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IFN Therapy (ifn + therapy)
Selected AbstractsInterferon Alfa-2b or Not 2b?DERMATOLOGIC SURGERY, Issue 1 2007Significant Differences Exist in the Decision-Making Process between Melanoma Patients Who Accept or Decline High-Dose Adjuvant Interferon Alfa-2b Treatment BACKGROUND Patients with thick (Breslow >4 mm) primary melanoma and/or regional nodal metastasis have a high risk of tumor recurrence. High-dose adjuvant interferon (IFN) alfa-2b offers ,10% improvement in relapse-free survival and overall survival with significant toxicity. OBJECTIVE The objective was to determine which prognostic factors and patient characteristics are significant in the decision to undergo IFN therapy. METHODS Of 781 patients who underwent sentinel lymph node (SLN) biopsy, 135 of 781 (17.3%) had positive SLN or thick melanomas and were informed of a ,50% risk of recurrence/disease-related mortality and offered IFN. Telephone surveys delineated reasons behind patients' decisions to accept IFN. RESULTS Acceptors, 60 of 135 (45%), decided to take IFN alfa-2b whereas 75 of 135 (55%) declined. Being female (OR, 2.4; 95% CI, 1.17,5.03; p=.017) and positive SLN status (OR, 2.2; 95% CI, 1.01,4.97; p=.048) were strongly associated with patients who chose IFN. Acceptors of IFN were younger, more influenced by physicians, and less affected by depression and side effect profile (p<.05 for all). Decliners were more concerned by strained relationships with family and social life (p<.05). CONCLUSIONS Gender and positive SLN were predictive of high-risk melanoma patients' acceptance of IFN treatment. Physician insight into melanoma patients' therapeutic decision-making process can guide patients through this difficult disease. [source] Psychopathological changes and quality of life in hepatitis C virus-infected, opioid-dependent patients during maintenance therapyADDICTION, Issue 4 2009Arne Schäfer ABSTRACT Aims To examine among maintenance patients (methadone or buprenorphine) with and without hepatitis C virus (HCV) infection (i) the frequency of psychopathological symptoms at baseline and 1-year follow-up; (ii) the association between antiviral interferon (IFN) treatment and psychopathological symptoms; and (iii) to explore whether IFN therapy has an effect on 1-year outcome of maintenance treatment. Design Naturalistic prospective longitudinal cohort design. Setting A total of 223 substitution centres in Germany. Participants A nationally representative sample of 2414 maintenance patients, namely 800 without and 1614 with HCV infection, of whom 122 received IFN therapy. Measures HCV infection (HCV+/HCV - ), IFN (IFN+/IFN - ) treatment status and clinical measures. Diagnostic status and severity (rated by clinician), psychopathology (BSI,Brief Symptom Inventory) and quality of life (EQ-5D,EuroQol Group questionnaire). Findings HCV+ patients revealed indications for a moderately increased psychopathological burden and poorer quality of life at baseline and follow-up compared to HCV - patients. HCV+ patients showed a marked deterioration over time only in the BSI subscale somatization (P = 0.002), and the frequency of sleep disorders almost doubled over time (12.8% at baseline; 24.1% at follow-up; P < 0.01). IFN treatment, received by 10% of HCV+ patients, did not impair efficacy or tolerability of maintenance therapy and was associated overall with neither increased psychopathological burden nor reduced quality of life. Conclusions Findings suggest no increased risk among HCV+ patients on maintenance therapy for depressive or other psychopathological syndromes. In our patient sample, IFN treatment was not associated with increased psychopathological burden, reduced quality of life or poorer tolerability and efficacy of maintenance treatment. [source] Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis,HEPATOLOGY, Issue 5 2007Norio Akuta We showed previously that amino acid (aa) substitutions in hepatitis C virus core region (HCV-CR) are negative predictors of virologic response to pegylated interferon (IFN) plus ribavirin therapy. HCV-CR induces hepatocellular carcinoma in transgenic mice, but the clinical impact is still unclear. To evaluate the impact of aa substitutions in HCV-CR on hepatocarcinogenesis, we performed a follow-up study on 313 noncirrhotic consecutive naïve patients infected with HCV genotype 1b who received IFN monotherapy. The median follow-up was 14.7 years. A sustained virologic response (SVR) after the first IFN was achieved by 65 patients (20.8%) (group A). Of 248 patients (79.2%) of non-SVR after first IFN, 112 (35.8%) did not receive additional IFN (group B), and the remaining 136 (43.5%) received multicourse IFN monotherapy (group C). As a whole, cumulative hepatocarcinogenesis rates in double wild-type (arginine at aa 70/leucine at aa 91) of HCV-CR were significantly lower than those in nondouble wild-type. Multivariate analyses identified 3 parameters (fibrosis stage 3, nondouble wild-type of HCV-CR, and group B) that tended to or significantly influenced hepatocarcinogenesis independently. With regard to hepatocarcinogenesis rates in group C according to HCV-CR and the mean alanine aminotransferase (ALT) during IFN-free period, significantly higher rates were noted in patients of nondouble wild-type with ALT levels of more than 1.5 times the upper limit of normal (25.7%) compared with the others (2.4%). Conclusion: Amino acid substitutions in the HCV-CR are the important predictor of hepatocarcinogenesis. In multicourse IFN therapy to nondouble wild-type, we emphasize the importance of reducing the risk of hepatocarcinogenesis by mean ALT during an IFN-free period below 1.5 times the upper limit of normal. (HEPATOLOGY 2007.) [source] Significance of interferon-, for the treatment of hepatitis C virus infection in hemodialyzed patientsHEPATOLOGY RESEARCH, Issue 9 2010Mikio Zeniya Aim:, We evaluated the adverse effects and efficacy associated with interferon-, (IFN-,) for the treatment of hepatitis C virus (HCV) infection in 20 hemodialyzed (HD) patients. Methods:, IFN-, was administrated at a dose of 3 MIU three times a week for 24 weeks simultaneously at the time of HD for the patients of genotype 2a whose viral loads were less than 150 KIU/mL and considered to respond well to IFN therapy. Results:, There was a sustained virological response (SVR) rate of this treatment in 90% of the patients, and sex, age and HD duration had no affect. Slight adverse effects such as fever, malaise and itching were observed during the treatment periods but none serious in any of the patients. Also, no significant difference in adverse effect was observed between 3 MIU and higher dose (6 MIU) groups. Conclusion:, Because IFN-, can be administrated easily into the circuit of HD, adverse effects can be monitored earlier and taken measures against quickly. Taken together, IFN-,-based therapy has a potential for HCV treatment in HD patients but further studies for the patients who have higher viral loads will be required to confirm this. [source] Effect of interferon ,-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitisHEPATOLOGY RESEARCH, Issue 5 2009Mika Kurokawa Aim:, The objective of this study was to elucidate the long-term effects of interferon (IFN),-2b plus ribavirin combination therapy and to clarify whether this therapy can reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. Methods:, A total of 403 patients infected with hepatitis C virus (HCV) were enrolled in a multicenter trial. All patients were treated with a combination of IFN-,-2b plus ribavirin therapy. We examined the incidence of HCC after combination therapy and analyzed the risk factors for liver carcinogenesis. Results:, A sustained virological response (SVR) was achieved by 139 (34%) of the patients. The cumulative rate of incidence of HCC was significantly lower in SVR patients than in non-SVR patients (P = 0.03), while there was no difference in the cumulative incidence of HCC between the transient response (TR) group and the no response (NR) group. Cox's regression analysis indicated the following risk factors as independently significant in relation to the development of HCC: age being > 60 years (P = 0.006), advanced histological staging (P = 0.033), non-SVR to IFN therapy (P = 0.044). The cumulative incidence rate of HCC was significantly lower in patients who had average serum alanine aminotransferase (ALT) levels of < 40 IU/L than in those who showed average serum ALT levels of , 40 IU/L after the combination therapy (P = 0.021). Conclusions:, These results suggest that the attainment of SVR or continuous normalization of ALT levels after IFN therapy can affect patients apart from HCC development. [source] Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: Is the addition of subcutaneous interferon-,-2b beneficial?HEPATOLOGY RESEARCH, Issue 3 2009Satoe Takaki-Hamabe Aim:, We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- ,-2b in patients with advanced HCC. Methods:, Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-,-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics. Results:, There were no significant differences in the response rate (patients with complete or partial response/all patients; P = 0.736) and survival (P = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child,Pugh score (P = 0.010), ,-fetoprotein level (P = 0.0047), and additional therapy (P = 0.002), to be significant prognostic factors. Conclusions:, We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-,-2b was not beneficial for advanced HCC. [source] Autoimmunity as a prognostic factor in melanoma patients treated with adjuvant low-dose interferon alphaINTERNATIONAL JOURNAL OF CANCER, Issue 11 2007Imke Satzger Abstract Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant high-dose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5,79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan,Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy. © 2007 Wiley-Liss, Inc. [source] Prospective study of short-term peginterferon-,-2a monotherapy in patients who had a virological response at 2 weeks after initiation of interferon therapyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2008Soocheol Jeong Abstract Background and Aims:, Long-term interferon (IFN) therapy is effective in eliminating hepatitis C virus (HCV). However, it carries the risk of adverse effects and reduced quality of life. To assess whether short-term IFN therapy effectively eliminates HCV, we performed a prospective pilot study of pegylated (peg)IFN-,-2a therapy for 8 or 24 weeks. Methods:, After excluding patients with high titers of genotype-1, 55 HCV patients received pegIFN-,-2a. Patients who became negative for HCV-RNA at week 2 were allocated to either an 8-week (n = 19) or 24-week (n = 15) course of IFN. We evaluated the efficacy of and tolerance to IFN therapy. Results:, The sustained virological response rate was excellent in the two groups (8 weeks, 89.5% [17/19]; 24 weeks, 100% [15/15], respectively,). IFN dose reduction was required in one patient of the 8-week group, but in six patients of the 24-week group (P = 0.028). Treatment was completed by all patients of the 8-week group, but discontinued in five patients of the 24-week group (P = 0.011). Conclusions:, The 8-week IFN therapy is more tolerable than the 24-week therapy and had similar outcomes. Excluding the patients with high titers of genotype-1, we recommend switching to an 8-week course of pegIFN-, monotherapy once patients show an ultra rapid virological response at week 2 from the start of IFN therapy. [source] Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2002RAJKUMAR C GUPTAN AbstractBackground and Aims : Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B infection. The efficacy of combination therapy to enhance the immunomodulatory effect of IFN by combining granulocyte-macrophage colony-stimulating factor (GMCSF) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. Methods : Twenty-four patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. The end-of-treatment response was assessed by hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg) determination. Results : All patients successfully completed both the treatment schedules. The mean age, alanine aminotransferase (ALT) levels, liver histology, HBV-DNA levels and distribution of HBV genotypes were comparable between the two groups. At the end of treatment there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60%) patients in group A and in seven of 14 (50%) patients in group B. During a mean follow-up of 15 ± 3 months, two of six (33%) patients in group A and three of seven (43%) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40% and 28%, respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. There was a trend in patients with genotype A compared with genotype D towards non-response to therapy, although the difference was not significant. Conclusions : The combination of IFN plus GMCSF or lamivudine was effective in non-responders to IFN monotherapy. Larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B. © 2002 Blackwell Publishing Asia Pty Ltd [source] Effect of interferon therapy on Japanese chronic hepatitis C virus patients with anti-liver/kidney microsome autoantibody type 1JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2001Yoshihiko Iijima Abstract Aim: The aim of this study was to determine the prevalence of anti-liver/kidney microsome autoantibody type 1 (anti-LKM-1) among hepatitis C virus (HCV)-infected Japanese patients at various stages (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma), and to assess the influence of anti-LKM-1 on interferon therapy. Methods: A total of 390 serum samples from 215 HCV-infected patients with chronic hepatitis (HCV-CH), 81 HCV-infected patients with liver cirrhosis (HCV-LC), and 94 HCV-HCC infected patients were subjected to examination. Ninety-one HBsAg-positive patients and 137 healthy subjects served as controls. Anti-liver/kidney microsome autoantibody type 1 was determined by using a newly developed ELISA using recombinant cytochrome P450 IID6 as the antigen. Results: Anti-liver/kidney microsome autoantibody type 1 was detected in six of the 390 (1.5%) chronic HCV-infected patients (four were HCV-CH and two were HCV-LC); in contrast, it was not detected in control groups. Among the 110 HCV-CH patients treated with interferon (IFN), four were positive for anti-LKM-1. No change in anti-LKM-1 immunoreactivity from negative to positive during interferon therapy was observed. Moreover, no increase in the serum alanine aminotransferase level was observed in these four patients with anti-LKM-1. Conclusion: Our study indicates that: (i) anti-LKM-1 does not aggravate the liver disease associated with HCV infection; and (ii) no change in anti-LKM-1 immunoreactivity from negative to positive or no aggravations of liver dysfunction were observed among HCV-CH patients during the IFN therapy for Japanese patients with liver disease. [source] Clinical significance of TT virus in chronic hepatitis CJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2001Xiang Wei Meng Abstract Background and Aims: Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A,G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). Methods: The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. Results: TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5, untranslated region (5, UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5, UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. Conclusion: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV. [source] Influence of RNA titre and amino acid changes in the NS5A region of GB virus C/hepatitis G virus on the effectiveness of interferon therapyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2000Tomoki Fujisawa Abstract Background: A relationship between the pretreatment RNA titre of GB virus C/hepatitis G virus (GBV-C/HGV) and the effectiveness of interferon (IFN) therapy has been reported previously. However, the influence of changes in the amino acid sequence of the NS5A region of GBV-C/HGV on the effectiveness of IFN therapy has not been examined, although this influence has been explored in patients with chronic hepatitis caused by hepatitis C virus. We examined the relationship between changes in the amino-acid sequence of the NS5A region and the effectiveness of IFN therapy. Methods: The subjects were 10 patients with chronic hepatitis C coinfected with GBV-C/HGV and treated with IFN. The pretreatment level of GBV-C/HGV-RNA (copies/mL) in their sera was measured by real-time detection polymerase chain reaction (PCR) assay. At 6 months after cessation of therapy, four of 10 patients had become negative for GBV-C/HGV-RNA (CR, complete response) and six patients were still positive for GBV-C/HGV-RNA (NR, non-response). We determined the nucleotide sequence of the NS5A region (amino acid residues 1865,2279; NS5A1865,2279) of pretreatment GBV-C/HGV-RNA by direct sequencing. Results: The pretreatment GBV-C/HGV-RNA level of CR patients (7.8 × 104,6.2 × 105, mean 3.30 × 105) was significantly lower than that of NR patients (6.3 × 107,7.2 × 108, mean 3.55 × 108; P < 0.01). The number of amino acid substitutions in NS5A1865,2279 was five to seven (mean 5.8 ± 1.0) in CR patients, and four to eight (mean 6.8 ± 1.6) in NR patients, a difference that is not significant. Moreover, there were no amino acid substitutions or sites of substitution in NS5A1865,2279 that were specific to either group. Conclusions: The effectiveness of IFN therapy for GBV-C/HGV is strongly related to the pretreatment GBV-C/HGV-RNA level, but is not related to changes in NS5A1865,2279. [source] Predictors of the efficacy of interferon therapy for patients with chronic hepatitis C before and during therapy: how does this modify the treatment course?JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2000Yasushi Shiratori Antiviral therapy for hepatitis C virus (HCV) infection should be based on the natural history of HCV infection; there is a sequential, but slow, progression from chronic hepatitis to cirrhosis, leading to death from either liver failure or hepatocellular carcinoma (HCC). The risk of HCC development increases in association with the advance of fibrosis, and antiviral therapy can reduce this risk. More than 30 indices have been proposed as ,predictors' of favourable response to IFN therapy: host factors (age, gender, duration of HCV-infection, alcohol intake, hepatic iron stores, platelet count, histological staging of the liver disease), viral factors (HCV RNA levels in serum, HCV subtype, diversity of the hypervariable region, mutation of non-structure 5A gene), and IFN factors (dose, duration of treatment, type, treatment regimens i.e. every day vs three times a week, escalating dose regimen). Before starting IFN therapy, HCV subtype and pretreatment HCV RNA load, as well as the fibrotic stage of the liver, should be determined. The response to IFN therapy should be monitored by the HCV RNA status in serum during therapy, and the treatment regimen modified, or discontinued as required. A sustained virological response should be checked at more than 3 months after the completion of therapy. Even though the risk of HCC is markedly reduced in sustained responders, it is possible to develop HCC several years after completion of IFN therapy. [source] Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infectionJOURNAL OF VIRAL HEPATITIS, Issue 3 2004F. Suzuki Summary. The biological activity of interferon (IFN) is mediated by the induction of intracellular antiviral proteins, such as 2,,5, oligoadenylate synthetase, dsRNA-activated protein kinase and MxA protein. Among these, MxA protein is assumed to be the most specific surrogate parameter for IFN action. This study was performed to elucidate whether a single nucleotide polymorphism (SNP) (G/T at nt-88) in the promoter region of the MxA gene influences the response to IFN therapy in patients with chronic hepatitis C virus (HCV) infection. Polymorphisms of the MxA gene in 235 HCV patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequency of SNP was compared between sustained-responders (n = 78) and nonresponders (n = 157), as determined by biochemical and virological responses to IFN. Multivariate analysis showed that among all patients, HCV genotype, HCV RNA level and the SNP of the MxA gene were independent and significant determinants of the outcome of IFN therapy [odds ratio 3.8 (95% confidence interval 2.0,7.0), P < 0.0001; 0.27 (0.15,0.50), P < 0.0001; 1.8 (1.0,3.4), P = 0.0464, respectively]. Furthermore, among patients with a low viral load (,2.0 Meq/mL), MxA-T-positive patients were more likely to show a sustained response compared with MxA-T-negative patients [2.87 (1.3,6.3); 62%vs 36%; P = 0.0075]. Our findings suggested that the SNP of the MxA gene is one of the important host factors that independently influences the response to IFN in patients with chronic HCV infection, especially those with a low viral load. [source] Dynamics of hepatitis C virus quasispecies turnover during interferon- , treatmentJOURNAL OF VIRAL HEPATITIS, Issue 6 2003M. von Wagner Summary. Interferon- , (IFN) has been shown to accelerate the evolution of hepatitis C virus (HCV) variants (quasispecies) in nonresponder patients. Different sensitivities of HCV variants to IFN are discussed as a possible mechanism. In the present study, quasispecies were investigated in detail by a newly established and validated direct solid-phase sequencing of the hypervariable region 1 (HVR1), during the initial 3 months of IFN therapy. According to single strand conformation polymorphism (SSCP) analysis, 14 of 26 (54%) virologic nonresponders with quasispecies evolution were identified. Six representative patients with SSCP changes were selected for frequent HVR1 sequencing. Pre-existing variants were identified by cloning and sequencing of the pretreatment serum HCV sample. In one patient the major type was substituted by a minor variant within 3 days of treatment while in the majority of patients the pretreatment major type did not decline before days 26,57 of treatment. Total serum HCV RNA levels remained constant in all patients. In conclusion, although quasispecies evolution during IFN therapy is common, it occurs after a wide range of time intervals after initiation of therapy. Thus, nonresponse to IFN cannot exclusively be explained by changes in the quasispecies. [source] Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirinJOURNAL OF VIRAL HEPATITIS, Issue 2 2003C.-H. Hung summary. Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV-1b patients who had received IFN- ,2b (3 or 5 MU three times weekly) and ribavirin (800,1200 mg per day) for 24 weeks. The amino acid sequences of the NS5A and PKR-eIF2, phosphorylation homology domain (E2-PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A,PKR binding domain (2209,2274), interferon sensitivity-determining region (ISDR) (2209,2248), and E2-PePHD sequence (659,670) in patients with and without SVR were 4.53 ± 3.31 vs 2.83 ± 1.78 (P = 0.094), 2.45 ± 2.74 vs 1.03 ± 1.32 (P = 0.042) and 0.25 ± 0.70 vs 0.03 ± 0.17 (P = 0.109), respectively. Patients with a mutant-type (, 4) NS5A,ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A,ISDR (, 4 vs < 4) was the only independent variable of treatment outcome. Our study showed that NS5A,ISDR mutations were correlated with the SVR to combination therapy in chronic HCV-1b patients in Taiwan. [source] Treatment of chronic hepatitis C virus infection in patients with cirrhosisJOURNAL OF VIRAL HEPATITIS, Issue 5 2000Zeuzem Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20,30% of patients and to hepatocellular carcinoma (HCC) in 1,5% of patients. Rates of sustained virological response with standard interferon-, (IFN-,) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients. [source] Genotype and viral load as prognostic indicators in the treatment of hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 4 2000Trepo Interferon-, (IFN-,), either alone or in combination with ribavirin, is the standard treatment for patients with hepatitis C. However, most patients do not achieve a sustained remission with this treatment regimen. A number of studies have demonstrated that genotype, baseline viral load and/or a decrease in viral load early after treatment induction are the major predictive factors for response to treatment with IFN. Patients with hepatitis C virus (HCV) genotype 1 are more resistant to treatment with IFN, whereas low viral load at baseline and a marked decline in the HCV RNA level during the first 2,12 weeks of IFN therapy are associated with enhanced treatment efficacy. These variables could potentially be used to develop treatment algorithms that tailor therapies for specific clinical situations. Continued development and refinement of such algorithms would facilitate both the selection of patients who are most likely to benefit from therapy and the development of optimal treatment regimens for different patient groups. Predictive factors will also enable clinicians to identify subsets of patients who are not expected to respond well to current treatment. The development of new delivery methods for IFN that produce sustained antiviral pressure may provide a means of treating these previously difficult-to-treat patient groups. [source] Methodological issues in papers on IFN therapy: time for reappraisalJOURNAL OF VIRAL HEPATITIS, Issue 3 2000Kondili We conducted an analytical review of 194 full papers on interferon (IFN) therapy for chronic hepatitis C to evaluate current methodology (i.e. study design, criteria for evaluating the efficacy of therapy and predictors of response). Of the papers evaluated, 64 were randomized controlled trials (RCT), 40 were non-randomized controlled trials (NRCT) and 90 were observational studies (OS). The methodological analysis was focused mainly on clinical trials. The number of patients enrolled in RCT was higher compared with the number enrolled in NRCT. Uniform enrolment criteria were used in less than 50% of the trials. Only 20% of RCT and 2.5% of NRCT used criteria for defining sample size. The response rate was calculated on an intention-to-treat basis in 36 of the RCT and in 14 of the NRCT. The outcome of treatment and the criteria employed to define the response to treatment were found to be far from standardized. In 51.5% of the RCT and 42.5% of the NRCT, normalization of alanine aminotransferase (ALT) level at the end of follow-up was the only marker of response studied. Only 57.6% of the trials considered histological evidence as an important outcome. Among the clinical trials, 71.1% evaluated predictors of good response to IFN therapy. In 51% of the OS, ALT normalization by the end of follow-up was the only criterion for defining response. In conclusion, to ensure a high level of reliability in comparing or combining the results of different studies, some basic general requirements must be followed when planning trials on antiviral therapy. [source] Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatmentLIVER INTERNATIONAL, Issue 2 2010Jin-Hai Chang Abstract Background: Double-stranded RNA-activated protein kinase (PKR), an interferon (IFN)-stimulated gene, is activated by binding with double-stranded RNA, a putative replicative intermediate of the hepatitis C virus (HCV). Activated PKR phosphorylates the , subunit of eukaryotic initiation factor-2 to inhibit the translation of viral protein. Aims/methods: We established stable PKR knockdown Huh7 cells using RNA interference and investigated the effect of PKR against HCV replication using a subgenomic replicon that expressed luciferase reporter protein and the JFH1 full-length HCV genome. Results: In stable PKR knockdown cells that harboured a subgenomic replicon, luciferase activity was approximately three times higher than that of control cells, indicating that the subgenomic replicon replicated with a higher efficiency in stable PKR knockdown cells than that in control cells. Furthermore, stable PKR knockdown cells secreted significantly more HCV particles than did control cells after transfection with the full-length HCV genome. The replication of the subgenomic replicon was suppressed by the addition of IFN-, in both cells. Although the extent of suppression was significantly lower in stable PKR knockdown than control cells using a low concentration (2.5,5 U/ml) of IFN-,, even 10 U/ml IFN-, suppressed the replication of subgenomic replicon by >98% in both cells. Conclusions: Double-stranded RNA-activated protein kinase plays an important role in suppressing HCV replication in an innate state, but may not be essential in IFN therapy. [source] Managing chronic hepatitis C in the difficult-to-treat patientLIVER INTERNATIONAL, Issue 10 2007Nyingi Kemmer Abstract Patients with chronic hepatitis C virus (HCV) infection and disease-related complications , among them cirrhosis and liver failure , pose a particular management challenge. Some of these patients may fail to respond to current therapy (non-responders), and some are affected so severely that treatment puts them at an unacceptable risk for complications. Treatment with pegylated interferon (peg-IFN) plus ribavirin improves hepatic enzyme levels and eradicates the virus in ,50% of patients; however, a significant number of patients do not respond to therapy or relapse following treatment discontinuation. Several viral, hepatic and patient-related factors influence response to IFN therapy; many of these factors cannot be modified to improve long-term outcomes. Identifying risk factors and measuring viral load early in the treatment can help to predict response to IFN therapy and determine the need to modify or discontinue treatment. Retreatment options for patients who have failed therapy are limited. Retreatment with peg-IFN has been successful in some patients who exhibit an inadequate response to conventional IFN treatment, particularly those who have relapsed. Consensus IFN, another option in treatment-resistant patients, has demonstrated efficacy in the retreatment of non-responders and relapsers. Although the optimal duration of retreatment and the benefits and safety of maintenance therapy have not been determined, an extended duration is likely needed. This article reviews the risk factors for HCV treatment resistance and discusses the assessment and management of difficult-to-treat patients. [source] A prospective study of interferon therapy modified by pre-treatment viral load in cirrhotic patientsLIVER INTERNATIONAL, Issue 4 2000Yasushi Shiratori Abstract:Background/Aims: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. Methods: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with "low" viral load (,105.8 copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with "high" viral load (,106.3 copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1404 MU). Results: HCV-RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with "low" viral load, in contrast to 14% in patients with "high" viral load. Sustained virological response was found in 40% of patients with "low" viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with "high" viral load. Viral eradication was found in approximately 50% of patients having a low virus load (,104.3 copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. Conclusions: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12-month course of intensive IFN therapy. This result indicates that there is a certain cut-off level of HCV RNA load which can not be eradicated. [source] Hepatitis C virus infection and interferon therapy in patients with Down syndromePEDIATRICS INTERNATIONAL, Issue 1 2008Yoko Miyoshi Abstract Background: The clinical features of hepatitis C virus (HCV)-associated liver diseases, or the efficacy of interferon (IFN) therapy in children with Down syndrome (DS) remain to be elucidated. The purpose of the present paper was to survey the features of liver diseases in this subset of children and evaluate the efficacy of IFN treatment in those patients. Methods: A questionnaire was sent to 41 members of the Japan Society of Pediatric Hepatology. Ten of them reported on 11 patients with DS who had concomitant chronic HCV infection, providing information on liver disease and the response to IFN treatment. Results: Interferon therapy of 24 weeks duration using natural IFN-, was instituted in six of the 11 patients with DS, but none of the six patients cleared HCV-RNA from their serum. Among 12 age- and sex-matched control children who were treated with IFN using the same regimen against chronic HCV infection, half of them had a favorable response to IFN therapy with a sustained clearance of HCV-RNA from their serum. The major baseline features including alanine aminotransferase levels, HCV genotype and viral load were not apparently different between the six patients with DS and the 12 controls. Conclusions: IFN therapy for HCV infection in patients with DS may be unfavorable as compared with non-DS children. [source] Longitudinal course of depression, fatigue, and quality of life in patients with high risk melanoma receiving adjuvant interferonPSYCHO-ONCOLOGY, Issue 8 2004Peter C. Trask Purpose: Treatment of malignant melanoma with interferon- , has been associated with a variety of side effects ranging from fatigue to depression, and a concomitant impact on quality of life (QOL), in a variety of case reports and cross-sectional clinical trials. Few, if any, studies have been conducted with the express purpose of assessing the longitudinal course of depression, fatigue, and QOL before and during interferon therapy. Description of study: The current study reports on 16 patients who were assessed at 6 points in time: baseline, post high dose, and 1, 2, 3, and 6 months post high dose treatment with interferon- , with the Brief Symptom Inventory, Beck Depression Inventory, Revised Piper Fatigue Scale, and Functional Assessment of Cancer Therapy-Biological Response Modifiers. Results: Results revealed consistent changes from baseline through 6 month assessment. Specifically, increased somatic complaints, depression, and fatigue were observed on the BSI, BDI, and RPFS, respectively. Additional reductions in QOL on the FACT-BRM were also identified. Clinical implications: The findings suggest that IFN has a significant effect on QOL, but that it may be the somatic symptoms of fatigue that contribute to changes on measures of mood. Limiting the amount of fatigue and depression would appear to be significant if individuals are to successfully complete IFN therapy. Copyright © 2003 John Wiley & Sons, Ltd. 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