Dataset Information

Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection.

ABSTRACT: The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a "real-life" cohort.We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N?=?6) or status post liver transplant (N?=?2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder.SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N?=?30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P?100 U/l (P?=?0.03) and albumin ?35 g/l (P?=?0.04) at baseline were associated with occurence of a SAE.The frequency of SVR in a "real-life" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.

SUBMITTER: Wehmeyer MH

PROVIDER: S-EPMC4102246 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection.

Wehmeyer Malte H MH Eißing Friederike F Jordan Sabine S Röder Claudia C Hennigs Annette A Degen Olaf O Hüfner Anja A Hertling Sandra S Schmiedel Stefan S Sterneck Martina M van Lunzen Jan J Lohse Ansgar W AW Schulze zur Wiesch Julian J Lüth Stefan S

BMC gastroenterology 20140505

<h4>Background</h4>The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a "real-life" cohort.<h4>Methods</h4>We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with ...[more]

PMID: 24884400

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Project description:The selection of resistance-associated variants (RAVs) against single agents administered to patients chronically infected with hepatitis C virus (HCV) necessitates that direct-acting antiviral agents (DAAs) targeting multiple viral proteins be developed to overcome failure resulting from emergence of resistance. The combination of grazoprevir (formerly MK-5172), an NS3/4A protease inhibitor, and elbasvir (formerly MK-8742), an NS5A inhibitor, was therefore studied in genotype 1a (GT1a) replicon cells. Both compounds were independently highly potent in GT1a wild-type replicon cells, with 90% effective concentration (EC90) values of 0.9 nM and 0.006 nM for grazoprevir and elbasvir, respectively. No cross-resistance was observed when clinically relevant NS5A and NS3 RAVs were profiled against grazoprevir and elbasvir, respectively. Kinetic analyses of HCV RNA reduction over 14 days showed that grazoprevir and elbasvir inhibited prototypic NS5A Y93H and NS3 R155K RAVs, respectively, with kinetics comparable to those for the wild-type GT1a replicon. In combination, grazoprevir and elbasvir interacted additively in GT1a replicon cells. Colony formation assays with a 10-fold multiple of the EC90 values of the grazoprevir-elbasvir inhibitor combination suppressed emergence of resistant colonies, compared to a 100-fold multiple for the independent agents. The selected resistant colonies with the combination harbored RAVs that required two or more nucleotide changes in the codons. Mutations in the cognate gene caused greater potency losses for elbasvir than for grazoprevir. Replicons bearing RAVs identified from resistant colonies showed reduced fitness for several cell lines and may contribute to the activity of the combination. These studies demonstrate that the combination of grazoprevir and elbasvir exerts a potent effect on HCV RNA replication and presents a high genetic barrier to resistance. The combination of grazoprevir and elbasvir is currently approved for chronic HCV infection.

Project description:Hepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge about the determinants of PI resistance for the highly prevalent genotypes 2 to 6 remains limited. Using Huh7.5 cell culture-infectious HCV recombinants with genotype 1 to 6 NS3 protease, we identified protease positions 54, 155, and 156 as hot spots for the selection of resistance substitutions under treatment with the first licensed PIs, telaprevir and boceprevir. Treatment of a genotype 2 isolate with the newer PIs vaniprevir, faldaprevir, simeprevir, grazoprevir, paritaprevir, and deldeprevir identified positions 156 and 168 as hot spots for resistance; the Y56H substitution emerged for three newer PIs. Substitution selection also depended on the specific recombinant. The substitutions identified conferred cross-resistance to several PIs; however, most substitutions selected under telaprevir or boceprevir treatment conferred less resistance to certain newer PIs. In a single-cycle production assay, across genotypes, PI treatment primarily decreased viral replication, which was rescued by PI resistance substitutions. The substitutions identified resulted in differential effects on viral fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was due primarily to decreased replication. Most combinations of substitutions that were identified increased resistance or fitness. Combinations of resistance substitutions with fitness-compensating substitutions either rescued replication or compensated for decreased replication by increasing assembly. This comprehensive study provides insight into the selection patterns and effects of PI resistance substitutions for HCV genotypes 1 to 6 in the context of the infectious viral life cycle, which is of interest for clinical and virological HCV research.

Project description:Background/Aims The addition of protease inhibitors to standard of care (SOC) dramatically increases treatment response in Hepatitis C Virus (HCV) genotype 1 patients. Moreover, Interleukin 28B (IL28B) genotyping helps predict responsiveness for these patients. However, the economic implications of incorporating IL28B genotyping in HCV genotype 2 or 3 infected patients are unknown. This study used a treatment algorithm that included IL28B genotype-guided therapy to examine the short and long-term cost-effectiveness of utilizing these single-nucleotide polymorphisms in treatment-naïve HCV genotype 2 or 3 infected patients. Methods A treatment algorithm was constructed to reflect a therapy regimen for treatment-naïve patients with HCV genotype 2 or 3 infection using pegylated-interferon, ribavirin, and telaprevir. To examine the role of the IL28B gene in affecting costs and health outcomes, a decision tree was derived from the treatment algorithm in order to populate a predictive cost model for therapy using our treatment algorithm. Results Expected short-term costs of therapy following our algorithm were $21,648.92 and $47,972.84 for the CC and TT genotypes at rs12979860, respectively, and $47,972.84 and $21,648.92 for patients with the CT genotype at rs12979860 and the TG/GG and TT genotypes at rs8099917, respectively. Predicted costs among patients undergoing SOC therapy were $20,758.92. Sustained virologic response (SVR) rates for genotypes 2/3 were predicted to occur in 82.2% (8,220 of 10,000) of patients overall—88.83% (8,883 of 10,000) and 65.91% (6,591 of 10,000) for the CC and TT genotypes at rs12979860 and 81.01% (8,101 of 10,000) overall for patients with the CT genotype at rs12979860 [72.08% (7,208 of 10,000) and 86.78% (8,678 of 10,000) for the TG/GG and TT genotypes at rs8099917]. Markov modeling predicted a 27.29 quality-adjusted life-expectancy (QALE) after following our treatment algorithm while adding $7,766.51 in long-term costs. The model predicted only a 26.65 QALE after SOC therapy (while adding $9,599.05 in long-term costs). Conclusions Although short-term treatment costs of an IL28B genotype-guided approach exceed those of SOC for treatment-naïve HCV genotype 2/3 infected patients, Markov modeling suggests that lower long-term costs and improved health outcomes may be achieved by the proposed algorithm and provides a dominant cost-effective strategy for treating this population of HCV infected patients.

Dataset Information

Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection.

Publications

Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection.

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