Download presentation
Presentation is loading. Please wait.
Published byAndrew Whitehead Modified over 9 years ago
1
SPRINT-2/RESPOND-2 Boceprevir Plus Standard of Care Phase 3 Clinical Trials Analysis of Resistance Associated Variants by HCV Genotype 1 subtypes 1a and 1b
2
Background ► Nearly 170 million people worldwide are chronically infected with Hepatitis C virus (HCV) – HCV genotype 1 is the most common and least responsive to peginterferon alfa and ribavirin with geographic differences in HCV genotype 1 subtypes: Genotype 1a is predominant in Northern Europe and North America Genotype 1b is predominant in Southern and Eastern Europe and Japan – Leading indication for liver transplantation in Europe and United States and is major etiologic factor in hepatocellular carcinoma ► Boceprevir - binds to the active site of the HCV NS3 protease – Victrelis TM (Boceprevir) approved by FDA for treatment use in combination with peginterferon alfa and ribavirin in adult patients (≥18 years of age) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
3
Objectives ► To compare the rate of sustained virologic response (SVR) of Boceprevir (BOC) dosed in combination with Peg- interferon alfa-2b (P) plus ribavirin (R) standard of care therapy in patients with Genotype 1a (G1a) and Genotype 1b (G1b) in the SPRINT-2 and RESPOND-2 clinical trials. ► To compare the frequency of Resistance Associated amino acid Variants (RAVs) between G1a and G1b viruses among non-SVR patients enrolled in SPRINT-2 and RESPOND-2
4
SPRINT-2/RESPOND-2 Phase 3 Trials ► SPRINT-2 - 1,097 previously untreated patients (two cohorts enrolled and analyzed separately) Cohort 1: 938 (86%) non-Black patients Cohort 2: 159 (14%) Black patients ► RESPOND-2 – 403 prior treatment failures to P/R (patients failing to attain sustained virologic response after an adequate course of therapy) ► Patient characteristics common to both studies – Patients mono-infected with chronic hepatitis C genotype 1 – Co-infection with HIV or HBV excluded – Adult (≥18 years) patients – Compensated liver disease with all degrees of fibrosis – Studies conducted primarily in North America and Western Europe
5
– Double-blind for BOC – 3 treatment arms ( all patients received a 4 week lead-in of P/R prior to having BOC or placebo added to their regimen) Arm 1: PR48 (Control) –4 weeks P/R then 44 weeks P/R + BOC placebo Arm 2: BOC RGT –4 weeks P/R then P/R + BOC using response guided therapy (RGT) Arm 3: BOC/PR48 –4 weeks P/R then 44 weeks P/R + BOC – Primary endpoint: SVR in each experimental arm compared to control arm COBAS TaqMan 2.0 (Roche) HCV Test Limit of Detection (LOD): 9.3 IU/ml Limit of Quantitation: 25 IU/ml All decisions based on LOD SPRINT-2/RESPOND-2 Phase 3 Trials
6
Methods ► Plasma samples were collected for resistance testing from patients at baseline and at or near the time of virologic failure in patients that did not achieve SVR. ► Viral genotype was determined at screening using the TruGene assay. Subsequently, genotyping was determined by a combination of NS5b sequencing and/or inferred from positive amplification using subtype-specific primers (Virco BVM, Belgium) ► Population sequencing of the NS3 region was performed by Virco. ► Sequences from G1a and G1b viruses were aligned to the H77S and Con 1 reference strains, respectively. Major RAVs identified based on changes at specified loci compared with reference strain sequences.
7
HCV Genotype 1 Subtype Analysis ● Many patients genotyped as 1a using the Trugene assay were inconsistent with methods 2 and 3 (low concordance) ● High concordance was observed between method 2 (used for final data analysis) and phylogenetic analysis of NS3/4a sequences
8
Patients Achieving SVR by HCV Genotype in SPRINT-2 and RESPOND-2 ● There was a consistent but small numerical advantage for patients Infected with G1b compared to G1a to achieve SVR in both Boceprevir arms of each study.
9
Detection of Resistance Associated Variants (RAVs) in Boceprevir Treated patients (SPRINT-2 and RESPOND-2) ●There was a consistently higher % of patients with RAVs detected in patients infected with HCV G1a compared to G1b in both BOC arms of each trial.
10
Frequency of RAVs in Non-SVR Patients by Genotype 1 subtype Patients infected with HCV Genotype 1b had lower % RAVs detected compared to Genotype 1a Infected patients † Expressed as a percentage of patients with sequence data available. RAVs=Resistance Associated Amino Acid Variants
11
G1a G1b Frequency Distribution of Boceprevir RAVs Detected Post Baseline Among Boceprevir Treated patients (SPRINT-2 and RESPOND-2) ● V36M and R155K were the predominant (>25%) RAVs in HCV G1a ● T54A/S, A156S and V170A were the predominant RAVs (>25%) in HCV G1b
12
RAVGenotypeWT CodonRAV Codon# changes V36MG1a G1b GTG GTT/C ATG 1212 R155KG1a G1b AGG CGG AAG 1212 T54AG1a G1b ACT GCT 1111 T54SG1a G1b ACT TCT 1111 A156SG1a G1b GCC GCC/T TCC TCC or TCT 1111 V/I170AG1a G1b ATC G/ATA/G GCC GCA/G 2121 Genetic Variation Between Genotype 1a and 1b Partially Explains Different RAV Frequencies ►V36M, R155K in G1b and V170A in G1a require 2 nucleotide changes and likely accounts for the different frequency observed between HCV G1a and G1b
13
RAVs Detected in a higher % of Non-SVR Patients with a poor Interferon Response at TW4 8 Patients missing TW4 viral load data and 42 with no sequence data are not included. RAV=resistance associated amino acid variant; SVR=sustained virologic response; TW=treatment week.
14
Frequency and Distribution of RAVs Detected at Baseline vs. Post-Baseline RAVs Associated With Virologic Failure (Boceprevir Arm of SPRINT-2 and RESPOND-2) All data based on population sequencing. RAVs=resistance associated amino acid variants. Baseline RAVsPost-Baseline RAVs Not associated with Viral Failure Associated with Viral Failure
15
SVR Rates By Treatment Week 4 Response in Patients With or Without Baseline RAVs
16
Summary Boceprevir, in combination with P/R significantly improved SVR rates compared with P/R alone in both treatment naïve and previously treated patients SVR rates among patients with G1b virus were consistently higher compared with G1a patients in both SPRINT-2 and RESPOND-2 phase 3 trials Detection of resistance variants was more common among G1a vs G1b viruses in both pivotal trials when analyzed by all boceprevir treated and subset not achieving SVR ►predominant RAVs for G1a : V36M and R155K ►predominant RAVs for G1b : T54A/S, A156S, V170A
17
Conclusions ► Genetic variation between G1a and G1b viruses likely contributes to the higher rate of SVR and lower rate of major RAV detection (in non-SVR patients) in HCV G1b patients treated with Boceprevir combination therapy ► non-SVR patients with a good Interferon response had fewer RAVs detected ► Majority of poorly interferon responsive non-SVR patients had RAVs detected at failure primarily due to the fact most patients failed during the BOC dosing period
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.