In
ACCELERATE Trial, Highest SVR Seen in Patients Who Received the Longest Duration
of Therapy with Pegasys and the Highest Mean Dose of Ribavirin Based on Body Weight
The
results of prior studies show that exposure to both peginterferon and ribavirin
(RBV) impacts SVR in patients with HCV genotype. The aim of the present study
was to examine the effect of cumulative drug exposure on SVR in genotype 2 (GT
2) and GT 3 pts enrolled in the ACCELERATE trial.
ACCELERATE
was a large prospective randomized trial (n=1469) that compared peginterferon
alfa-2a (Pegasys) 180 µg/wk plus RBV 800 mg/d for 16 or 24 wks. The
primary results of this study demonstrated that SVR was significantly greater
with 24 wks of treatment [EASL 2006; A734].
Complete data was available
in 1373 pts. The cumulative exposure to PEG-IFNa-2a and RBV on the probability
of SVR was assessed, while simultaneously controlling for other potential predictors
(age, gender, race, bodyweight, cirrhosis, genotype, baseline ALT and HCVRNA)
using logistic regression models.
Pegasys dose was expressed as a multiple
of the standard 180µg dose; RBV was expressed as mean daily dose.
Results
Cumulative Pegasys dose, mean daily RBV dose, genotype, baseline HCVRNA, cirrhosis
status, age and baseline ALT significantly and independently predicted SVR (Table).
SVR increased
stepwise with increasing cumulative Pegasys duration regardless of RBV dose.
In patients with mean RBV dose of <8.4 mg/kg/d (lowest quartile of RBV exposure),
SVR increased from 42% in pts who received <16 Pegasys doses to 67%
in pts with >17 Pegasys doses.
In patients with RBV exposure of ?11.5 mg/kg per day (top quartile of RBV exposure),
SVR was 77% and 87% in pts receiving <16 and >17 PEG-IFN?-2a
doses respectively.
Based
on these results, the authors conclude, "Total exposure to both Pegasys and
RBV affected SVR in pts with GT 2 and GT 3 independent of other factors."
"The
highest SVR (87%) was observed in pts who received the longest duration of therapy
and the highest mean dose of RBV based upon body weight."
"Since
all pts in this trial received an 800 mg/d fixed dose of RBV, the reduction in
RBV exposure was a function of increasing body weight."
"Whether
increasing RBV exposure in heavier GT 2 and GT 3 pts will improve SVR remains
uncertain."
Predictor
SVR (univariate)
Odds ratio [95% CI] (multivariate)
Cumulative PEG-IFNα-2a dose <17 x 180µg ≥17 or more x 180µg
63%
(423/673) 77%(542/700)
1.0
2.1 [1.6–2.7] (p<0.0001)
RBV average daily dose <9.9 mg/kg ≥9.9 mg/kg
62%
(429/693) 79% (536/680)
1.0
2.3 [1.7–2.9] (p<0.0001)
HCV genotype 3 2
68%
(465/688) 73% (500/685)
1.0
2.2 [1.6–2.9] (p<0.0001)
HCV RNA at baseline >400’000 IU/ml ≤400’000 IU/ml
66%
(715/1086) 87% (250/287)
1.0
3.8 [2.5–5.5] (p<0.0001)
Histological status cirrhosis / bridging fibrosis no cirrhosis / no bridging fibrosis
55%
(182/332) 75% (783/1041)
1.0
2.3 [1.7–3.1] (p<0.0001)
Age >47 years ≤47
years
66%
(413/625) 74% (552/748)
1.0
1.5 [1.1–1.9] (p=0.0051)
ALT quotient at baseline (x ULN) ≤2.3 x ULN >2.3 x ULN
70%
(491/703) 71% (474/670)
1.0
1.4 [1.1–1.8] (p=0.0091)
VCU
Medical Center, Richmond, VA, USA; St Luke's Center for Liver Disease, Houston,
TX, USA; Toronto Digestive Disease Associates, Toronto, ON, Canada; Servicio de
Digestivo, Hospital del Mar, Barcelona, Spain; Kaiser Permanente Medical Center,
San Diego, CA, USA; CHU Nancy, Vandoeuvre-Les-Nancy, France; Princess Alexandra
Hospital, Brisbane, QLD, Australia; Roche, Nutley, NJ, USA; Roche, Welwyn Garden
City, United Kingdom; Saarland University Hospital, Homburg/Saar, Germany.
11/03/06
Reference M
Shiffman, S Pappas, S Greenbloom, and others. Effect of drug exposure on sustained
virological response (SVR) in patients with chronic hepatitis C virus genotype
2 or 3 treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin
(COPEGUS®) for 16 or 24 weeks. 57th AASLD. October 27-31, 2006. Boston, MA.
Abstract 342.
Cumulative Pegasys dose, mean daily RBV dose, genotype, baseline HCVRNA, cirrhosis
status, age and baseline ALT significantly and independently predicted SVR (Table).
