Reply to: “Estimating ribavirin plasma exposure: Genetics or therapeutic drug monitoring?”
Authors: Monika Rau, Andreas Geier
Journal: Journal of Hepatology (2013)

We thank Dr. D’Avolio and colleagues for their critical comment on the measurement of ribavirin (RBV) plasma concentration during HCV therapy in general and its genetic basis in particular. This contribution adds further insight into the genetic basis of RBV bioavailability, which has been described in our study [[1]Rau M. Stickel F. Russmann S. Manser C.N. Becker P.P. Weisskopf M. et al.Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.J Hepatol. 2013; 58: 669-675Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. In their letter to the editor, D’Avolio et al. described an association between lower RBV plasma concentrations and a combination of “unfavorable” CNT2 SNPs (rs11854484, rs2413775, rs1060896) in 186 HCV patients. Interestingly, an association between RBV plasma concentrations and rs11854484 alone was not seen as reported in our study [[1]Rau M. Stickel F. Russmann S. Manser C.N. Becker P.P. Weisskopf M. et al.Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.J Hepatol. 2013; 58: 669-675Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. Since our study included patients with a different RBV dosage, drug serum levels were adjusted to dosage. To address this issue in the study design, we analyzed only RBV serum levels at weeks 4 and 8 before eventual dose modification. As an alternative approach to account for drug dose adjustment in pharmacokinetic studies, D’Avolio et al. adjusted RBV concentrations for the dose pro kilogram and for dose reduction in their HCV positive patients. Although their findings did not exactly replicate the results of our study, the described association between lower RBV plasma concentrations and a combination of “unfavorable” CNT2 SNPs must be taken as another hint towards a functional role of SLC transporter polymorphisms for RBV bioavailability and related clinical outcomes. We agree that these genetic associations in heterogeneous studies with a limited patient number need further replication to strengthen the importance of the investigated SNPs. Interestingly, our colleagues observed that RBV concentrations at week 2 have a predicting value for RBV concentrations at week 4. Therefore, early RBV serum measurement could help precocious adjustment of RBV dosage in HCV therapy. Most recent trials with direct-acting antiviral drugs indicate a continuous role of RBV in antiviral therapy regimens and further studies will clearly contribute to optimize RBV dosage. For routine clinical practice, comparative evaluations of pharmacogenetics versus early pharmacokinetics are rather dispensable in our opinion as drug level measurement will remain the key for clinical decision-making today. However, genetic studies like ours and the one of D’Avolio et al. contribute to the molecular understanding of pharmacokinetics and may guide the way towards a personalized HCV treatment strategy in the future. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infectionJournal of HepatologyVol. 58Issue 4PreviewIn the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. Full-Text PDF Estimating ribavirin plasma exposure: Genetics or therapeutic drug monitoring?Journal of HepatologyVol. 59Issue 3PreviewRau and colleagues described the impact of genetic polymorphisms in SLC28 genes, encoding concentrative nucleoside transporter 2 (CNT2) and 3 (CNT3) and inosine triphosphatase (ITPA) variants, on ribavirin (RBV) serum levels, hemoglobin drop, and therapeutic response in patients with HCV infection [1]. In their paper, they cited our observation that single nucleotide polymorphism (SNP) in the SLC28A2 encoding region (rs11854484) is an independent predictor of sustained virological response (SVR) [2,3]. Full-Text PDF Open Access