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To the Editor:

Bitetto et al. described how vitamin D serum level is complementary to the interleukin 28B (IL28B; rs12979860) polymorphism in predicting the achievement of sustained virological response (SVR) in treatment-naive patients receiving standard pegylated interferon (Peg-IFN) and ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus (HCV).1

It should be also noted how vitamin D serum levels may be influenced by polymorphisms in the gene coding for a related metabolic enzyme (cytochrome P450 27B1 [CYP27B1]).2 The association between responsiveness to therapy for difficult-to-treat HCV infections and IL28B (rs12979860 and rs8099917) single-nucleotide polymorphisms (SNPs) were evaluated.1, 3

Prior to the discovery of these new predictive factors, both dosage and pharmacokinetic exposure of RBV have been repeatedly found to be associated with the therapeutic outcome of chronic HCV hepatitis.4, 5 No data are, however, yet available on the interplay between RBV pharmacokinetics and these newly introduced predictive factors.

In the analysis of 91 patients with chronic genotype 1/4 HCV hepatitis who received standard Peg-IFN/RBV treatment, we found that further to IL28B (rs8099917) SNP (odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.08-7.39, P = 0.034) and CYP27B1 (rs4646536) SNP (OR = 3.90, 95% CI = 1.37-11.14, P = 0.011), the presence of RBV concentrations >2500 ng/mL (OR = 3.08, 95% CI = 1.21-7.85, P = 0.019) was an independent predictor of SVR.

It is worth noting (Fig. 1) how no patients with all three unfavorable factors had SVR, whereas a tendency to higher rates of SVR was seen according to the combination of favorable genetic and RBV pharmacokinetic factors. These results reveal that rs8099917 G allele, rs4646536 C allele (related to low 25-hydroxyvitamin D3 serum concentrations), and RBV plasma concentrations (<2500 ng/mL) could predict which patients are likely to experience treatment failure in this group of difficult-to-treat HCV-infected patients.

Based on these findings, we believe that in addition to these recently characterized human genetic factors, the individual pharmacokinetic exposure to RBV should not be neglected among the predictors of anti-HCV treatment outcome.

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Figure 1. Number and percentage of patients with SVR (white columns) and without SVR (black columns), stratified for each predictor factor combinations.

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References

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  • 1
    Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, et al. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology 2011; 53: 1118-1126.
  • 2
    Orton SM, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, Chao MJ, et al. Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am J Clin Nutr 2008; 88: 441-447.
  • 3
    Aparicio E, Parera M, Franco S, Perez-Alvarez N, Tural C, Clotet B, et al. IL28B SNP rs8099917 is strongly associated with pegylated interferon-alpha and ribavirin therapy treatment failure in HCV/HIV-1 coinfected patients. PLoS One 2010; 5: e13771.
  • 4
    Aguilar 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: 919-924.
  • 5
    van Vlerken LG, van Oijen MG, van Erpecum KJ. Ribavirin concentration is a more important predictor of sustained viral response than anemia in hepatitis C patients. Gastroenterology 2011; 140: 16931694.

Antonio D'Avolio Ph.D.*, Alessia Ciancio M.D., Ph.D.†, Marco Siccardi Ph.D.*, Lorena Baietto Ph.D.*, Marco Simiele Ph.D.*, Giuseppe Cariti Ph.D.*, Andrea Calcagno Ph.D.*, Antonina Smedile M.D.†, Jessica Cusato Ph.D.*, Stefano Bonora Ph.D.*, Mario Rizzetto Ph.D.†, Giovanni Di Perri Ph.D.*, * Department of Infectious Diseases, University of Turin, Turin, Italy, † Department of Gastroenterology University of Turin, Turin, Italy.