Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR

Alexander J. Thompson, Rosanna Santoro, Valeria Piazzolla, Paul J. Clark, Susanna Naggie, Hans L. Tillmann, Keyur Patel, Andrew J. Muir, Kevin V. Shianna, Leonardo Mottola, Daniela Petruzzellis, Mario Romano, Fernando Sogari, Domenico Facciorusso, David B. Goldstein, John G. McHutchison, Alessandra Mangia

Research output: Contribution to journalArticle

Abstract

Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10-6 for rs1127354 and P = 10-7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10-11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level <10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb <9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.

Original languageEnglish
Pages (from-to)389-395
Number of pages7
JournalHepatology
Volume53
Issue number2
DOIs
Publication statusPublished - Feb 2011

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Ribavirin
Antiviral Agents
Anemia
Genotype
Hemoglobins
Hepacivirus
Therapeutics
inosine triphosphatase
Hemolytic Anemia
Retrospective Studies
Inosine Triphosphatase Deficiency
Confidence Intervals
Weights and Measures
Genes

ASJC Scopus subject areas

  • Hepatology

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Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR. / Thompson, Alexander J.; Santoro, Rosanna; Piazzolla, Valeria; Clark, Paul J.; Naggie, Susanna; Tillmann, Hans L.; Patel, Keyur; Muir, Andrew J.; Shianna, Kevin V.; Mottola, Leonardo; Petruzzellis, Daniela; Romano, Mario; Sogari, Fernando; Facciorusso, Domenico; Goldstein, David B.; McHutchison, John G.; Mangia, Alessandra.

In: Hepatology, Vol. 53, No. 2, 02.2011, p. 389-395.

Research output: Contribution to journalArticle

Thompson, AJ, Santoro, R, Piazzolla, V, Clark, PJ, Naggie, S, Tillmann, HL, Patel, K, Muir, AJ, Shianna, KV, Mottola, L, Petruzzellis, D, Romano, M, Sogari, F, Facciorusso, D, Goldstein, DB, McHutchison, JG & Mangia, A 2011, 'Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR', Hepatology, vol. 53, no. 2, pp. 389-395. https://doi.org/10.1002/hep.24068
Thompson, Alexander J. ; Santoro, Rosanna ; Piazzolla, Valeria ; Clark, Paul J. ; Naggie, Susanna ; Tillmann, Hans L. ; Patel, Keyur ; Muir, Andrew J. ; Shianna, Kevin V. ; Mottola, Leonardo ; Petruzzellis, Daniela ; Romano, Mario ; Sogari, Fernando ; Facciorusso, Domenico ; Goldstein, David B. ; McHutchison, John G. ; Mangia, Alessandra. / Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR. In: Hepatology. 2011 ; Vol. 53, No. 2. pp. 389-395.
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abstract = "Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78{\%}) with genotype 2 and 53 (22{\%}) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10-6 for rs1127354 and P = 10-7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10-11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level <10 g/dL (hazard ratio = 0.25, 95{\%} confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb <9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.",
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T1 - Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR

AU - Thompson, Alexander J.

AU - Santoro, Rosanna

AU - Piazzolla, Valeria

AU - Clark, Paul J.

AU - Naggie, Susanna

AU - Tillmann, Hans L.

AU - Patel, Keyur

AU - Muir, Andrew J.

AU - Shianna, Kevin V.

AU - Mottola, Leonardo

AU - Petruzzellis, Daniela

AU - Romano, Mario

AU - Sogari, Fernando

AU - Facciorusso, Domenico

AU - Goldstein, David B.

AU - McHutchison, John G.

AU - Mangia, Alessandra

PY - 2011/2

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N2 - Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10-6 for rs1127354 and P = 10-7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10-11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level <10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb <9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.

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