Late Breaking Abstracts: Monday Nov 3: 4pm
Pipeline - General
Improves Early Viral Kinetics and Interferon Stimulated Gene Induction When
Added to Peginterferon and Ribavirin Therapy for Previous Hepatitis C
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
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.
To assess the effect of SAMe on
interferon signaling and early viral kinetics in previous non-responders to
peginterferon and ribavirin.
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.
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).
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.
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.
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.
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).
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
Acknowledgments: Supported by an
unrestricted grant from Roche-Farma, S.A.