IL-28B Genotype is a Major Determinant of the Induction of a Virological Response by High-Dose Peginterferon and Ribavirin in Null-responders to SOC Therapy: Pegasys double-dose significantly increased early virologic response

Reported by Jules Levin
AASLD Nov 2 2010 Boston
NATAP

Stephane Chevaliez1,2, Christophe Hezode1,3, Alexandre Soulier1,2, Bruno Costes2,4, Magali Bouvier-Alias1,2, Stephanie Rouanet5, Juliette Foucher6, Jean-Pierre Bronowicki7, Albert Tran8, Isabelle Rosa9, Philippe Mathurin10, Laurent Alric11, Vincent Leroy12, Victor De Ledinghen6, Ariane Mallat1,3, Mariem Charaf-Eddine5, Gerard Babany5, and Jean-Michel Pawlotsky1,2

1National Reference Center for Viral Hepatitis B, C and delta, Virology, Hôpital Henri Mondor, Creteil, France; 2INSERM U955, Creteil, France; 3Hepatology and Gastroenterology, Hôpital Henri Mondor, Creteil, France; 4 Biochemistry, Hôpital Henri Mondor, Creteil, France; 5Roche, Neuilly-Seine, France; 6Hepatology and Gastroenterology, Hôpital Haut-Levêque, Pessac, France; 7Hepatology and Gastroenterology, Hôpital de Brabois, Nancy, France; 8Hepatology and Gastroenterology, Hôpital de l'Archet, Nice, France; 9Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Creteil, France; 10Hepatology and Gastroenterology, Hôpital Claude Huriez, Lille, France; 11Internal Medicine, Hôpital Purpan, Toulouse, France; 12Hepatology and Gastroenterology, Hôpital de la Tronche, Grenoble, France

from Jules: we need to wait for the IL28B subanalyses from the telaprevir ADVANCE & boceprevir SPRINT2 studies in order to see how to use this information. Using double dose Pegasys in this study appeared to on average increase the virologic response quite a lot by weeks 4, 8 and 12 compared to prior use of the standard Pegasys dose for both TT and CT genotypes. CT genotype achieved better virologic response than TT genotype in this study, by week 24: 44% of TT and 70% of CT achieved >2 log viral load reduction. These data suggest that double-dose Pegasys 360 ug/week in combination with telaprevir or boceprevir may significantly increase virologic response and SVR. Conceivably, double-dose Pegasys during a lead-in and during therapy with telaprevir or boceprevir could increase SVR rates potentially quite a lot based on these data. There is a suggestion that an HCV protease resenesitizes the patient's internal interferon response so let's see how the TTs and CTs respond in the subanalyses from Advance & Sprint.

ABSTRACT:

Polymorphisms upstream of the region encoding IL28B have been shown to be associated with both natural and treatment-induced control of HCV infection. With new therapies using direct acting antiviral molecules, a null response to IFN is associated with treatment failure and selection of resistant viruses. Our goal was to assess, in null-responders to IFN-ribavirin therapy, whether the IL28B genotype has an influence and predictive value on the ability of high-dose pegylated IFN and ribavirin retreatment to induce a virological response.

METHODS:

83 genotype 1 null-responders received peg-IFN alpha-2a, 360 µg/week in one or two injections, plus ribavirin, 1000-1200 or 1200-1600 mg/d. Genotyping of the IL28B SNP rs12979860 was performed from host cell DNA by means of a real-time PCR method using minor groove binding probes. RESULTS: The IL28B genotype was determined in all 83 patients: 3 (3.6%) had a CC genotype and were removed to allow comparison between CT (n=55) and TT (n=25) patients. The difference between reductions in HCV RNA levels between TT and CT patients was significant at week 2 (<0.5 vs ≥0.5 Log, p=0.02), at week 4 (<1 vs ≥1 Log, p=0.008), and at weeks 12 and 24 (<2 vs ≥2 Log p=0.02). When comparing CT and TT patients, the odds ratio were 3.09 for a more than 0.5 Log drop at week 2; 3.86 for a more than 1 Log drop at week 4; 3.08 for a more than 2 Log drop at week 12; 3.10 for a more than 2 Log drop at week 24; and 3.57 for an undetectable HCV RNA at week 24.

CONCLUSIONS:

Most patients who fail to respond to pegylated IFN and ribavirin carry either TT or CT rs12979860 genotypes. CT patients are significantly more likely to respond to higher doses of IFN and the difference is significant at week 2. This indicates that the IL28B genotype is a marker of host cell responsiveness to IFN. These findings will have major implications in the treatment of HCV infection with higher peg-IFN doses in combination with ribavirin and direct acting antivirals.

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