Sunday Poster Sessions, November 4, 2007

 

Topic: Current Treatment - Pegasys

 

25. Prophylactic Peginterferon Alfa-2a/Ribavirin vs No Prophylaxis Following Orthotopic Liver Transplantation (OLT) for Hepatitis C: 24-Week Virologic and Safety Responses

M. R. Charlton; N. Bzowej; S. Rossi; D. R. Nelson

 

Introduction:

Recurrent HCV infection after OLT can cause graft failure and death, but safety concerns have limited prophylactic/early treatment with pegylated interferon/ribavirin.

Aim:

The Phoenix trial was designed to compare prophylactic administration of antiviral therapy before histological recurrence of HCV (Prophylaxis arm) with initiation of antiviral therapy only at the time of histologically apparent recurrence of HCV (Observation arm).

 

Methods:

Patients were randomized 10-26 wks after OLT. Patients in the Prophylaxis arm received 135 μg peginterferon alfa-2a/wk for 4 wks and 180 μg/wk for 44 wks; plus 400 mg/d ribavirin (initial dose), escalating over 12 weeks to 1000 or 1200 mg/day for 36 weeks. Patients in the Observation arm were treated with the same regimen only upon histologic recurrence of HCV (HAI >3 and/or FS >2), followed by 24-72 weeks of treatment free follow-up. The primary efficacy assessment is the proportion of patients in each group who experienced histological evidence of HCV recurrence at 120-weeks post-randomization. Here we report 24-wk interim data.

 

Results:

To date 115 patients have been enrolled and the first 24 week data is presented here. The patient characteristics in the prophylaxis arm and the observational arm were well matched. The virologic response at week 24 was 38% in the prophylaxis group compared to the control arm. Of patients in the Prophylaxis and Observation arms, 100% and 93%) respectively, have experienced at least 1 adverse event (AE); and 44% and 23%, respectively, have experienced at least 1 serious AE. In the Prophylaxis are 30% of the patients discontinued treatment due a adverse event compared to 25% in the Observational group. 75% of the patients in the prophylaxis group experienced at least one adverse event that led to treatment modification/interruption compared to 25% in the Observational group.

 

Conclusion:

o       On-treatment virologic response is achievable in OLT recipients with prophylactic or delayed treatment SVR data are not yet available

o       Although AEs were common during prophylaxis with peginterferon alfa-2a and ribavirin for post-OLT HCV recurrence, the incidence of clinically significant ACR was not increased by prophylaxis

o       ACR rates observed during prophylaxis were low

o       Rates of anemia and grade 3/4 neutropenia, secondary to HCV antiviral drug toxicity, were higher in the prophylaxis arm than in untreated patients in the observation arm

o       The incidence of clinically significant infections was low in both arms, and depression was not observed in any patient

o       Relative impact of prophylaxis versus no prophylaxis strategy on allograft histology remains to be determined


Topic: Liver Transplantation

 

29. Impact of HIV on Survival after Liver Transplantation. Analysis of United Network for Organ Sharing (UNOS) Database

A. Regev; A. L. Mindikoglu; L. S. Magder

 

Background:

The outcome of liver transplantation (LT) in patients infected with Human Immunodeficiency Virus (HIV) has been a matter of controversy. Patients coinfected with HIV and hepatitis C virus (HCV) appeared in several small studies to have poorer outcome after LT compared to patients with HCV monoinfection.

 

Methods:

A retrospective cohort study was performed to assess the impact of HIV on LT survival by using UNOS Standard Transplant Analysis and Research (STAR) files.

 

Results:

A total of 138 HIV(+) and 30,520 HIV(-) patients who were ≥ 18 years old and underwent LT during the HAART era (starting from January 1, 1997) in the US were included in the analysis. Of 138 HIV(+) patients, 58 were HCV antibody (HCVAb)(+) and 21 hepatitis B surface antigen (HBsAg)(+). Twenty four HIV(+) patients were neither HCVAb(+) nor HBsAg(+). Among all HIV(+) patients, the estimated 2-year survival probability was lower (70%) than among non-HIV patients (81%). This excess risk appeared entirely among those with coinfections, e.g. HIV with HBV or HCV, as none of the 24 HIV infected patients who did not have HBV or HCV died during an average of 1.2 years of follow-up per person. HIV/HCV coinfected patients had significantly lower survival rate compared to non-HIV patients with HCV (p=0.006) and without HCV (P=0.003) after LT (Figure 1). In contrast to HCV/HIV coinfected patients, there was no significant difference in survival rates between HIV/HBV coinfected patients and HBV patients without HIV coinfection. Controlling for age, coinfection, MELD scores and other potential confounders in a Cox proportional hazards regression analysis, HIV(+) patients had a hazard ratio (HR) of 1.41 (P= 0.14, %95 CI: 0.90-2.22) for mortality post LT.

 

Conclusion:

Patients who had HIV/HCV coinfection had lower survival rates after LT compared to HCV patients without HIV coinfection. Such difference was not observed in HIV/HBV coinfected patients compared to HBV monoinfected patients undergoing LT.

 

 


Topic: Experimental Therapies - GS-9190

 

49. Antiviral, Pharmacokinetic and Safety Data for GS-9190, a Non-nucleoside HCV NS5b Polymerase Inhibitor, in a Phase-1 Trial in HCV Genotype 1 Infected Subjects.

L. Bavisotto, . C. Wang; I. M. Jacobson; P. Marcellin; S. Zeuzem; E. J. Lawitz; M. Lunde; P. Sereni; C. O'Brien; D. W. Oldach; G. Rhodes

 

Background & Aims:

GS-9190 is a novel non-nucleoside HCV NS5b polymerase inhibitor with potent in vitro antiviral activity (0.6 nM EC50 in Genotype 1b replicon) and a high selectivity index in vitro. Initial results from an ongoing single-dose/multiple-dose escalation clinical trial of GS-9190 in HCV-infected volunteers are reported here.

 

Methods:

Study GS 196-0101 is a randomized, double-blind, placebo controlled trial designed to evaluate the safety/tolerability, phamacokinetics and antiviral activity of single (in Part A) and multiple (in Part B) doses of GS-9190 in subjects chronically infected with HCV genotype 1 (GT-1) without cirrhosis. Prospective subjects are 18-60 years of age and are HCV treatment nave.

In an already completed Part A, five successive cohorts of 6 subjects were randomized (5:1) to receive single ascending doses of GS-9190 (40, 120, 240, 240-with food, or 480 mg) or placebo. In ongoing Part B, four successive cohorts of 12 subjects are randomized (10:2) to receive multiple ascending doses of GS-9190 (40 mg BID, 120 mg BID, 240 mg QD, 240 mg BID) or placebo, over 8 days.

 

Results:

Thirty-one subjects enrolled in Part A were of mean age 43.6 years, predominantly male (20/31), Caucasian (25/31), and infected with either HCV Genotype-1a (24) or 1b (6). Median (range) baseline HCV viral load was 6.6 log10 RNA IU/mL (5.2-7.3). Single doses of GS-9190 were well tolerated, with no serious or treatment-limiting adverse events (AEs) reported. All AEs (except one moderate) were mild in severity, with the most common being headache. There were no Grade 3 or 4 treatment emergent laboratory abnormalities.

 

Median GS-9190 plasma half-life ranged from 10 to 15 hours across cohorts. Systemic exposure was increased approximately 2-fold when GS-9190 was administered with a high fat meal. Mean GS-9190 concentration 24 hours after the 240 mg fasted dose was ~7-fold higher than the protein binding adjusted in vitro HCV GT-1b replicon EC50 value. Following single-dose exposure, maximal antiviral effect was observed at 24 hours, with median declines ranging from 0.46 to 1.49 log10 HCV RNA IU/mL across cohorts. Individual HCV RNA declines among all GS-9190 recipients ranged from 0.19 to 2.54 log10 IU/mL following single-dose exposure.

 

Conclusions:

This study demonstrates potent dose-dependent antiviral activity of GS-9190, a novel non-nucleoside HCV polymerase inhibitor in HCV infected volunteers. Single dose exposure to GS-9190 was well tolerated and demonstrated favorable PK properties that may support QD or BID dosing. The multiple dose phase of this trial is ongoing, and updated results will be provided.

 


Topic: Experimental Therapies - Telaprevir

 

50. Telaprevir resistance mutations in patients with hepatitis C who relapsed after sequential therapy with telaprevir, peg-interferon alfa 2a and ribavirin

N. Forestier, S. Susser, M. W. Welker, C. J. Weegink, H. W. Reesink, S. Zeuzem1,; C. Sarrazin

Introduction:

Telaprevir (TVR) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease with highly effective blocking of HCV replication in patients with hepatitis C. Mutations have been identified in the NS3 protease gene at positions 36, 54, 155 and 156 conferring resistance to TVR in vitro and in vivo. For single resistance mutations an inverse correlation of resistance level and viral fitness has been described while combined mutations (i.e. V36/R155) display relative high resistance with compensatory effects on replication efficiency. Little is known about persistence of TVR resistance mutations in patients treated sequentially with TVR, peg-interferon and ribavirin (RBV).

 

Methods:

Fifteen patients received either TVR monotherapy or TVR peg-interferon alfa 2a combination therapy for 2 weeks followed by peginterferon alfa 2a plus RBV standard combination therapy for 24 or 48 weeks. In the present study, we performed amplification and clonal sequencing (approx. 50 clones per patient and time point) of the HCV NS3 protease gene in 5 patients who relapsed so far. All 5 patients were tested HCV RNA negative during therapy but relapse with increasing HCV RNA concentration was observed after the end of standard combination treatment for 24 or 48 weeks.

 

Results:

While in 2 patients no mutations conferring resistance to TVR were detected during different time points after relapse, in 3 patients known TVR resistance mutations within the NS3 protease gene were detected. Patient 1 with initial TVR monotherapy, 48 weeks of standard therapy, and relapse at week 4 after treatment discontinuation (433.000 IU/ml) showed mutations at positions V36 (100% of clones) and R155 (100% of clones). In patient 2 with initial TVR monotherapy, 24 weeks of standard treatment and relapse at week 4 (viral load pending) only single isolates with resistance mutations were observed at position V36 (2%) and A156 (2%). Finally, patient 3 received initially combination therapy followed by 48 weeks of standard treatment. In this patient relapse was detected at follow up week 8 (1.400 IU/ml) and resistance mutations were detected at position V36 (84% of clones) only. In both patients who received TVR monotherapy mutations at positions V36, T54, R155 and A156 were observed during the initial 2 weeks of treatment.

 

Conclusion:

In patients treated with TVR with and without peginterferon alfa 2a for 2 weeks followed by standard therapy with peginterferon and RBV for 24 or 48 weeks mutations conferring resistance to TVR can be detected after relapse. The significance of TVR resistance mutations for the probability of relapse has to be investigated in future studies.

 


Topic: Current Treatment - PegIntron

 

51. Sustained Virologic Response with albinterferon alfa-2b/ribavirin treatment in prior interferon therapy non-responders

D. R. Nelson; V. K. Rustgi; V. Balan; M. Sulkowski; G. L. Davis; A. Muir; L. Lambiase; R. C. Dickson; R. H. Wiesner; J. G. McHutchison1; E. Pulkstenis; P. Cronin; G. M. Subramanian

 

Background/Aim

Albinterferon alfa (alb-IFN) is a novel recombinant protein consisting of IFNa-2b genetically fused to human albumin. This randomized Phase 2 study evaluates the efficacy and safety of alb-IFN/ribavirin treatment in chronic Hepatitis C (CHC) patients who were non-responders (NR) to previous IFNa-based regimens.

 

Methods

Subjects were randomized into 3 alb-IFN treatment cohorts (900mcg Q2w, 1200mcg Q2w or 1200mcg Q4w) in combination with weight-based oral ribavirin (RBV) 1000-1200 mg/day. After evaluating safety data, 2 further cohorts were treated with higher doses of alb-IFN 1500mcg Q2w and 1800mcg Q2w. The treatment duration is 48 weeks and the primary efficacy end-point is sustained virologic response (SVR) at 24 weeks post-treatment. The protocol was amended to allow extended treatment (a total of 72weeks) for slow responders, ie, subjects who became RNA negative after w24.

 

Results

The demographics and antiviral response for the 115 patients enrolled are summarized in the table. The 1500 and 1800mcg treatment groups had more patients with baseline characteristics associated with poor response (eg, pre-treatment HCV RNA, PEG-IFN+RBV NR, % African-Americans). All doses were well tolerated and the safety profile in the 1500 mcg and 1800 mcg cohorts was comparable to the 900-1200mcg cohorts in incidence and types of adverse events. The overall SVR rate for the first 4 treatment groups was 19% (18/93), though lower in the genotype 1, PEG-IFN+RBV NR group 12% (7/57). Importantly, the 1800mcg group showed robust antiviral response (50% [6/12] achieved EVR12) in genotype 1 null-responders to prior PEG+RBV therapy.

 

Conclusions

Alb-IFN in combination with oral RBV is safe and effective. Treatment with 1800mcg Q2w demonstrates significant antiviral activity in prior IFNa non-responder patients.

 

 


Topic: Experimental Therapies - Bavituximab

 

53. Multiple dose safety and pharmacokinetic study of bavituximab in patients with chronic hepatitis C virus (HCV) infection

E. J. Lawitz; E. W. Godofsky; J. S. Shan

 

Background:

Bavituximab, an investigational monoclonal antibody targeting phosphatidylserine (PS) located on the surface of virus infected cells and enveloped viruses, is being developed as an anti-HCV agent. It has immunostimulatory effects in preclinical viral models. Single intravenous (IV) infusions of bavituximab up to 6 mg/kg were well-tolerated and showed transient antiviral activity in chronic HCV patients.

 

Methods:

To determine the safety, tolerability and pharmacokinetics of multiple IV infusions of bavituximab, sequential cohorts of 6 patients were given twice weekly 90 min IV infusions for two weeks at 0.3, 1, 3 or 6 mg/kg and followed until week 12. Vital signs, physical exams, safety laboratory parameters, serum bavituximab levels and serum HCV RNA levels were measured.

 

Results:

Twenty-four patients (15 male, mean age 49) were enrolled. Eleven were non-responders, 8 were relapsers and 5 were treatment-nave. Mean baseline viral load was 5,000,000 copies/mL and 15 were infected with genotype 1, 8 with genotype 3 and 1 with genotype 2. The infusions were well-tolerated. No serious adverse events (SAEs) or early discontinuations were reported. There was no dose-related increase in incidence or severity of adverse events (AEs). All AEs were mild or moderate and transient, except for grade 3 neck pain and arthralgia (drug-related) in a patient with a history of joint pain at 3 mg/kg bavituximab and grade 3 elevated blood glucose (unrelated) in another patient with diabetes at 0.3 mg/kg bavituximab. All other drug-related AEs were mild: hypertension in 1 patient at 0.3 mg/kg, headache in 1 patient and headache and pruritis in 1 patient at 1 mg/kg and flu-like illness/symptoms in 2 patients at 6 mg/kg after the first infusion. Bavituximab reaches Cmax at 2-3 h postdose with a mean elimination half-life of ~34 h. Bavituximab exhibited dose-proportional increases in Cmax and AUC in single and multiple dosing and did not lead to significant accumulation. All dose levels exhibited on therapy antiviral activity (decline of >0.5 log10 reduction in HCV RNA). The 3mg/kg cohort had the largest number of patients showing antiviral activity, as 5 of 6 subjects achieved >0.5 log decline in HCV RNA.

 

Conclusions:

Twice weekly IV doses of bavituximab up to 6 mg/kg were safe and well-tolerated. Single-dose and multiple dose pharmacokinetics of bavituximab are linear, predictable and no accumulation appears to occur over time. Two weeks of dosing is indicative of antiviral effect in a proportion of patients. Future studies designed to optimize the dosing schedule and investigate combining bavituximab with current standard therapy are planned.

 


Topic: Current Treatment - Pegasys

 

54. Rapid and early virological response rates are increased with 12 week 360 g/wk peginterferon alfa-2a (40KD) and standard ribavirin in HCV genotype 1 treatment naive patients: efficacy and safety analysis of the induction phase of the CHARIOT study

S. Roberts; M. D. Weltman; D. Crawford; W. Cheng; W. Sievert; G. W. McCaughan; P. V. Desmond; M. Yoshihara; J. E. Miller; J. Depamphilis; P. Marks; G. J. Dore; C.

 

Background:

The CHARIOT study evaluates the efficacy & safety of a 360 g/wk dose peginterferon alfa-2a (Peg-IFNα-2a) induction regimen compared to standard 180 g/wk Peg-IFNα-2a, in combination with standard ribavirin (RBV) in treatment-naive patients with chronic hepatitis C genotype 1. We report results of the planned interim analysis of on-treatment virological responses over the first 12 wks of therapy.

 

Methods:

In this international, multi-centre, open label study patients were stratified by baseline HCV RNA and randomised 1:1 to 180 g or 360 g Peg-IFNα-2a qw for 12 wks followed by 36 wks of 180 g Peg-IFNα-2a plus RBV 10001200 mg/d for 48 wks. Endpoints include virologic response at wks 4, 8 and 12.

 

Results:

845 patients were evaluable for efficacy & safety analysis. Age, gender, weight, BMI, ethnicity, viral load and fibrosis scores were similar in the two groups. At wks 4, 8 and 12, virological response rates were greater (p<0.001) in the 360 g/wk arm (Table). Significantly higher response rates (p<0.001) at wk 12 occurred in patients receiving 360 g dose in all subgroups including baseline HCV RNA ≥800,000 IU/mL (71% vs 55%) and <800,000 IU/mL (84% vs 71%), weight ≥85 kg (74% vs 56%) and <85kg (74% vs 62%), and age >40yrs (70% vs 54%) and ≤40yrs (84% vs 73%). Induction therapy was associated with higher rates of diarrhoea (17% vs 12%), pyrexia (14% vs 8%), chills (14% vs 7%) and weight loss (10% vs 3%). Depression and fatigue reports were similar. Discontinuations were similar in both groups, however induction therapy led to more dose modifications (Table). Use of haematopoetic growth factors was the same in both groups (4 patients [<1%]).

 

Conclusion:

Induction dosing with 360 g/wk Peg-IFNα-2a is more effective than standard 180 g/wk dosing in achieving early and rapid virological responses and is safe and well tolerated. The effect was independent of baseline viral load, weight, BMI and age.

 

 

Peg-IFN α-2a
180μg/wk (N=423)
n (%)

Peg-IFN α-2a
360μg/wk (N=422)
n (%)

Efficacy (HCV RNA <15IU/mL)

 

Wk 4 RVR

108 (26)

149 (35)*

Wk 8

209 (49)

256 (61)*

Wk 12

255 (60)

313 (74)*

Wk 12 EVR (HCV RNA <15IU/mL or ≥2log10 drop)

333 (79)

374 (89)*

Safety

 

Overall Tx discontinuations (d/c)

19 (4)

21 (5)

Tx d/c due to AEs or lab abnormalities

10 (2)

11 (3)

SAEs

13 (3)

18 (4)

Dose modifications (PEG-IFN α-2a)

60 (14)

93 (22)

Neutropenia (<0.5 x 109/L)

9 (2)

23 (5)

Thrombocytopenia (<50 x 109/L)

4 (<1)

15 (4)

Anemia (<10g/dL)

29 (7)

44 (10)

*Cochran-Mantel-Haenszel test p<0.001