-resistant cancer cells are crucial for the development of directed cancer therapies. In the present study, we investigated the effect of cell cycle regulators on interferon (IFN)-induced necroptosis as an alternative cell death mechanism to overcome apoptosis resistance. Here, we report a novel combination treatment of IFNs with cell cycle arrest-inducing compounds that induce necroptosis in apoptosis-resistant cancer cells and elucidate the underlying molecular mechanisms. Combination treatment of IFNs (i.e. IFNβ) with inhibitors of the cell cycle (e.g. vinorelbine (VNR), nocodazole (Noc), polo-like kinase-1 (Plk-1) inhibitor BI 6727) co-operate to induce necroptotic cell death upon caspase inactivation. The mode of cell death was confirmed by pharmacological inhibition and siRNA-mediated downregulation of the key necroptotic factors receptor-interacting protein (RIP) kinase 3 (RIP3) and mixed-lineage kinase-like (MLKL) in various cell lines. Mechanistically, we show that necroptosis upon VNR/IFNβ/zVAD.fmk treatment is RIP1-independent but relies on IFNβ-induced gene expression of Z-DNA-binding protein 1 (ZBP1) as shown by quantitative RT-PCR and genetic knockdown experiments. Interestingly, we find that RIP3 is phosphorylated in response to compounds that trigger mitotic arrest, even in the absence of IFNβ signaling and necroptosis induction. Together, the identification of a novel combination treatment that triggers necroptosis has implications for the development of molecular-targeted therapies to circumvent apoptosis resistance and point to an underestimated role of cell cycle regulation in cell death signaling.

The efficacy and safety of daclatasvir combined with asunprevir in the treatment of 26 cases with chronic hepatitis C

Objective To explore the efficacy and safety of daclatasvir (DCV) combined with asunprevir (ASV) for chronic genotype 1b (GT1b) hepatitis C. Methods Twenty-nine GT1b hepatitis C patients who were treated with DCV combined ASV in Henan Provincial People′s Hospital from September 2017 to November 2017 were included. Hepatitis C virus (HCV) RNA levels were tested before treatment, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks after treatment, and 12 weeks after the end of the treatment. The comorbidities, combined use of drugs and adverse clinical events were registered. T test was used to compare the measurement data with normal distribution and M (P25, P75) was used for measurement data with non-normal distribution. Results A total of 29 patients with GT1b were included, with 4 cirrhosis cases and 25 non cirrhotic cases. Seven patients had history of previous interferon and ribavirin combination treatment. There were 9 patients with comorbidity and 7 patients with combined medication. Finally, 25 patients completed a 24-week course of antiviral treatment; 3 patients were lost to follow-up, and 1 patient withdrew after 16weeks of antiviral treatment because of a virus rebound. Of the 26 followed up patients, 25 achieved sustained virological response at 12-week (SVR12), and one patient failed. And the HCV RNA NS5A resistance-associated variants (RAV) were detected in the patients with treatment failure. No severe adverse clinical events occurred in 26 patients. Conclusions DCV combined with ASV is effective and safe in the treatment of GT1b chronic hepatitis C. However, the effect of RAV on therapeutic efficacy should be concerned during the treatment. Key words: Hepatitis C, chronic; Daclatasvir; Asunprevir

LecT-Hepa facilitates estimating treatment outcome during interferon therapy in chronic hepatitis C patients.

BackgroundA combination treatment of interferon and ribavirin is the standard and the commonly used treatment for chronic hepatitis C (CHC). Developing noninvasive tests like serum indicators that can predict treatment outcome at an early stage of therapy is beneficial for individualized treatment and management of CHC. A glyco-indicator based on the glyco-alteration of serum α1-acid glycoprotein, LecT-Hepa, was discovered by glycomics technologies as a robust indicator of liver fibrosis. Here, we investigated the clinical utility of LecT-Hepa for evaluation of treatment outcome.ResultsFirstly, ninety-seven patients with CHC were used for comparison of LecT-Hepa in serum and plasma. We found no significant difference in the concentrations of LecT-Hepa in serum and plasma. And then, 213 serum specimens from 45 patients who received 48 weeks of treatment with interferon and ribavirin were followed up for 96 weeks, and were used for evaluation of the role of LecT-Hepa. We found that LecT-Hepa might reflect the change in fibrosis regression during the treatment process. Moreover, the change of LecT-Hepa at the first 12 weeks of treatment could already predict the antiviral treatment response, which was more superior to FIB-4 index and aspartate aminotransferase-to-platelet ratio index (APRI) in this study.ConclusionsThese results provide a new perspective that serum glycoprotein could be used as a joint diagnosis indicator for estimation treatment outcome of viral hepatitis at earlier stage of therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1559-0275-11-44) contains supplementary material, which is available to authorized users.

Pure red cell aplasia caused by pegylated interferon-α-2a plus ribavirin in the treatment of chronic hepatitis C

Pure red cell aplasia (PRCA) is a rare hematological disorder which is characterized by severe anemia, reticulocytopenia and almost complete absence of erythroid precursors in bone marrow. The pathophysiology of PRCA may be congenital or acquired. To our knowledge, there is only one case report in the English literature of PRCA after pegylated interferon combination therapy for chronic hepatitis C. We report a second case of PRCA after pegylated interferon combination treatment for chronic hepatitis C. The diagnosis of PRCA was confirmed by the typical findings of bone marrow biopsy. The possible etiologies of our case are also discussed in this paper.

Navigating the Maze of Hepatitis B Treatments

Navigating the Maze of Hepatitis B Treatments

An Artificial Neural Network Approach to the Drug efficacy of Interferon Treatments

Interferon taken alone or in combination with ribavirin can be used for the treatment of persons with chronic hepatitis C. It is highly desirable, both clinically and economically, to establish tools to distinguish responders from nonresponders and to predict possible outcomes of the treatments. In this work, our goal is to develop a prediction model resulting from the analysis of chronic hepatitis C patients' single nucleotide polymorphisms, viral genotype, viral load, age and gender, to predict the responsiveness of interferon combination treatment. We collected blood samples from 523 chronic hepatitis C patients that had received interferon and ribavirin combination therapy. Based on the current treatment strategy for chronic hepatitis C patients, we focused our search for candidate genes involved in pathways related to interferon signaling and immunomodulation. With artificial neural network algorithms, we then developed pattern recognition methodologies to achieve predictions among the patients. The artificial neural network model was trained by an algorithm with an adaptive momentum and learning rate. There were seven single nucleotide polymorphisms selected from six candidate genes including adenosine deaminase-RNA-specific, caspase 5, interferon consensus sequence binding protein 1, interferon-induced protein 44, phosphoinositide-3-kinase catalytic gamma polypeptide and transporter 2 ATP-binding cassette subfamily B genes. We further applied the artificial neural network algorithms with these seven single nucleotide polymorphisms, viral genotype, viral load, age and gender information to build tools for predicting the responsiveness of interferon. Based on the fivefold cross-validation method to evaluate the performance, the model achieved a high success rate of prediction. We demonstrated that a trained artificial neural network model is a promising method for providing the inference from factors such as single nucleotide polymorphisms, viral genotype, viral load, age and gender to the responsiveness of interferon.

Prospect of Individualized Medicine in Chronic Hepatitis C Therapy by Pharmacogenomics

Interferon-α and ribavirin combination therapy has been the current choice for treating chronic hepatitis C (CHC) patients. The treatment takes 6 to 12 months but the overall sustained response rate is only around 50% and often brings significant adverse effects to some patients. The treatment outcome has been shown to be associated with various viral factors, such as viral loads before and during treatment and, most importantly, viral genotypes and quasispecies. Host factors that may affect drug response include age, gender, ethnicity, HLA alleles and stage of liver fibrosis. Recent studies have further indicated an association between patients genotypes and their treatment efficacy. In this review article, we evaluate and summarize factors that may contribute to the treatment outcome of CHC. The content is divided into four categories: 1. viral factors: viral load, viral genotype and early viral response; 2. general host factors: gender, age, treatment period/dosage and kinds of IFN; 3. host genetic polymorphisms, particularly single nucleotide polymorphism (SNP) association studies; and 4. gene expression profiles in hepatitis C liver tissues. In summary, recent advances in pharmacogenomics have demonstrated the potential applications of genetic polymorphisms and expression patterns in determining treatment responsiveness in chronic hepatitis C. By combining both human and viral genotypes and their expression, it becomes plausible to satisfactorily assess the clinical outcomes prior to interferon combination treatment for CHC patients. Keywords: Pharmacogenomics, HCV, interferon, genetic polymorphism

Helper T cell cytokine response to ribavirin priming before combined treatment with interferon alpha and ribavirin for patients with chronic hepatitis C

The viral genotype and serum viral level influence the response to interferon (IFN) treatment in patients with chronic hepatitis C virus (HCV) viremia. The aim of this study was to investigate a possible relationship between early virological response and helper T (Th) cell cytokine expansion by 4 weeks of ribavirin (RIB) alone followed by IFN and RIB combined in patients with genotype 1b and a high HCV RNA level, patients reported not to respond well to IFN treatment. Eighty-one patients with genotype 1b and a high HCV RNA level, over 100 international unit per milliliter (KIU/mL) (by Amplicor HCV Monitor), were assigned to two groups: Group A ( N = 40) with a 4-week RIB administration followed by a 24-week combination treatment, and Group B ( N = 41) with a 24-week combination treatment only. Blood was obtained from each patient on the following schedule: at Baseline (4 weeks before day 0), on day 0 (initiation day of the RIB and IFN combination treatment), weeks 4 (4 weeks after the start of the combination treatment), and at the end of the combination treatment. Flow cytometry was used to investigate sequential changes of IFN-γ producing (Th1) and interleukin-4 producing (Th2) cells from whole blood samples after stimulation with PMA and ionomycin. Serum HCV RNA clearances were 32.5% at week 4, 43.2% at week 8, 85.7% at the end of the combination treatment, and 22.9% within the 24-week follow-up in Group A; and 17.1%, 27.0%, 66.7% and 19.4% in Group B, respectively. The mean Th1/Th2 ratio significantly increased from 15.9 at baseline to 17.6 at day 0 with a decrease of Th2 cells, and then significantly decreased from 17.6 at day 0 to 15.5 at week 4 in Group A, while there was no significant change in Group B between baseline and day 0. In Group A, 13 patients with HCV RNA clearance within 4 weeks had a significantly increased Th1/Th2 ratio, from 14.0 at baseline to 22.1 at day 0, and then a significantly decreased ratio, from 22.1 at day 0 to 15.0 at week 4, while the others had no significant change in the ratio. RIB administration preceding combined treatment of RIB with IFN was more effective in Th2 cell expansion than the usual combined treatment of IFN with RIB and led to a relatively early virological clearance in chronic hepatitis C patients with genotype 1b and a high HCV RNA level.

Lamivudine and alpha interferon combination treatment versus alpha interferon treatment in children with chronic hepatitis B infection

Lamivudine and alpha interferon combination treatment versus alpha interferon treatment in children with chronic hepatitis B infection

Lamivudine and alpha interferon combination treatment versus alpha interferon treatment in children with chronic hepatitis B infection

Lamivudine and alpha interferon combination treatment versus alpha interferon treatment in children with chronic hepatitis B infection

Therapy for chronic hepatitis C

Background/aims: in Hungary, over the past 5 years more than 900 patients with chronic hepatitis C have been examined for treatment with interferon at 16 major hepatology centres, using unified diagnostic and therapeutical criteria. Authors give an account of their experiences on the clinical features of patients with chronic hepatitis C and report the results of the interferon therapy. Methods: a total of 993 patients—virtually the entire Hungarian hepatitis C patient population who had been referred for interferon treatment—were included in the program. Actually, the sustained efficacy of the therapy was evaluated in 724 cases. Treatment protocols (dose of interferon and duration of therapy) have changed with time from a weekly dose of 3×3 MU IFN for 6 months in the first period, to 3×3–5 MU for 12 months in the second period, and finally in the third period a combination therapy with ribavirin has also been introduced. Results: in the first period, the end-of-treatment response (ETR) was 35%, sustained response (SR) 13%, the second phase schedule resulted in 42% ETR and 22% SR, while in the third period, ETR was 49% and SR 36%, respectively. Fibrosis in histology and baseline pretreatment HCV–RNA level appeared as predictors of response. The duration of treatment and the total dose of interferon exerted a moderate effect on therapeutic efficacy. Neither age nor gender influenced the outcome. Conclusions: our results—obtained in a Central East European country—are in accordance with findings of suboptimal efficacy of traditional interferon monotherapy for chronic hepatitis C reported in the West, and suggest the benefit of the combination treatment of interferon with ribavirin.

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

BACKGROUND, AIM, AND METHODSAlpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside...

Recombinant interferon-alpha combined with prednisone in metastatic renal cell carcinoma reduced toxicity without reduction of the response rate—a phase II study

Five responses (lung metastases, three; lymph node metastases, two) were observed in 23 patients with metastatic renal cell carcinoma who received recombinant interferon-alpha-2A (IFN) 18 X 10(6) U in three intramuscular doses each week combined with oral prednisone (10 to 20 mg daily). The response duration was 4+, 4+, 9, 11+, and 15+ months. In general, the combination treatment of interferon and prednisone lead to a significant reduction of the subjective side effects (flu-like symptoms) as compared to a previous experience in patients treated with interferon only. Reduction of the interferon dose or discontinuation of IFN treatment was necessary in only two of 23 patients receiving IFN plus prednisone. Prednisone, however, had little effect on the hepatic toxicity often associated with high-dose IFN treatment. The subjective tolerability of a high dose of IFN is significantly increased if oral prednisone (10-20 mg) is given concomitantly in patients with metastatic renal cell carcinoma without reducing the response rate. Randomized trials will be necessary to confirm the efficacy of the IFN and prednisone combination. In addition, higher doses of IFN combined with prednisone should be evaluated in this malignancy.