Non response to peginterferon alfa and ribavirin in IL28B CC & CT patients can be overcome by high dose continuous interferon alfa-2b administration in combination with ribavirin for chronic hepatitis C
R. Roomer; R. J. de Knegt; J. F. Bergmann; R. M. Scherer; B. Van Antwerp; J. Lande; E. Grovender; H. L. Janssen; A. Boonstra
Background: The pegylation of interferon (IFN) improved the pharmacokinetic profile with higher sustained virological response (SVR) rates in naïve chronic HCV patients compared to standard IFN. However, the SVR rates remain low in patients who experienced a previous failure to therapy (in the 8-12% range). We hypothesized that continuous delivery via an external pump of high doses of IFN may improve the SVR rates in previous non-responders. Recently, single nucleotide polymorphisms (SNP) in the IL28B region have been shown to correlate with the response to IFN/ribavirin therapy in HCV patients naïve to IFN. We now present the first analysis of the IL28B genotype in a cohort of patients who were classified as previous nonresponders to treatment.
Method: In this study, we delivered IFN-alfa-2b continuously via subcutaneous infusion using a modified insulin pump (Medtronic Minimed). Thirty subjects were randomly assigned to receive a daily dose of 6, 9 or 12 MU IFN combined with weight-based ribavirin. Viral kinetics was measured at baseline, weekly until week 4, and then at week 8, 12, 24 and 48 weeks. The “Duke” SNP rs12979860 was determined using competitive allele-specific PCR genotyping.
Results: In this cohort 20 patients had IL28B genotype CT, 3 patients had genotype CC and 6 patients had genotype TT. In 1 patient genotype determination failed. In our study there were differences among the CC, CT and TT groups with respect to viral decay at week 4, which was independent of the IFN-dose. CC subjects had an average viral decay of 2.9 log at 4 weeks, while CT subjects showed a 1.65 log reduction and TT subject showed a 1.25 log reduction (p=0.119). Of the 6 TT subjects however, only 2 subjects showed more than 1 log reduction at 4 weeks. More importantly, in the high dose group receiving 12 MU IFN/day, all 10 patients had more than 2 logs viral decay at week 4 of treatment regardless of their IL28B genotype. Of all 30 patients 6 achieved SVR, 2 in the CC group (one in each of the 6 and 9 MU group) and 4 subjects in the CT group, who all received 12 MU IFN/day. In the multivariate linear regression analysis both IL28B (p=0.036) and IFN dose (p=0.002) were significantly associated with viral decay at week 4.
Conclusion: These results show that the IL28B genotype can be a strong predictor of both viral decay rates and subsequent SVR. Moreover, high doses of IFN can potentially overcome the innate lack of IFN sensitivity that the IL28B naïve data predicts. Finally, these results also support the concept that continuous delivery of IFN in previous therapy failures can be a successful treatment strategy, especially those with CT and CC genotypes.