Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment

Abstract

Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients

“…Among these, the only modifiable feature is RBV pharmacokinetic exposure, which shows a remarkable variability among HCV-infected patients (Tsubota et al, 2003). In fact, early assessment of RBV concentration is suggested by some studies (Caviglia et al, 2012;D'Avolio et al, 2012a;Loustaud-Ratti et al, 2008;Morello et al, 2008;Rendon et al, 2005) in order to adjust individual RBV dose.…”

“…Beside ITPA polymorphisms, a series of individual features such as RBV concentration, age, platelet count, haemoglobin concentration and haptoglobin phenotype were found to have some degree of association with the risk of anemia (Caviglia et al, 2012;D'Avolio et al, 2012a;Lindahl et al, 2004;Nomura et al, 2004;Rendon et al, 2005;van Vlerken et al, 2011;Van Vlierbergh et al, 2001). Among these, the only modifiable feature is RBV pharmacokinetic exposure, which shows a remarkable variability among HCV-infected patients (Tsubota et al, 2003).…”

“…These were identified recently as the most significant variables influencing the risk of anemia (Fellay et al, 2010;Suzuki et al, 2011;Thompson et al, 2010a). In these studies, by using a genome-wide association approach, two functional variants of ITPA, including one coding and one intronic variant, were found to be associated with treatment-induced anemia in HCV-infected patients (Caviglia et al, 2012;D'Avolio et al, 2012a;Fellay et al;Ochi et al;Suzuki et al), as defined by the magnitude of Hb reduction after 4 weeks of treatment. This genetically determined vulnerability was subsequently confirmed in several ethnically heterogeneous clinical cohorts.…”

“…The introduction of the ITPA rs1127354 and rs7270101 genetic polymorphisms substantially improves our ability to predict the individual risk of treatment-induced anemia (D'Avolio et al, 2012a), but it is not clear how the non-functional rs6051702 ITPA polymorphism should be considered in this scenario.…”

“…Repeatedly, individual RBV dose and pharmacokinetic (Pk) exposure have been found to be consistent determinants of treatment-associated anemia, and recommendations on dose reduction have been released in order to mitigate the impact of RBV on the severity of anemia (Aguilar Marucco et al, 2008;D'Avolio et al, 2012a;Kubota et al;Lindahl et al, 2004;Mac Nicholas and Norris;McHutchison et al, 2006).…”