Original Article
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World J Gastroenterol. Nov 7, 2012; 18(41): 5879-5888
Published online Nov 7, 2012. doi: 10.3748/wjg.v18.i41.5879
Several factors including ITPA polymorphism influence ribavirin-induced anemia in chronic hepatitis C
Akihito Tsubota, Noritomo Shimada, Hiroshi Abe, Kai Yoshizawa, Rie Agata, Yoko Yumoto, Makiko Ika, Yoshihisa Namiki, Keisuke Nagatsuma, Hiroshi Matsudaira, Kiyotaka Fujise, Norio Tada, Yoshio Aizawa
Akihito Tsubota, Rie Agata, Yoko Yumoto, Yoshihisa Namiki, Kiyotaka Fujise, Norio Tada, Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan
Akihito Tsubota, Keisuke Nagatsuma, Hiroshi Matsudaira, Kiyotaka Fujise, Division of Gastroenterology and Hepatology, Kashiwa Hospital, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan
Noritomo Shimada, Makiko Ika, Yoshio Aizawa, Department of Gastroenterology, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba 270-0034, Japan
Hiroshi Abe, Kai Yoshizawa, Division of Gastroenterology and Hepatology, Katsushika Medical Center, The Jikei University School of Medicine, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-8506, Japan
Author contributions: Tsubota A, Shimada N, Tada N and Aizawa Y designed the study; Tsubota A, Shimada N, Abe H, Yoshizawa K, Agata R, Yumoto Y, Ika M, Nagatsuma K, Matsudaira H, Fujise K and Aizawa Y performed the research; Tsubota A, Agata R, Yumoto Y and Namiki Y analyzed the data; and Tsubota A and Aizawa Y wrote the paper.
Supported by Clinical Research Funds from Division of Gastroenterology and Hepatology, Katsushika Medical Center, The Jikei University School of Medicine
Correspondence to: Akihito Tsubota, MD, PhD, Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba 277-8567, Japan. atsubo@jikei.ac.jp
Telephone: +81-4-71641111 Fax: +81-4-71668638
Received: April 8, 2012
Revised: May 28, 2012
Accepted: June 28, 2012
Published online: November 7, 2012
Abstract

AIM: To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C.

METHODS: Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors.

RESULTS: Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10-17, odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10-4, OR = 0.962 (mL/min/1.73 m2)], rs1127354 (P = 5.75 × 10-4, OR = 10.94) and baseline hemoglobin [P = 7.86 × 10-4, OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia.

CONCLUSION: Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.

Keywords: Chronic hepatitis C virus infection; Ribavirin; Pegylated interferon α; Prediction model; Hemolytic anemia; Single nucleotide polymorphism