Standard Therapy For Hepatitis Research Articles

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C

The combination of interferon (IFN) and ribavirin (RBV) is the standard therapy for hepatitis C virus (HCV) infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet limited. This study aimed to investigate the mechanism of the poor response in a case of HCV genotype 2a infection.We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to IFN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 (JFH1) replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient's sequence from the pre/post-treatment, and the chimeric replicons' susceptibility to IFN were evaluated by relative Gausia Luciferase activity.The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN.During the course of the chronic infection, HCV population seems to be adapted to the patient's immunological system, and further to be selected by combination of IFN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region (ISDR) of NS5A during chronic infection and IFN/RBV therapy.

Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C.

The combination of interferon (IFN) and ribavirin (RBV) is the standard therapy for hepatitis C virus (HCV) infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet limited. This study aimed to investigate the mechanism of the poor response in a case of HCV genotype 2a infection. We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to IFN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 (JFH1) replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient's sequence from the pre/post-treatment, and the chimeric replicons' susceptibility to IFN were evaluated by relative Gausia Luciferase activity. The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN. During the course of the chronic infection, HCV population seems to be adapted to the patient's immunological system, and further to be selected by combination of IFN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region (ISDR) of NS5A during chronic infection and IFN/RBV therapy.

A Hepatitis C Virus-Host Interaction Involved in Viral Replication: toward the Identification of Antiviral Targets

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The current standard therapy for hepatitis C patients, which is based on a combination of pegylated interferons and ribavirin, results in viral clearance in about 50% of the treated individuals. Clinical trials of a variety of specific anti-HCV drugs, including several which target virus-encoded enzymes, are on-going, and some of these studies have reported impressive reductions of HCV levels in patients. However, the development of antivirals with diverse mechanisms of action is still required to eliminate this life-threatening virus. Besides specific viral proteins, targeting host cellular factors that are key to efficient viral replication could lead to the development of novel treatment strategies. Therapies against host factors are generally considered to present a low risk of generating drug-resistant viruses. The current understanding of anti-HCV drugs in clinical development and of virus-host interactions implicated in the regulation of HCV replication is summarized.

What to do if standard therapy for hepatitis C fails

The standard of care for treatment of individuals chronically infected with hepatitis C virus is pegylated interferon in combination with ribavirin. Efficacy is closely related to viral genotype. This review outlines potential therapeutic strategies for treatment failures and discusses some of the newer agents currently in development.

Normalized methodology for medical infrared imaging

A normalized procedure for medical infrared imaging is suggested, and illustrated by a leprosy and hepatitis C treatment follow-up, in order to investigate the effect of concurrent treatment which has not been reported before. A 50-year-old man with indeterminate leprosy and a 20-year history of hepatitis C was monitored for 587 days, starting from the day the patient received treatment for leprosy. Standard therapy for hepatitis C started 30 days later. Both visual observations and normalized infrared imaging were conducted periodically to assess the response to leprosy treatment. The primary end points were effectiveness of the method under different boundary conditions over the period, and rapid assessment of the response to leprosy treatment. The patient achieved sustained hepatitis C virological response 6 months after the end of the treatment. The normalized infrared results demonstrate the leprosy treatment success in spite of the concurrent hepatitis C treatment, since day 87, whereas repigmentation was visually assessed only after day 182, and corroborated with a skin biopsy on day 390. The method detected the effectiveness of the leprosy treatment in 87 days, whereas repigmentation started only in 182 days. Hepatitis C and leprosy treatment did not affect each other.

Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in Hepatitis C virus replicon

BackgroundAlpha interferon in combination with ribavirin is the standard therapy for hepatitis C virus infection. Unfortunately, a significant number of patients fail to eradicate their infection with this regimen. The mechanisms of IFN-resistance are unclear. The aim of this study was to determine the contribution of host cell factors to the mechanisms of interferon resistance using replicon cell lines.ResultsHCV replicons with high and low activation of the IFN-promoter were cultured for a prolonged period of time in the presence of interferon-alpha (IFN-alpha2b). Stable replicon cell lines with resistant phenotype were isolated and characterized by their ability to continue viral replication in the presence of IFN-alpha. Interferon resistant cell colonies developed only in replicons having lower activation of the IFN promoter and no resistant colonies arose from replicons that exhibit higher activation of the IFN promoter. Individual cell clones were isolated and nine IFN resistant cell lines were established. HCV RNA and protein levels in these cells were not altered by IFN- alpha2b. Reduced signaling and IFN-resistant phenotype was found in all Huh-7 cell lines even after eliminating HCV, suggesting that cellular factors are involved. Resistant phenotype in the replicons is not due to lack of interferon receptor expression. All the cell lines show defect in the JAK-STAT signaling and phosphorylation of STAT 1 and STAT 2 proteins were strongly inhibited due to reduced expression of Tyk2 and Jak-1 protein.ConclusionThis in vitro study provides evidence that altered expression of the Jak-Stat signaling proteins can cause IFN resistance using HCV replicon cell clones.

Chronic Paranoid Psychosis and Dementia Following Interferon-α Treatment of Hepatitis C: A Case Report

Low-dose interferon-alpha is a standard therapy for hepatitis C. Psychotic disorders have been described as a rare complication of such treatments that resolve with its termination. Here, we present a patient without significant risk factors for interferon-alpha-induced serious mental disorders who developed a psychotic disorder with a cognitive impairment achieving the level of dementia after seven months of interferon-alpha therapy. The disturbances have persisted for three years despite cessation of interferon and introduction of antipsychotic treatment. The possibility of severe neuropsychiatric adverse effects of interferon-alpha therapy in a susceptible individual may necessitate regular psychiatric consultations during the treatment.

Anti‐Golgi complex antibodies during pegylated‐interferon therapy for hepatitis C

Pegylated interferon (Peg-IFN) plus ribavirin is the standard therapy for hepatitis C. Peg-IFN has several antiviral mechanisms, but its role in hepatitis C treatment seems to be related to its immunomodulatory effect. Ribavirin, an antiviral agent, potentiates IFN activity when added to it. Both drugs are associated with adverse reactions of different magnitudes. Autoimmune phenomena have been reported with this treatment. In this paper, we describe cases of ALT/GGT flares during Peg-IFN plus ribavirin treatment, which related to the appearance of anti-Golgi antibody and disease progress. We investigated three patients with hepatitis C and severe ALT/GGT flares during Peg-IFN and ribavirin treatment coinciding with anti-Golgi complex antibody as the only marker of autoimmunity. We then reviewed the medical files and tested anti-Golgi antibody in stored sera from 25 patients treated with conventional IFN and in 14 patients treated with Peg-IFN. The three patients were male, over 45 years of age; all were relapsers and non-responders. Anti-Golgi antibody was positive during treatment coinciding with ALT/GGT flares but with hepatitis C virus (HCV)-RNA negativity, disappearing after stopping treatment, with normalization of ALT/AST levels. One patient had progression of fibrosis from F2 to F3 despite negativity of HCV-RNA. In the last group, only two patients treated with Peg-IFN experienced ALT/GGT flares but without anti-Golgi antibody The presence of anti-Golgi complex antibody could be a marker of a temporary autoimmune phenomenon and progressive disease.

Pharmacodynamics of PEG-IFN α differentiate HIV/HCV coinfected sustained virological responders from nonresponders

Pegylated interferon (PEG-IFN) has become standard therapy for hepatitis C virus (HCV) infection. We evaluated whether PEG-IFN pharmacodynamics and pharmacokinetics account for differences in treatment outcome and whether these parameters might be predictors of therapeutic outcome. Twenty-four IFN-naïve, HCV/human immunodeficiency virus-coinfected patients received PEG-IFN alpha-2b (1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg) for up to 48 weeks. HCV RNA and PEG-IFN alpha concentrations were obtained from samples collected frequently after the first 3 PEG-IFN doses. We modeled HCV kinetics incorporating pharmacokinetic and pharmacodynamic parameters. Although PEG-IFN concentrations and pharmacokinetic parameters were similar in sustained virological responders (SVRs) and nonresponders (NRs), the PEG-IFN alpha-2b concentration that decreases HCV production by 50% (EC50) was lower in SVRs compared with NRs (0.04 vs. 0.45 microg/L [P = .014]). Additionally, the median therapeutic quotient (i.e., the ratio between average PEG-IFN concentration and EC50 [C/EC50]), and the PEG-IFN concentration at day 7 divided by EC50 (C(7)/EC50) were significantly increased in SVRs compared with NRs after the first (10.1 vs. 1.0 [P = .012], 2.8 vs. 0.3 [P = .007], respectively) and second (14.0 vs. 1.1 [P = .016], 5.4 vs. 0.4 [P = .02], respectively) PEG-IFN doses. All 3 parameters may be used to identify NRs. In conclusion, PEG-IFN concentrations and pharmacokinetic parameters do not differ between SVRs and NRs. In contrast, pharmacodynamic measurements-namely EC50, the therapeutic quotient, and C(7)/EC50--are different in coinfected SVRs and NRs. These parameters might be useful predictors of treatment outcome during the first month of therapy.

New paradigms in the management of HIV and hepatitis C virus coinfection

Chronic hepatitis C virus infection is currently one of the leading causes of morbidity and mortality in HIV-infected individuals, mainly in hemophiliacs and intravenous drug users. The bidirectional interferences between hepatitis C virus and HIV have clinical consequences and complicate the management of coinfected individuals. There is an increased rate of liver complications among coinfected patients due to the decrease in opportunistic infections resulting from the use of potent antiretroviral therapy and accelerated progression to liver cirrhosis in the HIV setting. Conversely, the risk of hepatotoxicity of antiretrovirals is higher in the presence of chronic hepatitis C. While the standard therapy for hepatitis C in HIV is the combination of pegylated interferon plus ribavirin, overall treatment responses are lower in HIV-coinfected than in hepatitis C virus-monoinfected patients. Moreover, interactions between ribavirin and HIV drugs (i.e. didanosine, zidovudine) are associated with higher risks of side effects. Given the accelerated progression to end-stage liver disease in coinfected patients, treatment of hepatitis C should be a priority. While hepatitis C therapy should not be denied in the absence of contraindication, it should be re-assessed at week 12 and therapy continued only in patients showing more than 2 log drops in viremia, to avoid side effects. Most recent data suggest that adequate selection of candidates, expert management of side effects, and prescription of appropriate ribavirin doses (in genotypes 1-4) and extending treatment (in genotypes 2-3) all might allow response rates in coinfected patients to approach those seen in hepatitis C virus-monoinfected individuals.

Is the current standard therapy for hepatitis C of peginterferon and ribavirin an option for patients coinfected with HIV?

Is the current standard therapy for hepatitis C of peginterferon and ribavirin an option for patients coinfected with HIV?