Hepatitis C patients with ITPA gene variants exhibit lower risk of relapse after treatment

News: Mar 11, 2014

Researchers at the Sahlgrenska Academy have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment.

More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients.

Prevents incorporation in DNA

Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA.

Unexpectedly they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection.

Five times lower risk

Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment.

Relapse a significant problem

The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries.

- Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable, Martin Lagging said.

Important to other virus infections

According to Martin Lagging, the discovery may also have significance for other virus infections.

- A medication that interferes with the enzyme’s activity could have a broad antiviral effect, but this must be further investigated in future studies.

The article Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3 was published online in the journal Hepatology on 13 January 2014.

Contact:
Martin Lagging, researcher at The Sahlgrenska Academy, University of Gothenburg
martin.lagging@medfak.gu.se

Source: University of Gothenburg

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Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

J Hepatol. 2013 Dec;59(6):1323-30. doi: 10.1016/j.jhep.2013.07.014. Epub 2013 Jul 15.

Romero-Gómez M, Berenguer M, Molina E, Calleja JL.

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UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain.

Abstract

The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Anemia, BMI, Boceprevir, EPO, Epoietin, GWAS, HCV, Hepatitis C virus, ITPA, Pegylated interferon, Protease inhibitor, Ribavirin, SNP, Telaprevir, body mass index, erythropoietin, genome-wide association study, hepatitis C virus, inosine triphosphate pyrophosphatase, sRfT, single nucleotide polymorphisms, transferrin soluble receptor

PMID: 23867320 [PubMed - in process]

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Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients

J Hepatol. 2013 Nov;59(5):964-71. doi: 10.1016/j.jhep.2013.06.030. Epub 2013 Jul 10.

Scherzer TM, Stättermayer AF, Stauber R, Maieron A, Strasser M, Laferl H, Schwarzer R, Datz C, Rutter K, Beinhardt S, Steindl-Munda P, Hofer H, Ferenci P.

Department of Internal Medicine III, Medical University, Vienna, Austria.

Abstract

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1.

METHODS: Hemoglobin levels at baseline (Hb0) and the decline after 4weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180μg peginterferon-alpha 2a and ribavirin [1000-1200mg/d; females: mean (95% CI) 15.8mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.

RESULTS: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001].

CONCLUSIONS: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Age, GWAS, Gender, HCV, Hepatitis C virus, ITPA, RVR, Ribavirin-induced anemia, SNP, SVR, genome-wide association study, rapid virologic response, single nucleotide polymorphism, sustained virologic response

PMID: 23850877 [PubMed - in process]

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Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

J Hepatol. 2013 Oct;59(4):667-74. doi: 10.1016/j.jhep.2013.05.017. Epub 2013 May 23.

Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group.

Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.

Abstract

BACKGROUND & AIMS: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

METHODS: This prospective, multicenter study consisted of 292 patients (median age: 62years) infected with HCV genotype 1. All received 12weeks of TVR in combination with 24weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85g/L.

RESULTS: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135g/L (Hazard ratio [HR], 2.53; p=0.0013), estimated glomerular filtration rate <80ml/min/1.73m(2) (HR, 1.83; p=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p=0.0281).

CONCLUSIONS: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: AUROC, Anemia, CI, HCV, HR, Hb, Hepatitis C virus, ITPA, Inosine triphosohatase, PegIFN, Pegylated interferon, RBV, RVR, Ribavirin, SNP, SVR, TVR, Telaprevir, area under the receiver operating characteristic curve, confidence interval, eGFR, estimated glomerular filtration rate, hazard ratio, hemoglobin, hepatitis C virus, inosine triphosphatase, pegylated interferon, rapid virological response, ribavirin, single nucleotide polymorphism, sustained virological response, telaprevir

PMID: 23707372 [PubMed - in process]

Source

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

Journal of Hepatology

Article in Press

Received 5 March 2013; received in revised form 19 April 2013; accepted 13 May 2013. published online 28 May 2013.
Accepted Manuscript

Eiichi Ogawa, Norihiro Furusyo, Makoto Nakamuta, Eiji Kajiwara, Hideyuki Nomura, Kazufumi Dohmen, Kazuhiro Takahashi, Takeaki Satoh, Koichi Azuma, Akira Kawano, Yuichi Tanabe, Kazuhiro Kotoh, Shinji Shimoda, Jun Hayashi The Kyushu University Liver Disease Study (KULDS) Group

Abstract

Background & aims

Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PEG-IFN) α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PEG-IFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

Methods

This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb) <85 g/L.

Results

101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135 g/L (Hazard ratio [HR], 2.53; P=0.0013), estimated glomerular filtration rate <80 mL/min/1.73m² (HR, 1.83; P=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; P=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; P=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; P=0.0281).

Conclusions

Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Keywords: Hepatitis C virus, Anemia, Telaprevir, Inosine triphosohatase, Pegylated interferon, Ribavirin

Abbreviations: HCV, hepatitis C virus, PEG-IFN, pegylated interferon, RBV, ribavirin, SVR, sustained virological response, TVR, telaprevir, ITPA, inosine triphosphatase, SNP, single nucleotide polymorphism, Hb, hemoglobin, eGFR, estimated glomerular filtration rate, RVR, rapid virological response, HR, hazard ratio, CI, confidence interval, AUROC, area under the receiver operating characteristic curve

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