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  14th International Workshop on Clinical Pharmacology of HIV Therapy
April 22-24, 2013
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Ribavirin Trough Affects Early HCV Response With Unfavorable IL28B Profile
  14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
A ribavirin trough concentration above 1800 ng/mL correlated with early virologic response (EVR) in HCV-infected people starting pegylated interferon/ribavirin (PegIFN/ribavirin), but only in HCV genotype 1-infected people with an unfavorable IL28B 917 genotype [1].
HCV protease inhibitors are transforming treatment of HCV infection in people with and without HIV. For now, though, these direct-acting antivirals must still be prescribed with a standard PegIFN/ribavirin combination. With PegIFN/ribavirin, factors that weigh against virologic response are HCV genotypes 1 and 4 and certain IL28B polymorphisms: rs8099917 G>T (yielding a TT genotype) and rs1297860 T>C (yielding a CC genotype).
University of Turin researchers conducted this study in 67 treatment-naive people with HCV genotype 1 starting PegIFN/ribavirin. They aimed to determine whether ribavirin trough concentrations at treatment month 1 affected EVR (undetectable HCV RNA at 12 weeks) according to IL28B genotype.
The investigators limited the analysis to adults with HCV genotype 1 and those taking no drugs that may interact with PegIFN or ribavirin, with no hepatic or renal impairment, and with better than 95% self-reported adherence to PegIFN/ribavirin. The researchers determined ribavirin trough concentrations at treatment weeks 2, 4, and 12; they used the TaqMan Genotyping Array to determine IL28B 860 and 917 single-nucleotide polymorphisms.
Median ribavirin trough concentration at week 4 measured 1719 ng/mL (interquartile range 1214 to 2330). Forty-three of 67 people (64%) achieved EVR. When the Turin team considered the entire study group, 1-month ribavirin trough had no impact on EVR. But the IL28B 917 TT genotype predicted EVR (Spearman correlation 0.415, P < 0.001) and the IL28B 860 CC genotype predicted rapid (4-week) virologic response (Spearman correlation 0.437, P < 0.001).
In 29 patients with an unfavorable IL28B 917 TT genotype, 1-month ribavirin trough was significantly higher in the 12 with EVR than in the 17 without EVR (P = 0.015). In these 29 patients, a ribavirin trough above 1800 ng/mL improved chances of achieving EVR (Spearman correlation 0.460, P = 0.012), though only with a sensitivity of 69% and a specificity of 82%. Logistic regression analysis identified a ribavirin trough above 1800 ng/mL at 1 month as the only independent predictor of EVR in people with the unfavorable IL28B 917 TT genotype (P = 0.011). Factors that did not affect EVR chances in this analysis were gender, weight, age, baseline HCV RNA, baseline hemoglobin, ribavirin dose, and IL28B 860 CC genotype.
The Turin investigators believe their findings "underline the importance of the identification of IL28B genetic profile and the crucial role that Therapeutic Drug Monitoring of ribavirin might have in a genetic-specific subset of patients, in order to grant them an optimal pharmacokinetic exposure."
Whether ribavirin concentration will affect virologic response in people also taking an HCV protease inhibitor remains to be seen. For example, in the ADVANCE trial, telaprevir improved sustained virologic response rates across all IL28B genotypes [2]. But the Turin team maintained that high side effect rates with telaprevir and boceprevir mean PegIFN/ribavirin alone remains an option for some patients. The researchers proposed that their findings could be useful in selecting patients who need an HCV protease inhibitor.
1. De Nicolo A, Cusato J, Boglione L, et al. Early ribavirin concentration is a critical response factor in the sub-population of patients infected by HCV-1 and unfavourable IL28B genotype. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_18. 2. Jacobson IM, Catlett I, Marcellin P, et al. Telaprevir substantially improved SVR rates across all IL28B genotypes in the ADVANCE trial. 48th EASL. April 24-28, 2013. Amsterdam. http://www1.easl.eu/easl2011/program/Posters/Abstract7.htm and http://www.natap.org/2011/EASL/EASL_33.htm