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HCV Clinical Trials Abstracts

129. The IL28B genotype is a major determinant in the induction of a virological response by high-dose peginterferon and ribavirin in null-responders to standard-of-care therapyS. Chevaliez; A. Soulier; C. Hezode; B. Costes; J. Foucher; J. Bronowicki; A. Tran; I. Rosa; P. Mathurin; L. Alric; V. Leroy; M. Bouvier-Alias; S. Rouanet; P. Couzigou; A. Mallat; M. Charaf Eddine; G. Babany; J. Pawlotsky

Polymorphisms upstream of the region encoding IL28B have been shown to be associated with both natural and treatment-induced control of HCV infection. With new therapies using direct acting antiviral molecules, a null response to IFN is associated with treatment failure and selection of resistant viruses.

Goal: Our goal was to assess, in null-responders to IFN-ribavirin therapy, whether the IL28B genotype has an influence and predictive value on the ability of high-dose pegylated IFN and ribavirin retreatment to induce a virological response.

Methods: 83 genotype 1 null-responders received peg-IFN alpha-2a, 360 μg/week in one or two injections, plus ribavirin, 1000-1200 or 1200-1600 mg/d. Genotyping of the IL28B SNP rs12979860 was performed from host cell DNA by means of a real-time PCR method using minor groove binding probes.

Results: The IL28B genotype was determined in all 83 patients: 3 (3.6%) had a CC genotype and were removed to allow comparison between CT (n=55) and TT (n=25) patients. The difference between reductions in HCV RNA levels between TT and CT patients was significant at week 2 (<0.5 vs ≥0.5 Log, p=0.02), at week 4 (<1 vs ≥1 Log, p=0.008), and at weeks 12 and 24 (<2 vs ≥2 Log p=0.02). When comparing CT and TT patients, the odds ratio were 3.09 for a more than 0.5 Log drop at week 2; 3.86 for a more than 1 Log drop at week 4; 3.08 for a more than 2 Log drop at week 12; 3.10 for a more than 2 Log drop at week 24; and 3.57 for an undetectable HCV RNA at week 24.

Conclusions: Most patients who fail to respond to pegylated IFN and ribavirin carry either TT or CT rs12979860 genotypes. CT patients are significantly more likely to respond to higher doses of IFN and the difference is significant at week 2. This indicates that the IL28B genotype is a marker of host cell responsiveness to IFN. These findings will have major implications in the treatment of HCV infection with higher peg-IFN doses in combination with ribavirin and direct acting antivirals.

Log HCV RNA decrease according to IL28B rs12979860 genotype

Week 1

IL28B genotype

Failure

<0.5 Log decrease

0.5-1.0 Log decrease

1.0-2.0 Log decrease

≥2.0 Log decrease

Undetectable HCV RNA

TT

na

79.2%

20.8%

0%

0%

0%

CT

na

69.2%

21.2%

7.7%

1.9%

0%

Week 2

TT

na

64.0%

20.0%

16.0%

0%

0%

CT

na

36.5%

44.2%

17.3%

1.9%

0%

Week 4

TT

na

32.0%

40.0%

28.0%

0%

0%

CT

na

20.0%

20.0%

49.1%

10.9%

1.8%

Week 12

TT

4.0%

4.0%

24.0%

28.0%

40.0%

0%

CT

0%

9.1%

9.1%

14.5%

67.3%

14.5%

Week 24

TT

16.0%

4.0%

16.0%

20.0%

44.0%

12.0%

CT

12.7%

0%

12.7%

3.6%

70.9%

32.7%

 


130. Completely individualized treatment durations with peginterferon-alfa-2b and ribavirin in HCV genotype 1-infected patients and importance of IL28B genotype (INDIV-2 study).  C. Sarrazin; S. Schwendy; B. Moeller; N. Dikopoulos; P. Buggisch; J. Encke; G. Teuber; T. Goeser; R. Thimme; H. Klinker; W. O. Boecher; E. Schulte-Frohlinde; R. Prinzing; T. Berg; S. Zeuzem

Introduction: Tailoring treatment duration according to baseline viral load and virologic response during treatment is recommended by current treatment guidelines. The possibility of further individualization of treatment durations to 24, 30, 36, 42, 48, 60 and 72 weeks in genotype 1 patients was shown in the INDIV-2 study. The potential importance of IL28B genotype for precise determination of treatment duration is unknown.

Methods: 398 treatment-nave HCV genotype-1 patients were enrolled in a multicenter, randomized trial with peginterferon-alfa-2b and ribavirin. Patients received individualized treatment durations for 24,30,36,42,48,60 or 72 weeks according to low or high baseline viral load (LVL/HVL, cut-off 800.000IU/ml) and undetectable HCV-RNA at week 4,6,8,12 and 24 by a highly sensitive assay (TMA). The results were compared to a historical control (n=224) with identical treatment for 48 weeks. Treatment response (SVR, Relapse, Non-Response) was analyzed according to IL28B genotype (rs129797860)

Results: Overall SVR rates of 55% and 48% were obtained in patients treated with individualized durations and 48 weeks standard duration, respectively. IL28B genotype was obtainable in 305/398 patients which completed therapy. SVR rate of patients who completed therapy was 65%.
In non-responders 96% (65/68) are CT and TT IL28B genotypes. SVR was achieved in 85%, 58% and 46% of patients with CC, CT and TT IL28B genotype. However, overall relapse rates are similar for CC, CT and TT IL28B genotypes (13%, 19%, 21%, respectively). In patients with LVL at baseline relapse was uncommon for CC genotype (1/29, 3%) and equally frequent in CT and TT genotypes (18% and 23%, respectively) while for patients with HVL relapse was equally frequent in CC and CT genotypes (17% and 22%, respectively). Thus, longer treatment durations probably would have been required in these patients to prevent relapse. IL28B genotypes of patients who received standard treatment duration of 48 weeks will be presented at the meeting.

Conclusion: High SVR rates can be achieved in chronic hepatitis C genotype 1 infection with a complete individualized treatment schedule (24,30,36,42,48,60,72 weeks) with pegylated interferon 2b and ribavirin. In addition to baseline viral load and HCV RNA negativity during treatment IL28B genotype may be used to determine treatment duration.

 


211. Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Nave Patients: Final Results of Phase 3 ADVANCE Study.  I. M. Jacobson; J. G. McHutchison; G. M. Dusheiko; A. M. Di Bisceglie; R. Reddy; N. H. Bzowej; P. Marcellin; A. J. Muir; L. Bengtsson; A. Dunne; N. Adda; S. George; R. S. Kauffman; S.

Background: The ADVANCE study is a 3-arm double-blind, randomized, placebo-controlled Phase 3 study assessing efficacy and safety of two telaprevir (TVR, T)-based response-guided regimens compared with peginterferon alfa-2a 180 g/week and ribavirin 1000-1200 mg/day (PR) in treatment-nave patients with chronic genotype 1 HCV infection.

Methods: Treatment arms were

        (a)Telaprevir 750 mg q8h (every 8 hours) in combination with pegylated interferon plus ribavirin for 8 weeks, followed by additional weeks of pegylated interferon plus ribavirin;

        (b) Telaprevir 750 mg q8h in combination with pegylated interferon plus ribavirin for 12 weeks, followed by additional weeks of pegylated interferon plus ribavirin ;

        (c) Pegylated interferon plus ribavirin R for 48 weeks (control arm).

 

Patients in telaprevir arms achieving an extended rapid viral response (eRVR, undetectable HCV RNA at weeks 4 and 12) received a total of 24 weeks of therapy while those who did not achieve eRVR received a total of 48 weeks of therapy.

 

Randomization was 1:1:1 and patients were stratified by HCV RNA (<800,000 IU/mL, ≥800,000 IU/mL), and genotype 1a vs. 1b. The primary endpoint was SVR (undetectable HCV RNA 24 weeks after last planned dose of treatment).

Results:

        Of 1088 patients, 839 (77%) had HCV RNA ≥800,000 IU/mL, 631 (58%) were genotype 1a, 636 (58%) male, 94 (9%) black, 117 (11%) Latino/Hispanic, 231 (21%) had bridging fibrosis or compensated cirrhosis.

        Group (a) 69 % SVR in the group that received 8 weeks of triple combo (Telaprevir, pegylated interferon plus ribavirin) followed by either 12 or 36 weeks of pegylated interferon plus ribavirin.

        Group (b) 75% SVR in the group that received 12 weeks of triple combo (Telaprevir, pegylated interferon plus ribavirin) followed by either 12 or 36 weeks of pegylated interferon plus ribavirin.

        Group (c) 44% SVR in the control group (pegylated interferon plus ribavirin without telaprevir)

        58% of the patients received a total of 24 weeks of (eRVR group)Telaprevir triple for 8 weeks 83% SVR; Telaprevir triple for 12 weeks89% SVR.

        In the groups that were treated with telaprevir triple therapy for 12 weeks the SVR rates by liver disease state, race and ethnicity were as follows:

o   Blacks: 62% SVR vs. 25% in control arm

o   Hispanics: 74% SVR vs. 39% SVR in control arm

o   Bridging fibrosis/cirrhosis: 62% SVR vs. 33% in control arm

 

Safety:

        The most common (>25%) AEs in the telaprevir arms were fatigue, pruritus (itching), nausea, headache, anemia, rash, influenza-like illness, insomnia, pyrexia, and diarrhea.

        Discontinuation of treatment due to AEs occurred in 8% in T8PR, 7% in T12PR and 4% in PR48; due to rash occurred in 0.5%, 1.4% and 0.0% and due to anemia occurred in 3.3%, 0.8% and 0.6% in T8PR, T12PR and control arms, respectively.

Conclusions:

        A significantly greater proportion of patients achieved SVR with 12-week and 8-week telaprevir-based combination regimens (75% and 69%, respectively) compared with PR48 control arm (44%, P<0.0001).

        The safety and tolerability profile of telaprevir in the ADVANCE trial was consistent with the profile previously reported, with an improvement in treatment discontinuation rates due to adverse events, including rash and anemia.

        These first Phase 3 results confirm the clinical benefit previously reported in Phase 2.


216. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/RibavirinB. R. Bacon; S. C. Gordon; E. Lawitz; P. Marcellin; J. M. Vierling; S. Zeuzem; F. Poordad; N. Boparai; M. Burroughs; C. A. Brass; J. K. Albrecht; R. Esteban

Background: Boceprevir (BOC) is an oral inhibitor of HCV-NS3 protease. RESPOND-2 assessed the safety and efficacy of BOC plus PEGINTRON (P) and Ribavirin (R) in the re-treatment of previous non-responders (NRs) and relapsers to Peginterferon/R therapy.

Methods: In this double-blind placebo controlled trial, 403 genotype 1 Peginterferon/R treatment failure patients from the US, Canada and Europe were randomized 1:2:2 to receive either

        Arm 1: pegylated interferon plus ribavirin (without boceprevir) control arm ,

        Arm 2: 4 wks of pegylated interferon plus ribavirin (lead-in) then response guided therapy (RGT) with pegylated interferon plus ribavirin plus 800 mg boceprevir three times a day (TID), or

        Arm 3: Pegylated interferon plus ribavirin for 4 weeks (lead-in) followed by 44 weeks of pegylated interferon plus ribavirin plus 800 mg BOC TID

All patients with detectable HCV-RNA at wk 12 were discontinued for futility. The primary endpoint was sustained virologic response (SVR) at 24 wks post-treatment (Roche TaqMan LLD <15 IU/mL).

Results:

        Patient distribution was 67% male, 12% black, and 12% cirrhotic.

        The addition of BOC following a 4 week lead-in with pegylated interferon plus ribavirin significantly increased SVR over controls by 37% (Arm 2; 59% vs. 21%) and 45% (Arm 3; 66% vs. 21%).

        For all arms, prior relapsers had higher SVR than previous null responders

        The highest SVR (79%) was observed in patients with a ≥1 log decline at week 4 following the 4 week P/R lead-in (non-null) who were then treated with 800 mg boceprevir TID for 44 weeks.

        Notably, SVR in Arms 2 and 3 was significantly higher than Arm 1 for the null responders who represented ~28% of the population in Arms 2/3.

Safety:

        Discontinuation due to adverse events was reported in 3%, 8% and 12% of patients in Arms 1, 2 and 3, respectively, with none related to rash.

        The most common reason for discontinuation was lack of response at wk 12.

        The adverse events were similar across all treatment arms except anemia and dysgeusia (taste changes) were higher in the boceprevir containing arms.

Conclusions:

        Triple therapy was generally well-tolerated

o   Anemia and dysgeusia occurred more often in the boceprevir groups than the control group

        Boceprevir added to PR significantly increased SVR compared to PR control

o   Can be used to treat patients with all categories of interferon responsiveness

        Response guided therapy and boceprevir, pegylated interferon plus ribavirin therapy for 48 weeks were equally effective for treatment failure patients

        Pegylated interferon lead-in allow for real time assessment of patients interferon responsiveness

o   Poorly responsive: 33-34% achieved SVR vs. 0% in control group

o   Responsive: 73-79% achieved SVER vs. 26% in control group.

 


227. Long-term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis of the EXTEND Study.  S. Zeuzem; M. S. Sulkowski; F. Zoulim; K. E. Sherman; A. Alberti; L. J. Wei; B. van Baelen; J. Sullivan; T. L. Kieffer; S. De Meyer; G. Picchio; F. Tomaka; C. S. Graham; J. G. McHutchison

Background: Telaprevir (TVR) is a potent, specific hepatitis C virus (HCV) protease inhibitor that in combination with pegylated interferon alfa-2a (P) and ribavirin (R) led to higher sustained virologic response (SVR) rates than PR alone in both treatment-nave and treatment-experienced genotype 1 HCV patients in Phase 2 clinical trials. EXTEND is a 3-year virology follow-up study on some of these patients. Here, we report an interim analysis of durability of virologic response in patients who had achieved SVR as well as changes in HCV variants in patients who had not achieved SVR.

Methods: 867 patients who received at least one dose of TVR in PROVE1, PROVE2, PROVE3 or Study 107 and from whom baseline HCV sequences were available were eligible for enrollment; 202 entered the study. Patients who achieved SVR (n=123) were observed for a median time of 22 months post-SVR. Patients who did not achieve an SVR as defined in previous studies (n=79) were observed for a median time of 22 months after the end of the prior study. HCV RNA levels were assessed with the COBAS TaqMan HCV Test (version 2.0). Viral sequence was determined by nested RT-PCR followed by population sequencing of the NS3 protease (detecting variants present in >~20% of viral population). Amino acid (AA) positions 36, 54, 155, and 156 that are associated with decreased susceptibility to TVR in genotype 1 HCV patients were analyzed. We report on patients who possessed identified variants with decreased susceptibility to TVR at time of treatment failure.

Results: Ninety-nine percent (122 out of 123) of patients maintained SVR during follow-up; one patient from PROVE2 experienced a late relapse 47 weeks after early discontinuation from study dosing, as previously presented. Variants were no longer detectable in 89% (50 out of 56) of patients who had NS3 variants after failing to achieve an SVR. NS3 variants in each of the four AA positions associated with decreased susceptibility to TVR were no longer detectable in 89% of patients. In this cohort, there was no evidence to suggest that the time to undetectability of variants varied as a function of treatment arm, duration of TVR dosing, or non-response type (e.g., virologic breakthrough on treatment versus relapse).

During the follow-up period there were no serious clinical events observed in the group who achieved an SVR. In the Non-SVR group, two patients developed: patient one with cirrhosis at the beginning of the study, developed HCC and liver decompensation (ascites) with liver transplant. Patient two who had bridging fibrosis at the beginning of the study, developed hepatic encephalopathy.

Conclusions:

        In this final analysis, SVR after telaprevir-based therapy was durable, with 122 of 123 subjects maintaining HCV RNA undetectable during a median 22 months follow-up.

        In patients who did not achieve SVR during telaprevir treatment, resistant variants were replaced withWT virus:

o   89% of subjects no longer had detectable resistant variants (median follow-up time: 25 months from the end of prior study.

 


79. 36 versus 48 weeks of treatment with peginterferon alfa-2a plus ribavirin for genotype 1/4 patients with undetectable HCV RNA at week 8: Final results of a randomized multicenter study.  S. S. Lee; M. Sherman; A. Ramji; S. Greenbloom; M. Elkashab; H. Pluta; N. Hilzenrat; R. Balshaw; C. Usaty; R. P. Myers

Background: Individualizing the duration of treatment with peginterferon (PegIFN) plus ribavirin (RBV) is a well established practice in patients with HCV genotype 1/4 infection. Abbreviated 24-week durations are suitable for many patients with a rapid virological response (RVR) at week 4 and 48 week treatment durations are recommended for those who have an early virological response (EVR) at week 12. The suitability of intermediate treatment durations (e.g., 36 weeks) for patients who become HCV RNA negative between week 4 and 12 has not previously been studied.

Methods: Treatment-nave adults with HCV genotype 1/4 infection initiated treatment with PegIFNα2a 180 g/week plus RBV 1000/1200/1400 mg/day (bodyweight <75/≥75/≥85 kg) and were randomized to individualized treatment durations on the basis of their HCV RNA status at week 4, 8 or 12. Those who were HCV RNA negative (Roche Taqman Limit of detection 15 IU/mL) at week 4 (RVR) were randomized to 24 or 48 weeks of treatment; those who were negative at week 8 were randomized to 36 or 48 weeks and those with an EVR (negative or ≥2-log drop) at week 12 were randomized to 48 or 72 weeks of treatment. Sustained virological response (SVR) was defined as undetectable HCV RNA after 24 weeks of untreated follow-up.

Results: A total of 236 patients started treatment and 195 were randomized at week 4 (n=50), 8 (n=61) or 12 (n=84) and included in the ITT population. Patient groups randomized at week 4, 8 and 12 were well matched. SVR rates were highest in patients randomized at week 4 (42/50, 84%) and week 8 (45/61, 74%) and lowest in those randomized at week 12 (37/84, 44%). SVR rates were similar in patients randomized to 24 or 48 weeks of treatment at week 4 (84% and 84%, respectively),those randomized to either 36 or 48 weeks at week 8 (73% and 74%, respectively) and those randomized to 48 or 72 weeks at week 12 (49% versus 40%, p=NS). Rates of premature withdrawal were highest in patients randomized at week 12. The overall SVR rates were similar in patients randomized to individualized treatment durations (60/98, 61%) and the standard 48-week duration (64/97, 66%).

Conclusion: The most novel finding of this prospective randomized multicenter trial is that a 36 week treatment duration provides similar SVR rates to a standard 48-week treatment duration in genotype 1/4 patients who become HCV RNA negative between week 4 and 8 of treatment with PegIFNα2a plus RBV. Such patients may be considered for a shorter 36-week treatment duration.

 


797. High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) plus Ribavirin (R) Therapy: Results from the IDEAL Trial.  F. Poordad; M. S. Sulkowski; J. G. McHutchison; B. R. Bacon; J. McCone; J. M. Vierling; S. Noviello; N. Boparai; J. K. Albrecht; C. A. Brass

Background: The objective of this retrospective analysis was to investigate the correlation between HCV viral load decline at treatment weeks (TW) 4 and 12 in patients from the IDEAL study in order to delineate a TW4 null response definition.

Methods: 3070 treatment-nave, HCV genotype 1 infected patients were treated for up to 48 weeks with ribavirin 800-1400mg/day plus PEG2b 1.5 or 1 mcg/kg/week, or PEG2a 180mcg/week plus ribavirin 1000-1200mg/day. Simple linear regression was used to assess the relationship between TW4 and TW12 log viral decline, and Pearsons correlation coefficient (r) was computed. Concordance in patients who had data at both TWs 4 and 12 was assessed using a definition for null response of <1 log decline at TW4 vs <2 log at TW12. Testing for IL28B was performed in 1604 patients.

Results: There is a high positive correlation between HCV viral load decline at TWs 4 and 12 for patients receiving standard of care therapy: PEG2b 1.5/R (r=0.76), PEG2a/R (r=0.73), or PEG2b 1.0/R (r=0.78) (p<0.001 for each). Null response defined as a <2 log decline at TW12 corresponds to ~0.7-1.1 log decline at TW4 for PEG2b 1.5/R. Concordance of null or non-null response defined by both TW4 and TW12 definitions was high for each of the treatment arms (Table) and for all 3 arms combined 89% (2459/2777) regardless of IL28B genotype, CC 98% (466/474) and CT/TT 83% (785/943). Nearly all patients who met the TW4 or TW12 definition for null response had the less favorable CT or TT allele.

Conclusions: TW4 viral load decline of <1 log approximates to that of <2 logs at TW12 and is an earlier predictor of null response. The TW4 definition of null response may have increased utility in aiding early treatment decisions.

Concordance of TW4 <1 log Viral Decline and TW12 <2 log Viral Decline from Baseline

TW12 Response

ALL

IL28B* CC

IL28B* CT/TT

TX

TW4
Response

Null

Non-Null

Null

Non-null

Null

Non-null

PEG2b1.5/R

Null

150

56

5

0

68

29

Non-null

55

639

0

141

30

182

Concordance

88%

 

100%

 

81%

 

PEG2a/R

Null

148

65

4

0

70

31

Non-null

52

710

0

151

9

219

Concordance

91%

 

100%

 

88%

 

PEG2b1.0/R

Null

235

51

4

3

113

28

Non-null

69

577

5

161

31

133

Concordance

87%

 

95%

 

81%

 

 

* Not all patients had IL28B genotyping available. <2 log viral load decline from baseline. <1 log viral load decline from baseline.


798. Predictive value of IL-28 polymorphism of effect of interferon therapy in patients with genotype 2a and 2b chronic hepatitis C.  T. Kawaoka; H. Ochi; N. Hiraga; M. Tsuge; M. Imamura; Y. Kawakami; H. Aikata; S. Takahashi; K. Chayama

Background and Aims: Common IL-28 locus polymorphisms (SNPs rs8099917 and rs12980275) have been reported to affect PEG-IFN (pegylated-interferon) plus ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1b, but no reports have examined genotypes 2a and 2b.

Methods: We analyzed 796 patients with chronic HCV genotype 2a and genotype 2b infection (590 and 206, respectively). All patients were treated with PEG-IFN or IFN with or without ribavirin ( peg-interferon plus ribavirin(n=160),interferon plus ribavirin(n=76), interferon mono-therapy(n=560)) between 2002 and 2008 and agreed to participate in the study. We evaluated predictive factors including HCV RNA, histological findings, and the genotype of the IL-28 rs8099917 and rs12980275 SNP contribute to sustained virological response (SVR).

Results: Multivariate analysis showed that HCV RNA level (OR=2.68; P<0.001), ribavirin use (OR=2.32; P<0.001), and rs8099917 genotype (OR=1.67; P=0.009) independently contributed to the effect of the therapy in all patients. On the other hand , HCV RNA level (OR=6.89; P=0.010), fibrosis stage F1-2 (OR=8.4; P=0.008) and rs8099917 genotype (OR=8.6; P=0.010) independently contributed to the effect of the therapy in nave 2b patients. In nave patients with HCV genotype 2b, HCV RNA level of (T/T) in rs8099917 genotype were more decrease than that of (GG or TG ) in rs8099917 genotype at 4 weeks.

We observed that 5 of 160 (3.1%) genotype 2 patients develop resistance against therapy during administration of PEG-IFN with ribavirin.

Conclusions: The genotype of rs8099917 in the IL-28 locus is a significant independent predictor of SVR with pegylated-interferon plus ribavirin combination therapy in genotype 2b nave patients.

 


799. No evidence of drug resistance or baseline S282T resistance mutation among GT1 and GT4 HCV infected patients on nucleoside polymerase inhibitor RG7128 and Peg-IFN/RBV combination treatment for up to 12 weeks: Interim analysis from the PROPEL study.  S. Le Pogam; J. Yan; A. Kosaka; Y. Ji; N. Gonzaludo; A. Ewing; K. Klumpp; I. Najera

Background: RG7128 is a novel nucleoside analog inhibitor of hepatitis C virus (HCV) polymerase that has demonstrated rapid and profound reductions in HCV RNA and displayed a high barrier to the development of drug resistance as monotherapy (14 days), in combination with HCV protease inhibitor RG7227 (13 days), and in combination with Peg-IFN α-2a plus ribavirin (SOC) (28 days). The S282T mutation has not been identified in treatment-naive patients in several independent analyses. The aim of this study was to monitor for the potential development of resistance to RG7128 after 8 or 12 weeks of triple combination therapy of RG7128 and Peg-IFN α-2a (40KD) and ribavirin (standard of care [SOC]).

Methods: The NS5B polymerase coding region was amplified and population sequencing performed on baseline samples from all patients. On-treatment viral kinetics were monitored for all patients. Population sequence and phenotypic analyses of the NS5B polymerase coding region were performed on samples from patients who, during RG7128 treatment, experienced: i) rebound, ii) non-response, or iii) partial response. Clonal sequence analysis was also performed on selected samples.

Results: At the time of this protocol-defined interim analysis, viral kinetics in 367 patients who had completed either 8 weeks (79 patients) or 12 weeks (288 patients) of triple combination therapy with RG7128 had been analyzed. No HCV RNA rebound or non-response was observed in any patient during triple therapy who was adherent to treatment. Ten of 367 (2.7%) patients had an HCV RNA ≥1000 IU/mL at the end of triple therapy: five patients treated for 8 weeks with RG7128 1000mg BID, four treated for 12 weeks with RG7128 500mg BID, and one patient treated for 12 weeks with RG7128 1000mg BID. None of these 10 patients had the RG7128 resistance mutation S282T, or any other common mutation in the NS5B coding region before or at the end of triple therapy. Sequencing analysis at baseline obtained so far of 86 GT1 and in 26 GT4 HCV samples has detected no S282T.

Conclusions: To date no HCV RNA rebound or non-response has been observed during 8 weeks or 12 weeks of RG7128/SOC combination therapy in treatment-naive patients with HCV GT1 or GT4 in this large Phase 2b trial. Limited replicative capacity of the S282T in vitro and lack of the S282T at baseline may contribute to the lack of clinical resistance. Complete evaluation, including clonal sequence and drug susceptibility phenotypic data, are underway. The high barrier to resistance, promising safety and tolerability profile continue to support nucleosides as potential backbone of future combination regimens for HCV.

 


80. Safety and efficacy of albinterferon-alfa-2b every four weeks plus ribavirin for treatment of chronic hepatitis C genotype 2/3.  S. Zeuzem; S. Pianko; G. R. Foster; V. Bain; W. Chuang; S. K. Sarin; R. Flisiak; C. Lee; S. R. Shah; P. Andreone; T. Piratvisuth; Y. Yin; G. Feutren; I. M. Jacobson

Background: Albinterferon-alfa-2b (albIFN) is a fusion protein of recombinant human albumin and rIFN-α2b with a half-life of 8 days. An active controlled study evaluated the safety and efficacy of albIFN q4w in treatment-naive patients with chronic HCV-2-3 hepatitis.

Methods: 391 patients were randomized 4:4:4:3 to one of 4 open-label treatment groups, in combination with oral ribavirin 800 mg/d: albIFN q4wks 900g, 1200g or 1500g (6 injections) or PEG-IFNα2a 180g q1wk (24 injections) for 24 weeks. An interim safety evaluation was conducted after all patients had completed the end of treatment while the interim efficacy endpoint was HCV RNA < LOD (20 IU/mL) at week 12 after end of treatment (SVR12). Patients were enrolled at 55 sites in Europe, Asia, Australia and Canada.

Results: Rates of treatment discontinuation due to adverse events were 1.0%, 2.9%, 3.8%, and 1.3% in the albIFN 900g, 1200g, 1500g and PEG-IFNα2a groups respectively (p=NS). Serious AEs occurred in 4.9%, 2.9%, 2.9%, and 2.6% respectively (p=NS). No statistically significant increase in serious or severe respiratory events was noted in any albIFN arm as compared to PEG-IFNα2a. Rates of cough on albIFN were 21.6%, 21.4% and 26.7% respectively vs 19.2% on PEG-IFNα2a (p=NS). Rates of alopecia were 35.3%, 37.9%, 47.6% and 28.2% respectively (p=0.05).

Overall, there were fewer hematology reductions on albIFN, leading to fewer IFN and ribavirin dose reductions. ANC reductions <750/mm3 were 5.0%, 13.7% and 8.6% for albIFN 900g, 1200g, 1500g groups vs 17.9% on PEG-IFNα2a (p=0.0279) while hemoglobin reductions <10g/dL were 11.9%, 18.4% 28.6% vs 25.6% respectively (p=0.0175).

SVR 12 rates were 76%, 75%, 81% for albIFN 900g, 1200g and 1500g, vs 82% for PEG-IFNα2a (intent to treat; p=NS). Corresponding rates of Rapid Virologic Response at week 4 (HCV RNA < 43 IU/mL) were respectively 49% (p<0.0001 vs PEG-IFNα2a) 60% (p=0.01), 71% (p=NS) vs 78% for PEG-IFNα2a. The higher than expected rates of SVR12 given the lower RVR rates were due to higher SVR12 in non-RVR patients in the albIFN groups.

Conclusion: AlbIFN given once every 4 weeks was generally well tolerated, with evidence of promising antiviral activity in chronic HCV GT2/3 infections.


800. Real- Time PCR Comparison of 48-Week and 72-Week Therapy with Peginterferon Alfa-2a(40kd) and Ribavirin for Cevr Cases in a Multicenter Clinical Trial: R-Zero StudyY. Yasui; G. Yamada; M. Kaito; K. Kariyama; S. Nishiguchi; S. Hashimoto; N. Izumi

Background: According to the concept of response-guided therapy (RGT) using the peginterferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC) infected with genotype 1, 48 weeks treatment has been recommended for patients achieved cEVR (HCV-RNA positive at week 4 and negative at week 12) and 72 weeks treatment has been recommended for patients achieved slow responder (HCV-RNA positive at week 12, but achieved negative at week 24 ), and the SVR rates has improved. However, the concept of RGT was established based on the lower sensitivity HCV-RNA qualitative test and the relapse rates of about 24% is seen in patients with cEVR after 48 weeks of PEG-IFN plus RBV therapy (Shiffman et al.;HEPATOLOGY vol.48,No.4(Suppl),879A,2008).

Aim: A multicenter, open label clinical trial was performed using real time PCR to investigate whether 72-weeks PEG-IFN alfa-2a(40KD) plus RBV therapy was effective for patients with cEVR.

Methods: The subjects were 114 CHC patients with genotype 1 and high viral load (≥ 5.0 Log IU/mL) in whom HCV-RNA was positive at week 4 after starting PEG-IFN alfa-2a(40KD) 180μg/wk plus RBV 600-1000mg/day therapy but negative at week 12, and who has evaluated sustained virologic response (SVR)/non-SVR by real time PCR. The subjects had a mean age of 56 years old, a male/female ratio of 47/67, and a mean HCV-RNA titer of 6.4 Log IU/mL. 50 patients had a previous IFN treatment. The SVR rates in 48-week and 72-week therapy were compared in 74 patients with HCV-RNA negative at weeks 5 to 8 and in 40 patients with HCV-RNA negative at weeks 9 to 12 to evaluate the benefit of the 72-week therapy for cEVR cases.

Results: SVR rates were 77% (51/66) and 75% (6/8) for 48-week and 72-week therapy, respectively, in patients in whom HCV-RNA turned negative at week 5 to 8 after initiation of PEG-IFN alfa-2a(40KD) plus RBV. In contrast, the respective SVR rates were 48% (15/31) and 78% (7/9) for patients in whom HCV-RNA turned negative at week 9 to 12, with a higher rate for the 72-week therapy . In patients in whom HCV-RNA turned negative at week 9 to 12 after initiation of therapy, the SVR rate for 48-week therapy was significantly lower in patients aged over 60 years old compared to those under 60 years of age (p=0.017), while the SVR rate for 72-week therapy showed no dependence on age (p=0.927).

Conclusion: cEVR was achieved with PEG-IFN alfa-2a(40KD) plus RBV therapy, but SVR was less likely to be obtained with 48-week therapy in patients in whom HCV-RNA turned negative in weeks 9-12, especially if the patient was over 60 years old. This suggests that the administration period should be extended to 72 weeks for cEVR week 9 to 12.

 


801. Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir Plus PEGINTRON (PegInterferon Alfa-2b)/Ribavirin in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1).  J. M. Vierling; P. Y. Kwo; E. Lawitz; J. McCone; E. R. Schiff; D. Pound; M. Davis; J. S. Galati; S. C. Gordon; N. Ravendhran; L. Rossaro; F. Anderson; I. M. Jacobson; R. Rubin; L. Pedicone; E. I. Chaudhri; X. Tong; P. Qiu; R. J. Barnard; C. A. Brass; J. K. Albrecht; P. Mendez; R. Ralston

Background: Boceprevir (BOC), a NS3 protease inhibitor, added to PEGINTRON (P) and Ribavirin (R) leads to high rates of sustained viral response (SVR) in CHC G1 patients who are treatment nave, non-responders or relapsers to prior Peginterferon/R therapy. We evaluated treatment nave CHC G1 patients who received BOC/P/R in a Phase 2 trial open-label trial (SPRINT-1) to determine factors associated with a differential frequency of resistance-associated variants (RAVs).

Methods: 595 patients were randomized to a control arm of P (1.5 μg/kg) + R (800-1400 mg/day) for 48 wks or one of 5 BOC treatment arms, including P/R for 4 wks (lead-in) followed by BOC 800 mg TID plus P/R for 44 wks (dosing regimen used in Phase 3 trials) and P + low dose R followed by BOC. HCV-RNA was detected using Roche Taqman (LLD <15 IU/mL). Amino acid variants at BOC resistance loci in the NS3/4A protease were detected using population sequencing.

Results: SVR was significantly higher in all BOC arms (54-75%) compared to control (38%). Of 595 patients, 401 (67%) were HCV G1a and 188 (32%) were G1b. Of 109 patients who developed RAVs on-study (i.e. those without RAVs at baseline), 78 were G1a, 30 were G1b and 1 could not be subtyped. The most frequently detected on-study RAVs in G1a patients were R155K (77%), V36M (68%), and T54S (37%) whereas the most frequently detected in G1b patients were T54S (57%), T54A (37%), A156S (43%), and I170A (43%). Among the 109 patients that developed RAVs on-study, 2 achieved SVR (both from BOC arms) and 107 were non-responders, relapsers or breakthroughs. Over 90% of subjects experiencing virologic breakthrough and 26% who experienced virologic relapse had RAVs detected on-study. Patients randomized to low dose R had the highest frequency of on-study RAVs (24/59 patients; 41%) whereas those assigned 4 wk P/R lead-in followed by 44 week BOC/P/R has the lowest frequency (11/103 patients; 11%). Notably, 24 of 595 patients (4%) had known RAVs at baseline, and the majority (17/24; 71%) achieved SVR. Among the 3 most frequent RAVs, T54S was observed less frequently in patients receiving lead-in therapy (on-study) (2/103 patients assigned 4 wk P/R lead-in followed by 44 wk BOC/P/R vs 10/119 patients assigned BOC/P/R for 48 wks and 3/103 assigned 4 wk P/R lead-in followed by 24 wk BOC/P/R vs 12/107 assigned 28 wk BOC/P/R).

Conclusions: The profiles of on-study RAVs differed between G1a and G1b patients. As in prior studies, the most common RAVs in G1a patients not achieving SVR were V36M, T54S and R155K. Lead-in therapy may reduce on-study mutations, such as T54S. Despite having RAVs at baseline, the majority of such patients achieved SVR.


802. Low rate of viral load rebound observed among treatment-naive genotype 1 patients with chronic hepatitis C treated with danoprevir (RG7227) plus PegIFN α-2a (40KD) (PEGASYS) plus ribavirin: interim analysis.  S. Le Pogam; M. Chhabra; J. Yan; M. J. Ilnicka; Y. Ji; D. J. Chin; N. Gonzaludo; K. Klumpp; I. Najera

Background: The danoprevir resistance pathway observed in 14-day monotherapy studies was largely restricted to the NS3 protease amino acid substitution R155K, unlike in the case of other hepatitis C virus protease inhibitors. The aim of this study was to monitor and characterize the potential development of resistance to danoprevir after 12 weeks of combination therapy with PegIFN α-2a (40KD) plus ribavirin (standard of care [SOC]).

Methods: The NS3/4A and/or NS3 protease coding region was amplified and population sequencing was performed on all baseline samples. Viral load kinetics were monitored for all patients. Population sequencing and phenotypic analyses were performed on samples from patients that, while on danoprevir treatment, experienced: i) viral load rebound, ii) non-response, iii) partial response.

Summary/Conclusions

        This analysis shows that the incidence of viral load rebound (3.1%) or partial response (1%) is low in patients receiving treatment with danoprevir at dosages of 300 mg q8h or 600 mg q12h in combination with peginterferon alfa-2a (40KD) plus ribavirin. Neither viral load rebound nor partial response was observed in any patient treated with the higher dose of danoprevir (900 mg q12h) that completed the 12 weeks treatment.

        Viral load rebound was only observed in genotype 1a infected patients and was observed predominantly in Group A (5/6) with only one patient from dosing Group B.

        Partial response was only observed in two genotype 1a patients from dosing Group B.

        All cases of viral load rebound and partial response were associated with the emergence of the R155K mutant, and with reduced susceptibility to danoprevir.

        R155K was not detected at baseline in any of these eight patients. However, four of the patients who experienced a viral load rebound did have variants (at low frequency) containing protease inhibitor resistance mutations V36A, T54A, A156T, or D168N/G. The lack of enrichment for any of these variants shows that they were not associated with the viral load rebound or partial response observed in these danoprevir-treated patients.

        Viral load rebound has not been observed to date in genotype 1b infected patients; this may be due to the higher genetic barrier of genotype 1b that requires two nucleotide substitutions to select for R155K (as opposed to one in genotype 1a).

 


803. Vitamin D Metabolites Inhibit Replication of the Hepatitis C Virus.  J. A. Gutierrez; K. A. Jones; R. L. Fitzgerald; J. Allina; A. D. Branch; D. L. Trump; R. T. Schooley; D. L. Wyles

Introduction: Vitamin D is a potent activator of the innate immune system and modulator of the cell cycle, while persistence of hepatitis C (HCV) infection may be due to derangement of these same systems. Furthermore, preliminary data suggest that vitamin D supplementation to a serum level of 32 ng/mL is associated with an improvement in virologic response to pegylated interferon plus ribavirin therapy. In this study, we tested the ability of vitamin D and its metabolites to inhibit the replication of HCV replicons and infectious HCV in cell culture.

Methods: Cell lines stably expressing luciferase reporter BM4-5 (gt 1b replicon), SGR-JFH-1 (gt 2a replicon), or J6/JFH (infectious gt 2a) were generated. Supernatants from cells replicating J6/JFH were used to infect nave cells at an MOI of 0.01 (HCVcc). HCV expressing cells were incubated in the presence of D2, D3 or 1,25(OH)2 D3 at concentrations from 0.5 M to 25 M for 120 hours. HCV expression was measured by relative light unit reporter assays after 120 hours and analyzed for EC50s using GraphPad Prism 4.03. HPLC was performed on supernatant to determine 25(OH) D3 after 24 hours of exposure to vitamin D3. Expression of vitamin D receptor (VDR) and core protein was examined by immunoblot in lysate from cells infected with J6/JFH.

Results: In the genotype 1b replicon, the EC50 of vitamin D2, D3 and 1,25(OH)2 D3 were 14 M, 3.8 M and 1.1 M, respectively. The EC50s in genotype 2a replicon cells were similar (13 M, 8.4 M and 4.7 M). The EC50 in HCVcc for vitamin D3 was 2.1 M. The mean CC50 at 120 hours of D2, D3 and 1,25(OH)2 D3 was 42 M, 55 M, and 23 M. Conversion of 1 M, 5 M and 25 M vitamin D3 to 25(OH) D3 was found to be 2 ng/mL, 24 ng/mL, and 191 ng/mL. In J6/JFH infected cells, we found that D3 and 1,25(OH)2 D3 increased protein expression of the VDR receptor after 24 hours of exposure, but was similar to controls at 72 and 120 hours. Conversely, HCV core production in treated cells was similar to controls at 24 hours, and then decreased at 72 and 120 hours.

Conclusions: This study shows the ability of vitamin D to inhibit HCV replication in model systems. Conversion of vitamin D3 to 25(OH) D3 was about 1% at 24 hours, and the EC50s of vitamin D3 generally had 25(OH) D3 levels that are comparable to those found in serum (25-50ng/mL). Intriguingly, vitamin D3 increased VDR protein expression and inhibited HCV expression. This suggests that Huh-7.5.1cells generate metabolites of vitamin D3 that activate the VDR leading to anti-HCV effects. Our future studies will be aimed at understanding the mechanism of how vitamin D affects hepatocytes and HCV.

 


804. Virological Response and Safety of 4 weeks treatment with the protease inhibitor BI 201335 combined with 48 weeks of Peginterferon alfa 2a and Ribavirin for treatment of HCV GT-1 patients who failed peginterferon / ribavirin.  T. Berg; D. T. Dieterich; J. P. Lalezari; M. Bonacini; R. Gnther; M. Bourliere; M. P. Manns; Y. Benhamou; J. L. Calleja; M. Schuchmann; M. Biermer; G. Steinmann; J. O. Stern; J. Scherer; W. O. Boecher

Background: BI 201335 is a highly potent and specific HCV NS3/4A protease inhibitor. BI 201335 given at 240 mg once daily demonstrated a median maximum viral load (VL) reduction by 4.4 LOG10 (IU/mL) during 14 days of monotherapy in treatment-nave HCV GT-1 patients, and by 5.3 LOG10 in combination with peginterferon alfa (PegIFN) 2a and ribavirin (RBV) for 28 days in treatment-experienced patients. This phase I study describes safety and efficacy of BI 201335 in GT-1 patients with virological failure to PegIFN/RBV.

Methods: Patients were randomised to open-label treatment with 240 mg once (QD; n=15) or twice daily (BID; n=15) in combination with PegIFN (180 mcg/week) and RBV (1000/1200 mg/d) for 28 days, followed by PegIFN/RBV until week 48. Patients with cirrhosis were excluded. All patients received an initial loading dose of 480 mg of BI 201335. Plasma HCV RNA was measured by Roche COBAS TaqMan assay.

Results: Mean age was 50 years, BMI 26 kg/m2. Mean VL at baseline was 6.6 LOG10 (IU/mL). Most patients were null- (40%), or partial (47%) responders to previous treatment, while 3 patients had breakthroughs and 1 relapsed. During 4 weeks of treatment with BI 201335 and SOC, all patients showed a rapid VL decline. Mean VL reduction on day 28 was -5.1 LOG10 in both groups. All 30 patients continued SOC treatment beyond day 28. Virological Responses until week 48 are displayed in the table. Sustained virological response (SVR) rates will be available at the meeting. One virologic breakthrough (≥1 log rebound from VL nadir or VL >100 IU/mL after undetectable VL) was observed during BI 201335 treatment. Treatment was generally safe and well tolerated. Adverse events were mainly mild to moderate and typical of PegIFN/RBV. There were no SAEs. Bilirubin elevations of 2.5-6x upper limit of norm were observed in 8 and 10 patients at 240 mg QD and BID and were exclusively caused by isolated unconjugated hyperbilirubinemia, likely due to UGT1A1 inhibition. Other lab analyses showed decreases of ALT and blood cell counts typical of PegIFN/RBV.

Conclusions: Four weeks of BI 201335 240 mg once or twice daily combined with PegIFN/RBV exhibited similarly potent on-treatment efficacy in PegIFN/RBV non-responder patients. These data support further studies of both doses in these patients.

Virological Response

240 mg QD
(n=15)

240 mg BID
(n=15)

Week 4
BLQ*
BLD*


9/15 (60%)
4/15 (27%)


10/15 (67%)
4/15 (27%)

Week 12
BLQ
BLD


9/15 (60%)
8/15 (53%)


9/15 (60%)
6/15 (40%)

Week 48
BLD


8/15 (53%)


6/15 (40%)

Week 72 (SVR)

pending

pending

 


805. No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based regimen in HCV Genotype 1 Treatment-Naive Patients: Subanalysis of C208 Study.  L. Serfaty; X. Forns; T. Goeser; P. Ferenci; F. Nevens; G. Carosi; J. P. Drenth; I. Lonjon-Domanec; R. DeMasi; G. Picchio; M. Beumont; P. Marcellin

Background: Insulin resistance is a well-known predictor of poor response with peginterferon and ribavirin (PEG-IFN/RBV; PR) in chronic hepatitis C (CHC) genotype 1 (G1) patients, but no data have been reported so far with Direct-acting Antiviral-based regimens. The objective of this exploratory analysis was to assess the impact of metabolic factors and insulin resistance measured by HOMA index on virologic response in European CHC G1 patients treated with telaprevir (TVR).

Methods: 161 G1 patients were equally randomized into 4 arms to receive 12 weeks of TVR 750mg q8h with PEG-IFN-alfa-2a/RBV (1000 or 1200mg/day) or PEG-IFN-alfa-2b/RBV (8001200mg/day), or TVR 1125mg q12h with PEG-IFN-alfa-2a/RBV or PEG-IFN-alfa-2b/RBV. Subsequently, patients received 12 or 36 weeks of additional PR based on on-treatment response criteria. Multiple regression analysis was used to explore the prognostic significance of baseline (BL) HOMA and other factors on virologic response at W4, W12, end of treatment (EOT) and 24 weeks after EOT (FU24).

Results: Among 161 patients randomized, 147 had BL HOMA assessment (mean age 44 yrs, 50% male, 91% caucasian, 24% with bridging fibrosis/cirrhosis, 81% with viral load >800000IU/mL, mean BMI 25, 3.4% with diabetes, 12% with hypertension). The proportion of patients with HOMA <2 was 55.8%; 24:31.3% and >4:12.9%. Independent factors that correlated with BL HOMA were BMI (OR=1.31) and viral load (OR=2.0). In intent to treat analysis, sustained virologic response (SVR) was similar across the 4 treatment arms (8185%). Neither response rates at W4, W12, EOT and FU24 nor viral load decline at W4 were significantly influenced by BL HOMA (figure). In multivariate analysis only fibrosis stage was predictive of SVR (OR=0.58, 95%CI:0.35, 0.97). At FU24, HOMA was significantly lower in SVR patients compared to non SVR (p<0.05).

Conclusions: In this retrospective analysis of G1 patients treated with TVR based regimen 1) BL HOMA was not predictive of virologic response; 2) SVR was associated with an improvement of HOMA. These results suggest that metabolic factors and insulin resistance do not have significant impact on treatment efficacy. These results warrant further confirmation.


http://aasld2010.abstractcentral.com/user_images/aasld2010/1909/895564/C208_HOMA_EDA2_b+w.jpg

 


806. High Rapid Virologic Response (RVR) with PSI-7977 QD plus PEG-IFN/RBV in a 28-day Phase 2a Trial.  E. Lawitz; J. P. Lalezari; M. Rodriguez-Torres; K. V. Kowdley; D. Nelson; E. DeJesus; J. G. McHutchison; M. Mader; E. Albanis; W. Symonds; M. Berrey

PSI-7977 is a novel nucleotide analog in development for HCV.

Methods: 63 treatment-nave non-cirrhotic patients infected with HCV genotype 1 (GT-1) were enrolled at 7 sites in the US. Patients were stratified by IL28B status (C/C vs any T allele) into 4 cohorts: PSI-7977 100mg, 200mg, 400mg QD or matching placebo with SOC for 28 days.

Results: Treatment groups were well-balanced for age, race, BMI, baseline HCV RNA (~6.6 log10 IU/mL), and HCV GT 1a vs 1b. Significant and consistent antiviral activity was observed following 28d of PSI-7977/SOC with no on-treatment viral breakthrough.

In patients receiving PSI-7977 100mg QD/SOC 88% (14/16) achieved rapid virologic response (RVR), or HCV RNA below the limit of detection (<15 IU/mL). In patients receiving PSI-7977 200mg QD/SOC 94% (17/18) achieved RVR. One patient who received 200mg QD was lost to follow up at D14 after a 4.7 log10 decline in HCV RNA. In patients receiving PSI-7977 400mg QD/SOC 93% (14/15) achieved RVR. In patients who received placebo/SOC 21% (3/14) achieved RVR. There were no differences in response for HCV GT 1a vs 1b. After discontinuation of PSI-7977, no rebound in HCV RNA was detected in any patient who received PSI-7977 200mg QD/SOC through week 8. Of the 14 patients who received PSI-7977 400mg QD/SOC and achieved RVR, 12 remained below LOD at week 8. Preliminary safety and tolerability for the 28 day treatment period were similar for PSI-7977/SOC and placebo/SOC. There were no serious adverse events (SAEs) reported, and no adverse events (AEs) led to treatment discontinuation. A majority of AEs reported were mild intensity. AEs reported were similar to clinical experience with SOC. There were no dose-related changes in safety laboratory assessments, vital signs or ECGs. A dose-dependent decrease in serum ALT was observed coincident with HCV RNA decline.

Conclusions:

        RVR rates of 88-94% were observed with PSI-7977/SOC in treatment-nave, HCV genotype 1 subjects, far superior to placebo/SOC (21% RVR)

        The regimen of PSI-7977 plus SOC was well-tolerated with no dose-limiting toxicities identified; the incidence and severity of lab abnormalities and AEs was similar to SOC alone

        Following cessation of PSI-7977, the durability of antiviral response was greatest in the 200 and 400 mg groups

        No viral resistance to PSI-7977 has been detected to date

        Results from this study supported initiation of a 12 week study of PSI-7977, 200 and 400 mg with SOC compared with SOC alone

        PSI-7977 antiviral efficacy in genotype 1 subjects in the current study coupled with broad genotype in vitro activity support the exploration of PSI-7977 in all HCV genotypes

Intent-to-Treat (ITT-last observation carried forward) RVR and week 8 HCV RNA

Study Arm

n

Mean Δ in HCV RNA
(log10 IU/mL) at Day 28

% of Patients with HCV RNA <15 IU/mL at Day 28

(RVR)

% of Patients with HCV RNA <15 IU/mL at Week 12

(cEVR)

PSI-7977 100mg QD/SOC

16

-5.3

88% (14/16)

75% (17/16)

PSI-7977 200mg QD/SOC

18

-5.1

94%* (17/18)

94%* (17/18)

PSI-7977 400mg QD/SOC

15

-5.3

93% (14/15)

87% (13/15)

Placebo + SOC

14

-2.8

21% (3/14)

64% (9/14)

 


807. Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-infected Patients.  D. M. Brainard; A. Petry; K. Van Dyck; R. B. Nachbar; I. M. De Lepeleire; L. Caro; J. A. Stone; P. Sun; M. Uhle; F. D. Wagner; E. O'Mara; J. A. Wagner

Background: MK-5172 is a novel, competitive inhibitor of the HCV NS3/4a protease with selective, potent in vitro activity against viral variants that are resistant to other protease inhibitors in development. This placebo-controlled study assessed the safety, tolerability and antiviral efficacy of MK-5172 administered as 7 days of monotherapy to adult male patients with chronic genotype (GT) 1 or 3 HCV infection.

Methods: Males, 18-65 years old with HCV RNA > 105 IU/mL, and GT 1 or 3 chronic HCV infection without clinical evidence of cirrhosis, were randomized to receive placebo or 400 mg MK-5172 once daily for 7 days (MK-5172:placebo ratio of 5:1 for separate panels of GT1 and GT3 patients). Patients were followed for up to 2 months after the last dose. Safety and tolerability were evaluated using laboratory values, electrocardiogram (ECG), and evaluation of adverse experiences (AEs). Antiviral efficacy was assessed through quantitation of plasma HCV RNA using the Roche Cobas TaqMAN 2.0 assay (lower limit of detection = 3.8 IU/mL) at multiple time points.

Results: Data are reported here for 9 patients (6 GT1, 3 GT3) who received placebo or 400 mg MK-5172 once daily for 7 days. There were no serious AEs reported and no discontinuations due to AEs. The most commonly reported AE was headache (N=4) and AEs were limited in number, transient, and rated mild to moderate in intensity. No clinically relevant laboratory safety signals or ECG abnormalities were observed. Several patients on therapy showed transient reductions in liver function tests correlating with reductions in HCV RNA. Mean maximum reductions from baseline of HCV viral RNA (SEs) were 5.40 (0.21) and 3.98 (0.22) log10 IU/mL for GT1 and 3, respectively. No on-treatment viral rebound was observed in any patient. Five GT1 patients had decreases in HCV RNA to levels below the lower limit of detection during the study period, and the mean time to nadir was more than 2 days after the last dose. By the 1 month follow-up visit, plasma levels of HCV-RNA had returned to baseline levels for those patients for whom these data were available. Pharmacokinetic values of MK-5172 in HCV-infected patients were higher than values observed in healthy subjects.

Conclusions: MK-5172 has potent antiviral activity during 7 days of monotherapy in patients with chronic GT1 and 3 HCV infections. Antiviral activity persisted for several days beyond the treatment period in GT1 patients. MK-5172 was generally well-tolerated with no serious AEs, discontinuations due to AEs or safety laboratory abnormalities. These findings support further clinical investigation of MK-5172 for the treatment of chronic HCV infection

 


808. Virologic and Metabolic Responses in Chronic Hepatitis C (CHC) Genotype 1 (G1) Patients With Insulin Resistance (IR) Treated With Pioglitazone (PIO) and Peginterferon alfa-2a Plus Ribavirin (P/R) Final Results of Week 12 Early Virologic ResponseJ. M. Vierling; A. Prabhakar; J. Han; S. A. Harrison

Background: Improving insulin sensitivity in CHC G1 patients with IR may increase the sustained virologic response to P/R therapy. The Sensitize study is designed to compare virologic and metabolic responses in CHC G1 patients with IR randomized to receive P/R alone or PIO + P/R. The primary efficacy endpoint is the change in HCV RNA from randomization to Wk 12 of HCV therapy.

Methods: This is a multicenter, randomized, open-label study designed to treat 240 CHC G1 patients with IR. Patients stratified by homeostasis model assessment score (HOMA) of >2<4 or ≥4 were randomized to 2 treatment arms (P/R alone [control] vs PIO + P/R [PIO]). All patients received PegIFN-2a 180 g/wk + RBV 10001600 mg/d for 48 wks and were followed for a 24-wk antiviral-free period. Patients in the PIO arm were treated with PIO alone for 16 wks (30 mg/d 8 wks then 45 mg/d 8 wks) prior to adding P/R for 48 wks. PIO 45 mg/d was continued during the 24-wk antiviral-free period. We report the final results of the primary efficacy endpoint.

Results: Due to slow enrollment, only 155 patients were randomized; 150 were included in the ITT population (control arm, n=73; PIO arm, n=77). Five excluded patients had no post-baseline HCV RNA data. At baseline, more patients in the PIO vs control arm were black (25% vs 14%), had ALT >3ULN (22% vs 15%), and had HCV RNA ≥800,000 IU/mL (83% vs 77%); glycemic variables were similar between arms. In the PIO vs control arm, similar declines were seen in median log10 HCV RNA from baseline to Wks 4 ( 2.1 vs 2.1 IU/mL) and 12 ( 4.0 vs 4.2 IU/mL) of anti-HCV therapy; results were consistent in patients with HOMA ≥4. In the PIO vs control arm, undetectable HCV RNA levels (<28 IU/mL) were seen in 6.5% (5/77) vs 16% (12/73) of patients at Wk 4, and 34% (26/77) vs 49% (36/73) at Wk 12 (15 dropouts in the PIO arm during lead-in counted as nonresponders); in patients with HOMA ≥4, 3% (1/37) vs 15% (5/34) and 24% (9/37) vs 38% (13/34) were HCV RNA undetectable at Wks 4 and 12, respectively. Median changes from baseline in HbA1c, HOMA, insulin, and glucose at Wk 12 were 1.1%, 1.6, 39.2 pmol/L, and 0.6 mmol/L in the PIO arm vs 1.4%, 0.5, 10.5 pmol/L, and 0.2 mmol/L in the control arm, respectively. Five out of 79 patients (6%) in the PIO arm and 3/76 (4%) in the control arm withdrew due to adverse events; 23/79 (29%) in the PIO arm and 10/76 patients (13%) in the control arm withdrew for non-safety reasons.

Conclusions: Improvements in glycemic variables with PIO treatment prior to and during P/R therapy did not improve early virologic responses in CHC G1 patients with IR compared with patients treated for 12 weeks with P/R alone.

 


809. Vitamin D supplementation improves viral response in chronic hepatitis C genotype 2/3 patients treated with peg interferon alpha-and ribavirin.  S. Abu Mouch; N. Assy

Background: We have shown previously that adding vitamin D to conventional Peg/RBV therapy for nave, genotype 1 patients with chronic HCV infection significantly improves early and sustained viral response Aim: to examine whether vitamin D could improve the viral response in HCV genotype 2/3 patients and to determine if vitamin D levels predicts treatment outcome.

Methods: 40 patients with chronic HCV genotype 2/3 were randomized into two groups: Treatment group [20 subjects, age 4814 yrs, [BMI] 296, 65% male] who received pegylated interferon-2a plus oral ribavirin 800-1200 mg/d together with oral vitamin D3 (1000-4000 IU/d, normal serum level >32 ng/ml) for 24 weeks and control groups (20 subjects, age 4510, [BMI] 265, 60% male] who received identical therapy without vitamin D. HCV RNA was assessed by (RT-PCR). Undetectable HCV RNA at week 4, 12 and 24 wks post treatment were considered as rapid virologic response (RVR), complete early virologic response (EVR) and SVR respectively.

Results: The treatment group with vitamin D had higher BMI (296 vs 26, P<0.001), and high viral load (>600,000 IU/ml, 45% vs 40%, P<0.01 ) than controls. 95% of treated patients were HCV RNA negative at week 4 and week 12 respectively. At 24 weeks post treatment (SVR), 95% (19/20) of treated patients and 85% (17/20) of controls were HCV RNA negatives (P<0.01). Adverse events were mild and typical of Peg/RBV. Baseline serum vitamin D levels were lower at base line (2611 ng/ml) and increased after 4 weeks of vitamin D treatment to a mean level of (367) respectively. Logistic regression analysis identified serum vitamin D levels (OR 3.9, P<0.01) and BMI (OR 2.6, P<0.001) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV.

Conclusion: Low vitamin D levels predicts negative treatment outcome and adding vitamin D to conventional Peg/RBV therapy for genotype 2/3 HCV patients significantly improves viral response.

 


81. High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study.  D. M. Jensen; H. Wedemeyer; R. W. Herring; P. Ferenci; M. M. Ma; S. Zeuzem; M. Rodriguez-Torres; N. H. Bzowej; P. Pockros; J. M. Vierling; D. Ipe; G. Z. Hill

Background: RG7128 is a novel nucleoside analog polymerase inhibitor of HCV. This Phase 2b study evaluated safety and efficacy of RG7128 in combination with 180 μg/wk PegIFN alfa-2a + 1000/1200 mg/day ribavirin (standard of care [SOC]) in HCV GT 1 and 4 treatment-naive patients.

Methods: Patients were randomized across 5 treatment arms:

        Arm A: RG7128 500mg twice a day (BID)/SOC x 12 weeks (n=80);

        Arm B: 1000mg BID/SOC x 8 weeks (n=81);

        Arm C: 1000mg BID/ SOC x 12 weeks (n=82);

        Arm D: 1000mg BID/SOC x 12 weeks (n=81);

        Arm E: SOC x 48 weeks (n=84).

Patients on Arms A, B, and C who maintained HCV RNA <15 IU/mL from week 4 to 22 stopped all treatment at week 24. Patients who did not have an RVR, and patients randomized to Arms D or E continued SOC to complete 48 weeks.

Virological response was measured by the Roche COBAS TaqMan assay (Limit of Detection ≥15 IU/mL). Efficacy results are from a planned interim analysis of data through week 12. The safety database included all data available at the time of the snapshot, including patients beyond 12 weeks.

Results: 408 patients were enrolled; ~20% had histological diagnosis of cirrhosis. Independent of cirrhosis, all RG7128 triple combination arms demonstrated potent antiviral effects greater than SOC alone. RG7128 triple combination (500 or 1000mg BID + SOC) was safe and well tolerated with a safety profile similar to SOC. No hematological, renal, GI, dermatological or other organ system events different than those expected with SOC were detected. No viral rebound or RG7128 resistance mutations including S282T were observed during triple therapy.

Conclusion:

        RG7128 with SOC for 8 or 12 weeks was safe and well-tolerated and demonstrated potent antiviral efficacy as measured by RVR and cEVR rates in treatment-naive genotype 1 and 4 patients with and without cirrhosis.

        The 12 week regimen was associated with higher rates of cEVR than the 8 week regimen.

        No resistance-related breakthrough occurred during triple therapy, consistent with the high barrier to resistance noted in earlier clinical studies.

        The safety, efficacy, and lack of resistance supports further clinical development of RG7128.

http://aasld2010.abstractcentral.com/user_images/aasld2010/1909/889957/Table_for_submission.JPG

 


810. Hepatitis C trials that combine investigational agents with pegylated-interferon-α should be stratified by IL28B genotype .  A. J. Thompson; A. J. Muir; M. S. Sulkowski; K. Patel; H. L. Tillmann; P. J. Clark; S. Naggie; J. Fellay; D. Ge; J. McCarthy; D. B. Goldstein; J. G. McHutchison

Background: Genotype 1 HCV patients treated with pegIFN/RBV who carry the good response IL28B variant (C/C, rs12979860) have dramatically improved early viral kinetics. Current strategies for the clinical development of directly-acting anti-HCV agents involve combination with pegIFN/RBV to restrict the development of antiviral resistance. Given the population frequency of the good response IL28B variant it is possible for small early phase efficacy trials to be confounded by imbalance for IL28B genotype across treatment arms.

Methods: We statistically modeled the probability of an imbalance for the C/C IL28B genotype between treatment arms for 3 hypothetical situations a phase 1 (n=60), 2a (n=120) and 2b (n=240) trial, each involving 3 randomized arms. We then modeled the implication of such an imbalance for the primary outcome of viral load reduction at week 4 in studies that combine a direct antiviral with pegIFN plus RBV. We assumed i) a population frequency of C/C = 33%; and ii) median viral load reduction at 4 weeks of treatment of 3.8 logIU/mL vs 1.4 logIU/mL in C/C vs non-C/C patients due to pegIFN alone, as previously reported for North American Caucasians (Thompson,Gastro,Apr 15, Epub).

Results: The probability of an imbalance in one treatment arm of 10% (<23% or > 43%) was 31%, 18% and 6% for the phase 1, 2a and 2b trials, and for an imbalance 20% was 10%, 0.4% and <0.01%. In a phase 1 trial, an imbalance for the good response C/C genotype of 10% - 20% could lead to differences of 0.2 - 0.5 log between treatment arms at week 4, due to pegIFN alone (Table 1).

Conclusion: Knowledge of IL28B genotype distribution is important for interpreting early phase clinical trial results, particularly dose-finding studies where dose-related antiviral potency must be weighed against toxicity. Confounding by IL28B genotype imbalance between treatment arms might affect the decision to advance a compound from proof-of-concept to the next stage of clinical development.

Table 1. Apparent differences in antiviral efficacy may result from imbalance of IL28B genotype frequency between treatment arms in early phase trials.

 

Arm A
Placebo
+ PegIFN / RBV
N=20

Arm B
Antiviral, dose 1
+ PegIFN / RBV
N=20

Arm C
Antiviral, dose 2
+ PegIFN / RBV
N=20

10% imbalance between treatment arms

N (C/C IL28B-type)

23%

33%

43%

N (non-C/C IL28B-types)

77%

67%

57%

Mean VL reduction at 4 weeks (log10 IU/mL)

2.0

2.2

2.4

20% imbalance between treatment arms

N (C/C IL28B-type)

13%

33%

53%

N (non- C/C IL28B-type)

87%

67%

47%

Mean VL reduction at 4 weeks (log10 IU/mL)

1.7

2.2

2.7

Assumptions: 1) Candidate drug has no antiviral activity; 2) Frequency of the good response (C/C) IL28B-type = 33%; 3) Good response (C/C) IL28B-type - viral load reduction at week 4 = 3.8 log10 IU/mL; 4) Poor response (non-C/C) IL28B-type - viral load reduction at week 4 = 1.4 log10 IU/mL

 


811. Ex vivo induction and expansion of HCV core antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells.  W. Liu; W. Wu; H. Zhu; Z. Chen

Background: Hepatitis C virus infection (HCV) has become quite serious with occurrence of increasing population co-infected with human immunodeficiency virus. However, there is no effective therapeutic vaccine for HCV until present. People infected HCV usually develop into chronic infection, even into liver cirrhosis and hepatocellular carcinoma if not cured. Many studies have confirmed that clearance of HCV was closely associated with antigen-specific CTLs. Although the typical approach to generating antigen-specific CTLs in vitro was based on dendritic cells (DCs), quantity and quality of DCs obtained from individuals were variable. Accordingly, induction of antigen-specific T cells by DCs would be affected. Artificial antigen-presenting cells (aAPCs) technology developed by Oelke et al. has been demonstrated a valuable method to expand and maintain antigen-specific CTLs ex vivo. HLA-Ig-based aAPC induced antigen-specific CTLs could also recognize endogenously processed antigen presented on target cells. Therefore, we attempted to apply the technique to expansion of HCV antigen-specific CTLs.

Methods: Chronic hepatitis C virus patients enrolling in the study were HLA-A2.1 phenotyped by flow cytometry. Peripheral blood mononuclear cells (PBMC) were isolated by lymphocyte-H density gradient centrifugation. CD14+ mononuclear cells and CD8+ T lymphocytes were sequentially separated from PBMC by magnetic sorting. CD14+ cells were cultured to generate mature DCs for peptides pulsing. The peptide-pulsed DCs were used to stimulate CD8+ T cells to induce and proliferate CTLs. aAPCs were made by coating Dynal M-450 Epoxy beads with HLA-Ig and anti-CD28 monoclonal antibody. HCV core antigen epitope-loaded aAPCs were utilized to activate and expand CTLs.

Results: The present study indicated that antigen-specific CTLs were successfully induced from CD8+ T of some donors. Generally, CD8+ T cells were activated and started to quickly expand after having been stimulated with peptide-pulsed aAPCs for 7 days. Co-cultured with peptide-pulsed aAPCs, CD8+ T cells were able to continuously proliferate after having been re-plated. In addition, we found that frequency of antigen-specific T cells induced was limited by states of CD8+ T cells separated from peripheral blood of donors.

Conclusions: Frequency of antigen-specific T cells could be obviously augmented in vitro by approach of HCV core peptide-loaded aAPCs even though there was variable in yield among chronic hepatitis C patients.

Acknowledgments: This work was supported by The National S&T Major Project for Infectious Diseases Control (2008ZX10002-013).

 


812. Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to therApy (OPERA)-1 study.  O. Lenz; L. Vijgen; T. Lin; M. Peeters; G. . De Smedt; G. Picchio

Aim: OPERA-1 (TMC435-C201; NCT00561353) is a Phase IIa study of TMC435, a hepatitis C virus (HCV) NS3/4A protease inhibitor, in HCV genotype-1-infected patients. Treatment-nave patients (Cohorts 1 and 2) received 7 days of monotherapy with TMC435 25, 75, or 200 mg once daily (QD), or placebo, followed by 21 days of TMC435 plus pegylated interferon (PegIFN)α-2a and ribavirin (RBV) (Panel A), or 28 days of triple therapy (Panel B). Patients who had failed prior IFN-based therapy received 28 days of triple therapy with TMC435 75, 150, or 200 mg QD, or placebo (Cohort 4). We investigated the relationship between specific NS3 variants at baseline and response, and characterized emerging viral variants in patients with viral breakthrough (vBT).

Methods: Viral variants were characterized by population sequencing and transient replicon assays, with replicons harboring either single mutations or NS3 protease domains obtained from patient isolates. vBT was defined as >1 log10 IU/mL increase in HCV ribonucleic acid (RNA) from nadir.

Results: We previously showed that the NS3 Q80K mutation confers low level resistance to TMC435 in vitro (fold change [FC] in 50% effective concentration [EC50] ~8). Analysis of patients in OPERA-1 with a Q80K variant at baseline showed 6/8 treated with TMC435 ≥75 mg QD achieved HCV RNA levels <25 IU/mL at Day 28. HCV RNA levels in the other 2 patients (prior non-responders to IFN-based therapy) declined >2 log10 IU/mL from baseline at Day 3 and was 30 and 411 IU/mL at Day 28, respectively. 0/4 patients with Q80K mutations at baseline treated with TMC435 25 mg QD had a >2 log10 IU/mL decline in HCV RNA at Day 3 and 2/4 achieved HCV RNA <25 IU/mL at Day 28. No vBTs were observed during the 28-day period in treatment-nave patients receiving triple therapy, or in treatment-experienced patients receiving triple therapy with TMC435 200 mg QD. Eight patients who received initial monotherapy experienced a vBT; in these patients, ≥1 of the following emerging mutations was observed: Q80R or K; R155K; D168E, N, or V. While baseline isolates from vBT patients were susceptible to TMC435 in vitro (FC in EC50 <1), emerging variants showed significantly reduced susceptibility (FC in EC50 >101000). Similar emerging mutations to those observed in subjects with vBT were identified in some patients with continuous decline in HCV RNA levels.

Conclusions:

        The presence of Q80K variants at baseline did not appeara to affect viral response at Day 28 for TMC435 ≥75 mg QD.

        No viral breakthroughs were observed during the 28-day TMC435 treatment period in treatment-nave patients receiving 28 days of triple therapy or in treatment-experienced patients receiving triple therapy with TMC435 mg QD.

        Viral breakthrough was infrequent, associated with initial monotherapy or failure of prior IFN-based therapy, and was characterized by the emergence of variants with reduced susceptibility to TMC435.

        These findings provide the first insights into the relevance of viral variants with reduced susceptibility to TMC435 and treatment response.

 


813. PACIFIC: A phase III, randomized, multicenter, dose escalation, efficacy and safety study examining the effects of treatment with peginterferon alfa-2a in patients with Childs A or B cirrhosis in chronic hepatitis C virus infection.  S. Tanwar; M. Wright; G. R. Foster; S. D. Ryder; P. R. Mills; M. E. Cramp; J. Parkes; W. M. Rosenberg

Background: Trials have found conflicting results about the efficacy of pegylated interferon alpha (PIFN), with or without pretreatment including ribavirin, as an antifibrotic agent in patients with established cirrhosis due to persistent HCV infection. We have investigated the use of an escalating dose of PIFN2a monotherapy for 48 weeks in the treatment of patients with established cirrhosis due to persistent HCV infection.

Methods: A multicenter, randomized prospective controlled trial of escalating dose PIFN2a treatment of patients with HCV infection and Childs A or B cirrhosis. 39 patients were enrolled at 5 UK centers and randomized to standard clinical care, or 48 weeks treatment with PIFN2a at 90mcg p.w. escalating each month by 45mcg to 180mcg p.w. if tolerated and followed for 140 weeks. Primary outcomes were liver related death (LRD); liver related morbidity (LRM) including variceal haemorrhage, ascites and SBP, hepatocellular cancer, transplantation and all cause mortality. Secondary outcomes were health related quality of life (HRLQ). There was no significant difference in the baseline characteristics between treatment and control groups (male 71:77%; mean age 55.2:52.1; Childs score 5.35:5.32; MELD 8.23:7.95).

Results: Treatment was well tolerated. 15/17 (88%) completed 48 weeks treatment; 1 at 45mcg; 1 at 90mcg; 2 at 135mcg; 11 at 180mcg.

There were no differences between groups in HRQL except pain scores that were increased in the treatment group (Score=50.7:70.5, p=<0.01). Recruitment to the study was halted by the DSMC on publication of HALT-C and EPIC trial results.

Conclusion: Escalating PIFN2a monotherapy is associated with HCV clearance and a reduction in liver related mortality in this small RCT. The differences from HALT-C and EPIC, and similarity to COPILOT may relate to marked differences in methodology (specifically the omission of therapy in the control arm), cirrhosis stage or sample size. These findings warrant further investigation of PIFN2a for patients with advanced cirrhosis for whom there is no other treatment and where transplantation is associated with graft infection and rapid progression to cirrhosis.

Acknowledgements: Roche provided free drug and support for pharmacovigilence and viral diagnostics. The study was supported by the British Liver Disease Clinical Interest Group, BASL, BSG and the Wellcome Trust through the Southampton Clinical Research Facility.

 

SVR
n(%)

Liver related morbidity n (%)

Liver related mortality n (%)

All cause mortality n (%)

Intervention (n=17)

3 (18)

2 (12)

0

0

Control (n=22)

0

6 (26)

5 (23)

6 (27)

p value

>0.001

0.23

0.035

0.019

 


814. Individualized Concentration Monitored High Dose Ribavirin in Combination with Peginterferon to Hepatitis C Genotype 1 Patients with Previous Nonresponse.  K. Lindahl; E. Hrnfeldt; T. Carlsson; A. Hollander; L. Stahle; O. Weiland; R. Schvarcz

Background: Gt 1 infected patients, previous non-responders (NR)to treatment with pegylated interferon (peg-INF) and ribavirin (RBV) are a difficult-to-treat population. We have previously shown that high doses of RBV (2550 mg/d) offered high treament response (SVR) in treatment-nave patients with hepatitis C genotype 1. The aim of this study was to evaluate the efficacy, safety and tolerability of individualized concentration monitored high doses of RBV in combination with standard dosed peg-INF in previous NR.

Methods: This prospective, open label, singel-centre, pilot study investigates efficacy, safety and tolerance of RBV concentrations of more than 15 mmol/L in combination with standard dosed PEG-IFN in patients who previously failed treatment with PEG-IFN and RBV. 20 patients with HCV gt 1 were treated with individualized high dose of RBV in combination with peg-INF a-2a 180mg/week for 48 weeks. NR were defined as not achieving HCV-RNA <50 IU/mL at any time during previous treatment. The initial RBV dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function aiming at a high steady state concentration of RBV of 16 mmol/L. Plasma RBV concentrations were measured by HPLC and the RBV dose was adjusted to reach target concentration. All patients received erythropoietin (epo) at doses 10,000-60,000 IU/week, from 2 weeks prior to initiation of antiviral treatment.

Results: We enrolled 20 patients, mean age 52 yr and 12 patients with fibrosis F3,F4. The mean initial RBV dose was 2130 mg/d (range 1600-3000). The mean baseline HB level was 16.3 g/dL, at treatment week 12 mean HB level was 11.0 g/dL. Two patients required blood transfusions. Mean baseline viral load was 6.6 x 106 IU/mL, at treatment week 12 the mean viral drop was 3.1 log, vs previously standard treatment 2.0 log (p<0.001). Sixteen patients reached an EVR. Three patients stopped treatment at w15-17 due to lack of viral response (n=2) and side effects (n=1). Twelve patients were neg in HCV-RNA (<15 IU/mL,COBAS TaqMan) at w24 and 1 patient reached SVR.

Conclusion: Individualized high-dosed RBV in combination with peg-INF alfa-2a resulted in a mean 3.1 log HCV-RNA decline within 12 weeks in previous non-responders to standard-dosed combination therapy. High-dosed RBV treatment is feasible and seems to be safe, but requires attention regarding anemia. Erythropoietin probably contributes to tolerability. In previous NR this treatment model did not significantly improve treatment outcome in SVR but the viral on-treatment response is significantly increased (p<0.001) supporting that the antiviral effect of RBV is related to plasma concentrations.

 


815. IL28B SNP Geographical Distribution and Antiviral Responses in a 28-day Phase 2a Trial of PSI-7977 Daily Dosing plus PEG-IFN/RBV.  J. G. McHutchison; D. B. Goldstein; K. Shianna; E. Lawitz; J. P. Lalezari; M. Rodriguez-Torres; K. V. Kowdley; D. Nelson; E. DeJesus; W. Symonds; M. Mader; E. Albanis; M. Berrey

A recent genome wide association study identified a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, shown to demonstrate an association of C/C genotype with outcome of treatment with PEG-IFN/RBV. PSI-7977 is a novel nucleotide analog in development for the treatment of HCV. Enrollment for the Phase 2a trial was stratified by IL28B status to ensure balance across dosing cohorts.

Methods: 121 treatment-nave HCV-infected patients were screened, and 63 patients enrolled across 7 sites in the U.S. No patients were excluded based on IL28B status. Patients were excluded for HCV RNA <100,000 IU/mL, non-1 HCV genotype, or cirrhosis. Patients were stratified into cohorts only by IL28B status: C/C vs any T allele. The four cohorts included PSI-7977 100mg, 200mg, 400mg QD or placebo with SOC for 28 days.

Summary/Conclusion:

        The percentage of IL28B distribution various from 6% Puerto Rico to 44 percent in the Pacific Northwest. Stratification on only IL28B status did not result in treatment cohorts balanced for baseline HCV RNA or gender

o   Baseline HCV RNA influences PSI-7977 antiviral activity and should be a stratification criterion

        IL28B genotype did not influence on-treatment viral kinetics in subjects on PSI-7977 at any dose in combination with SOC

        IL28B C/C subjects on PSI-7977 at all doses achieved RVR and maintained HCV RNA below the level of detection during SOC follow-up with no rebound

        Two subjects with high baseline HCV RNA and IL28B C/C genotype achieved SVR after only 28 days of total therapy. Shorter durations of interferon therapy should be explored

 


816. Impaired Fasting Glucose is Associated with Lower Rates of Sustained Virologic Response (SVR) in Patients with Genotype 1 Chronic Hepatitis C (CHC): Retrospective Analysis of the IDEAL Study.  M. S. Sulkowski; S. A. Harrison; L. Rossaro; K. Hu; E. Lawitz; M. L. Shiffman; A. J. Muir; G. Galler; J. McCone; L. Nyberg; W. M. Lee; R. H. Ghalib; J. Long; S. Noviello; C. A. Brass; L. Pedicone; J. K. Albrecht; J. G. McHutchison; J. W. King

Background/Aims: Impaired fasting glucose is independently associated with reduced likelihood of SVR with current therapy (NEJM, 2009;361:580). However, the relationship between SVR, fasting blood glucose (FBG) and HBA1c has not been defined.

Methods: 3070 treatment-naive, CHC genotype 1 patients (pts) received peginterferon (PegIFN) alfa-2b or alfa-2a plus ribavirin (RBV). All pts underwent pretreatment FBG determination and were categorized by their medical history of diabetes. Based on American Diabetes Association definition, pts with FBG ≥100mg/dL were defined as having impaired fasting glucose (IFG). Per protocol, pts with known diabetes and/or FBG ≥116mg/dL underwent HBA1c testing; those with HBA1c >8.5% were excluded. Pts with FBG between 100 and 115mg/dL did not have HBA1c testing. Virologic response rates were analyzed.

Results: 3068 pts were included in the analysis. The frequency of IFG of ≥100mg/dL was 28.7% (880/3068) and of a medical history of diabetes was 6.7% (206/3068). Among those who underwent testing (n=324), median HBA1c was 6.1% (interquartile range 5.6% - 6.6%). SVR according to baseline FBG for all pts and according to HBA1c for the subset with testing are shown (Table). SVR rate was significantly lower among pts with IFG compared to those with FBG <100mg/dL (P<0.001); relapse rate was also higher in those with IFG. Pts with a history of diabetes had lower SVR rates than those without (21.4% [44/206] vs 41.0% [1161/2833]). However, among those tested, the SVR rate was not associated with HBA1c level (<6% vs ≥6%; P=0.88).

Conclusions: Impaired fasting glucose and the clinical diagnosis of diabetes were each strongly associated with lower SVR and higher relapse rates in CHC genotype 1 pts treated with PegIFN/RBV. Among those who underwent testing, no association between HBA1c level and SVR was apparent; however, pts with HBA1c >8.5% were excluded from treatment. These data suggest that FBG should be routinely assessed prior to therapy; randomized trials are needed to determine if improvement in glucose control prior to treatment will lead to improved viral response.

SVR Rate (%)

EOT Response Rate (%)

Relapse Rate (%)

Fasting Blood Glucose (pretreatment)

All Patients (n=3068)

40

56

26

<100 mg/dL (n=2188)

43

58

22

100 125 mg/dL (n=747)

31

50

34

>125 mg/dL (n=133)

25

44

40

HBA1c (pretreatment)

Pts with protocol-defined criteria of diabetes and/or FBG ≥116mg/dL (n=324)

26

45

40

<6% (n=139)

25

45

44

6 <7% (n=133)

23

46

46

7 8.5% (n=52)

33

40

15

 


817. Impact of PegIntron (PEG) maintenance therapy (MT) on fibrosis biomarkers (FibroTest[FT]/Fibrosure) in prior nonresponders with METAVIR fibrosis scores (MFS) of F2/F3: Final results from the EPIC3 program.  T. Poynard; M. Munteanu ; J. Bruix; E. R. Schiff; M. Diago; T. Berg; R. Moreno-Otero; L. G. Lyra; F. J. Carrilho; N. Boparai; L. H. Griffel; M. Burroughs; C. A. Brass; J. K. Albrecht

Background & Aims: The EPIC3 F2/3 study, designed to evaluate the efficacy of low dose PEG-2b (0.5 mcg/kg/week) MT vs observation (OBS) on improvement of MFS in previous non responders did not demonstrate efficacy of MT. The aim of the present study was to assess if there was a treatment effect on FT and Actitest (AT), two validated sensitive non-invasive markers of fibrosis with similar prognostic values, compared to liver biopsy (LBx) (FT: clinical event/mortality at up to 5 years, AT: necroinflammatory activity).

Methods: Patients with F2/F3 MFS who failed retreatment (ReRx) were randomized to PEG or OBS for 36 months. Blinded LBx obtained before ReRx and after MT were evaluated using MFS and MAS. FT-AT were assessed by a blinded reviewer using predetermined cutoffs. The primary biochemical endpoint was the percentage of patients who did not progress at least 0.20 for FT or 0.25 for AT corresponding to 1 MFS and 1 activity grade respectively, at the last assay in comparison with baseline.

Results: Of 540 randomized, 358 were included,(170 with <2 FT and 12 with not interpretable FT not included). Baseline characteristics were similar to those in the overall trial: PEG (n=174) and OBS patients (n=184): 72% male, mean age 50 years, mean weight 76kg, 70% viral load >600,000IU/mL, and 94% genotype 1, median FT 0.65, AT 0.62. Using FT equivalence of MFS, significantly more patients worsened in OBS vs PEG (14% vs 6%; P = .02) and using AT equivalence more PEG patients improved in activity METAVIR grade AS vs OBS (16% vs 5%; P =.001).
There was significant worsening in fibrosis estimated using last FT, in OBS vs patients treated with PEG, as well as for necro-inflammatory activity estimated using last AT (Table). Impact by time is in the Table.

Conclusions: Using biomarkers this randomized trial demonstrated improvement of both fibrosis and necroinflammatory estimates with PEG maintenance therapy. Due to the risk of under powered conclusions, using biopsy as the main endpoint in maintenance therapy clinical trials should be revisited.

 

FibroTest

ActiTest

 

1 year

2 years

3 years

Last

1 year

2 years

3 years

Last

PEG-IFN

-0.003
(-0.02:0.02)

-0.004
(-0.03:0.02)

-0.01
(-0.01:0.03)

0.00
(-0.01:0.03)

-0.03
(-0.06:-0.00)

-0.07
(-0.10:-0.04)

-0.09
(-0.12:-0.05)

-0.09
(-0.12:-0.05)

Control

+0.02
(-0.01:0.04)

+0.03 (0.01:0.05)

+0.06 (0.04:0.09)

+0.05 (0.03:0.07)

+0.01
(-0.02:0.04)

+0.01
(-0.02:0.04)

+0.02
(-0.01:0.05)

+0.02
(-0.01:0.05)

Significance

0.31

0.05

0.003

0.01

<0.0001

0.0001

<0.0001

<0.0001

 


820. Three-Day, Dose-Ranging Study of the HCV NS3 Protease Inhibitor GS-9451.  E. Lawitz; J. M. Hill; T. C. Marbury; M. Rodriguez-Torres; M. p. DeMicco; J. Quesada; P. Shaw; S. C. Gordon; M. J. Shelton; D. H. Coombs; J. Zong; A. Bae; K. A. Wong; H. Mo; E. Mondou; K. R. Hirsch; W. E. Delaney

Background and Aims: GS-9451 is a novel HCV NS3 protease inhibitor with potent in vitro activity against HCV genotype 1 (in-vitro EC50 ranging from 7-10 nM in HCV 1a or 1b replicon assays). The aims of this study were to evaluate the safety, antiviral activity, pharmacokinetics (PK), and resistance profile of GS-9451 in genotype 1 (GT1) HCV infected subjects.

Methods: A double-blind, placebo-controlled, multiple ascending dose study enrolled 41 treatment-nave, non-cirrhotic GT1 infected HCV subjects. Sequential cohorts were randomized to GS-9451 as monotherapy or placebo (ratio of 8:2 per dosing group) for 3 days at 60mg, 200mg, and 400mg QD (GT1a) or at 200mg QD (GT1b). GS-9451 or placebo was administered as a tablet formulation with a meal of moderate fat content (25-30%).

Results: 40/41 enrolled subjects completed three days of dosing (one subject discontinued after receiving incorrect dose for 2 days and was replaced). Median changes from baseline in HCV RNA at Day 3 were -0.73, -3.2, and -3.6 log10 IU/mL for GT1a subjects receiving GS-9451 60mg, 200mg and 400 mg QD, respectively, and -3.5 log10 IU/mL for GT1b subjects at GS-9451 200mg QD. GS-9451 plasma exposure was greater than dose proportional in the dose range from 60 to 400 mg QD. Median half-life ranged from ~14 to 18 hours. For 200 and 400mg QD, Day 3 mean Ctau were ~6- and ~17-fold, respectively, above protein-binding adjusted mean EC50 for GT1. Genotypic analyses from Days 4 or 14 identified the NS3 protease mutations R155K/R and D168E/V/G R155K among subjects who received GS-9451 200 mg or 400 mg QD only. Among 33 subjects receiving GS-9451, treatment-emergent adverse events (AEs) were generally mild to moderate; the only AEs occurring in ≥ 2 subjects at any dose were headache (7 subjects) and dyspepsia (2 subjects). There were no serious adverse events related to GS-9451, although one subject died of an unrelated heroin overdose 5 days after the last dose of GS-9451. Grade 3/4 laboratory abnormalities included a grade 4 elevation in total bilirubin (n=1 subject at GS-9451 200mg QD), asymptomatic grade 3 elevations in amylase with normal lipase (n=1 GS-9451; n=2 placebo), and grade 3 elevations in prothrombin time (increased from grade 1 in three days and was not confirmed upon repeat testing) and urine glucose (n=1 each, both GS-9451).

Conclusions: GS-9451 is a novel NS3 protease inhibitor with potent antiviral activity in genotype 1 HCV patients. In addition to potency, a long plasma half-life and once daily dosing make GS-9451 a promising candidate for development in combination with other anti-HCV agents.

 


821. Pegylated Interferon Lambda (PEG-IFN-λ) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Nave HCV Patients (Genotypes 1, 2, 3 or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12.  A. J. Muir; E. Lawitz; R. H. Ghalib; N. L. Sussman; F. Anderson; G. T. Everson; I. M. Jacobson; J. Lopez-Talavera; J. L. Hillson; T. E. Gray; D. Fontana; E. L. Ramos; M. Rodriguez-Torres

Background: PEG-IFN-λ (IFNλ) exerts antiviral effects through a unique receptor with limited distribution and is expected to have an improved safety profile compared to alpha IFNs. We assessed safety and viral response (VR) of 4 fixed doses of IFNλ and PEG-IFN-alfa2a (IFNα).

Methods: 55 patients (pts) received a single dose of IFNλ 80, 120, 180, or 240 μg (n=45) or IFNα 180 μg (n=10) for PK, followed 2 weeks later by weekly doses of IFNλ or IFNα with RBV for 24 (HCV 2,3) or 48 (HCV 1,4) weeks. Safety data were analyzed through 12 weeks (n=34), or through last visit for pts who had not reached week 12 (n=10) or who discontinued prior to week 12 (n=11, including 4 due to AEs [1 on IFNα, 3 on IFNλ]). Efficacy is presented at 2 and 4 weeks for all pts. Week 12 efficacy is presented for G2,3 pts only, because 10 G1,4 pts had not yet reached week 12. Host genotype was determined for 48 pts (CC [n=15] or CT/TT [n=33] at rs12897986).

Results: Demographics except race were similar across arms. Observed VR (undetectable HCV RNA) varied with HCV genotype and, among HCV 1,4 pts, by IFNλ dose, race, and host genotype. Combining the 3 highest IFNλ doses, VR for G1,4 at 2 and 4 weeks was 71% and 71% for patients with CC genotype, compared to 8% and 25% for CT/TT. IFNα host genotype data (n=2) were insufficient for comparison.

Clinical AEs ≥Grade 2 occurred in 5/10 (50%) IFNα vs. 15/45 (33%) IFNλ pts (not dose dependent). Grade 2 anemia (Hgb ≤10 g/dL) occurred in 20% IFNα vs. 2% IFNλ pts, leading to more RBV dose reductions with IFNα. Median decline in neutrophils was 2.4 x 109/L IFNα vs. 0.86 x 109/L IFNλ. Increased ALT/AST occurred in all arms (Gr 2,3: 30% IFNα, 20% IFNλ). 3 IFNλ pts (7%) required dose reduction (2 on 240 μg, 1 on 180 μg), all due to ALT/AST elevations which resolved within 1 week and remained stable. One IFNα pt required dose reduction for depression.

Conclusions: PEG-IFN-λ is associated with rapid viral decline and is well-tolerated at doses up to 240 μg, with less hematologic toxicity compared to PEG-IFN-alfa2a. Response was influenced by race, HCV and host genotype. PEG-IFN-λ shows promise across a broad range of doses and viral genotypes, and in difficult to treat host genotypes.

VR Following 2, 4, and 12 Weeks on Combination Therapy

ITT Analysis

IFNλ 80 μg

IFNλ 120 μg

IFNλ 180 μg

IFNλ 240 μg

IFNα 180 μg

HCV Type

G1,4
(n=7)

G2,3 (n=5)

G1,4
(n=7)

G2,3 (n=4)

G1,4
(n=6)

G2,3 (n=5)

G1,4
(n=7)

G2,3 (n=4)

G1,4
(n=5)

G2,3 (n=5)

Race

White (n=5)

Black (n=2)

 

White (n=6)

Black (n=1)

 

White (n=5)

Black (n=1)

 

White (n=4)

Black (n=3)

 

White (n=4)

Black (n=1)

 

VR wk 2 (%)

0

0

40

17

100

75

40

0

60

50

0

75

25

0

80

VR wk 4 (%)*

0

0

60

33

100

100

40

0

80

75

0

100

50

0

100

VR wk 12 (%)^

-

-

80

-

-

100

-

-

80

-

-

100

-

-

100

 

*Not directly comparable to published RVR rates, due to PK dose ^Data at 12 weeks not yet available for G1,4

 


822. Analysis of Site Performance in Academic and Community-Based Centers in the IDEAL Study.  J. H. Jou; M. S. Sulkowski; R. Reddy; S. L. Flamm; N. H. Afdhal; J. Levin; V. K. Rustgi; R. S. Brown; J. Long; S. Noviello; L. Pedicone; J. K. Albrecht; J. G. McHutchison

Background: 76 academic and 42 community-based US centers participated in the IDEAL study, providing an opportunity to evaluate various metrics of quality and site performance in this large multicenter study

Methods: 3070 treatment-naive, HCV genotype 1 infected patients received peginterferon (PEG) alfa-2b 1.5 or 1 g/kg/wk plus ribavirin (RBV) 800-1400 mg/d or PEG alfa-2a 180 g/wk plus RBV 1000-1200 mg/d for up to 48 weeks. We retrospectively evaluated rates of screen failure, completion and discontinuation of treatment and follow-up, treatment adherence, and virologic response by site type.

Results: Of 4469 subjects screened, 63% and 37% were in academic and community centers, respectively. Screen failure rates were similar (30-32%). Of the 1905 (62%) and 1165 (38%) patients treated in academic and community centers, respectively, baseline characteristics were comparable, except more African Americans (21% vs 15%) were treated at academic centers, and more Hispanics were treated at community centers (10% vs 5%) (Table). End-of-treatment (EOT) response, relapse and sustained virologic response (SVR) rates in academic and community centers did not differ. 9% of patients in academic and 12% in community centers achieved rapid virologic response (undetectable HCV RNA at week 4); 39% and 42% achieved complete early virologic response (undetectable HCV RNA at week 12). Adherence to ≥80% of PEG and RBV dosing for ≥80% assigned duration was also similar (46% in academic and 47% in community centers). 54% of patients in both academic and community centers completed treatment; there were similar discontinuation rates for treatment failure and adverse events.

Conclusions: No differences in adherence, incidence of adverse events, rates of discontinuation, on-treatment virologic response, and SVR were found when comparing academic and community sites. This large trial further supports that outcomes for patients are largely similar when comparing academic versus community based treatment for chronic hepatitis C.

Academic Centers

Community Centers

Screen failures
Due to lost to follow-up

32%
2%

30%
2%

Median / mean (SD) treated patients/site

18.5 / 25.7 (22.8)

21.5 / 27.7 (25.7)

Male

59%

61%

Mean age, yrs

47.6

47.4

Caucasian / Black / Hispanic

71% / 21% / 5%

72% / 15% / 10%

METAVIR F3/4

10%

11%

Treatment phase:
Completed
Discontinued
due to treatment failure
due to adverse events
due to lost to follow-up


54%
46%
27%
12%
2%


54%
46%
27%
11%
3%

Week 24 follow-up phase:
Completed
Discontinued
Never entered


79%
9%
12%


78%
9%
13%

SVR / EOT / Relapse Rates

40% / 55% / 25% (248/996)

39% / 57% / 27% (163/614)

 


823. Continuous Subcutaneous Administration of High-Dose Interferon Alfa-2b Combined with Ribavirin in Chronic Hepatitis C Patients: A Dose-Finding And Safety Study in Treatment-Experienced PatientsR. Roomer; J. F. Bergmann; B. L. Haagmans; B. E. Hansen; A. J. van Vuuren; A. Heijens; H. L. Janssen; R. J. de Knegt

Background: The pegylation of interferon (IFN) improved the pharmacokinetic profile with higher sustained virological response (SVR) rates in nave patients compared to standard IFN. However SVR rates in previous non-responders remain low (range 8-12%). We hypothesize that elevated doses of fully potent interferon will lead to higher SVR rates, and that continuous delivery of IFN via an external pump might prevent peaks associated with adverse events (AEs) as well as subtherapeutic trough levels associated with viral breakthrough.

Methods: We randomized 30 HCV genotype 1 (n=24) and 4 (n=6) patients in a 1:1:1 ratio to receive 6, 9 or 12MU IFN alfa-2b daily by continuous subcutaneous administration using an insulin pump (Medtronic MiniMed 508) for 48 weeks. All patients received weight-based ribavirin (1000-1600mg). The aims of the study were to assess safety and tolerability and to study viral kinetics in patients who had previously failed therapy (non-response: n=20; relapse: n=7; or viral breakthrough: n=3). In the 6, 9 and 12MU group cirrhosis was present in 3, 3 and 7 patients respectively.

Results: Virological responses are shown in the table. At wk 4, a mean HCV RNA decline of 1.19 (95%CI 0.55-1.83), 1.21 (95%CI 0.38-2.04) and 2.67 (95%CI 2.38-2.97) log10 IU/ml was found with 6, 9 and 12MU IFN/day, respectively (12MU vs. 9MU/6MU, p<0.0001). Out of the 20 previous non-responders 9 became HCV RNA negative by PCR during therapy and 3 achieved SVR (2 received 12MU/day and 1 received 9MU/day). AEs were mostly mild to moderate and were typical of IFN therapy but 5 patients developed irritation and/or abscesses at the injection site. Six serious adverse events (SAEs) were reported in 5 subjects; this led to permanent discontinuation in 3 subjects. All SAEs were consistent with high dose IFN therapy. Of the discontinuations due to SAEs, 2 subjects received the 12MU/day and 1 patient received the 9MU/day dose.

Conclusions: High doses of IFN can be delivered safely using continuous pump therapy in this difficult-to-treat population. Typical IFN-related AEs appeared dose-dependent. In the intention-to-treat analysis SVR rate was 20% (6/30). In the per-protocol analysis SVR rate was 25% (6/24) of which 4 of the 6 in the high-dose arm reached SVR. If side effects can be managed successfully, continuous delivery of IFN may show significant clinical benefit.

Virological response (undetectable HCV RNA by COBAS Ampliprep/COBAS TaqMan HCV test, LLD <15 IU/mL)

Treatment group

Wk4

Wk12

Wk24

Wk48

WkFU24

Subjects Completing Protocol

6mu/day

1/10

1/10

2/10

2/10

1/10

10/10

9mu/day

0/10

2/10

5/10

5/10

1/10

8/10

12mu/day

0/10

4/10

5/10

4/10

4/10

6/10

 


824. Safety, pharmacokinetics, and antiviral activity of single oral doses of the HCV NS3 protease inhibitor GS 9256.  R. Goldwater; M. p. DeMicco; J. Zong; G. E. Chittick; G. J. Yuen; S. West; J. Kagel; A. Bae; H. Mo; D. Oldach ; W. E. Delaney; J. W. Findlay

Background: GS-9256 is a novel HCV NS3 serine protease inhibitor. Two single-dose studies of GS-9256 were conducted to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of GS-9256 in healthy volunteers and genotype 1 (GT1) HCV-infected subjects.

Methods: Study 1 was a first-in-human study which evaluated single ascending doses of GS-9256 in healthy subjects. Approximately 7 subjects in each of three sequential dose groups were randomized 6:1 (GS-9256:placebo) to receive a single fasting dose (150, 300, or 600 mg, or placebo) in a double-blind fashion. In Study 2, a total of 32 HCV GT1-infected, treatment-naive subjects were randomized in double-blind fashion to receive a single fasting dose of GS 9256 (150, 300 or 450 mg, or placebo) in one of four parallel dose groups. Resistance analyses were performed by RT-PCR amplification of the NS3 gene from patient samples followed by population sequencing.

Results: GS-9256 was generally well-tolerated at all doses studied (150-600 mg) in both populations. There were no SAEs, Grade 3 or Grade 4 laboratory abnormalities in either study. In Study 1: Peak plasma GS 9256 concentrations (Cmax) occurred 4-5 hours after dosing with a median terminal elimination half-life (T1/2) of 7-8 hours. There were greater than dose-proportional increases in exposure between 150 and 600 mg. In Study 2: Cmax occurred 4-6 hours after dosing, with a median T1/2 of 8-9 hours. Plasma exposure of GS-9256 also showed greater than dose-proportional increases from 150 to 450 mg. GS-9256 plasma exposures were slightly higher in HCV patients (~ 1-1.3 and 1.4-1.5-fold higher in Cmax and AUCinf, respectively). The mean C12 at 150 mg was ~ 8X > protein binding-adjusted EC50 for GT1. Median maximum HCV RNA declines were -1.8, -2.4, and -2.8 log10 IU/mL after single doses of 150, 300, and 450 mg, respectively. A strong correlation between plasma exposure of GS-9256 and HCV RNA suppression was observed. The NS3 protease mutations R155K or D168E/V were identified in 4/8 patients who received 450 mg. These protease mutations were positively correlated with both GS-9256 exposure and virologic response. Protease mutations were no longer detectable on Day 8 or at later timepoints. These mutations displayed reduced phenotypic susceptibility to GS-9256, but maintained wild-type sensitivity to IFN-α, ribavirin, and other HCV inhibitors.

Conclusions: The pharmacokinetic profile of GS-9256 following single-dose administration is similar in healthy volunteers and HCV-infected patients. The potent antiviral activity observed in patients supports continued development of GS-9256 for the treatment of chronic HCV infection.


825. Efficacy and safety of an intensified regimen of pegylated interferon alfa-2a plus ribavirin (RBV) in HCV genotype 1 non-responders: final results of the SYREN trial.  C. Hezode; J. Foucher; J. Bronowicki; V. Leroy; A. Tran; D. Larrey; P. Mathurin; I. Rosa; L. Alric; C. Barrault; A. Nani; M. Bouvier-Alias; S. Rouanet; P. Couzigou; A. Mallat; M. Charaf Eddine; J. Pawlotsky

Background: Treatment options are limited for patients who do not respond to a standard regimen of peg-IFN plus RBV. The objective of the SYREN trial was to evaluate the efficacy and safety of long-term administration of high doses of peg-IFN -α2a, combined with standard or high doses of RBV in HCV genotype 1 patient who did not respond to previous course of peg-IFN-α2a plus RBV at standard doses.

Methods: Eligible patients were non-responders, as defined by a decrease in HCV RNA < 2 log10 at week 12. Patients were randomized into 1 of 4 regimens: peg-IFN alfa-2a 360g/week plus RBV 1000/1200 mg/day (arm A) or 1200/1600 mg/day (arm B) for 72 weeks; peg-IFN alfa-2a, 180g twice per week plus RBV, 1000/1200 mg/day (arm C) or 1200/1600 mg/day (arm D) for 72 weeks. Serum HCV RNA was measured by Roche Cobas TaqMan HCV test (LOD <15 IU/mL). Data from all arms were combined for the ITT analysis at week 24.

Results: 104 patients were enrolled and ITT data were analyzed in 98 nonresponders who received at least one dose of study drug and the safety analysis included 101 patients. Baseline characteristics were: male: 71% (70/98), mean age: 508 years, mean BMI: 264 kg/m2, compensated cirrhosis: 43% (42/98), HCV RNA ≥ 6 log10 IU/mL: 87% (85/98), mean week 12 HCV RNA decrease during previous treatment: -0.90.6 log10 IU/mL.

At week 12, HCV RNA drop ≥2 log was achieved in 53% (52/98) of the patients and was maintained, observed in 56% (55/98) at week 24. Undetectable HCV RNA gradually increased from 8% (8/98) at week 12 to 33% (32/98) at week 48 and was 22% (22/98) at the end of treatment (week 72). Mean log10 HCV RNA decline was: -1.00.7, -2.31.5, -3.51.8, -4.41.5, and -5.01.1 at weeks 4, 12, 24, 48 and 72, respectively. At week 96, sustained virological response (SVR) was observed in 5% (5/98) of the patients. EPO was used in 48% (48/101) of patients. Grade 4 neutropenia and thrombocytopenia were observed in 8% (8/101) and 1% (1 patient), respectively.

Conclusion: In HCV genotype 1 patients who did not respond to standard therapy, a virological response (HCV RNA drop ≥ 2 log) can be achieved in 56% of cases after 24 weeks of an intensified regimen of PegIFN-α2a in combination with standard or high doses of RBV. However, SVR rate is low (5%). Adherence and safety profile were acceptable. The reinforced strategy is not useful to achieve SVR without adding direct antiviral agent (DAA). However, when a DAA is used, combining with the intensified peg-IFN plus RBV regimen that restores an antiviral response to IFN could be the utmost value to achieve an SVR in prior null responders to a standard regimen of peg-IFN plus RBV.

 


827. Co-administration of BMS-790052 and BMS-650032 does not result in a Clinically Meaningful Pharmacokinetic Interaction in Healthy Subjects.  M. Bifano; H. Sevinsky; B. R. Bedford; J. J. Coumbis; S. Huang; D. M. Grasela; T. Eley; R. J. Bertz; M. Medlock

Background: NS5A plays a central role in HCV viral replication. BMS-790052 is a first-in-class and potent NS5A Inhibitor with broad genotypic coverage. BMS-650032 is a potent HCV NS3 inhibitor with in vitro activity against genotypes 1a and 1b. Proof-of-concept multiple-dose studies in HCV subjects for each compound demonstrated a robust decline in HCV RNA when administered as monotherapy. Combinations of 2 or more DAA are expected to be part of future HCV therapy; therefore, assessment of a potential drug-drug interaction (DDI) with these two compounds together is warranted prior to commencement of clinical trials in HCV patients.

Methods: The objective of this open-label, randomized, multiple-dose study was to assess the pharmacokinetics, safety, and tolerability of BMS-790052 (14 patients) and BMS-650032 (14 patients) when co-administered in healthy subjects for 14 days. Subjects received either 60 mg BMS-790052 QD or 600 mg BMS-650032 Q12h for 7 days during a lead-in period followed by co-administration of 30 mg BMS-790052 QD and 200 mg BMS-650032 Q12h for 14 days. Plasma concentrations were obtained via LC/MS/MS. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for BMS-790052 and BMS-650032 PK were estimated by general linear mixed effects models.

Results: BMS-790052 and BMS-650032 exposures following doses of 30 mg QD and 200 mg Q12h administered together were comparable with those of historical data at similar doses for each compound administered alone. The GMR (90% CI) for BMS-790052 and BMS-650032 AUC(TAU) were 1.156 (0.895,1.491) and 1.025 (0.734,1.433), respectively. Following dose normalization to 60 mg, BMS-790052 exposure (AUC(TAU)) after co-administration of 30 mg QD with BMS-650032 200 mg Q12h for 14 days was similar to exposure observed following 7 days of BMS-790052 60 mg QD in the lead-in period with a GMR (90% CI) of 1.202 (1.113,1.298). Following dose normalization to 600 mg Q12h, BMS-650032 exposure (AUC(TAU)) after co-administration of 200 mg Q12h with BMS-790052 30 mg QD was similar to exposure observed in the lead-in period with a GMR (90% CI) of 0.868 (0.726,1.038).

Discussion:

        The PK interaction observed in the nonclinical species was not observed in normal healthy subjects.

        Exposure to BMS-650032 appear greater after the PM dose relative to the AM dose. The increase in exposure appears to be dose dependent

        Diurnal (morning vs. evening) variation observed was a likely due to food effect

        The multiple-ascending-dose and proof-of-concept studies for BMS-650032 were dosed in the same manner; therefore, the increased PM exposures have been factored into the dose selection and safety evaluation

Conclusions:

        Co-administration of BMS-790052 and BMS-650032 in healthy subjects for 14 days did not result in a clinically meaningful PK interaction; a clinically meaningful PK interaction is not anticipated when BMS-790052 and BMS-650032 are co-administered in HCV patients.

        Co-administration of BMS-790052 30 mg QD and BMS-650032 200 mg Q12 for 14 days was well-tolerated in this study.

        A dose-dependent AM/PM difference was observed for BMS-650032 exposure, which may be due to the temporal relationship of food and BMS-650032 administration.

Based on the results of this study, a clinical trial with BMS-790052 and BMS-650032 both with and without Peginterferon/ribavirin has commenced to assess the effect of dual NS5A plus NS3 inhibition in HCV therapy


828. Activity of Telaprevir Monotherapy or in Combination with Peginterferon-alfa-2a and Ribavirin in Treatment-nave Genotype 4 Hepatitis-C Patients: Final Results of Study C210Y. Benhamou; J. Moussalli; V. Ratziu; P. Lebray; K. de Backer; A. Ghys; R. van Heeswijk; D. Luo; G. Picchio; M. Beumont

Background: Telaprevir (TVR) in combination with peginterferon-alfa-2a (P) and ribavirin (R) produces rapid and consistent reductions in HCV-RNA plasma levels in genotype (G) 1 patients. C210 was a randomized, partially blinded, exploratory, Phase-2a study to evaluate the activity of TVR, administered alone or with PR in treatment-nave non-cirrhotic G4 HCV patients.

Methods: HCV G4 patients were randomized to receive TVR (T) 750mg q8h alone (T2&PR48; n=8), T with P 180μg/week and R1000-1200mg/day (T2/PR48; n=8), or placebo with PR (Pbo/PR48; n=8) for 15 days. Subsequently patients continued PR to complete 48 weeks of therapy. Viral load was measured with the Roche Taqman assay (LOQ =25 IU/mL) and genotyping was based on NS5B. Viral breakthrough (vBT) was defined as >1 log10 increase in HCV-RNA above nadir or >100 IU/mL HCV-RNA if previously undetectable. Early viral kinetics and SVR were assessed using ITT analysis. Emerging viral variants were studied by population sequencing.

Results: 38% of enrolled patients were Egyptian origin and 66.7% were Caucasian; 54.2% had HCV-RNA >800,000 IU/mL. Genotype 4a was the most prevalent subtype (47.8%). During the TVR dosing phase, five patients receiving TVR monotherapy developed a vBT; no vBTs were observed in the other two arms during the same period. Two of four vBTs with available sequence results had viral variants with previously characterized mutations at position 54 (T54A) and one of these also had a mutation at position 170 (I170M), while another vBT had a V170A mutation. These three patients with vBTs achieved a SVR after continued treatment with PR. Overall incidence of adverse events (AEs) was similar across arms and the most common AEs in the TVR arms were skin-related events, asthenia, and influenza-like illness, as observed in other Phase 2 studies. One patient in T2/PR24 arm discontinued TVR prematurely due to cholecystitis considered to be unrelated to TVR.

Conclusions: TVR in combination with PR had greater activity against HCV G4 than PR alone, or TVR monotherapy, suggesting synergy between these agents. All patients harboring variants with mutations at position 54 and 170 achieved a SVR with continued PR treatment. TVRs AE profile was similar to that observed in other Phase 2 studies.

 

 

T2&PR48 N=8

T2/PR48 N=8

Pbo/PR48 N=8

Median (range) log10 HCV RNA change from baseline
Day 3
Day 15


-1.21 (-2.5, -0.1)
-0.77 (-2.9, 0.3)


-2.23 (-3.6, -1.1)
-4.32 (-5.2, 0.0)


-0.67 (-2.2, 0.0)
-1.58 (-4.0, -0.8)

Median (range) log10 maximum HCV-RNA change from baseline by Day 15

-1.47 (-2.4, -0.2)

-4.32 (-5.2, 0.0)

-1.58 (-4.0, -0.8)

HCV RNA undetectable by Day 15 (n, %)
SVR (n, %)

0
5 (62.5%)

1 (12.5%)
4 (50%)

0
5 (62.5%)

Relapse (n)

1

2

1

 


829. Clinical efficiency of the HCV NS3 Protease N-terminal 181 amino acid region on a large panel of clinical trial isolates using a subtype-specific genotyping assay.  T. Pattery; D. Koletzki; K. Van Soom; B. Fvery; A. Van Cauwenberge; N. Hartmans; L. Vanhooren; J. Villacian

Objective: The majority of new anti-HCV drugs currently in clinical trials are direct-acting antivirals (targeting a component of the virus or replication cycle) that include NS3-4A protease, NS5B polymerase or NS5A inhibitors. We report on the subtype-specific genotyping assay performance for the NS3 protease region (N-terminal 181 amino acid: 181AA), whose efficiency was determined on a large panel of clinical isolates.

Methods: Population 181AA genotyping was performed on 7093 clinical isolates. Externally (or internally) derived subtype information (Trugene HCV 5NC, Siemens Healthcare), viral load (VL) data and country of origin was available for a majority of the genotyped samples.

Results: Positive 181AA results were obtained for 6412/7093 clinical isolates (90.3% efficiency). Among the 6412 positives, the complete protease NS3/4A region (containing 181AA) was available for 4771 samples (74.4%) while 1641 samples (25.6%) were only positive for 181AA. Percentage success based on VL data were 59.6% (108/181; 0-1000 IU/mL); 81.6% (241/295; 1001-10,000 IU/mL); 85.9% (404/470; 10,001-100,000 IU/mL) and 92.1% (5580/6056; >100,000 IU/mL). VL information was unavailable for 91 samples. Percentage success based on external geno- and/or subtypes were 93.3% for G1 (2695/2998 for 1a, 1967/2100 for 1b, 364/396 for 1 and 48/49 for 1a1b); 75.4% for G2 (16/23 for 2a, 8/14 for 2b, 3/4 for 2 and 3/3 for 2k); 78.4% for G3 (40/42 for 3a, 2/5 for 3b, 1/1 for 3d), 84.4% for G4 (16/18 for 4a, 11/13 for 4c, 3/9 for 4 and 1/1 for 4f, 4g and 4i); 100% for G5 (16 for 5a) and G6 (2 for 6n and 6; 1 for 6a and 6b). External geno- or subtype information was unavailable for 1393 internally subtyped and processed samples. Percentage success based on geographical distribution were 92.9% for Americas (3767/4051; USA, Argentina and Canada), 87.1% for Europe (2379/2731), 75.86% for Australia, New Zealand (88/116) and 82.3% for Thailand (14/17). No information was available on sample source for 178 isolates.

Conclusions: An overall success rate of 90% was observed for our subtype-specific 181AA genotyping platform and the percentage success improved with increasing VL (59-92%). Performance based on geno- and subtype information showed that the 181AA genotyping platform was optimal for genotyping all G1-G6 strains, irrespective of the subtype or geographical source. The diversity of our NS3 181AA database (containing a large panel of clinical isolates from ongoing clinical trials) could in the future enable analysis of resistant variants/mutation(s) pathways that may provide guidance for optimization of therapy with respect to potential drug combinations and treatment duration.

 


830. Pharmacokinetics of PEG-Interferon Lambda (PEG-IFN-λ) Following Fixed Dosing in Treatment-Nave Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2a Study).  K. A. Byrnes-Blake; J. A. Freeman; L. Rapalus; S. Pederson; D. Fontana; J. Lopez-Talavera; V. Kansra; D. M. Miller

Background: PEG-IFN-λ exerts antiviral effects through a unique receptor with limited distribution and is anticipated to have an improved safety profile compared to alpha IFNs. Pegylated IFN-λ1 (PEG-IFN-λ) is currently under development as a therapeutic agent for chronic HCV infection. Pharmacokinetic data from a previous Phase 1b study suggested that weekly administration of fixed Peg-IFN-λ doses may be appropriate; however, the drug was administered on a weight basis in that study. This report describes data from an ongoing Phase 2a study, the first part of which was designed to evaluate the pharmacokinetics of PEG-IFN-λ over a broad range of fixed doses.

Methods: Treatment-nave HCV subjects (genotypes 1, 2, 3, or 4) received a single subcutaneous fixed dose of PEG-IFN-λ (80, 120, 180 or 240 μg; 11-12 subjects/dose group). Serial serum samples were collected over a two week period postdose. Samples were analyzed by validated MSD electrochemiluminescent assay. Noncompartmental and compartmental analyses were performed to estimate pharmacokinetic parameters and allow simulation of multiple dose pharmacokinetics. The relationship of several covariates, including dose level and body weight, to PEG-IFN-λ exposure were examined graphically.

Results: The mean PEG-IFN-λ elimination t1/2 ranged from 37 to 52 hours. Estimated CL/F and Vz/F values were relatively consistent across the 120, 180, and 240 μg dose groups (approximately 2 L/hour and 100 L, respectively; CL/F and Vz/F were lower in the 80 μg dose group at 1.04 L/hour and 46 L, respectively). The mean Tmax was approximately 24 hours, with a range of 4 to 73 hours. Mean AUC0-168h and Cmax increased in a dose-dependent manner. Based on the single dose data, steady-state is predicted to be reached after 2 to 3 weeks of once weekly dosing. There was no apparent effect of body weight on PEG-IFN-λ exposure. Other covariates, such as HCV genotype, host IL-28B genotype, and other subject characteristics (age, race, sex, and body mass index) do not appear to affect PEG-IFN-λ exposure.

Conclusions:

        Based on the data from this study, PEG-IFN-λT max is approximately 1 day and the elimination half-life is approximately 2 days.

        Exposure following fixed doses of 120, 180 or 240 μg pegIFN λ is consistent with that following weight-based dosing in the phase ib study.

        There appears to be little influence of common baseline demographics such as age, race, sex, body weight, body mass index or disease specific parameters, such as HCV genotype or host IL-28B genotype, on the pharmacokinetic properties of PEG-IFN-λ.

        Collectively, the data on demographics and time to steady state support the use of fixed SC doses of PEG-IFN-λ on a once-weekly schedule.

 


831. The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2a Study of PEG-Interferon Lambda (PEG-IFN-λ) in Hepatitis C Patients.  J. A. Freeman; T. E. Gray; D. Fontana; J. Lopez-Talavera; D. M. Miller; J. L. Hillson

Background: PEG-IFN-λ (lambda) exerts antiviral effects through a unique receptor with limited distribution and is anticipated to have an improved safety profile compared to alpha IFNs. The safety and efficacy of PEG-IFN-λ is currently under investigation in a Phase 2 study. This report describes an exploratory evaluation of early HCV viral kinetic data collected in the Phase 2a portion of this study.

Methods: 57 treatment nave patients infected with HCV genotype 1, 2, 3, or 4 were randomized to receive 80, 120, 180, or 240 g PEG-IFN-λ or 180 g peginterferon alfa-2a (PEG-IFN-α2a). Early HCV viral kinetics (first and second phase slopes) and rapid and early virologic response (RVR and EVR) were estimated from plasma HCV RNA measurements. IL-28B genotype at rs12979860 was determined for all consenting subjects. The effect of HCV genotype, IL28B genotype, and treatment group on first and second phase slope was evaluated using a multivariable linear regression model. The effect of HCV genotype and PEG-IFN-λ dose on virologic response was evaluated using logistic regression.

Discussion/Conclusion:

        The rate of HCV RNA decline and virologic response in subjects treated with 120, 180, or 240 up PEG-IFN-λ may be equivalent to, or exceed, those observed and reported for patients treated with pegIFNa-2a

        The rate of HCV RNA decline upon treatment with pegIFN λ may be faster in subjects with an IL28B CC genotype than in subjects with an IL28B CT or TT genotype

        The rate of HCV RNA decline in subjects with an IL28B CT/TT genotype treated with pegIFN λ approached that observed in subjects with an IL28B CC genotype treated with pegIFNa-2A

        The relationship between early viral decline and sustained virologic response will be evaluated.

 


833. Antiviral Response and Resistance Analysis of Treatment-Nave HCV Infected Subjects Receiving Single and Multiple Doses of GS-9190.  J. Harris; A. Bae; S. C. Sun; E. S. Svarovskaia; M. D. Miller; H. Mo

Background: GS 9190 is a novel non nucleoside HCV NS5B polymerase inhibitor. In vitro, mutations associated with NS3 protease inhibitors, nucleoside NS5B inhibitors, and ribavirin remains fully susceptible to GS-9190. In vitro resistance to GS-9190 includes the C316Y, C445F, Y448H and Y452H HCV NS5B mutations. Efficacy and resistance development to GS-9190 were evaluated in vivo in Study GS-US-196-0101.

Methods: GS US 196 0101 was a Phase 1, randomized, double-blind, placebo controlled dose-escalation study of single and multiple doses of GS 9190 in treatment-nave subjects with chronic HCV genotype (GT) 1 infection. HCV RNA was measured by Roche COBAS TaqMan; resistance development was evaluated by population sequencing of NS5B. An allele-specific PCR (AS-PCR) assay for the detection of Y448H quasispecies was developed with a cut-off of 0.5%. Phenotypic analyses were performed to assess mutant susceptibility to GS-9190 and other anti-HCV drugs.

Results Summary:

        Single and multiple doses of GS-9190 resulted in mean maximal HCV RNA reductions ranging from -1.22 and -1.95

        No NS5B polymerase mutations were observed by population sequencing in the single dose cohorts

        Sequence analysis showed the Y448H NS5B polymerase mutation in 58% of subjects in the multidose cohorts

        Y448H+Y452H was only observed in 1b subjects (2/36)

        In subjects receiving GS-9190, AS-PCR detected pre-existing Y448H at baseline in 8% of subjects. At the end of dosing, low levels were detected in 21% of subjects in the single dose cohort and 92% of subjects in the multidose cohorts

        Levels of Y448H declined after therapy was stopped suggesting impaired replication of this mutant

        Phenotypic analysis of clinical isolates with the Y448H alone or in combination with Y452H showed reduced susceptibility to G2-9190

        Clinical isolates with GS-9190 resistance mutations remained sensitive to interferon-a, ribavirin as well as HCV NS3 protease and NS5B polymerase inhibitors

Conclusions:

        Significant reductions in HCV RNA were observed in genotype 1 HCV-infected subjects receiving single or multiple doses of GS-9190

        HCV resistant variants are pre-existing and can be detected when wild-type virus is inhibited by treatment with GS-9190

        The lack of cross-resistance of GS-9190-resistanct isolates to VX-950, SCH-50304, IFN and RBV supports the use of GS-9190 in combination with these anti-HCV agents.

 


834. Genotypic characterisation of filibuvir (PF-00868554) resistance in patients receiving four weeks co-administration of filibuvir with pegIFN/RBV.  J. Mori; J. L. Hammond; S. Srinivasan; S. Jagannatha; E. van der Ryst; C. Craig

Background and Aims: Filibuvir is a non-nucleoside inhibitor of HCV polymerase with potent activity against HCV genotype 1. In vitro evaluations and monotherapy studies in HCV-infected patients demonstrate NS5B residue 423 variants provide the predominant resistance genotype.

Methods: Study A8121007 was a Phase 2 randomized, double-blind, placebo-controlled, study investigating pegIFN/RBV +/- filibuvir (doses: 200, 300 and 500 mg BID) in treatment nave patients chronically infected with HCV genotype 1. The study duration was 72 weeks (4 weeks pegIFN/RBV + filibuvir or placebo; 44 weeks pegIFN/RBV alone; 24 weeks off-treatment follow-up). Samples from all patients receiving filibuvir who did not achieve a RVR or who showed virus rebound were investigated by population sequencing.

Results: Thirty-five patients were randomised, 34 completed Week 4 and 21 completed Week 48. All doses of filibuvir resulted in a more rapid decline in plasma HCV RNA when added to a regimen of pegIFN/RBV compared to pegIFN/RBV alone. Overall, 17 of 26 filibuvir-treated patients achieved RVR, and 20 of 26 achieved cEVR. Virus from 6 of the 9 filibuvir-treated patients not achieving RVR selected variants at position 423. Five of these patients met the criterion for IFN null response at Week 12 (<2-log reduction). Later samples (Week 28) are available for 2 patients; M423 variants were not detectable at this time point suggesting re-establishment of wild-type virus. Viral breakthrough at Week 24 was observed for 1 of the 17 filibuvir-treated patients with RVR, with no evidence of filibuvir resistance at this time point. Following discontinuation of pegIFN/RBV therapy at Week 48, 6 filibuvir-treated patients with undetectable HCV RNA at Week 48 relapsed. Sequencing data is available for 4 of these at the time of relapse and in each case M423 variants were not detected. M423 variants were not detected at baseline (Day 1) in any of the patients failing therapy.

Conclusions: The majority of patients achieved RVR and cEVR following filibuvir therapy. Position 423 variants were predominant in patients who did not achieve RVR. This finding supports the monotherapy observations that selection of NS5B residue 423 variants is the preferred pathway for filibuvir resistance. Discontinuation of filibuvir led to the re-establishment of wild-type virus. Relapse with wild type virus among those who had an end of treatment response at week 48, suggests that dosing of filibuvir beyond four weeks may help prevent relapse.

 


835. Undetectable HCV RNA after Silibinin iv treatment is associated with high on treatment response rates in HCV nullresponders T. Scherzer; R. E. Stauber; A. Maieron; H. Laferl; M. Gschwantler; S. Beinhardt; K. Rutter; A. Stttermayer; P. E. Steindl-Munda; H. Hofer; P. Ferenci

Background: Intravenous silibinin is a potent antiviral drug in chronic Hepatitis C patients not responding to the standard of care treatment (SOC) with Peg-Interferon alpha 2a/b and Ribavirin. Silibinin inhibits the HCV replication in vitro. Experience with this therapy is limited. Thus we analyzed the virologic response in patients currently in an Austrian multicenter trial.

Methods: HCV null responders to SOC treatment receive iv Silibinin (15-20mg/kg) for 2 to 3 weeks. After 8 days of silibinin monotherapy SOC treatment (180 g peginterferon alpha-2a/week) and ribavirin (HCV-1 and 4: 1000/1200mg; HCV-2 and 3: 800mg) was added. The primary study endpoint was defined as on treatment response (OTR; undetectable HCV RNA) at week 25. In patients with undetectable HCV RNA at week 25 SOC was continued, the total treatment duration was at the discretion of the investigators.

Results: To date 63 HCV non responders to SOC treatment [HCV-1: 47, HCV-3: 3, HCV-4: 13; male: n=44, female: n=19, age: 51.010.6 (meanSD), BMI: 25.64.0, fibrosis: F0-2: n=22, F3/4: n=22, not assessed: n=19] have been included in this multicenter trial. 28/63 patients [44.4%; baseline viral load: 6.0 0.9 IU/mL (meanSD)] had a HCV RNA under the limit of quantification (< LOQ: 15IU/mL) at the end of iv silibinin treatment (day 15 or 22), 11 of them (39.3%) with an OTR at week 25 (4 HCV RNA negative did not reach 25 weeks yet). Considerably less patients [3/35 (8.6%); baseline viral load: 6,60,6 IU/mL] with detectable HCV RNA (> 15 IU/mL) at the end of Silibinin iv treatment achieved OTR. Another patient is HCV RNA negative on SOC treatment. To date 9 patients finished treatment and follow up; 3 achieved an SVR (HCV-1:n=2, HCV-4:n=1), 6 relapsed (HCV-1: n=4, HCV-3: n=2).

Conclusion: IV silibinin is a treatment option for nullresponders to SOC. Irrespective of the length of silibinin iv administration undetectable HCV RNA at the end of iv silibinin treatment is the most important factor to achieve OTR. Administration of silibinin should be extended until HCV RNA becomes undetectable. This approach may increase OTR rates.

 


836. Selecting the right IL28 SNPs analysis of the IL28A/IL28B inverted gene duplication.  G. Johnston; J. M. Reynolds; K. Loomis; F. A. Sanders; S. A. Paciga

GWAS and targeted genetic association studies have recently identified SNP genotypes upstream, within and downstream of the IL28B gene that are associated with clearance of Hepatitis C virus (HCV) and a patients response to treatment with Interferon-α and ribavirin. The IL28B gene (1.6KB) is 97% identical to IL28A gene that lies about 15KB upstream of IL28B. The two genes presumably arose due to a duplication/sequence inversion event during evolution.

IL28B is located on the negative DNA strand whereas IL28A is on the positive strand. In silico examination of a 7.3KB region containing IL28B was 95% identical (excluding major gaps) to a similar region spanning IL28A. Examination of 25bp of DNA sequence both 5 and 3 of each of 9 IL28B SNPs that have been associated with HCV clearance and treatment response revealed that the sequence surrounding 3 SNPs (rs12980275, rs8099917, rs7248668) was unique to IL28B, whereas the sequence surrounding 6 other SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs12979860) was >93% identical between IL28B and IL28A.

The number of base pair differences between IL28B and IL28A in the 50bp surrounding the 6 SNP locations ranged from 0bp to 3bp. It was also noted that for 5 out of 6 of the reported SNP alleles, one was present in the NCBI (Build 37) database sequence for IL28B and the other was present in IL28A sequence.

For these 6 SNPs, careful design of genotyping assays is required to allow specific detection of IL28B alleles. The close proximity and high homology of these two related genes, along with the need for specific genotyping assays, led us to perform a detailed DNA sequencing and de novo assembly of the region encompassing the IL28A and IL28B loci. The results of re-sequencing of this region will be reported.