icon-folder.gif   Conference Reports for NATAP  
  EASL 47th Annual Meeting
April 18th - 22nd 2012
Barcelona, Spain
Back grey_arrow_rt.gif
Low rate of on-treatment resistance to danoprevir bosted by ritonavir (DNVr) combined with peginterferon alfa-2a (40KD)/ribavirin: 12 week interim analysis from the DAUPHINE study
  Reported by Jules Levin
EASL 2012

S. Le Pogam,1 M.T. Navarro,2 L. Bu,3 A. Voulgari,4 M. Ilnicka,5 J.M. Yan,1 K. Klumpp1 and I. Najera1
1Virology Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA; 2Biostatistics, Genentech, South San Francisco, CA, USA; 3Biostatistics, Roche Pharma Development in Asia Pacific, Shanghai, China; 4Clinical Development Roche Products Ltd, Welwyn, UK;
5Discovery Technologies, Hoffmann-La Roche, Nutley, New Jersey, USA


· In this 12-week interim analysis, a low rate of resistance to DNV was observed among HCV genotype 1 patients receiving DNVr plus P/R (4.6%).

· Resistance while on treatment with DNVr was associated with:

-- The NS3 R155K substitution

-- Occurred predominantly in the lower dose

-- Among patients with HCV genotype 1a infection.

· One patient showed a viral load profile meeting the definition for non-response. Phenotypic analysis of the baseline HCV sample from this

patient (with the Q/H41 mutation) showed susceptibility to DNV, with an EC50 value similar to the reference control. Thus, non-response was

unlikely to be due to the presence or rapid selection of DNV-resistant virus.

· These observations are consistent with the higher genetic barrier to selection of danoprevir resistance in patients infected with HCV

genotype 1b.


· Danoprevir (DNV; RG7227) is a potent macrocyclic, second-generation hepatitis C virus (HCV) protease inhibitor that is active against HCV genotypes 1, 4 and 6.[1, 2]

· The combination of DNV plus peginterferon alfa-2a (40KD) and ribavirin (P/R) produced sustained virological response rates of up to 85% in treatment-naive HCV genotype 1-infected patients enrolled in the phase II ATLAS trial.[3]

· DNV in combination with ritonavir increases antiviral potency at substantially lower systemic exposures of DNV alone.[4]

· The efficacy and safety of ritonavir-boosted DNV (DNVr) plus P/R in treatment-naive HCV genotype 1- or 4-infected patients is currently being evaluated in the phase II DAUPHINE study.[5]

· As shown in Figure 1, patients randomised to arms A, B and C in DAUPHINE received different doses of DNVr in combination with P/R for 24 weeks, while patients randomised to arm D received a 12- or 24-week response-guided regimen of DNVr plus P/R. Patients in the control arm (E) received P/R for 48 weeks. Patients in arm E who did not achieve a virological response, but had a ≥1 log10 IU/mL decrease in HCV RNA titre at week 12, were eligible to enter a 24-week DNVr plus P/R roll-over regimen.

Figure 1. Study design showing number of patients who were randomised and received at least one dose of study medication[5]


DNVr = oral danoprevir plus ritonavir; P/R = peginterferon alfa-2a (40KD) plus ribavirin; eRVR2 = extended rapid virological response (undetectable HCV RNA, <15 IU/mL) at week 2 maintained through week 10.

Peginterferon alfa-2a (40KD) was administered subcutaneously at a dosage of 180 μg/week; Ribavirin was administered orally at a dosage of 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight

≥75 kg) in two divided doses. *Treatment followed by a treatment-free follow-up period of up to 24 weeks.


· The objective of this study is to report the results of an interim week 12 analysis of viral resistance development from patients enrolled in the DAUPHINE study.