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 therapy. S. 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-naïve 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-Naïve
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 µg/week and ribavirin 1000-1200 mg/day (PR) in
treatment-naïve 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
weeks—89% 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)/Ribavirin. B. 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 patient’s 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-naïve 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-naïve adults with HCV
genotype 1/4 infection initiated treatment with PegIFNα2a 180 µg/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-naïve, 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 Pearson’s 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 |
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 naïve 2b patients. In naïve 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 naïve 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 900µg, 1200µg or 1500µg (6
injections) or PEG-IFNα2a 180µg 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 900µg, 1200µg, 1500µg 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 900µg, 1200µg,
1500µg 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 900µg, 1200µg and
1500µg, 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 Study. Y. 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 naïve,
non-responders or relapsers to prior Peginterferon/R therapy. We evaluated
treatment naïve 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 naïve 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
µM to 25 µM 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 µM, 3.8
µM and 1.1 µM, respectively. The EC50s in genotype 2a replicon cells were
similar (13 µM, 8.4 µM and 4.7 µM). The EC50 in HCVcc
for vitamin D3 was 2.1 µM. The mean CC50 at 120 hours of D2, D3 and 1,25(OH)2
D3 was 42 µM, 55 µM, and 23 µM. Conversion of 1 µM, 5 µM and 25 µM 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. Günther; 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-naïve 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 |
240 mg BID |
|
Week 4 |
|
|
|
Week 12 |
|
|
|
Week 48 |
|
|
|
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
(800–1200mg/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%; 2–4:31.3% 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 (81–85%). 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.
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-naïve 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-naïve, 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 |
% 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
Response. J. 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 µg/wk + RBV 1000–1600
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 >3×ULN (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 naïve, 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
48±14 yrs, [BMI] 29±6, 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 45±10, [BMI] 26±5, 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 (29±6 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 (26±11 ng/ml) and increased after 4 weeks of vitamin D treatment
to a mean level of (36±7) 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.
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 |
Arm B |
Arm C |
|
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-naïve 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-naïve 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 >10–1000). 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-naïve 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 Child’s
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 Child’s 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; Child’s 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 |
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. Hörnfeldt; 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-naïve 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-naïve 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 |
-0.004 |
-0.01 |
0.00 |
-0.03 |
-0.07 |
-0.09 |
-0.09 |
|
Control |
+0.02 |
+0.03 (0.01:0.05) |
+0.06 (0.04:0.09) |
+0.05 (0.03:0.07) |
+0.01 |
+0.01 |
+0.02 |
+0.02 |
|
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-naïve, 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-Naïve 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 |
G2,3 (n=5) |
G1,4 |
G2,3 (n=4) |
G1,4 |
G2,3 (n=5) |
G1,4 |
G2,3 (n=4) |
G1,4 |
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 µg/kg/wk plus ribavirin
(RBV) 800-1400 mg/d or PEG alfa-2a 180 µg/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 |
32% |
30% |
|
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: |
|
|
|
Week 24 follow-up phase: |
|
|
|
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 Patients. R.
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 naïve 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 360µg/week plus RBV
1000/1200 mg/day (arm A) or 1200/1600 mg/day (arm B) for 72 weeks; peg-IFN
alfa-2a, 180µg 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: 50±8 years, mean BMI: 26±4 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: -0.9±0.6 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:
-1.0±0.7, -2.3±1.5, -3.5±1.8, -4.4±1.5, and -5.0±1.1 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-naïve
Genotype 4 Hepatitis-C Patients: Final Results of Study C210. Y. 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-naïve 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. TVR’s 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 |
|
|
|
|
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, %) |
0 |
1 (12.5%) |
0 |
|
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. Févery; 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 5’NC, 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-Naïve 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-naïve 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 naïve patients infected
with HCV genotype 1, 2, 3, or 4 were randomized to receive 80, 120, 180, or 240
µg PEG-IFN-λ or 180 µg 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-Naïve 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-naïve 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 naïve 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. Stättermayer; 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 µg 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:
51.0±10.6 (mean±SD), BMI: 25.6±4.0, 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 (mean±SD)] 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: 6,6±0,6 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 patient’s
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.