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