IL28B But Not ITPA Polymorphism Is Predictive of Response to Pegylated Interferon, Ribavirin, and Telaprevir Triple Therapy in Patients With Genotype 1 Hepatitis C

J Infect Dis. 2011 Jul;204(1):84-93.

 

Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, Nakamura Y, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H.

Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN.

Abstract

Background. Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. Methods. We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. Results. Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. Conclusions. Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.

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Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir †

Hepatology
Early View (Articles online in advance of print)

Fumitaka Suzuki1,*,‡, Yoshiyuki Suzuki1, Norio Akuta1, Hitomi Sezaki1, Miharu Hirakawa1, Yusuke Kawamura1, Tetsuya Hosaka1, Masahiro Kobayashi1, Satoshi Saito1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Kazuaki Chayama3, Naoyuki Kamatani4, Yusuke Nakamura5, Yuzo Miyakawa6, Hiromitsu Kumada1

Article first published online: 18 JAN 2011
DOI: 10.1002/hep.24058
Copyright © 2011 American Association for the Study of Liver Diseases

Abstract

Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (−1.63 ± 0.92 vs. −0.48 ± 0.75 g/dL, P = 0.001) and week 4 (−3.5 ± 1.1 vs. −2.2 ± 0.96, P = 0.001), as well as at the end of treatment (−2.9 ± 1.1 vs. −2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). Conclusion:ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes. (Hepatology 2011)

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Also See: Evaluating patients for genetic variations impacts adherence to antiviral therapy

Evaluating patients for genetic variations impacts adherence to antiviral therapy

25. January 2011 08:39

In two recent studies, researchers have identified two functional variants in the inosine triphosphatase (ITPA) gene that protect patients with hepatitis C virus (HCV) against anemia brought on by antiviral treatment. The ability to identify those patients protected against treatment-induced anemia will ensure completion of antiviral therapy and successful elimination of the virus. Full findings of these studies appear in the February issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

Chronic HCV affects up to 170 million individuals worldwide and is a leading cause of end-stage liver disease. While HCV is curable with treatment of pegylated interferon (pegIFN) and ribavirin (RBV), many patients have difficulty tolerating these antiviral drugs. Prior studies have shown that 9% to 22% of patients enrolled in phase III trials of pegIFN plus RBV require modification of their dose due to hemolytic anemia brought on by the drugs. A reduction in RBV limits treatment efficacy, thus impacting the viral clearance success rate.

Alessandra Mangia, M.D., from Casa Sollievo della Sofferenza Hospital in Italy, and colleagues evaluated the association between ITPA variants and anemia in a cohort of 238 Caucasian patients treated with variable pegIFN and weight-based doses of RBV. The research team found that the ITPA variants were strongly and independently associated with protection from anemia, but did not provide an increase in sustained virological response.

"When anemia develops only four weeks after the start of treatment, physicians are required to immediately reduce ribavirin dosages. This early reduction will affect the overall duration of treatment which, with the combination of pegIFN and RBV, lasts 24 weeks for patients infected with HCV genotypes two and 3 (G2/3) and 48 weeks for patients with HCV genotype one (G1) infection. Currently, only the use of the drug erythropoietin (EPO)—an expensive drug that due to its high cost cannot be reimbursed in several countries—might prevent unsuccessful antiviral treatment in these cases," explained Dr. Mangia.

"Our findings demonstrated that ITPA variants are strongly associated with protection from week four anemia and help us in selecting in advance who will need early ribavirin dose reduction and possibly supportive EPO treatment. This may lead to a more rational use of economical resources and to an individualized use of supportive EPO treatment," concluded Dr. Mangia. "Patients with a genetic profile that included the two ITPA variants may be safely administered higher doses of RBV, increasing the likelihood of HCV elimination after treatment—an important finding given that to achieve viral clearance high dosages of RBV need to be used in the early phases of treatment."

A related study led by Fumitaka Suzuki, M.D., from Toranomon Hospital in Japan found similar results in its cohort of 61 Japanese patients with HCV. Patients in this study received a triple therapy of pegINF, RBV and the protease inhibitor, telaprevir. Dr. Suzuki and colleagues found that ITPA variants impacted blood levels; however a sustained virological response could be achieved with careful monitoring of anemia and prompt adjustment of RBV dose. The authors suggest that future investigation of the influence of ITPA gene variants on RBV-induced anemia are needed on larger scales and on patients of various ethnicities.

SOURCE Hepatology

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