Late Breaking Abstracts: Monday Nov 3: 4pm

HCV Drug Pipeline - General

LB5. SAMe Improves Early Viral Kinetics and Interferon Stimulated Gene Induction When Added to Peginterferon and Ribavirin Therapy for Previous Hepatitis C Non-Responders.

J. J. Feld; A. A. Modi; G. Ahlenstiel; R. El-Diwany; Y. Rotman; C. Koh; R. Titerence; Y. Park; M. Ghany; T. Heller; J. H. Hoofnagle; T. Liang

Background:

Over 50% of patients infected with genotype 1 HCV do not respond to peginterferon and ribavirin. S-adenosyl methionine (SAMe) has been shown to enhance interferon signaling in cell culture and animal models by acting as a methyl donor to STAT1, leading to improved STAT1-DNA binding.

Aim:

To assess the effect of SAMe on interferon signaling and early viral kinetics in previous non-responders to peginterferon and ribavirin.

Methods:

Previous genotype-1 non-responders to peginterferon/interferon and ribavirin were recruited. Patients were given 2 weeks of peginterferon-alfa-2a and ribavirin to establish baseline responses (Course A). Treatment was stopped for a 1-month washout period. Patients then received SAMe 1600 mg daily for 2 weeks, at which point, peginterferon and ribavirin were restarted with SAMe for a planned duration of 48 weeks (Course B). Early viral kinetics and interferon stimulated gene (ISG) expression in PBMC were compared with and without SAMe.

Results:

Of the 9 patients in the study, all have completed Course A and the first 2 weeks of Course B and 7 have completed 12 weeks of Course B. HCV RNA decline from time 0 to 48 hours was similar between courses (Phase 1 kinetics). There was a significant improvement in the second phase slope of viral decline in 8/9 patients and in the group as a whole with SAMe (A -0.11±0.07 vs B -0.33±0.1 log/week, p=0.007). Five of 7 patients, all previous non-responders, have achieved an early virological response (EVR), including 3 who are PCR negative. ISG15 induction in PBMC was statistically significantly greater in 6 of 9 patients and for the group as a whole during Course B than Course A (AUC: A 133±24 RU vs B 187±26 RU, p=0.001). ISG15 fold induction was greater at all time points, with the greatest difference seen at 24 hours (A 171±54 RU vs B 350±166 RU, p=0.04). A similar pattern was observed with MxA. ISG15 and MxA expression were greater at time 0 in Course B than A, after receiving 2 weeks of SAMe alone. During 2 weeks of SAMe monotherapy, ALT values decreased significantly (mean change 37 U/ml, p=0.004) but HCV RNA levels increased slightly (mean change 0.22 log, p=0.05).

Conclusions:

SAMe appears to improve early viral kinetics in interferon non-responders and the observation that it leads to greater ISG induction suggests that the effect may be through improved interferon signaling.

Treatment – Pegasys

LB6. Metformin with Peginterferon Alfa-2a and Ribavirin in the Treatment of Naïve Genotype 1 Chronic Hepatitis C Patients with Insulin Resistance (TRIC-1): Final Results of a Randomized and Double-Blinded Trial.

M. Romero-Gomez; M. Diago; R. J. Andrade; J. Calleja; J. Salmeron; C. M. Fernández-Rodriguez; R. Solà; J. M. Herrerías; I. Carmona; J. García-Samaniego; R. Moreno-Otero; R. Morillas; C. Ramírez; M. De la Mata; P. Giner; A. Olveira; O. Nuñez; F. Jorquera; S. Duran; R. Martin-Vivaldi

Background & Aims:

Insulin resistance affects sustained virological response (SVR) in patients with chronic hepatitis C (CHC). We sought to determine if the addition of metformin to the standard of care regimen could improve SVR in naïve patients with genotype 1 CHC and insulin resistance.

Methods:

In a prospective, multicenter, randomized, double-blinded, placebo-controlled trial (TRIC-1), 125 consecutive patients with genotype 1 CHC and insulin resistance (HOMA > 2) received either metformin 425 mg t.id during the first month and 850 mg t.i.d. from week 4 to 48 (Arm A; n=59) or placebo (Arm B; n=64) in addition to peginterferon alfa-2a 180 micrograms weekly and ribavirin 1000-1200 mg daily. Treatment was withdrawal in patients without early virological response (EVR) or HCV-RNA positive at week 24. No baseline differences between arms A and B were seen in the following demographic, biochemical and virological data: age (47+/-8 vs. 48+/-8 years); HOMA (4.3+/-2.2 vs. 4.4+/-2.6); Sydney index (0.43+/-0.27 vs. 0.45+/-0.31); baseline viral load (6.33+/-0.73 vs. 6.48+/-0.76 log10 UI/ml); p=ns for all comparisons. Virological response was assessed at week 4, 12, 24 and 72 by intention-to-treat (ITT) analysis.

Results:

In the ITT analysis viral clearance was seen in 54.2% vs. 48.4% at week 12, in 74.6% vs. 75% at week 24, and in 52.5% vs. 42.2% at week 72 (SVR rate) in arm A and arm B respectively. In females (n=54), viral clearance was higher in the metformin arm at week 12 (57.7% vs. 39.3%) at week 24 (80.8% vs. 71.4%) and SVR (57.7% vs. 28.6%;p=0.031). In patients receiving metformin (arm A) viral load decreased during the first 12 weeks in a gender-dependent manner (-4.18+/-1.18 vs. -4.02+/-1.68 log10 IU/ml;p=0.044). SVR was 56.3% in women showing a weight higher than 75 Kg. Patients in arm A showed a greater decrease in their HOMA index than those in arm B (-1.6+/-2.14 vs. -0.87+/-2.11; p=0.008). Triple therapy was well tolerated. Gastrointestinal discomfort, mainly mild diarrhea, was more often seen in arm A (34.1% vs. 11.4%; p<0.05).

Conclusions:

Triple therapy with metformin, peginterferon and ribavirin was well tolerated, decreased insulin resistance and increased SVR in this difficult-to-treat group of patients. This therapy was especially effective in females in whom metformin raised significantly the SVR rate. It agrees to the improved sensitivity to metformin reported in obese women. Our data suggest that triple therapy should be the standard of care for females with hepatitis C genotype 1 and insulin resistance.

Acknowledgments: Supported by an unrestricted grant from Roche-Farma, S.A.