Negative Predictive Value of IL28B, SLC28A2, and CYP27B1 SNPs and Low RBV Plasma Exposure for Therapeutic Response to PEG/IFN-RBV Treatment

Abstract

In this study, we found that additional polymorphisms and RBV plasma exposure are also able to influence the achievement of response. Regardless of the magnitude of RBV pharmacokinetic exposure, the negative predictive value of the polymorphisms here investigated is much stronger than the positive one.

Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines

“…While the first two factors have already been described the evidence of SLC28A2 variants is novel but lacks in vitro confirmation: however CNT2 is expressed on the apical surface of proximal tubule cells and it is known to transport the nucleoside analogues zidovudine and ribavirin. [26][27][28] An alternative role of CNT2 on TFV pharmacokinetics could be on the side of intestinal absorption (as it is expressed in gut tissue and at higher concentrations in the jejunum), since here such association was found on plasma rather than urinary concentrations. 29 TFV urinary concentrations showed a high variability and were influenced by several transporters-encoding gene variations (including OAT1, MRP-4 and PgP): this would support the results of Kohler and colleagues 30 that found significant high TFV-associated tissue damage in ABCB1 and SLC22A6 knock-out mice.…”

Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics

“…The influence of SNPs rs12979860 and rs8099917 in the IL28B region has been shown to be associated with PEG IFN/RBV treatment outcomes in HCV-1 patients [8,14]. In the current work, C allele carriers showed a higher S isomer PBMC/plasma concentration ratio, suggesting higher intracellular penetration of the active diastereoisomer.…”

“…Regarding dual therapy, the TT genotype of SLC28A2 124 SNP was associated with sustained virological response in patients infected by HCV-1 and -4 genotypes [8]. We observed an association of the C allele and higher S isomer PBMC/plasma concentration ratio values, suggesting a potential facilitation of this variation in drug compartmentalisation.…”

“…The genetics of IL28B and inosine triphosphate pyrophosphohydrolase (ITPA) have played an important role in predicting outcome and toxicity in dual therapy as well as the pharmacokinetics of RBV [7][8][9].…”

Treatment optimization of naïve HCV-1 patients using IL28B, RVR and fibrosis stage

“…As we previously demonstrated in HCV-1 (Boglione et al, 2014b) and HCV-4 (Boglione et al, 2014a) patients, the rs12979860 evidenced a major effect on the early response (Stattermayer et al, 2011), while rs8099917 polymorphism is crucial on the SVR (D' Avolio et al, 2011Avolio et al, , 2012Luo et al, 2012). Then, the combination of both rs8099917/ rs12979860 IL28B polymorphisms increases the predictivity on the SVR (or failure) (D'Avolio et al, 2012). For example, the patients with unfavorable TC at rs12979860 but favorable TT at rs8099917 showed a good rate of SVR (68.2% global, 85% in F0-F1, 71.4% in F2-F3) and could be treated with dual therapy (Fig.…”