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Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis.

ABSTRACT: AIM:To investigate the predictability of interleukin-28B single nucleotide polymorphism rs12979860 with respect to sustained virological response (SVR) in chronically hepatitis C virus (HCV) genotype-1 patients treated with a protease-inhibitor and pegylated interferon-? (Peg-INF-?) based triple-therapy. METHODS:We searched PubMed, the Cochrane Library and Web of Knowledge for studies regarding the interleukin 28B (IL-28B)-genotype and protease-inhibitor based triple-therapy. Ten studies with 2707 patients were included into this meta-analysis. We used regression methods in order to investigate determinants of SVR. RESULTS:IL-28B-CC-genotype patients achieved higher SVR rates (odds 5.34, 95%CI: 3.81-7.49) than IL-28B-non-CC-genotype patients (1.88, 95%CI: 1.43-2.48) receiving triple-therapy. The line of therapy (treatment-naïve or -experienced for Peg-INF-?) did not affect the predictive value of IL-28B (P = 0.1). IL-28B-CC-genotype patients treated with protease inhibitor-based triple-therapy consisting of Boceprevir, Simeprevir, Telaprevir or Vaniprevir showed odds of 3.38, 14.66, 7.84 and 2.91, respectively. The odds for CC genotype patients treated with Faldaprevir cannot be quantified, as only a single study with a 100% SVR rate was available. CONCLUSION:IL-28B-SNP predicts the outcome for chronic HCV genotype-1 patients receiving protease inhibitor-based triple-therapy. The predictive value varies between the different protease inhibitors.

SUBMITTER: Mechie NC

PROVIDER: S-EPMC4209421 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis.

Mechie Nicolae-Catalin NC Röver Christian C Cameron Silke S Amanzada Ahmad A

World journal of hepatology 20141001 10

<h4>Aim</h4>To investigate the predictability of interleukin-28B single nucleotide polymorphism rs12979860 with respect to sustained virological response (SVR) in chronically hepatitis C virus (HCV) genotype-1 patients treated with a protease-inhibitor and pegylated interferon-α (Peg-INF-α) based triple-therapy.<h4>Methods</h4>We searched PubMed, the Cochrane Library and Web of Knowledge for studies regarding the interleukin 28B (IL-28B)-genotype and protease-inhibitor based triple-therapy. Ten ...[more]

PMID: 25349647

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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.

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:BackgroundPeginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.MethodsWe conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.ResultsA total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.ConclusionsThe addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

Dataset Information

Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis.

Publications

Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis.

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