Estimating ribavirin plasma exposure: Genetics or therapeutic drug monitoring?
Authors: Antonio D’Avolio, Jessica Cusato, Andrea Calcagno, Giovanni Di Perri
Journal: Journal of Hepatology (2013)

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 Reply to: "Estimating ribavirin plasma exposure: Genetics or therapeutic drug monitoring?"Journal of HepatologyVol. 59Issue 3PreviewWe 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]. 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. Full-Text PDF Open Access Rau 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]Rau M. Stickel F. Russmann S. Manser C. Becker 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 (35) Google Scholar]. 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) [2D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Patanella S. et al.SLC28A2 65C >T predict sustained virological response in patients with hepatitis C treated with interferon and ribavirin, considering all HCV genotype and genotype 1/4.J Hepatol. 2010; 52: S463Abstract Full Text PDF PubMed Google Scholar, 3D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2 and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar]. Our hypothesis was that this effect could be explained by the different ability of CNT2 forms to internalize RBV within cells, and not by a direct effect on RBV plasma levels. In the era of dual PEG-interferon (PegIFN)/RBV therapy, most of the studies that investigated the role of RBV pharmacokinetics (Pk) found a clear association between higher RBV exposure and a higher chance of both SVR and anaemia, as expected on the basis of the recognized proportionality between RBV daily dose and these two outcomes [[4]Snoeck E. Wade J.R. Duff F. Lamb M. Jorga K. Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.Br J Clin Pharmacol. 2006; 62: 699-709Crossref PubMed Scopus (75) Google Scholar]. Even in most recent studies, where patients were stratified according to human genetic polymorphisms, RBV Pk retained its significant role in predicting both efficacy and toxicity in PegIFN/RBV intakers [2D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Patanella S. et al.SLC28A2 65C >T predict sustained virological response in patients with hepatitis C treated with interferon and ribavirin, considering all HCV genotype and genotype 1/4.J Hepatol. 2010; 52: S463Abstract Full Text PDF PubMed Google Scholar, 3D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2 and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar, 5D'Avolio A. Ciancio A. Siccardi M. Smedile A. Baietto L. Simiele M. et al.Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.Ther Drug Monit. 2012; 34: 165-170Crossref PubMed Scopus (37) Google Scholar, 6D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Cariti G. et al.Ribavirin pharmacokinetics and interleukin 28B plus cytochrome P450 27B1 single-nucleotide polymorphisms as predictors of response to pegylated interferon/ribavirin treatment in patients infected with hepatitis C virus genotype 1/4.Hepatology. 2011; 54: 2279Crossref Scopus (27) Google Scholar, 7Aguilar Marucco D. Gonzalez de Requena D. Bonora S. Tettoni C. Bonasso M. De Blasi T. et al.The use of trough ribavirin concentration to predict sustained virological response and haematological toxicity in HIV/HCV-co-infected patients treated with ribavirin and pegylated interferon.J Antimicrob Chemother. 2008; 61: 919-924Crossref PubMed Scopus (42) Google Scholar]. While the need for RBV as part of new triple therapies has been proven in development trials [[8]Hezode C. Forestier N. Dusheiko G. Ferenci P. Pol S. Goeser T. et al.Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.N Engl J Med. 2009; 360: 1839-1850Crossref PubMed Scopus (979) Google Scholar], it remains to be determined whether RBV Pk has still any impact on treatment outcomes with highly effective direct acting antivirals (DAAs). Then, the ability to early predict, with genetics or therapeutic drug monitoring (TDM), ribavirin plasma concentrations at steady state retains its clinical importance. Rau and colleagues described the association between CNT2 SNPs and RBV plasma concentrations. It should be noted that these PK/PG analyses were conducted on 67 patients only, without dose correction verification, including patient with modified dosage. In addition, they only reported a trend for statistical significance for the association of RBV concentration and SLC28 genotypes [[1]Rau M. Stickel F. Russmann S. Manser C. Becker 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 (35) Google Scholar]. Our observations did not support this association [2D'Avolio A. Ciancio A. Siccardi M. Baietto L. Simiele M. Patanella S. et al.SLC28A2 65C >T predict sustained virological response in patients with hepatitis C treated with interferon and ribavirin, considering all HCV genotype and genotype 1/4.J Hepatol. 2010; 52: S463Abstract Full Text PDF PubMed Google Scholar, 3D'Avolio A. Ciancio A. Siccardi M. Smedile A. Simiele M. Cusato J. et al.Negative predictive value of IL28B, SLC28A2 and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.Ther Drug Monit. 2012; 34: 722-728Crossref PubMed Scopus (31) Google Scholar]: CNT2 SNPs were not associated with plasma RBV concentrations (after 4 weeks) while adjusting for the dose pro kilogram and for dose reduction, and only using several SNPs (rs11854484, rs2413775 and rs1060896) in "unfavorable" (for lower ribavirin concentrations) combinations (on 186 HCV+ patients), it was possible to demonstrate a statistical significance (p = 0.009) (Fig. 1). On the contrary, week 4 RBV plasma exposure seems to be nicely predicted by week 2 concentrations, suggesting a possible early use of TDM to adjust the drug exposure both to enhance efficacy and reduce toxicity (p <0.001) [9Caviglia G. D'Avolio A. Ciancio A. De Nicolò A. Boglione L. Abate M. et al.F-33 early ribavirin plasma concentration and ITPA polymorphisms as determinants of anemia after one month of anti-HCV therapy.Dig Liver Dis. 2012; 44: S42Abstract Full Text PDF Google Scholar, 10Slavenburg S. Huntjens-Fleuren H.W. Dofferhoff T.S. Richter C. Koopmans P.P. Verwey-Van Wissen C.P. et al.Ribavirin plasma concentration measurements in patients with hepatitis C: early ribavirin concentrations predict steady-state concentrations.Ther Drug Monit. 2011; 33: 40-44Crossref PubMed Scopus (22) Google Scholar]. We therefore have no clear answer to the question as to whether genetic SLC28 transporter polymorphisms predict ribavirin plasma levels. If RBV plasma exposure maintains its clinical impact in new anti-HCV treatment studies comparative evaluations of pharmacogenetics vs. early pharmacokinetics are warranted. It should also be highlighted that the cost of a single early (2 weeks) determination of ribavirin plasma concentration does not significantly impact on the overall expenditure associated with the use of (triple) anti-HCV therapy and may well contribute to a fruitful tailored management. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.