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

Suzuki, Fumitaka; Suzuki, Yoshiyuki; Akuta, Norio; Sezaki, Hitomi; Hirakawa, Miharu; Kawamura, Yusuke; Hosaka, Tetsuya; Kobayashi, Masahiro; Saito, Satoshi; Arase, Yasuji; Ikeda, Kenji; Kobayashi, Mariko; Chayama, Kazuaki; Kamatani, Naoyuki; Nakamura, Yusuke; Miyakawa, Yuzo; Kumada, Hiromitsu

doi:10.1002/hep.24058

Cited by 90 publications

(105 citation statements)

References 28 publications

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“…Studies have shown that polymorphisms of the ITPA gene cause a deficiency of this enzyme resulting in decreased incidence of anemia during treatment of HCV with RBV and decreased need for RBV dose reduction [12]. A study by Suzuki et al [13] looked at how the ITPA polymorphism impacted hemoglobin levels on triple therapy with telaprevir in Japanese patients, and found that there was a protective effect of the ITPA polymorphisms from patients with RBV induced hemolysis. In our study, we did not have the appropriate resources to test for the ITPA polymorphism and therefore were not able to account for this confounding effect.…”

Section: Discussionmentioning

confidence: 99%

Anemia in Patients with Chronic Hepatitis C Infection during Triple Therapy with Telaprevir or Boceprevir - A Controlled Study

Singh¹

2013

J Antivir Antiretrovir

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IntroductionChronic hepatitis C virus (HCV) infection affects 180 million people worldwide [1], and the growing complication of hepatocellular carcinoma has been contributing to increased number of deaths [2]. The sustained virologic response (SVR) for patients with HCV genotype 1 infection was approximately 40% with this previous standard of therapy of pegylated interferon (PEG) and ribavirin (RBV) [3]. In 2011, protease inhibitors, telaprevir and boceprevir, were brought out of phase III clinical trials into the real life setting and have since played a revolutionary role in the treatment for hepatitis C virus genotype 1 infection [4]. Higher SVR rates of 68-79% were achieved in hepatitis C treatment naive patients who received combination therapy of boceprevir or telaprevir along with RBV and PEG during these trials [5,6]. However, the use of these medications as part of triple therapy resulted in increased adverse events and drug-drug interactions. Anemia has emerged as the most significant adverse event associated with both protease inhibitors.Recent phase III trials have shown that triple therapy with telaprevir and boceprevir can cause additional drops in hemoglobin levels when compared to treatment with PEG and RBV alone [5][6][7][8]. The SPRINT-2 trial and RESPOND-2 trial used boceprevir in treatment naïve and treatment experienced HCV patients, respectively, and had a significant anemia event rate of 49% in SPRINT-2 and 43-46% in 7]. The ADVANCE trial and REALIZE trial used telaprevir in treatment naïve and treatment experienced HCV patients respectively, and had a significant anemia event rate of 36% in ADVANCE and 30% in REALIZE [5,8]. The control groups for the boceprevir trials had anemia event rates of 20-29% and the telaprevir trials had anemia event rates of 15-19% [6,7]. During the clinical trials with telaprevir, anemia was treated by dose-reducing RBV, whereas in the boceprevir trials, anemia was treated by RBV dose reduction and the use of epoetin alfa injections (EPO).It is clear that significant anemia was more common in patients treated with protease inhibitors, but this has only been exhibited in the clinical trials. In this study, we investigated the development, natural history, and management of anemia in patients who were treated with telaprevir or boceprevir in the real life setting outside of clinical trials. AbstractIntroduction: Triple therapy with protease inhibitors, telaprevir and boceprevir, is the new standard of treatment for hepatitis C virus (HCV) genotype 1 infection. In this study, we investigated the natural history of anemia in patients treated with triple therapy compared to those treated with pegylated-interferon and ribavirin (PEG/RBV) in the real-life setting.

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Section: Discussionmentioning

confidence: 99%

Anemia in Patients with Chronic Hepatitis C Infection during Triple Therapy with Telaprevir or Boceprevir - A Controlled Study

Singh¹

2013

J Antivir Antiretrovir

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“…In this setting, two Japanese studies have shown that ITPA polymorphisms are still able to influence hemoglobin levels during triple HCV therapy (7,30).…”

Section: Discussionmentioning

confidence: 99%

Association of ITPA Gene Polymorphisms and the Risk of Ribavirin-Induced Anemia in HIV/Hepatitis C Virus (HCV)-Coinfected Patients Receiving HCV Combination Therapy

Domingo

Guardiola

Salazar

et al. 2012

Antimicrob Agents Chemother

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“…Recent studies have reproducibly identified polymorphic variation of the ITPA gene leading to enzymatic ITPA deficiency as a major determinant of RBV induced hemolytic anemia [26][27][28][29]. ITPA deficiency results from two SNPs rs1127354…”

Section: Discussionmentioning

confidence: 99%

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection

Rau¹,

Stickel²,

Russmann³

et al. 2012

Z Gastroenterol

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BACKGROUND AIMS: In the last decade pegylated interferon-(Peg-INF-) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed to study genetic determinants of RBV kinetics, efficacy and treatment associated anemia. METHODS: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101 and followed regarding treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients RBV serum levels were additionally measured during treatment. RESULTS: Patients with SLC28A2 rs11854484 genotype TT had higher dosage-and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop 3 g/dl during treatment in genotype (relative risk (RR)=2.1, 95%CI 1.3-3.5) as well as in allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as in allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV induced anemia and treatment response may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

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

Cited by 90 publications

References 28 publications

Anemia in Patients with Chronic Hepatitis C Infection during Triple Therapy with Telaprevir or Boceprevir - A Controlled Study

Anemia in Patients with Chronic Hepatitis C Infection during Triple Therapy with Telaprevir or Boceprevir - A Controlled Study

Association of ITPA Gene Polymorphisms and the Risk of Ribavirin-Induced Anemia in HIV/Hepatitis C Virus (HCV)-Coinfected Patients Receiving HCV Combination Therapy

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection

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