Article

Managing chronic hepatitis C in the difficult-to-treat patient

Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, United States
Liver international: official journal of the International Association for the Study of the Liver (Impact Factor: 4.41). 01/2008; 27(10):1297-310. DOI: 10.1111/j.1478-3231.2007.01613.x
Source: PubMed

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 approximately 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.

0 Followers
 · 
116 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development and demonstration of short, robust and chromatography-free sequences for the preparation of a (1R,2S)-1-amino-2-vinylcyclopropane-carboxylic acid-derived sulfonamide and ethyl ester in ≥99% ee are described. Both compounds are common building blocks in multiple preparations of potent HCV NS3 protease inhibitors. The robustness of the asymmetric cyclopropanation of (E)-N-benzylideneglycine ethyl ester under phase transfer catalysis conditions is significantly improved based on a detailed mechanistic investigation that included an analysis of the catalyst decomposition pathway, a postulated model for the stereo-selectivity that was guided by calculations and rigorous quality control of the starting materials and reagents. Wet milling has been demonstrated to dramatically accelerate this phase transfer reaction. A bench stable benzylidene-protected primary 1-amino-2-vinylcyclopropane amide intermediate was isolated and its reliable enantiomeric enrichment was achieved by a controlled crystallization process. A chemical resolution procedure was identified using di-p-toluoyl-(d)-tartaric acid to access (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic ester in high ee.
    Organic & Biomolecular Chemistry 09/2013; 11(39):6796-805. DOI:10.1039/c3ob41394b · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Specific antibodies against poly(ethylene glycol) (anti-PEG) were induced in animals following exposure to PEG-conjugated proteins and particles, resulting in rapid clearance of PEG-conjugated agents. In humans, induction of anti-PEG was observed following exposure to a PEG-conjugated drug, and pre-existing anti-PEG was identified in over 25% the healthy population. In clinical studies, the presence of anti-PEG was strongly associated with rapid clearance of PEG-asparaginase and PEG-uricase. PEGylation of therapeutic agents will continue to be of significant value in medicine to reduce immunogenicity, antigenicity and toxicity as well as markedly reducing renal clearance, while maintaining drug efficacy. It is important to recognize that PEG itself may possess antigenic and immunogenic properties. Further comprehensive studies are warranted to fully elucidate the effect of anti-PEG on PEG-conjugated agents and if confirmed in a prospective trial, patients should be screened and monitored for anti-PEG, and strategies developed to overcome the potential negative effect of anti-PEG on drug clearance to improve the effectiveness of therapy.
    01/1970: pages 147-168;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recombinant human consensus interferon (rh-cIFN) is an artificially engineered interferon developed by recombining and reordering the protein sequences that exist in standard interferon. This recombination resulted in to a drug that has the potential to work better than natural, standard interferon. In present study we described optimized conditions for high level expression and recovery of biological active consensus interferon from inclusion bodies. A synthetic gene coding 166 amino acid of consensus interferon was cloned under T7 promoter. Escherichia coli strain BL21DE3Plys was used to transform expression construct. For high level expression, shake flask fermentation conditions were standardized. For isolation of inclusion bodies sonication method was optimized. Variety of chaotropic agents including guanidine hydrochloride, urea, SDS, and detergents were studied for solubilization of inclusion bodies. For re-naturation of solubilized denatured protein by dilution process, parameters of dilution factor, temperature and L-argine were optimized. One step chromatography method was developed for high yield purification of consensus interferon. Recombinant human cIFN was characterized by SDS-PAGE, western blot, HPLC. Purified protein has molecular weight of 19.5 kDa and specific activity was 2.0×108 as determined by cytopathic inhibition assay. This study concludes that by using optimized conditions, we obtained a yield of 100mg/L of biologically active rhcIFN, which is highest ever reported according to available data.This article is protected by copyright. All rights reserved
    Biotechnology and Applied Biochemistry 11/2014; DOI:10.1002/bab.1320 · 1.32 Impact Factor

Preview

Download
0 Downloads
Available from