Telaprevir is effective given every 12 h at 750 mg with pegylated interferon-α2b and ribavirin to Japanese patients with HCV-1b IL28B rs8099917 TT
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. Antiviral therapy
(Impact Factor: 3.02).
11/2013; 19(3). DOI: 10.3851/IMP2706
The aim of this study is to explore the efficacy, safety and pharmacokinetics of 750mg telaprevir (TVR) given at 8 or 12 hour intervals during triple therapy with peg-interferon-alfa-2b (PEG-IFN) and ribavirin (RBV) for patients with chronic hepatitis C virus (HCV) infection.
52 patients with high viral loads of genotype 1b who were expected to respond well to therapy (rs8099917 TT genotype or relapse to previous therapy) were randomly assigned to two groups who were given 750mg TVR at either 8 or 12 hour intervals (q8h or q12h) in combination with PEG-IFN and RBV for 12 weeks, followed by an 12 additional weeks of treatment with PEG-IFN and RBV alone. The primary end point of the study was undetectable HCV RNA at 12 weeks after the end of treatment (SVR12).
SVR12 rates were 92.3% (24/26) for both q8h and q12h. The changes in mean log10 HCV RNA levels and viral response were also similar in q8h compared to q12h, whereas pharmacokinetic properties such as Cmax, AUC0-24h and Ctrough of TVR were slightly higher in q8h than in q12h (P>0.2). The frequency of TVR discontinuation due to anemia or renal damage was significantly higher in q12h than in q8h (6/26(23%) vs. 0/20, respectively; P=0.02).
TVR given at 12 hour intervals should be considered for patients with lower body weight, especially patients with prior relapse and with IL28B polymorphisms at rs8099917 TT (interferon lambda 4 ss469415590 polymorphism TT/TT) genotype in patients with genotype 1b HCV infection.
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ABSTRACT: The predictive value of the recently identified interferon lamda (IFNL) 4 polymorphism on the outcome of telaprevir (TVR), peg-interferon (PEG-IFN) plus ribavirin (RBV) combination therapy for chronic hepatitis C is unknown.
We assessed predictive factors for sustained virological response (SVR) for TVR, PEG-IFN plus RBV combination therapy in 283 genotype 1 chronic hepatis C patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.
SVR rates for patients with IFNL4 TT/TT genotype were significantly higher than for those with the IFNL4 TT/ΔG or ΔG/ΔG genotypes (93% and 59%, respectively, P<0.0001). In a multivariate regression analysis, prior treatment history (treatment-naive patients or patients who relapsed during prior treatment) (OR 2.385, P=0.028), rapid virological response (OR 6.800, P<0.0001) and ss469415590 TT/TT genotype (OR 8.064, P <0.0001) were identified as significant independent predictors for SVR. In patients with IFNL4 TT/ΔG or ΔG/ΔG genotypes, SVR rates for non-RVR patients were significantly lower than RVR patients (22% and 75%, respectively, P<0.0001).
Analysis of IFNL4 polymorphism is a valuable predictor in patients receiving TVR triple therapy.
Available from: Yuichi Yoshida
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ABSTRACT: Triple therapy with telaprevir (TVR), pegylated interferon and ribavirin has improved antiviral efficacy in patients with chronic hepatitis C (CH-C). However, the severe adverse effects caused by TVR are important to resolve. In this prospective, randomized, multicenter, open-label study, the antiviral efficacy and safety in the reduced administration of TVR were examined.
A total of 81 CH-C Japanese patients with HCV genotype 1 were randomized into two regimens of TVR 2250 mg (TVR-2250) or 1500 mg (TVR-1500) and treated with triple therapy for 24 weeks.
The mean HCV RNA at start, 2 and 4 weeks of treatment were 6.69 ± 0.70, 1.05 ± 0.74, 0.22 ± 0.48 log10 IU/ml in the TVR-2250 group and 6.70 ± 0.62, 1.02 ± 0.62, 0.13 ± 0.41 log10 IU/ml in the TVR-1500 group. The SVR rates were 85 % in both groups (35/41 and 34/40, respectively). There were no patients with viral breakthrough in either group. As for adverse effects, rash more than moderate and severe anemia with <8.5 g/dl of hemoglobin were higher in the TVR-2250 group than in the TVR-1500 group (p = 0.046, p < 0.001, respectively). The increase in serum creatinine levels and decrease in estimated glomerular filtration rates were higher in the TVR-2250 group than in the TVR-1500 group.
The lower dose of TVR (1500 mg/day) can result in similar SVR rates and lower treatment-related adverse effects compared to the higher dose of TVR (2250 mg/day) in triple therapy (UMIN: 000007313, 000007330).
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ABSTRACT: Treatment success of chronic hepatitis C virus genotype 1 infection has improved with the advent of telaprevir plus peg-interferon/ribavirin triple combination therapy. However, the effect of inosine triphosphatase (ITPA) polymorphism on dose reduction during triple therapy, especially during the postmarketing phase, has not been sufficiently evaluated. We analysed 273 patients with genotype 1 infection who were treated with triple therapy and assessed the effect of the ITPA polymorphism on dose reduction. ITPA and IFNL4 SNP genotypes were determined by the Invader assay. A stepwise multivariate regression analysis was performed to identify factors associated with outcome of the therapy. The overall sustained viral response (SVR) rate 12 weeks after the end of therapy was 80.2% (219/273). Decline of haemoglobin was significantly faster, and ribavirin was more extensively reduced in patients with ITPA SNP rs1127354 genotype CC than CA/AA. Extensive reduction of ribavirin resulted in mild reduction of telaprevir and peg-interferon, but no significant increase in viral breakthrough. Although the amount of telaprevir given was slightly higher in CA/AA patients, the total dose of peg-interferon and the SVR rate did not differ between the two groups. Multivariate analysis showed that IFNL4 but not ITPA SNP genotype, platelet count and peg-interferon adherence were significantly associated with outcome of therapy. Postmarketing-phase triple therapy resulted in a high SVR rate in spite of extensive ribavirin dose reduction in a diverse patient population, indicating the importance of treatment continuation and appropriate management of adverse events.
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