frequencies of resistance-associated amino acid variants following combination treatment with...
TRANSCRIPT
Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir (BOC) Plus PEGINTRON (PegInterferon Alfa-2b) and Ribavirin (P/R) in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1)
Richard J.O. Barnard, Lisa D. Pedicone, Eirum Chaudhri, Xiao Tong, Ping Qiu, Clifford A. Brass, Janice K. Albrecht, Patricia Mendez, and Robert Ralston
SPRINT-1 Methods
• Phase 2 study of previously untreated adults with genotype 1 HCV
• Part 1 - 520 patients randomized to receive Peg-interferon (P)/Ribavirin (R) for 48 weeks (control) or one of four boceprevir regimens
– Arms 3 and 5 of Part 1 received a 4 week lead-in with P/R prior to the addition of boceprevir to:
o Achieve steady state of P/R prior to adding 3rd drugo Up-regulate immune response elementso Decrease viral load and quasispecies, thereby
decreasing resistance• Part 2 - 75 patients randomized to receive P/R and low-
dose ribavirin
Definitions
• Sustained Virologic Response (SVR): Plasma HCV-RNA level below the lower limit of detection at follow-up week 12
• Incomplete Virologic Response (IVR): A ≥2 log10 increase in HCV-RNA viral load compared with the previous two visits and HCV viral load ≥50,000 IU/mL
• Viral Breakthrough (BT): Undetectable HCV-RNA and subsequent HCV-RNA ≥2 log10 elevation during therapy
• Relapse (RL): Undetectable HCV-RNA at end of treatment and detectable HCV‑RNA at follow-up week 24
• Nonresponder (NR) (treatment failure): o Subjects in Arm 1 with detectable HCV-RNA at treatment week 24 who crossed
over to boceprevir o Subjects in any of the seven treatment arms with detectable HCV-RNA at end of
therapy and at follow-up week 24 o Subjects in any of the seven treatment arms with missing HCV-RNA values at
follow-up week 24 and do not have an undetectable HCV-RNA at follow-up week 12
• Resistance Associated Amino Acid Variant (RAV)
SPRINT-1 Study Design and Sustained Virologic Response
Table 1. Subjects with Baseline RAVs Previously Demonstrated to Confer Reduced Susceptibility to Boceprevir in vitro
Number of RAVs Detected by HCV Genotype
49%
52%
Number of Subjects Having RAVs Detected Post-baseline, Including All Patients Treated with Boceprevir
30 1
5
53
0
11
3
29
51
60
1
138
14
1 00
10
20
30
40
50
60
70
V36AV36G V36I V36LV36MQ41HT54AT54CT54SV55AR155IR155KR155MR155TA156SA156TV158IV158MI170A
Patients, n
01
0 01 1
11
0
17
5
0 0 0 0
13
34
0
13
0
2
4
6
8
10
12
14
16
18
V36AV36G V36I V36LV36MQ41HT54AT54CT54SV55AR155IR155KR155MR155TA156SA156TV158IV158MI170A
Patients, n
Frequency of RAVs for Different Treatment Response Categories
IVR = Incomplete Virologic Response, BT = BreakthroughRL = Relapse, NR = Non-responder
0
10
20
30
40
50
60
70
80
IVR BT RL NR
Patients, n
Subjects with Variants Detected
Subjects with no Variants Detected
RAVs Detected in BOC 28 and 48 Week Treatment Arms
Lead-in - + - + - -
0
20
40
60
80
100
120
Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 Arm 7
Patients, n
SubjectsSubjects with RAVsSubjects without RAVs
RAVs Detected with No Lead-in (Arm 2) vs. Lead-in (Arm 3) Study Arms (i.e. Arms where Patients Received a Shorter Duration of Treatment with Boceprevir)
01
01
12
0
3
1
12
2
0
14
0
32
01
0 0 0 0
5
0
5
0
2
4
6
8
10
12
14
16
V36AV36GV36IV36LV36MQ41HT54AT54CT54SV55AR155IR155KR155MR155TA156SA156TV158IV158MI170AI170TV36ApctV36GpctV36IpctV36Lpct
Patients, n
Lead-in
No Lead-in
RAVs Detected with No Lead-in (Arms 4) vs. Lead-in (Arm 5) Study Arms (i.e. Arms where Patients Received a Longer Duration of Treatment with Boceprevir)
Lead-in
No Lead-in
1
0 0
1
8
0
21
7
0 0
10
0
1 1
0
1
0 0 00
2
4
6
8
10
12
V36AV36GV36IV36LV36MQ41HT54AT54CT54SV55AR155IR155KR155MR155TA156SA156TV158IV158MI170AI170T
Patients, n
0 0 0 0
5
0
3
0
2 2
0
7
0
1 1 1 1 1
0 00
2
4
6
8
10
12
V36AV36GV36I V36LV36MQ41HT54AT54CT54SV55AR155IR155KR155MR155TA156SA156TV158IV158MI170AI170T
Patients, n
Conclusions
• In SPRINT-1, combination therapy with boceprevir and peginterferon plus ribavirin increased SVR rates with shorter treatment durations
• In Non-SVR patients, most frequent RAVs were;o Genotype 1a; V36M, T54S, and R155Ko Genotype 1b; T54A, T54S, A156S, and V170A
• In subjects with detectable RAVs at baseline, the majority achieved SVR
• The use of lead-in period led to increased SVR rates and reduced the frequency of T54S variant