DDW 2007: Monday Abstracts:
Topic: Treatment – Disease Progression
T. Kawaguchi; T. Ide;
E. Taniguchi; E. Hirano; M. Itou; S. Sumie; Y. Nagao; C. Yanagimoto; S. Hanada;
H. Koga; M. Sata
Backgrounds:
HCV infection is associated with increased insulin
resistance. We have previously shown that HCV down-regulates hepatic expression
of insulin receptor substrate (IRS) 1/2, central molecules for insulin
signaling, through up-regulation of suppressor of cytokine signaling 3. Thus,
HCV itself seems to play an important role for the development of insulin
resistance. However, the effects of antiviral treatment on impaired glucose
metabolism remain unclear. The aim of this study is to examine the effects of
eradication of HCV on hepatic expression of IRS1/2 and insulin resistance.
Subjects and Methods:
We analyzed 80 biopsy-proven patients with chronic HCV
infection. Patients were received interferon-α or interferon-α plus
ribavirin for 6 months and were classified into three groups at 6 months after
the conclusion of antiviral therapy according to their response to antiviral
therapy: sustained responders (n = 26), relapsers (n = 11), and non-responders (n
= 43). Insulin resistance was assessed by the homeostasis model assessment
method (HOMA-IR). Hepatic expression of IRS1/2 was evaluated by immunoblotting
and immunostaining in 14 sustained responders.
Results:
In non-responders, BMI significantly decreased to 21.5 ± 1.4
kg/m2 from 22.9 ± 3.1 kg/m2 (p < 0.05) at the end of follow-up. However,
there were no significant changes in HOMA-IR values at the end of follow-up
compared to those before antiviral therapy (HOMA-IR: 3.9 ± 1.5 vs. 3.7 ± 1.5,
N.S.). In relapsers, no significant differences were seen in BMI (21.9 ± 1.5
kg/m2 vs. 22.0 ± 1.4 kg/m2, N.S.) and HOMA-IR values (3.5 ± 1.6 vs. 3.6 ± 1.1,
N.S) at the end of follow-up compared to those before antiviral therapy. In
sustained responders, there was no significant difference in BMI at the end of
follow-up (22.3 ± 1.7 kg/m2 vs. 22.1 ± 1.8 kg/m2, N.S). On the other hand,
HOMA-IR values significantly decreased to 2.3 ± 1.1 from 3.2 ± 0.9 (p <
0.01) by the end of follow-up. Immunoblotting showed a 3-fold increase in
hepatic expression of IRS1/2 after eradication of HCV. Immunostaining revealed
that increased IRS1/2 expression occurred in hepatocytes, but not
non-parenchimal cells.
Conclusions:
We demonstrated that eradication of HCV improves hepatic
expression of IRS1/2 and insulin resistance.
Topic: Treatment General
362. Restoration Of
Innate Immunity And Inhibition of Essential Host Factor For Replication Achieve
Better Clinical Effect In Patients With Chronic Hepatitis C
K. Inoue; T. Watanabe;
M. Yoshiba
Background/Aim:
Persistent infection is a distinguishing feature of hepatitis
C virus. A crucial strategy against innate immunity is impairment of the IRF-3
pathway, which results in low response of IFN induction system. Recent
improvement of infectious culture system revealed that cyclosporineA or other
cyclophilin inhibitors can suppress HCV replication. Cyclophilins are essential
host factor for HCV replication. We adopted divided administration of
IFN-β to restore the immune response with cyclosporine A as a cyclophilin
inhibitor in induction and intensified therapy based on recent advances in
molecular virology. We report here a better clinical effect of our protocol.
Method:
Patients (n= 70; 45 men and 25 women; average age, 61) were enrolled
into the present study to confirm the efficacy, safety and tolerability of the
new treatment. Serum HCV RNA level was 1600 KIU/ml (420-15000 KIU/ml) and
genotype 1b. The treatments consisted of an induction therapy, an intensified
therapy and a maintenance therapy. The induction therapy comprised intravenous
1 MU IFNβ every 4 hours for the first 3 days, 1.5 MU IFNβ every 6
hours for the next 4 days and 2 MU IFNβ every 8 hours for the following 3
weeks, totaling 168 MU of IFNβ. The intensified therapy was induction
therapy shortened to 2 weeks. The maintenance therapy comprised of pegylated
IFNa2b and ribavirin. CsA was given 4 times daily for a total dose of 200 mg
during the induction and the intensified therapies. Ribavirin was given twice
daily for a total dose of 800 mg (body weight over 60 kg) or a total dose of
600 mg (body weight equal to or less than 60 kg) during the maintenance
therapy. This protocol was approved by the institute review board.
Results:
The sustained virological response rate of the present study
was 65.8% (47/70). The sustained biochemical response rate of the present study
was 80.4% (55/70). Safety analysis showed that 22 patients had mild
retinopathy, 5 had severe proteinuria and one had encephalopathy, which was
probably related to CsA. Administration of CsA was discontinued in 4 cases. All
adverse effects were completely reversible. The treatment protocol was well
tolerable.
Conclusion:
Recent advances in molecular virology related HCV revealed
the mechanism of HCV persistence and HCV replication. Rational attempt based on
recent progress in HCV basic research can overcome the persistence of HCV and
achieve better clinical effect. Host factor targeted treatment will be a
promising new HCV treatment.
Topic: Experimental Therapies (both HCV-976 and 503034)
R. Ralston; A. Y.
Howe; R. Chase; A. Skelton; X. Tong; M. Flint; S. Mullen; C. Broom; E. Emini
Background:
Cell-culture replicon studies evaluated the combined
antiviral effects of two novel inhibitors of hepatitis C virus (HCV):
SCH-503034 (Schering-Plough), a NS3 protease inhibitor, and HCV-796
(Wyeth/ViroPharma), a non-nucleoside polymerase inhibitor. Each inhibitor
demonstrated significant antiviral activity in early clinical studies. Replicon
studies demonstrated that genetic variants exhibiting reduced susceptibility
can be selected from each compound. Because SCH-503034 and HCV-796 target
different viral enzymes, a potential exists for enhanced in vivo antiviral
effect if the inhibitors are used in combination, as well as the potential for
forestalling in vivo selection of clinically resistant HCV. The present replicon
studies were performed to ascertain the likelihood of achieving these goals.
Methods:
The combined antiviral effect of SCH-503034 and HCV-796 was
evaluated using genotype 1b HCV replicon cells. Each compound was individually
assessed for its ability to inhibit the activity of variant replicons
exhibiting reduced susceptibility to the other inhibitor.
Results:
The combination of SCH-503034 and HCV-796 notably enhanced
replicon inhibition in treated cells, in a dose-dependent manner, compared with
the effect of each inhibitor used alone. The antiviral effect of the
combination was at least additive. No cytotoxicity was
observed. SCH-503034 exhibited equivalent inhibitory activity against the
wild-type replicon and replicon variants expressing single polymerase amino
acid substitutions that engender reduced susceptibility to HCV-796. The
inhibitory effect of HCV-796 against replicon variants with protease amino acid
substitutions mediating reduced susceptibility to the protease inhibitor was
found to be identical to that observed against the wild-type replicon. The
combination significantly reduced the frequency of emergence of resistant
colonies compared to each inhibitor used alone.
Conclusions:
·
The
anti-replicon activity of the combination of SCH-503034 and HCV-796, as well as
the activity of each compound against replicons with reduced susceptibility to
the other compound, strongly support the combined use of these two inhibitors
in clinical trials.
·
The
cell-culture replicon data suggest that the in vivo antiviral effects of the
combination will be notably improved over the effects seen to date with
monotherapy.
·
Importantly,
compared with monotherapy, the combination will likely impose a greater genetic
barrier to the selection of clinically resistant viral variants.
Topic: Disease Progression
366. TLR-stimulated non-parenchymal liver cells are
potent suppressors of HCV replication.
R. Broering; J. Wu; G.
Gerken; J. F. Schlaak
Aims and Background:
Only little is known about the role of non-parenchymal liver
cells (NPC) of the hepatic sinusoid (Kupffer cells (KC) and liver sinusoidal
endothelial cells (LSEC)) in the antiviral defence against HCV. Therefore, the
aim of this study was to further elucidate their role in the local innate
immune response against HCV in the liver using a murine replicon system.
Materials and methods:
To study the effect of type I and II IFNs murine MH1 cells
harbouring the HCV-Con1 replicon I377/NS3-3 were cultured in the presence or
absence from various concentrations of IFN-α, IFN-β and IFN-γ.
In addition, the cells were cultured with cell culture supernatants from KC and
LSEC stimulated with TLR-ligands 1-9 for 20 h. Then, total RNA of the MH1 cells
was isolated and the HCV replicon concentration was measured by quantitative
real-time PCR.
Results:
The replicon RNA is increasing over a time course of 60 h
with a fold change about four, independent from the passage number and
confluence of the cells. Treatment of these cells with IFN-α, -β or
-γ led to decreased HCV replication in a dose dependent manner with IC50s
that were comparable to data from human HCV replicon systems (2-10 U/ml). All
three IFNs led to a maximal suppression of HCV replication of about 80%. Only cultivation
of MH1 cells with supernatants from TLR3- and 4-stimulated KC or LSEC
stimulated with TLR3 led to a marked inhibition of HCV replication by NPC.
While TLR3- and 4-stimulated KC could suppress HCV replication by about 80% in
our system, supernatants of TLR 3-stimulated LSEC could suppress HCV
replication by about 60%, respectively. The suppressive effect of TLR3- and -4
stimulated cells could be completely blocked by preincubation with antibodies
against IFN-β.
Conclusions:
In conclusion, these results show that the HCV-Con1 Replicon
I377/NS3-3, when replicated in a murine system, is sensitive to IFN-α,
-β and -γ. Furthermore, TLR3-stimulated NPC are potent suppressors of
HCV replication which is possibly mediated through IFN-β. These novel
findings are of particular relevance for the control of HCV replication by the
innate immune system of the liver.
Topic: Diagnostic tools – Biochemical/imaging
G. Lalazar; O. Pappo;
B. Müllhaupt; O. Goetze; M. Margalit
Background:
Significant liver disease may be present in a seemingly
healthy population with normal liver enzymes and minimal symptoms. The serum
ALT level may not reflect the degree of liver damage, and liver biopsy has been
the gold standard for assessment of fibrosis and inflammation. The point of
care non-invasive BreathID® continuous online 13C methacetin breath test (MBT)
reflects hepatic microsomal function (CYP1A2) and has been shown to correlate
with hepatic fibrosis.
Aim:
To assess the ability of the
BreathID® 13C MBT to differentiate patients with significant liver inflammation
and/or fibrosis from healthy controls.
Methods:
184 patients with chronic HCV infection, who had undergone a
liver biopsy within 9 months, and 81 healthy controls (no known liver disease,
normal liver enzymes and ultrasound) matched for age and sex, underwent 13C MBT
following ingestion of 75mg of methacetin. Forty three controls and 11 patients
underwent the MBT at least twice to determine test reproducibility. MBT
parameters included PDR peak (percentage dose recovered) and CPDR10, 20, 30, 60
(cumulative PDR10, 20, 30 and 60 minutes after ingestion of methacetin,
respectively). Correlations between breath test parameters and HAI (Hepatic
Activity Index) inflammation score or METAVIR fibrosis score were evaluated. We
compared MBT parameters between controls and patients grouped by HAI and
METAVIR scores.
Results:
In HCV patients, all MBT parameters correlated significantly
with inflammation and fibrosis scores (p<0.0001). MBT accurately
differentiated between controls and patients with significant periportal and
bridging inflammation (HAIa > 2), any inflammation type (total HAI ≥
4) (AUC 0.87 and 0.82, 95%CI 0.78-0.97 and 0.74-0.91; sensitivity 88% and 74%;
specificity 78% and 77%; NPV 97% and 84%; and PPV 45% and 65%, respectively),
or patients with significant fibrosis (METAVIR > 2) (AUC 0.96, 95%CI
0.92-1.00; sensitivity 96%, specificity 86%, NPV 97%, and PPV 81%). Inter-test
variability was ≤ 13% (95%CI 0.11-0.15). Results were independent of BMI
in patients and healthy controls.
Conclusions:
The point of care BreathID® continuous online 13C MBT
accurately differentiates patients with significant liver inflammation and/or
fibrosis from healthy controls. This test may prove to be a powerful
non-invasive tool for detecting occult liver dysfunction.
Topic: Disease Progression
438a. A
comparison of risk factors for intra- and extrahepatic cholangiocarcinoma in
the
T. M. Welzel; B. I.
Graubard; H. B. El-Serag; Y. H. Shaib; A. W. Hsing; J. A. Davila; K. A. McGlynn
Background:
Cholangiocarcinomas can be anatomically classified as
extrahepatic (ECC) or intrahepatic (ICC) tumors. Despite differences in their
clinical and pathological presentation, ECCs and ICCs share some common risk
factors such as PSC. In contrast, some recent evidence suggests that the
etiopathogenesis of ECC and ICC may differ. For example, ICC and hepatocellular
carcinoma (HCC) may arise from common progenitor cells. Also in support of this
hypothesis are the divergent temporal trends in ECC and ICC incidence in the
Methods:
Using the Surveillance, Epidemiology and End Results
(SEER)-Medicare linked database, all ICC and ECC
patients diagnosed between 1993 and 1999 were identified. Controls were chosen
at random from among individuals with no cancer diagnosis in the underlying
populations of the SEER11 regions. Logistic regression analysis was used to
calculate adjusted odds ratios.
Results:
549 ECC, 535 ICC cases and 102,782 controls met the inclusion
criteria. In addition to established risk factors, such as choledochal cysts,
cholangitis and inflammatory bowel disease, several other medical conditions
were significantly associated with increased risk of ECC and ICC, including
biliary cirrhosis (ECC, ICC: p=0.0001), cholelithiasis (ECC, ICC:
p=<0.0001), alcoholic liver disease (ECC p<0.0001; ICC p=0.01),
nonspecific cirrhosis (ECC, ICC: p<0.0001), diabetes (ECC, ICC: p=<0.0001),
thyrotoxicosis (ECC p=0.006; ICC p=0.04) and chronic pancreatitis (ECC, ICC:
p=<0.0001). Conditions only associated with ICC were obesity (ECC p=0.75;
ICC p<0.01), chronic non-alcoholic liver disease (ECC p<0.08; ICC
p=0.02), hepatitis C virus (HCV) infection (ECC p<0.67; ICC p=0.01) and
smoking (ECC p=0.07, ICC p=0.04).
Conclusions:
This study identified several novel conditions that were
significantly associated with both ECC and ICC risk. In addition, the current
study found that HCV infection, obesity, chronic non-alcoholic liver disease,
and smoking are significantly associated with ICC, but not ECC risk. As several
of these pre-existing conditions (HCV infection, obesity, chronic
non-alcoholic liver disease) are increasing in the
Topic: Exprimental Therapies – HCV – 796
440. Pharmacodynamic Analysis of the Antiviral
Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Combination With Pegylated Interferon Alfa-2b in Treatment-Naïve
Patients With Chronic HCV.
E. S. Maller; D.
Raible; P. Chandra; D. Harper; J. Speth; P. Shaw; G. Bichier; S. Villano
Background:
HCV-796 is an inhibitor of
hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated
antiviral activity across multiple HCV genotypes, both in vitro and in Phase 1
clinical studies.
Methods:
In a randomized, double-blind
study, adult patients with chronic HCV infection who were naïve to treatment
were randomized to receive oral HCV-796 (100, 250, 500, or 1000 mg) or placebo
every 12 hours for 14 days. All patients were to receive pegylated interferon
alfa-2b (PEG, 1.5 μg/kg) on day -1 (one day before start of
HCV-796/placebo) and day 7. Each cohort receiving HCV-796+PEG enrolled 9-12
patients. Virologic response was analyzed by individual pharmacokinetic (PK) parameters
and various demographic/baseline characteristics. HCV RNA was assayed with a
lower limit of detection of 50 IU/mL.
Results:
Overall, the mean baseline HCV
RNA level was 6.4 log10, and 66% of patients were infected with HCV
genotype 1. At day 14, the mean reduction in HCV RNA ranged from 3.3-3.5 log10
in the combination therapy groups vs. 1.6 log10 in the PEG group.
Activity differed by HCV genotype. Mean reductions at day 14 for genotype 1
ranged from 2.6-3.2 log10 in the combination therapy groups vs. 1.2
log10 for PEG. For genotype non-1 the respective reductions were
3.5-4.8 log10 vs. 2.6 log10. Based on individual HCV RNA
plots over time, there was somewhat greater variability in virologic response
in the HCV-796 100 mg q12h combination group compared with higher dose groups.
However, analyses of individual virologic responses in the combination therapy
groups did not reveal correlations with individual
Conclusions:
The combination of HCV-796 and
PEG provides antiviral activity across multiple HCV genotypes that is greater than either agent used alone. Pharmacodynamic
analyses suggest similar short-term antiviral activity at HCV-796 doses of 250
mg q12h or higher when combined with PEG. Clinical studies of more long-term
administration of combination therapy are in progress to determine if these
effects are durable.
Topic: Current Therapy - Pegasys
441. Peginterferon Alfa-2a (40KD) Plus Ribavirin for 16 or 24 Wks in Pts With HCV Genotype
2/3 Infection and Advanced Fibrosis/Cirrhosis.
M. L. Shiffman; F.
Suter; B. R. Bacon; D. R. Nelson; H. Harley; R. Solá; S. D. Shafran; K.
Barange; A. Lin; G. Hooper; S. Zeuzem
Background:
Chronic hepatitis C (CHC) pts with cirrhosis have a higher
risk of developing severe complications and are in particular need of
treatment. In the ACCELERATE trial of peginterferon alfa-2a plus ribavirin
(RBV) in pts with HCV genotype 2 or 3 (G2/3) infection, cirrhosis was a
significant negative prognostic factor of a sustained virologic response (SVR).
We further analyzed the ACCELERATE database to compare the efficacy of
treatment in pts with and without cirrhosis, and whether on-treatment virologic
response would assist treatment optimization.
Methods:
Pts (n=1469) received peginterferon alfa-2a (PEGASYS®)
180μg/wk plus RBV (COPEGUS®) 800mg/d for either 16 or 24wks. SVR
(undetectable [<50IU/mL] HCV-RNA at 24wks post-treatment) was analyzed
according the presence or absence of baseline cirrhosis in 1309 pts receiving
treatment as defined by the protocol. Cirrhosis included advanced
fibrosis/transition to cirrhosis (Knodell ≥3, Metavir ≥3, or Ishak
modified HAI score of 4 [with nodules or >3 bridges] or ≥5).
Additional analyses determined SVR rates in pts with and without rapid
virologic response (RVR; undetectable HCV-RNA [<50IU/mL] at treatment wk 4).
Results:
Cirrhotic pts had lower SVR rates than non-cirrhotic pts; for
both groups, SVR was higher with 24 vs. 16wks’ treatment (Table). RVR was
achieved by 56% of pts with cirrhosis and 71% of non-cirrhotic pts.
Non-cirrhotic pts with RVR had SVR rates of 85% with only 16wks’ treatment;
extending treatment to 24wks resulted in an SVR rate of 91% (p=0.02; two-sided
Fisher’s exact test). In cirrhotic pts with RVR, 24wks’ treatment resulted in
higher SVR rates than with 16wks (87% vs. 71%; p=0.01). In pts without an RVR, both
cirrhotic and non-cirrhotic, 24wks’ treatment produced higher SVR rates than
16wks (p=0.04 and p<0.0001, respectively).
Conclusions:
·
Higher
SVR rates with peginterferon alfa-2a plus RBV therapy are achieved in G2/3 pts
without cirrhosis, supporting early treatment before progression to advanced
liver disease.
·
In
pts with RVR, 24wks’ treatment resulted in SVR rates >87% in both cirrhotic
and non-cirrhotic pts. Cirrhotic pts without RVR have a chance of SVR of only
30% with the currently recommended 24-wk regimen; in these pts, longer
treatment durations might be beneficial.
·
Assessing
on-treatment virologic response at wk 4 thereby allows treatment optimization
in both cirrhotic and non-cirrhotic pts with HCV G2/3 infection.
|
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Topic: Experimental Therapies – Celgosivir
442.
Phase II Study of
celgosivir in combination with Peginterferon alfa-2b and ribavirin in chronic
hepatitis C genotype-1 non-responder patients
K. D. Kaita; E. M.
Yoshida; D. Kunimoto; F. Anderson; M. Sherman; P. Marotta; L. J. Scully; K. M.
Peltekian; R. A. Enns; F. Diaz-Mitoma; S. S. Lee; L. Worobetz; J. Pankovich; A.
Petersen
Introduction:
Celgosivir is a new class of antiviral medicine in clinical
development for the treatment of chronic hepatitis C virus (HCV) infection.
Researchers tested this new antiviral medicine and measured its potential to
offer improved treatment outcomes when combined with other anti-HCV drugs.
Methods:
The current study evaluated 57 chronic HCV genotype-1
patients, separated by prior treatment status into non-responders or partial
responders and randomized to three treatment groups:
1. celgosivir 400 mg once daily in
combination with peginterferon alfa-2b and ribavirin (PRC);
2. celgosivir 400 mg once daily in
combination with peginterferon alfa-2b (PC); or
3. placebo with peginterferon alfa-2b and
ribavirin (PR, active control).
All patients were treated for 12 weeks. The non-responders
cohort enrolled 36 patients (PRC: 15; PC: 11; PR: 10) and the partial responder
cohort had 21 patients (PRC: 3; PC: 9; PR: 9).
Results:
For prior non-responder patients, an Early Viral Response
(EVR) was achieved in 42 percent (5/12) of those in which celgosivir was added
to the standard peginterferon alfa-2b and ribavirin therapy compared with only
10 percent (1/10) of patients receiving just peginterferon alfa-2b and
ribavirin. Non-responder patient study results also demonstrate an improved
mean decrease in HCV viral loads when celgosivir is added to peginterferon
alfa-2b and ribavirin of 1.63 log10 IU/mL versus 0.92 log10 IU/mL in patients
treated with peginterferon alfa-2b and ribavirin alone. Eleven of the 36
non-responder patients were classified as a very difficult-to-treat patient
subgroup (null responders) as they were shown to have a prior HCV treatment
response of =0.4log10 to optimized therapy. In the present study, the mean
decrease in HCV viral loads in these null responder patients was 1.86 log10
IU/mL with celgosivir plus peginterferon alfa-2b and ribavirin while the two
null responder patients treated with peginterferon alfa-2b and ribavirin was
0.32 log10 IU/mL. The observed difference in mean viral load between the PRC
and PR treatment groups provides evidence that the combined effect of
celgosivir with peginterferon alfa-2b and ribavirin provides a clinically
significant treatment benefit for difficult-to-treat chronic HCV infected
patients.
Conclusion:
"This study is the first demonstration that celgosivir
in combination with peginterferon alfa-2b and ribavirin results in a clinically
significant decrease in HCV viral loads in patients highly resistant to current
standard treatment," said Kelly D. Kaita, M.D., of the University of
Manitoba in Canada, and lead author of this study. "Further clinical
research on the best dosing regimen and combinations is warranted to optimize
the potential of this innovative combination for chronic HCV patients."
Source; DDW press release
Topic: Experimental therapies – Telaprevir VX 950
A. Khunvichai; H. Chu;
V. Garg; J. G. McHutchison; E. Lawitz; M. Rodriguez; T. Kieffer; J. Alam
Background:
HCV protease inhibitors, such as telaprevir, inhibit viral
replication and have induced marked decline of plasma HCV RNA titers in
genotype-1-infected (GT-1) patients. Viral dynamic (VD) modeling assuming
homogenous wild-type (WT) viral population suggested that protease inhibitors
may significantly shorten treatment duration required to eradicate the virus (
Methods:
Plasma HCV RNA data from 12 treatment-naïve, GT-1-infected
patients dosed for 4 weeks with telaprevir co-administered with
peginterferon-alfa-2a (Peg-IFN) and ribavirin (RBV) (Lawitz, 2006 DDW #686F)
were analyzed using a VD model (Neumann, Science 1998) incorporating the
pharmacokinetics (PK) of telaprevir. Simulations were performed with model
parameter values obtained from VD model (ε, δ, etc.) and PK
parameters, for patients with predominately WT virus and low levels of
resistant variants (assuming an initial variant level of 100-3000 IU/mL, a
variant IC50 value ~7-to 20-fold increase from WT, and similar fitness between
resistant variants and WT (Sarrazin, 2005 AASLD #LB06)). Because resistant
variants were shown to be sensitive to IFN or RBV in vitro (Lin, 2006 AASLD
#89) the effectiveness of Peg-IFN/RBV in blocking virion production was assumed
to range 80%-95% against both WT and variant, consistent with clinical
observations.
Results:
The results of the simulations (Figure 1) indicate that
treatment duration with co-administration of telaprevir with Peg-IFN/RBV
required to suppress WT and low-level resistant variants below 1 copy (total
body burden) is less than 12 weeks.
Conclusions:
These results indicate that even in the presence of resistant
variants, co-administration of a potent protease inhibitor with Peg-IFN/RBV may
result in rapid viral eradication, allowing a substantial reduction in
treatment duration from the current 48 weeks. The model supports the study of
telaprevir-based treatment with Peg-IFN/RBV for 12 weeks. This hypothesis is
being tested in ongoing clinical trials.
Topic: Current therapies – Pegasys
M. G. Swain; M. Lai;
M. L. Shiffman; W. E. Cooksley; A. Abergel; A. Lin; E. Connell; M. Diago
Background:
The current standard of care in chronic hepatitis C virus
(HCV) infection is combination therapy with peginterferon and ribavirin.
Sustained virologic response (SVR) rates of up to 66% have been reported in pts
with HCV mono-infection. The durability of SVR is being investigated in a
long-term follow-up study of pts treated for chronic HCV infection. Here we
present the latest results of this ongoing study.
Methods:
Pts who took part in one of nine randomized trials of
peginterferon alfa-2a (40KD) (PEGASYS®) as monotherapy or in combination with
ribavirin (COPEGUS®), and who were negative for serum HCV-RNA (<50IU/mL) at
the final virologic assessment were eligible for inclusion in the long-term
follow-up study. Serum HCV-RNA was determined annually for 5 years from the
date of last treatment.
Results:
To date 997 pts are undergoing long-term follow-up, including
163 HCV mono-infected pts treated with peginterferon alfa-2a (40KD)
monotherapy, 741 mono-infected pts treated with combination therapy, and 93
HIV-HCV co-infected pts treated with either monotherapy or combination therapy.
The overwhelming majority of pts (989/997; >99%) remain HCV-RNA negative at
a mean of 4.1 (range 0.4-7) years after treatment cessation (an outcome we consider
to be consistent with a cure). Eight pts became HCV-RNA positive (>50IU/mL)
between 1.1-2.9 (mean 2.0) years after completing treatment. There were no
consistent patterns in terms of age, gender or HCV genotype among these 8 pts
and none showed evidence of liver cirrhosis. Two pts had low baseline viral
load (<400,000IU/mL) while the remaining 6 pts had a baseline viral load
ranging from 700,000–12 millionIU/mL. The proportion of these incidents
representing new infections or true ‘relapse’ is currently unknown.
Conclusions:
·
These
results show that an SVR following treatment with peginterferon alfa-2a alone
or in combination with ribavirin is durable in almost all (99.2%) pts with
chronic HCV infection, validating the use of the word ‘clincially cured’ for
those achieving an SVR.
·
The
author noted that of the 8 patients who became HCV positive during follow-up,
that one was a clear case of reinfection because that
patients tested positive for a different genotype than the genotype in
the original study.
·
The
authors are not sure if the other 7 patients are from reinfection or because
the virus returned after therapy.
Another physician stated that because there is a 1% false-positive
result that there cold be a possibility that the viral load tests have been
false positive. Unfortunately, those
patients have not lost to follow-up.
|
Treatment (population) |
Number of studies |
N |
Mean years after treatment |
Pts with detectable HCV RNA
(n) |
|
Monotherapy (elevated ALT)a |
4 |
163 |
4.6 |
2 |
|
Combination (elevated ALT)a |
4 |
666 |
4.2 |
5 |
|
Combination (‘normal’ ALT) |
1 |
75 |
3.2 |
0 |
|
Mono and combination (HIV-HCV co-infection) |
1 |
93 |
3.2 |
1 |
a1
study contained monotherapy and combination therapy arms.
Topic: Experimental therapies – general
Background and Aims:
HCV replication depends on membrane constituents for assembly
and release of the polyprotein. HMG CoA reductase (HMGR) inhibition reduces
cellular sterol proteins such as geranylgeraniol, and markedly suppresses in
vitro HCV replication. Our aims were to prospectively evaluate HMGR inhibition
changes in lipid profiles, and HCV RNA levels in prior CHC non-responders(NR).
Methods:
For this open-label ascending dose cohort study, 11 CHC
genotype-1 NR, received Rosuvastatin (Crestor) initially at 20mg qd for 4 wks, and 40 mg qd for a further 8 wks. HCV RNA (NGI
SuperQuant), fasting lipid and biochemical profiles were obtained at baseline,
at intervals during the 12 week dosing period, and at 4 wks after treatment.
Associations between changes in lipid profiles and liver transaminases or HCV
RNA were determined by nonparametric Spearman’s
Results:
Our study cohort was mostly male (M/F=8/3) mean age 50.8 ±
4.1 yrs. Statin therapy was tolerated without a significant ALT flare (×3
baseline). Despite favorable reductions in LDL and cholesterol, no single
patient achieved >1log HCV RNA decline during treatment, a trend towards
inverse correlation between HDL and HCV RNA was apparent at baseline (
Conclusions:
Short-term rosuvastatin
therapy results an improved lipid profile that is not associated with
significant changes in HCV RNA or serum ALT in CHC genotype-1 NR. This could relate in part to an
inability to achieve adequate HMGR inhibition in vivo. Assessment of HCV RNA in
specific lipid fractions is in progress. Associations between changes in TG,
HDL and HCV RNA during statin therapy require further evaluation.
|
Topic: Disease progression – metabolic disorders
513. Associate Factors Of Nonalcoholic Fatty Liver Disease : Results From A Population-Based Study.
A. Colecchia; A.
Vestito; E. Paltrinieri; M. Bacchi-Reggiani; A. Di Biase; G. Mazzella; M.
Montagnani; F. Lodato; A. Morselli-Labate; F. Pasqui; D. Festi
Introduction:
Nonalcoholic fatty liver disease (NAFLD) represents one of
the most common liver disease; however a few studies
assessed its prevalence in general population and its association with abnormal
liver enzymes is not still clear.
Aim:
to evaluate the prevalence and
associated factors of NAFLD in a general population and its relationship with
abnormal liver enzymes.
Material and Methods:
We carried out a cross sectional study in a general
population, aged 18-84 yrs, of a small town; 1534 out of 1646 ( 93%) subjects
agreed to participate to the study. All subjects underwent abdominal
ultrasound, physical examination, fasting blood specimen collection, seven day
dietetic diary.
Results:
479 out of 1534 ( 31.2%) subjects were excluded (391 alcohol,
20 HBV, 63 HCV and 5 autoimmune); thus analyses were performed on 1055 subjects
(68%). 382 out of 1055 subjects ( 36.1%)( males 57.8%, mean age: 52.1 ± 12.7)
had NAFLD evaluated by US. 88 out of 1055 subjects ( 8.3%) had abnormal ALT (
15.7% in NAFLD vs 4.2 % in normal subjects; p< 0.001); prevalence of NAFLD was
higher in subjects with abnormal ALT than those with normal ALT [ 60 out of 88
(68.2%) vs 319 out of 967( 33%)( p< 0.001)]. Frequency of NAFLD was related
to increased BMI,; however 80 out of 382 ( 20%)
subjects had normal BMI. Associated factors were, at univariate analysis, male
sex, aging , blood hypertension, diabetes, hypercholesterolemia, low
HDL-cholesterol, Tg/Hdl ratio ≥ 3.5, hypertriglyceridemia, BMI, large
waist circumference and abnormal ALT, AST and gGT; while, at multivariate
analysis, they were sex male (OR:1.89), systolic hypertension (OR:1.9),
hyperglicemia (OR:1.9), visceral obesity (OR:4.9), Tg/HDL ratio (OR:2.9), ALT
(OR:2,5) and gGT (OR:1.8).
Conclusion:
NAFLD is highly prevalent in general population; among the
associated factors, obesity and Tg/HDL ratio (marker of insulin resistance)
were the strongest ones. Furthermore, abnormal liver enzymes (namely ALT) are
significantly associated with NAFLD; however, since they largely underestimate
the disease prevalence, they cannot be used as markers of NAFLD.
Topic: Epidemiology
M1001. Cost-Effectiveness of Testing for Hepatitis A Immunity Prior to Initiating Hepatitis A Vaccination
in Patients with Chronic Hepatitis C.
M. K. Chapko; H. S.
Yee; A. Monto; J. A. Dominitz
Objectives:
Individuals with hepatitis C (HCV) are at risk for more
fulminant courses of acute hepatitis A (HAV) should they acquire this
infection. Thus, HAV vaccination is recommended for this population. The
relative cost-effectiveness of universal vaccination versus first testing for
prior immunity is unclear. Testing may reduce the proportion of patients
acquiring immunity because some may not return for test results prior to
immunization.
Methods:
Decision analysis compared two strategies: (1) vaccinate all
patients without testing for immunity and (2) test for hepatitis A antibodies
followed by immunization in those who are susceptible. Parameters in the model
included prevalence of prior HAV immunity and incidence of future HAV
infection; vaccine effectiveness after each dose; proportion completing each
dose; vaccine cost; HAV testing cost, plus cost and quality of life associated
with future HAV.
Results:
Testing first costs less (mean cost per individual = $97.10)
than vaccinating without testing for immunity ($119.37) when baseline values
for parameters are used and when the prevalence of hepatitis A immunity is 30%
prior to immunization. However, vaccinating without testing
results in a larger proportion of individuals who achieve immunity (88.1%
versus 76.5% when 30% are HAV antibody positive prior to immunization).
The added cost of vaccinating without testing for immunity is $191.82 per
additional individual protected from HAV. The incremental cost of vaccinating
without testing for immunity is $91,319 and $182,453 per quality adjusted life
year (QALY), when the prevalence of HAV immunity is 20% and 30%, respectively,
prior to immunization. Sensitivity analyses indicate that the incremental cost
per QALY of vaccinating without testing for immunity decreases dramatically as
the future incidence of HAV increases. The incremental cost
per QALY of vaccinating without testing for immunity increases dramatically as
the prevalence of existing HAV immunity increases and as the severity of the
patient’s cirrhosis increases.
Conclusions:
HAV vaccination without testing for immunity is only
cost-effective when the prevalence of HAV immunity in the group being
vaccinated is 20% or less, when using a cost-effectiveness threshold of
$100,000 per QALY.
Topic: HIV/HCV Coinfection
S. Dhalla; C. T.
Tenner; N. E. Shukla; A. Aytaman; G. Villanueva; G. Punla; C. Patterson; J.
Comas; E. J. Bini
Background:
Hepatitis A virus (HAV) superinfection is associated with a
high risk of mortality in patients with chronic liver disease. HAV vaccination
is recommended for all patients with chronic hepatitis C virus (HCV) infection,
as well as for those with HIV infection. Although patients with HIV-HCV have a
dual indication for HAV vaccination, it is unknown how many of these
individuals receive the vaccine in clinical practice. We hypothesized that
HIV-HCV coinfected patients would be more likely to receive the HAV vaccine than
those with HIV or HCV monoinfection.
Methods:
Patients with known HIV and HCV status completed a detailed
questionnaire at the time of their scheduled visit to the outpatient primary
care or gastroenterology clinic at 3 study sites. Data collected included
patient demographics, personal vaccination history, and barriers to
vaccination.
Results:
Among the 2,038 patients, 715 were uninfected, 121 had HIV,
893 had HCV, and 309 had HIV-HCV. Overall, 360 of the 2,038 patients (17.7%)
were told by their doctor that they had been exposed to HAV, including 4.2% of
the uninfected patients, 15.7% of those with HIV, 23.2% of those with HCV, and
33.7% of the coinfected subjects (P <0.001). Among the 1,650 patients who
were not previously exposed to HAV, only 412 (25.0%) reported that they
received the vaccine, 900 (54.5%) were not vaccinated, and 338 (20.5%) did not
know if they were vaccinated. The proportion of patients vaccinated against HAV
differed significantly according to infection status (12.9% in uninfected vs.
28.0% in HIV vs. 37.3% in HCV vs. 22.8% in HIV-HCV patients; P <0.001). In
the 900 subjects who were not vaccinated, there were significant differences in
the types of barriers according to infectious status (see table).
Conclusions:
1. Although HIV-HCV coinfected patients
were more likely to be vaccinated than uninfected patients, there were no more
likely to receive the vaccine than those with either HIV or HCV monoinfection.
2. There are marked differences in the
types of barriers to HAV vaccination.
3. Public health programs to increase
awareness of HAV vaccination among uninfected, HIV-infected and HIV/HCV coinfection.to overcome
barriers to immunization are needed.
|
Topic: Current therapies – general
M1005. Prevalence and clinical significance of hepatitis G
virus coinfection in patients with chronic hepatitis C undergoing antiviral
therapy.
H. Hofer; M.
Schoeniger-Hekele; C. Mueller; C. Gurguta; P. Steindl-Munda; P. Ferenci
Background and Aim:
Hepatitis G virus (HGV) infection per se is not associated
with liver disease. Coinfection with HGV in patients with chronic hepatitis C
(CHC) may influence the clinical course and response rates of antiviral therapy
with interferon/ribavirin. Aim of the study was to investigate prevalence of
HGV coinfection and outcome of antiviral combination therapy in HGV/HCV
coinfected patients.
Patients:
Three hundred and four patients with chronic hepatitis C
(m=93, age:42 [18-65] median were investigated. These patients participants from previous
randomized controlled trials. HGV RNA
detection was done by polymerase chain reaction prior to initiation of
interferon/ribavirin combination therapy with standard (N=111) or peyglated
interferon (N=193) and after six month follow up period. A pre-treatment liver biopsy was done and
stage of fibrosis was determined according to the metavir scoring system.
Results:
A HGV/HCV Co-infection could be identified in 37 (12.2%) out
of 304 patients (available data).
The predominant HCV-genotype in HGV coinfected individuals
was HCV-2a (51.4%) and the most common source of infection was intravenous drug
abuse (N=21). HGV coinfection was more
common in patients with HCV-3 compared to HCV-1 or HCV-4 (19/52 (36.5%) vs.
14/187 (7.5%) vs. 4/61 (6.5%), p<0.01).
As compared to patients with HCV infection alone, patients
with HGV/HCV confection were younger (35(18-56)) vs. 41 (19-65), years; median [range],
p<0.01) and advanced fibrosis (F3-F4) was less frequent (21.6% vs. 33%,
p<0.05.
A sustained virological response (undetectable HCV-RNA) was
achieved in 26/34 [76.5%) HCV-3a: 14/16 (87.5%); HCV-1: 9/14 (64.2%), HCV-4:
3/4 (75%) HGV/HCV co-infected patients as compared to 116/222 (52.3%) (HCV-3a:
22/26 (84.6%), HCV-1: 63/147 (42.8%), HCV-4: 31/47 (65.9%)) in monoinfected
patients (p<0.01).
After antiviral treatment HGV RNA became undetectable in
23/32 (71.8%) patients. In patients with
still detectable HGV RNA (but a sustained virological response of HCV) (N=4),
ALT levels remained within the normal range at the end of follow-up.
Discussion:
Intravenous drug abuse is a major risk factor for HGV
coinfection in patients with chronic hepatitis C. Coinfection with HGV does not aggravate
clinical course of chronic hepatitis C or diminish response of HCV to antiviral
therapy. Due to the younger age, less
fibrosis and the high frequency of HCV -3a HGV confected patients show a
favourable response to antiviral combination therapy. Interferon/ribavirin combination therapy also
clears HCV infection in a high proportion of cases.
Topic: Epi – Psychosocial
M1015. Rates and Predictors of Depression in an
Out-patient Hepatology Practice
G. S. Sayuk; S.
El-Dirani; J. E. Elwing; P. Lustman; M. Lisker-Melman; J. S. Crippin; R. E.
Clouse
Introduction:
Depression interferes with all aspects of daily living,
adherence to medical recommendations, and treatment outcomes. Depression may be
under-recognized in patients with chronic liver disease (CLD) because many of
its symptoms overlap with symptoms attributable to liver dysfunction. The rate
of depression symptoms across types of chronic liver disease is not known. We
administered a commonly used depression assessment instrument, the Beck
Depression Inventory (BDI), to out-patients attending a university-based
practice to determine the rate of current depression symptoms and predictors of
elevated scale scores.
Methods:
345 pts with chronic liver disease [51.1 ±11.9 yr; 193
(55.9%) female; 104 (30.1%) cirrhotic] completed the 21-item Beck Depression
Inventory during an office visit (max score 63).
Etiologies of liver disease were:
·
Hepatitis
C (HCV) 115 (33.3%),
·
NASH/cryptogenic
78 (22.6%),
·
Primary
sclerosing cholangitis (PSC) 18 (5.2%),
·
Primary
biliary cirrhosis (PBC) 13 (3.8%),
·
Hepatitis
B (HBV) 16 (4.6%),
·
Autoimmune
hepatitis (AIH) 25 (7.2%) and,
·
Other
chronic liver disease 52 (15.1%).
Prevalence rates of pts having total BDI ≥16, an
accepted cut-off for suspecting major depressive disorder, and a score ≥10
on the cognitive symptom scale (cBDI, excludes overlapping somatic symptoms)
were determined per chronic liver disease group.
Predictors of total Beck Depression Inventory score were
determined from a linear regression model that included demographic (age, sex,
BMI), clinical [type 2 diabetes (T2DM), prednisone use, interferon use, IV drug
use (IVDU), current alcohol use], and liver disease variables (MELD score,
encephalopathy, AST).
Results:
Beck Depression Inventory scores ≥16 were found in
37.4% of the total subject group, ranging from 25.0 – 42.6 % without
significant difference across the represented disorders:
·
Hepatitis
C - 42.6%,
·
NASH/cryptogenic
- 34.6%,
·
Primary
sclerosing cholangitis 38.9%,
·
Primary
biliary cirrhosis 38.5%,
·
Hepatitis
B (HBV) 25%,
·
Autoimmune
hepatitis 40% and,
·
Other
chronic liver disease 29.6%
(χ2 = 3.96, p=0.78)
Beck Depression Inventory scores ≥10 were found in
24.6% of chronic liver CLD, ranging from 12.5 – 27.8% across disorders:
·
Hepatitis
C – 27.8%,
·
NASH/cryptogenic
– 26.9%,
·
Primary
sclerosing cholangitis 27.8%,
·
Primary
biliary cirrhosis 23/1%,
·
Hepatitis
B 12.5%,
·
Autoimmune
hepatitis 24.1%
(χ2=3.65, p=0.81).
In regression models of all CLD subjects, younger age, female
sex, type 2 diabetes, and IVDU predicted higher total Beck Depression Inventory
and higher cBDI scores (p<0.05 for each). Liver disease variables were not
independent predictors of Beck Depression Inventory scores in either model.
Conclusions:
·
High
levels of current depression symptoms are present in a large proportion of
out-patients with chronic liver disease.
·
This
finding is not related solely to chronic liver disease symptoms that might
mimic depression and is not conspicuously affected by type of chronic liver
disease.
·
Depression
symptoms are best predicted by clinical features associated with depression in
non-chronic liver disease populations (female sex, type 2
diabetes, IVDU) rather than type of liver disease or measures of liver
disease severity.
Topic: Epi - General
M1024. Prevalence of Hepatitis C Among Arab & Chaldean Americans in
L. H. Jamil; M. C. Duffy;
M. Fakhouri; E. Barkho; R. Khoury; H. Fakhouri; H. Jamil
Background:
The prevalence of Hepatitis C antibodies (anti-HCV) in the
Methods:
Retrospective review of data collected during an HCV public
awareness and education program conducted by the Arab American and Chaldean
Council (ACC), a non profit organization, in the Arab/Chaldean American
population residing in
Results:
A total of 492 subjects’ data from 62 different zip codes in SE
MI., were reviewed. Analysis was performed on 484 subjects. Excluded subjects
were either born in the U.S (8), not of Arab/Chaldean descend (3), or tested
indeterminate (2). Mean age was 43.2 years (range 18-77 years), males were
50.1%, and 30% did not speak English.
The mean number of years of residence in the U.S was 10.4 (range 0.5-52
years).
The overall prevalence of anti-HCV was 5.4% (20 subjects, 9
males, 11 females), with 30% (6 subjects) between ages 40-49. Prevalence among
Chaldeans was 2.3%, and among Arab Americans 5.1%. Highest prevalence was among
Jordanians 20% (2 out of 10), followed by Egyptians 7.6% (8 out of 105).
Five subjects (20%) reported having an episode of
“hepatitis”, and 4 subjects (20%) reported jaundice. Risk factors included
needle prick or shared needle (65%), shared personal hygiene (60%), tattoos and
body piercing (40%), blood transfusion before 1992 (25%), medical therapy by
non-sterile instruments (15%),
Discussion:
This is the first study to examine the prevalence of anti-HCV
among the Arab and Chaldean Americans in the
Conclusion:
·
Prevalence
of Anti-HCV is 5.4% in the Arab/Chaldean American Community residing in
·
Among
those testing positive, 46% were male, 615% were between 40-59 years of age,
69% had less than or equal to years of education, and 65% had to health
insurance.
·
Risk
factors: IVDA 72%, 62% risky sexual
behaviour, 52% shared personal hygiene products, 15% had received a blood
transfusion prior to 1992, and 13% have received an injection by a non-sterile
needle.
Topic: Disease Progression - General
M1779. Hyperlipidemia is very infrequent but is
undertreated in chronic HCV.
C. A. Munroe; J. Chan ; H. Zheng; R. T. Chung
Introduction:
The prevalence of hyperlipidemia in the
1. The prevalence of hyperlipidemia in
chronic HCV;
2. The use and safety of statins in HCV;
and
3. The influence of concurrent statin
use on SVR rates after treatment with PEG-IFN and ribavirin (RBV).
Methods:
We retrospectively analyzed the records of patients with chronic
HCV referred to our clinic between 2001 and 2006. Patients selected were either
(1) currently on statins or (2) candidates for therapy by NCEP/ATPIII criteria
but not on a statin. Of those receiving statins, discontinuation rates and
serial LFT data were analyzed. Those hyperlipidemic patients who received at
least 12 weeks of PEG-IFN and RBV therapy for HCV were also analyzed.
Results:
A total of 1,262 anti-HCV positive patients were seen between
2001 and 2006. Of these patients, 54 (4.3%) were on statins, and another 58
(4.6%) met criteria for initiation of statin therapy but were not started on
treatment. In total, only 8.9% of patients with HCV were hyperlipidemic. In
contrast, analysis of NHANES III showed that 47% of the
Statins used included atorvastatin (85%), simvastatin (11%)
and pravastatin (4%). The mean ALT values before and during statin therapy was
42.6 +/- 26.8 U/L and 47.9 +/- 43.3 U/L, respectively (p=0.54).
The mean ALT of the patients in the non-statin group was 57.4
and 54.1 U/L. Only 2 (4%) patients had to discontinue statins because of
adverse events, one of which was an LFT flare.
Seven patients already on statins (2 genotype 1, 5 genotype
2) were treated with pegIFN and RBV, and 5 (1 genotype 1, 4 gentoype 2)
achieved SVR (71%). In contrast, 7 of 23 (30%) patients (17 genotype 1, 4
genotype 2, 1 genotype 4, 1 genotype not recorded (NR)) in the hyperlipidemic
non-statin group experienced SVR (5 genotype 1, 1 genotype 2 and 1 genotype not
recorded) (p=0.22).
Conclusions:
1. Hyperlipidemia warranting statin
therapy was observed in only 9% of patients with HCV.
2. Only half of hyperlipidemic patients
in this cohort were treated for their dyslipidemia.
3. Statins can safely be administered to
patients with chronic HCV.
4. Statins may enhance the antiviral
effectiveness of PEG-IFN and RBV.
These findings suggest that hyperlipidemia in chronic HCV is
very infrequent, but when present, is undertreated. Further study is warranted
to determine whether statins augment the antiviral effect of pegIFN and RBV.
Topic: Disease Progression - General
M1783. Statins Improve ALT values in Chronic Hepatitis
C Patients with Abnormal Values.
T. Bader; M. Madhoun;
S. Rizvi; K. Seres; J. Fazili
Introduction:
There are no prospective reports of HCV pts taking statins.
FDA inserts for statins list “active liver disease” as a contraindication, but
the meaning of this is unclear. As part of an IRB and FDA approved 14 day study
looking at the antiviral effect of fluvastatin (FLV) in vivo, we report the
total bilirubin (TB) and ALT results and compare it to our retrospective
hepatitis C registry data.
Results:
All 3 pts who started with abnormal ALTs made significant
improvement (see table). 9 pts who started with normal ALTs stayed normal.
There were no significant changes in TB (TB data not shown). These benign
results occurred despite FLV doses that were up to 4X the highest FDA approved
dose of 80 mg.
ALT improvement in those who started with abnormal values
caused us to look at our HCV registry in a different way. Instead of noting
changes in ALT between HCV pts who do or do not take a statin, we asked how
many who had abnormal ALTs when they started the statin improved their
subsequent value, and how many who were normal at initiation of a statin stayed
normal.
13 of 60 pts started a statin with abnormal ALT values; of
these 13, 12 improved their ALT and one pt stayed unchanged. Of the 47
beginning in the normal range, 45 stayed normal; the remaining 2 who developed
a mildly abnormal ALT (<85 IU/ml) after beginning a statin had heavy alcohol
use.
Conclusions:
This is the first report of prospectively using a statin in
HCV pts. 2 remarkable observations were that pts who start with abnormal ALTs
improve their ALTs and those who start with normal ALTs stay within range. The
look-back at our registry supports the prospective data findings.
Retrospectively, others (Clin Gast Hepat 2006; 4:902-907; Hepatology 2006;(suppl 1)44:520A) [total of 340 HCV statin users in
both studies] have also not noted any significant ALT changes among HCV pts who
take statins versus those who do not. However, the latter studies did not
report the distinctions we have made. The data reported here not only support
the lack of harm in this situation, but also seem to suggest a possible
salutary effect that needs further study.
ALT values (normal < 64 IU/ml)
|
FLV dose |
Pre- |
Day 7 |
Day 14 |
Day 21 |
|
80 |
81* |
74 |
68 |
64 |
|
160 |
34 |
59 |
56 |
49 |
|
240 |
33 |
39 |
36 |
46 |
|
320 |
24 |
26 |
27 |
31 |
*ALT values that are
out-of-range before study. †pt had a flu-like reaction "possibly"
related to drug for 5d; the 7d value was taken 2d after stopping FLV.
Significant changes in ALT were defined as a 10% change from baseline and for
total bilirubin it was +/- 1 mg/dl.
Topic: Epi – General
M1786. Hepatitis C and Diabetes: An Update from the National
Health and Nutrition Examination Survey.
F. K. Friedenberg
Background:
Previous epidemiologic studies using the NHANES database have
revealed a higher than expected prevalence of Diabetes in patients infected
with HCV. It has been hypothesized that insulin resistance may be the etiologic
link although a precise cause and effect relationship remains unclear.
Aim:
This study's aim was to clarify the relationship between HCV
and diabetes using the most recent iteration of the NHANES survey (2003-2004).
Methods:
Demographic, physical examination, and laboratory data from
the 2003-04 NHANES survey were combined into a single database using SPSS
v.14.0. HCV status was determined using an ELISA, confirmed by RIBA. Diabetes status was classified based on the
subject's self-reported medical history. Cases coded as missing or
indeterminate for either disorder were censored.
Results:
The final database included 7,283 persons; 87 (1.2%) had HCV
and 486 (6.7%) were diagnosed with Diabets. Mean age was 35.7± 23.6 (29.4% age ≥
50); 50.7% female, 42.5% Caucasian.
In univariate analysis, Diabetes and HCV status were closely
linked (chi-sq = 7.2;p=0.007). In HCV positive
patients 13.8% were diagnosed with Diabetes; in HCV negative patients the
prevalence was 6.6%. Alternatively, 2.5% of patients with Diabetes were HCV
positive, while only 1.1% diabetes negative patients were infected. However,
there was no relationship between HCV status and levels of glycohemoglobin,
C-peptide, insulin, and plasma glucose. Not surprisingly, Diabetes was strongly
linked to family history of Diabetes, Body Mass Index, waist circumference, and
age ≥ 50 (all p < 0.01). Diabetes status was not associated with race
or gender. A logistic regression model (Diabetes status as dependent variable)
demonstrated that age ≥ 50 (p<0.01), Family history of DM (p<0.01),and BMI (p<0.01), but not HCV status (p=0.17) were
associated with Diabetes status. Waist circumference was not used in the model
due to excessive co-linearity with Body Mass Index.
Conclusion:
·
There
appears to be a relationship between HCV status and prevalence of diabetes.
·
HCV
status is not associated with markers of insulin resistance.
·
In
regression analyses, after consideration of relevant confoundersm, HCV status
is not associated with diabetes status.
Topic: EPI - Veterans
M1787. The Validity of Viral Hepatitis and Chronic Liver
Disease Diagnoses in VA Administrative Databases.
J. R. Kramer; J. A. Davila;
E. Miller; P. A. Richardson; T. P. Giordano; H. B. El-Serag
Introduction
Veterans Affairs (VA) administrative databases can be useful
tools for epidemiological and outcomes research by employing ICD-9 codes to identify
individuals with specific clinical conditions. The validity of the codes for
viral hepatitis and chronic liver disease is unknown.
Aims
We aimed to determine the positive predictive value (PPV),
negative predictive value (NPV), % agreement and kappa for the ICD-9 codes for
HCV, alcoholic liver disease (ALD), and cirrhosis.
Methods
We conducted a retrospective study comparing the VA
administrative data to the gold standard chart-abstracted data in the Michael
E. DeBakey VA Medical Center between 9/1998 and 7/2004. We identified 4537
patients in VA inpatient and outpatient databases with an ICD-9 code for HCV
(070.41, 070.44, 070.51, 070.54 or V02.62) or ALD (571.0, 571.1 or 571.3).
Patients
We selected 300 patients from this group, oversampling for
cirrhosis codes (571.2, 571.5 or 571.6). A trained clinician abstracted the
medical record. The gold standard for HCV was defined as a positive HCV ELISA
or PCR RNA test or presence of an HCV diagnosis in the progress notes of the
medical chart. ALD was defined by a diagnosis of ALD in the progress notes.
Cirrhosis was defined as either stage 4 on liver biopsy; any 2 of the following
on imaging: cirrhosis, ascites, HCC, or portal hypertension; or the presence of
at least 2 of the following conditions in the progress notes: cirrhosis,
ascites or peritonitis, varices, HCC, hepatorenal syndrome, hepatic
encephalopathy, or 2 of the following labs: albumin <3.0, total bilirubin
>2.0, or INR >1.2. The PPV (probability that HCV in administrative data
is present according to gold standard) for any HCV code was 92.8% and the NPV
(probability that HCV absent in administrative data is absent according to gold
standard) was 92.3%. This yielded 93% agreement and kappa=0.62. For ALD, the
PPV and NPV was 65.4 and 92.3, with 90% agreement and kappa=0.57. Requiring at
least 1 inpatient or 2 outpatient ALD codes improved the PPV to 81.3 with 91%
agreement, while the NPV and kappa stayed the same. For cirrhosis, the PPV and
NPV of the ICD-9 codes was 92.9 and 87.6 with 88% agreement and kappa=0.63.
Among those with an ICD-9 code for HCV, the PPV and NPV for cirrhosis was 91.3
and 88.6, with 89% agreement and kappa=0.61; while among those with an ICD-9
code for ALD, the PPV and NPV was 96.9 and 77.3, with 84% agreement and kappa=0.69.
Conclusion
In conclusion, diagnostic codes for HCV, ALD and cirrhosis in
VA data are highly predictive of the presence of these conditions in medical
records, and therefore can be reliably used for research purposes. We offer
algorithms to further improve the accuracy of these codes.
Topic: Disease Progression
M1788. Liver disease in hepatitis C virus carriers
found at the occasion of blood donation and outcomes with or without interferon
treatment: A study on
1019 carriers followed for 5-10 years.
J. Tanaka; K.
Katayama; M. Mizui; H. Yoshizawa
Methods:
Liver disease was diagnosed in 1019 individuals for whom
ongoing infection with hepatitis C virus (HCV) was identified on blood
donation, and they were followed for 5-10 years with or without interferon
treatment.
Results:
At the baseline, chronic hepatitis was detected in 529
(51.9%) carriers at a frequency higher in men than women (62.6% [229/478] vs.
42.5% [230/541], p < 0.01); cirrhosis was diagnosed in 5 (0.5) and
hepatocellular carcinoma (HCC) in 1 (0.1%) (Table.1). Of the carriers who were
followed for 5 years or longer, the loss of HCV RNA from serum was achieved in
61 (31.0%) of the 197 with interferon (IFN) treatment and only 1 of the 211
(0.5%) without it (p < 0.0001). HCC developed in 8 (4.1%) with IFN, of whom
7 did not respond to it, and 6 (2.8%) without IFN (Table 2). Follow-ups of the
949 carriers identified older age (p < 0.002), male gender (p < 0.01) and
cirrhosis (p < 0.0001) as factors accelerating the development of HCC.
Relative risk for HCC, estimated by the Cox proportional hazard model, was 1471
fold for the initial diagnosis with cirrhosis, 188 fold for the age >60
years and 2.08 fold for the male gender(Table 3).
Conclusion:
Based on the results obtained, identification of HCV carriers
among the general population, followed by treatment with IFN on those indicated, would help decrease the development of HCC and
lessen medical as well as economical burdens associated with it.
Topic: HIV/HCV Coinfection
M1789. Prevalence and Impact of Alcohol Use Among Patients with HIV-HCV Coinfection: A Prospective
E. J. Bini; S. Currie;
B. S. Anand; H. Shen; N. Brau; W. N. Schmidt; R. Cheung; T. R. Morgan; K.
Chang; M. C. Pedrosa; A. Aytaman; T. L. Wright; V.
Background:
Alcohol use among patients with HIV is not only associated
with decreased antiretroviral therapy (ART) adherence and decreased HIV
suppression, but also increased risk of ART-induced hepatotoxicity and
high-risk sexual behavior. Although patients with HIV-HCV coinfection are at
increased risk of developing ART-associated hepatotoxicity as compared to those
with HIV, little is known about alcohol use and its effects in coinfected
subjects. The aims of this study were to determine the prevalence of alcohol
use among patients with HIV-HCV vs. HCV monoinfection, and to evaluate the
impact of alcohol use on the prevalence of advanced liver disease, elevations
in ALT levels, and HCV treatment candidacy in coinfected subjects.
Methods:
Data on alcohol use were prospectively collected from 280
HIV-HCV coinfected and 2,958 HCV monoinfected patients seen at 24 medical
centers throughout the U.S. Alcohol use was categorized as follows:
non-drinkers vs ever drinkers, maximum number of drinks consumed on a regular
basis (<6 vs. ≥6 drinks/day), CAGE score <2 vs. ≥2, and
recent alcohol use (past 12 months). Advanced liver disease was defined as a
history of ascites, encephalopathy, or variceal bleeding. Treatment candidacy
was assessed using 2 methods: standardized published criteria and the opinion
of the treating clinician.
Results:
There were no significant differences in age or sex between
the 2 groups, although coinfected patients were more likely to be non-white
(75.9% vs. 42.1%, P <0.001). Coinfected patients were less likely to consume
≥6 drinks/day on a regular basis (52.3% vs. 62.6%, P = 0.002) and were
less likely to have a CAGE score ≥2 (49.6% vs. 62.3%, P <0.001).
However, the proportion who were ever drinkers (78.9% vs. 83.0%, P = 0.10) and
recent alcohol use (35.4% vs. 36.7%, P = 0.66) was similar in coinfected and
HCV monoinfected patients. Among the 280 coinfected patients, recent alcohol
use was associated with total bilirubin levels ≥2.0 mg/dl (9.2% vs. 2.8%,
P = 0.02) and evidence of advanced liver disease (7.3% vs. 1.1%, P = 0.006),
but not with elevated ALT levels (72.9% vs. 76.8%, P = 0.47). Coinfected
patients who reported recent alcohol use were less likely than non-drinkers to
be a HCV treatment candidate using published criteria (16.2% vs. 29.8%, P =
0.01) and clinician opinion (23.7% vs. 40.1%, P = 0.006).
Conclusions:
·
Recent
alcohol use is common among coinfected patients, and is associated with
advanced liver disease and a lower likelihood of being a HCV treatment
candidate.
·
Screening
for alcohol use and abuse should be routine part of clinical care for HIV/HCV
coinfected patients.
·
HIV-HCV
coinfected patients should receive counseling about the hazards of ongoing
alcohol consumption.
Topic: Epi
M1790. Molecular Epidemiology Of Hepatitis C Virus In
A. Lwin; T. Shinji; M.
Khin; N. Win; M. Obika; S. Okada; N. Koide
Aim:
This study aimed to describe the prevalence and distribution
of Hepatitis C virus (HCV) genotypes in
Results:
The overall prevalence of HCV infection in general was 11.6%
(154/1333) and regionally, it was 13.5% (47/349), 12.8% (64/501), 4.2% (16/380)
and 26.2% (27/103) in northeastern, northwestern, southern and western city,
respectively.
HCV was genotyped in 145/154 (94.2%) samples by reverse
transcriptase polymerase chain reaction, direct DNA sequencing and phylogenetic
analysis on the partial core genome. Genotype 6 was the most prevalent genotype
in this study [71/145 (49%)], followed by genotype 3 [57/145 (39.3%)], genotype
1 [16/145 (11%)], and genotype 2 [1/145 (0.7%)]. We successfully characterized
multiple HCV genotypes/subtypes as 1a, 1b, 2a, 3a, 3b, 6m, 6n, and a new 6
subtype. Among them, subtype 6n was the most predominant subtype (38.6%),
followed by subtype 3b (29.7%), 3a (9.6%), 6m (9%), 1b (6.9%), 1a (4.1%), new 6
subtype (1.4%) and 2a (0.7%). Subtype 6n was more widely distributed in the
northern cities whereas subtype 3b in the western city.
Conclusion:
This study revealed the regional differences of HCV genotype
distribution in
Topic: HIV/HCV Coinfection
M1791. The Prevalence and Risk Factors for Abnormal Liver
Enzymes in HIV Positive Patients without Hepatitis B or C Coinfections.
R. K. Sterling;
Introduction:
Abnormal liver enzymes (LFTs) are frequently seen in those
with HIV. Because HCV and HBV overshadow other possible variables, little is
known about the prevalence and predictive factors of abnormal LFTs in the
absence of viral hepatitis.
Methods:
We performed a retrospective analysis of HIV clinic patients
to determine the prevalence and factors associated with abnormal LFTs, defined
as > 1.25 ULN. Multiple logistic regression was used to identify independent
predictors of elevated LFTs. Variables were determined at the onset of abnormal
LFTs or by history and included diabetes mellitus (DM), hypertension (HTN),
dyslipidemia, HCV and HBV status, HAART use (NRTI, NNRTI, and PI) and metabolic
syndrome (MS), defined as 2 or more of the following features: DM, HTN,
dyslipidemia, or BMI > 30.
Results:
Of over 1600 patients, charts on 1208 adults were available
for review. The mean age was 42, 64% were male, 25% were Caucasian, 24% had HCV
and 7% HBV, mean BMI 26.5, 22% had BMI > 30, DM in 7.6%, HTN in 27%,
dyslipidemia in 25%, MS in 22%, 41% had HIV RNA < 400 copies/ml, mean CD4
was 445, and 24% had CD4 < 200. Those without HCV or HBV (n=679) were
younger (40 vs. 46 yrs), Caucasian (26 vs. 13%) had a BMI > 30 (25 vs. 17%)
and had dyslipidemia (28 vs. 18%) compared to those with coinfection (n=294).
The prevalence of elevated LFTs in those without HCV or HBV were AST 20%, ALT
15%, and ALP 43% compared to 64%, 46%, and 63% in those with HCV or HBV (all
p<.0001). The majority of elevated LFTs (98%) were mild-moderate (grade 1-2;
1.25-5 x ULN) and AST was highly correlated with ALT (r=.80; p<.0001); however,
neither were associated with increased ALP. Of those without HCV or HBV,
increased AST was associated with HTN (p=.014), lower HIV RNA (p=.0012), and
absence of PI use (p<.0001); increased ALT was associated with HTN (p=.01),
HIV RNA (p=.02), CD4 < 200 (p=.005), MS (p=.04), and absence of PI use
(p=.0038); increased ALP was associated with age (p=.007), BMI (p=.02), CD4%
(p=.0002), DM (p=.037), and NRTI use (p=.006).
Conclusions:
These data are the first attempt to quantify the prevalence
and factors associated with elevated LFTs in HIV patients without HCV or HBV
coinfection. We observed that mild-moderate increased liver enzymes are common
in those infected with HIV and, in the absence of HCV or HBV coinfections,
increases in ALP were the most common abnormality seen in 43%. Absence of PI
use was independently associated with elevations in both AST and ALT while
features typical of hepatic steatosis (DM and BMI) were only associated with
increased ALP. The clinical significance of these findings needs further study
and histologic assessment.
Topic: Disease Progression - Race
M1792. Clinical cirrhosis in chronic hepatitis c (CHC)
varies by race-ethnicity.
S. Iwata; M. Kohla; R.
Taylor; R. Ea; S. Keyhan; M. Bonacini
Introduction:
Liver fibrosis progression in HCV, based on a single liver
biopsy, appears to be in part determined by race-ethnicity. Cirrhosis was found
to be more common in Asian patients in the U.K (Clin Gastroenterol Hepatol 2005;3:910-17).
Little is known of the frequency of clinical cirrhosis in
Asian patients in the
Aim:
To compare histological and clinical
features of CHC in a multiethnic cohort of liver patients.
Methods:
Retrospective query of an electronic
medical record for CHC patients evaluated from 1999-2005. We excluded patients who had HIV,
HBV, had died or received a liver transplant. Histologic cirrhosis was defined
as either advanced fibrosis (Metavir) at biopsy. Clinical cirrhosis was defined
as any of: varices, ascites or splenomegaly. Liver Cirrhosis (LC) was defined
as histological or clinical cirrhosis. Chi-square, t-tests were performed with
Statview.
Results:
714 patients were categorized into 5 groups: 21
American-Indian (AmInd), 288 Caucasian), 150 Hispanic (H), 122 African-American
(AA), 133 Asian (As) patients, and). Median age of AA (54 years) and As (53) was higher than C (52), H (50) or AmInd (49)
(p<0.05). Forty-one to 56% were male (NS). BMI was significantly lower in
Asians. AmInd (62%) and H (37%) had a higher percentage of alcohol abuse than
AA and C (32%) and As (8%) (p<0.0001).
There was no statistical difference in HCV RNA levels, but favorable genotypes
were less common in As and AA (table). LC was found in
25% of the cohort: 5% histologic, 14% clinical cirrhosis, and 6% both.
Histologically, H had higher hepatic fibrosis score vs. As
and C. H and C patients had the same likelihood of having LC, higher than AA or
As (table).
Conclusion:
In our cohort, severity of CHC is affected by race. Using
only histology, cirrhosis is significantly underestimated. Asians in the
|
N= |
21 Am |
288 C |
150 H |
122 AA |
133 As |
|
Fibrosis mean |
2.6±1.3 |
2.1±1.3 |
2.6±1.3 # |
2.25±1.3 |
2.1±1.1 |
|
Histologiccirrhosis |
2 (10%) |
36 (13%) ## |
29 (19%) * |
9 (7%) |
8 (6%) |
|
Clinical/histo cirrhosis (LC) |
5 (26%) |
90 (31%)* |
47 (31%) * |
17 (14%) |
22 (17%) |
|
HCC (%) |
1 (5%) |
3 (1%) |
4 (3%) |
5 (4%) |
9 (6%) |
# ANOVA; p=0.02 vs. As, p=0.002 vs. C ## p<0.05 vs. AA,
As * p<0.01 vs. AA and As
Topic: Epi
M1793. High Prevalence of Hepatitis C in Recently Released
Prisoners and Missed Opportunities for Treatment and Care.
S. Currie; D. P.
Tracy; R. K. Fox; K. Page-Shafer
Background:
HCV prevalence in incarcerated populations is 30 – 50%, over
20 times higher than the general population. Upon release from correctional facilities,
prisoners return to the community through parole programs, after a median
duration of 23 months of incarceration. These parolees often face barriers to
accessing health care due to a lack of health insurance and lack of access to
overloaded public programs. Veteran parolees with health benefits do not have
this difficulty. Little is known about the prevalence and management of HCV
among parolees in the VA.
Objective:
To determine HCV prevalence among veterans recently paroled
from prison and, in those who are HCV positive, examine the number who had
received HCV management and care, including HCV antiviral treatment and
immunizations.
Methods:
A convenience sample of 73 veterans who had been released
from prison in the past 6 months participated in the study through self,
correctional, community or medical referral. Data were collected at baseline
for socioeconomic, behavioral and incarceration histories. Serum was also
collected and tested for HCV antibody, RNA and HCV genotype (GT). Clinical data
were abstracted from patient medical records; those with a positive anti-HCV
and detectable HCV RNA were classified as having chronic HCV.
Results:
Of the 73 parolees, 37(50.7%) were Black, 26(35.6%) were Caucasian,
10 (13.7%) other. This group was poor (83% had an annual income less than
$10,000), had low levels of education (47.9% had ≤12 years education);
76.7% reported a history of injection drug use (IDU), and 56% reported a
history of mental health problems. Anti-HCV prevalence was 79%; 51(89.5%) of
those had chronic HCV, the majority with Genotype 1 (82.4%). The majority of
parolees had accessed a number of health services at the VA Medical Center: 67%
had received medical care since their release either through regular and urgent
care (56.9%) or urgent care alone (9.8%) and 71% had accessed a drug and
alcohol program, 37.3% had obtained prescriptions, however, only 11(21.6%) of
the 51 had reported that they had accessed HCV care and 29.4% had not yet been
vaccinated for HBV.
Conclusions:
·
HCV
prevalence is extremely hight among veteran parolees.
·
Most
veterans know their HCV positive status.
·
Although
the majority of veterans were accessing the VHA for regular, urgent, alcohol
and drug and prescription health care services, very few had
accessed services specifically for HCV.
·
More
integrated HCV care should be considered with primary and other health services
to reduce the number of missed opportunities in this highly prevalent
population.
Topic: Experimental therapies – General
J. G. McHutchison; M.
L. Shiffman; E. Schiff; P. Pockros; J. Spandon; G. Burgess
Background:
In patients with chronic HCV, elevated serum levels of AST
and ALT, and increased rates of hepatocyte apoptosis and activated caspases,
reflect hepatocellular damage. The pancaspase inhibitor, PF-03491390, reduced
elevated AST and ALT levels in patients with chronic HCV infection, during a
12-week double-blind treatment phase of a multicenter, parallel-group,
dose-ranging study.1
Methods:
A total of 39 patients with documented chronic HCV and liver
fibrosis, randomised to placebo for 12 weeks in the double-blind treatment
phase of a previously reported study, received open-label PF-03491390.
Patient characteristics:
·
25
males; 14 females
·
Caucasians-28;
Black-6, Hispanic-4, Asian-1
·
Age
(years) – 51 (37-69)
·
Body
mass index—29 (20-41)
35 of 39 patients completed the study; two patients were lost
to follow-up; two patients prematurely discontinued from the study for other
reasons (one relocated, one study side error).
Subjects received oral PF-03491390 5 mg twice daily for the
first week of active treatment, commencing at Week 13. If their
aminotransferase levels remained above the normal range, the dose of
PF-03491390 was incrementally escalated: 10 mg (Weeks 15–17); 25 mg (Weeks
18–20); 50 mg (Weeks 21–22), and 100 mg (Weeks 23–25), all administered twice
daily. Serum aminotransferase levels and adverse events were monitored from
Week 13 to Week 29.
Results:
Median AST and ALT levels decreased within one week of
initiating PF-03491390 treatment and these reductions were maintained
throughout the 12-week treatment period. (Table 1).
Increasing the dose of PF-03491390 did not appear to intensify these effects.
Dose escalation occurred in all patients, with 0, 3, 5, 8 and 21 patients,
respectively, taking 5, 10, 25, 50 and 100 mg twice daily doses at Week 25. AST
and ALT levels rapidly returned to near-baseline values when PF-03491390 was
discontinued. The majority of adverse events were of mild or moderate severity
and there were no discontinuations or dose reductions due to adverse events.
Safety:
A total of 17 (44%) of patients reported a total of 34
adverse events during the study. The
majority of adverse events were of mild to moderate severity. Only four adverse events were reported by
more than one patients: fatigue, arthralgia, headache and rash. Neither of the adverse events were rated as
severe were related to the study drug.
Conclusions:
·
PF-03491390
effectively reduces AST and ALT levels in patients with chronic HCV infection;
these effects occur early and are maintained for ≥ 12 weeks on treatment.
·
Results
confirm those previously reported for the double-blind phase of the study.
·
PF-03491390
is generally well tolerated by patients with chronic HCV infection.
·
Initial
observations suggest that doses of PF-03491390 in the range of 5-10 mg twice
daily may be sufficient;
pharmacokinetic/ pharmcodynamic modeling for PF-03491390 is
currently in progress.
·
Further
studies are required to determine whether longer duration of treatment with
PF-03491390 has continued effects on liver enzymes, which may influence liver
histology in patients with chronic HCV infection and liver fibrosis.
Reference 1. Shiffman ML, et al. Hepatology 2006;44(suppl A):224A, Abst 95.
Topic: Experimental therapies: Valopicitabine
M. Rodriguez-Torres;
N. H. Afdhal; E. J. Lawitz; E. Godofsky; B. Belanger; B. Fielman Constance; S.
Knox; J. Leone; N. A. Brown
Background:
This Phase IIa study was designed to assess the potential for
a pharmacokinetic (PK) drug interaction between NM283 and pegylated interferon
alfa-2b (peg-IFNα-2b) in treatment naïve patients with HCV-1 infection.
The safety, tolerability and comparative antiviral activity of NM283 alone and
in combination with peg-IFNα-2b was also to be assessed, prior to
longer-term studies.
Methods:
Key eligibility criteria: HCV RNA >5 log10 IU/mL, ALT
<5x ULN, compensated liver disease, and no previous antiviral therapy for
hepatitis C. Thirty patients (pts) were to be randomized 2:3 to receive 800 mg
NM283 (n=12) or 800 mg NM283/peg-IFNα-2b (n=18). NM283 was to be dosed
orally once-daily for 28 days in both groups. Pts randomized to NM283/peg-IFNα
combination treatment were to receive weekly doses of peg-IFNα-2b (1.0
μg/kg) starting on Day 8. Through serial amendments treatment up to 72
weeks was permitted according to virologic response and tolerance of study
treatment. Serum HCV RNA levels were assessed at each visit by the TaqMan™ PCR
assay (>10 IU/mL).
Results:
31 pts were enrolled and randomized to NM283 (n=12) or
NM283/peg-IFNα-2b (n=19). Two
patients assigned to NM283/peg-IFNα-2b withdrew prior to the first dose of
peg-IFN. Patients were predominantly male, with a mean age 45 yrs and mean
baseline HCV RNA = 6.1 log10 IU/mL. Overall, 71% of pts were of
Latino or African American descent who have
historically have shown lower response rates than predominantly Caucasian
populations. Study treatment was satisfactorily tolerated, with no serious
adverse events or dose limiting toxicities.The most common adverse events were
nausea, headache, vomiting, and occasional diarrhea. Nausea, vomiting, and
diarrhea were more common with the combination regimen compared to NM283 alone,
but were rarely treatment-limiting.
The PK results indicated that measures of NM283 systemic
exposure (Cmax, 24-hr AUC) were unaltered by co-administration of
peg-IFNα-2b. No pts receiving NM283 monotherapy met efficacy criteria to
continue treatment beyond Week 24. Of the 17 pts who received
NM283/peg-IFNα-2b, 9 completed at least 48 weeks of treatment, 8 of whom
achieved PCR-nondetectable HCV RNA by week 48 (EOT). Final data will be
presented at the meeting, including post-treatment SVR data.
Conclusions:
With no PK interaction between NM283 and peg-IFNα, and
no notable increase in treatment-limiting side effects, these Phase IIa results
support the use of NM283 with peg-IFNα in longer-term treatment trials.
Treatment with NM283 plus pegIFNα-2b, in the absence of ribavirin use,
demonstrated a satisfactory safety and tolerability profile and consistent
antiviral activity in this pilot study.
Topic: Epi
M1797. Insulin Resistance In Viral Hepatitis B And C And Non Virus Related Chronic
Hepatitis.
F. Lodato; M.
Montagnani; F. Azzaroli; M. Tame; A. Colecchia; P. Cecinato; R. Muratori; D.
Festi; G. Mazzella
Background/Aims
Insulin resistance (IR) is the background of many
cryptogenetic liver diseases. In genotype 1 and 2 HCV chronic hepatitis (CH-C)
the virus seems to induce insulin resistance (IR). In HBV chronic hepatitis
(CH-B) the virus role in steatosis and IR is to be clarified. Aim of our study
is to evaluate IR and the relationship with disease severity, in patients with
CH-C, CH-B or with non-virus related hypertransaminasemia (NV-H).
Methods
Twenty-eight outpatients with NV-H and 50 outpatients in
follow-up for Chronic hepatitis B (n=23) or Chronic hepatitis C (n=27) were
consecutively enrolled between January and May 2006. Patients with alcohol
consumption >10 gr/day were excluded. Abdominal circumference (AC), Body
Mass Index (BMI), fasting blood glucose (FBG) insulinemia, OGTT, HOMA-r and
liver ultrasonography were evaluated. ANOVA, Mann-Whitney test and chi square
were used for statistical analysis. Data are expressed as mean ±SE.
Results
Groups were comparable for age, BMI, AC and FBG; males were
prevalent in Chonic hepatitis B (M:F 21:2 vs Chonric
hepatitis C:
At multivariate analysis HOMA-r was associated with age, Body
Mass Index, AC and steatosis and independently related to AC in NV-H, to
cirrhosis and antiviral treatment in CH-B, to AC and cirrhosis in CH-C.
Discussion
Insulin resistance is associated with cirrhosis regardless of
underlying disease when evaluated by HOMA-r. In CH-B, inhibition of viral
replication by necleos(t)ide analogues seems to
protect from IR, possibly through:
·
Reduction
in liver inflammation secondary to inhibition of viral replication.
Topic: Experimental therapies – Omega Interferon
M1798. Phase 2 Study of Omega Interferon Alone or in Combination with Ribavirin in Interferon-naïve
Subjects with Genotype-1 Chronic Hepatitis C
V. Novozhenov; N.
Zakharova; E. Vinogradova; I. Nikitin; V. Gorbakov; A. Yakovlev; S. Pak; V.
Rafalski; P. Bogomolov; T. Alessi; D. Blanchett; J. McNally; B. R. Bacon
Background:
Omega interferon is a naturally occurring human type 1
interferon that is 60% homologous with alpha interferon and 30% homologous with
beta interferon. Omega interferon monotherapy has demonstrated an antiviral
effect in hepatitis C genotypes 1, 2 and 3 in prior clinical studies in the
Methods:
102 subjects have been randomized; 35 to receive 25μg
omega interferon
Results:
Early virological response was observed in 21/35 (60.0%)
subjects treated with omega interferon alone and 56/67 (83.6%) subjects treated
with omega interferon plus ribavirin. 2/35 (6%) subjects treated with omega
interferon alone and 24/67 (36%) subjects treated with omega interferon plus
ribavirin had undetectable levels of HCV RNA at week 72 weeks (SVR – 24 weeks
post treatment), (limit of detection = 50
IU/ml).
Overall, treatment was well tolerated. The most frequently
reported adverse events (> 10% of subjects) were: influenza like illness,
neutropenia, asthenia, pyrexia, leukopenia, fatigue, anemia, ALT increases,
headache, hyperthermia, and serum bilirubin increases. Four serious adverse
events (SAE) were reported. The most common causes for dose reduction were
anemia and neutropenia. Study discontinuation due to adverse events occurred in
two subjects, one with hyperbilirubinemia and one with allergic dermatitis.
Conclusions:
·
Omega
interferon and ribaviirn resulted in EVR and SVR rates similar to those
reported with the combination of alpha interferon and ribavirin in
interferon-naïve HCV genotype-1 patients.
·
EVR
and SVR rates achieved with omega interferon plus ribavirin were superior to
those achieved with omega interferon alone.
·
Omega
interferon given alone or in combination with ribavirin was well tolerated with
few patients requiring dose reductions or treatment discontinuation.
·
25 µg/day is an appropriate starting dose to evaluated continuous
delivery Omega DUROS therapy in combination with ribavirin in future studies.
Topic: Current HCV Treatment - General
H. M. Elgouhari; I.
Hanouneh; C. O. Zein; A. E. Feldstein; N. N. Zein
Background:
Insulin resistance is a major feature of type II Diabetes
mellitus (DM) and has recently been linked to treatment failure in HCV.
However, there is paucity of data on treatment outcome in diabetic HCV patients.
Aims:
1. To determine the rate of SVR in HCV
patients with Diabetes compared to those without DM;
2. To assess the safety of combining
insulin sensitizing agents (ISA) with Peg IFN/RBV in HCV patients.
Methods:
Case-controlled retrospective assessment
of prospectively collected data. All HCV plus diabetes patients (n=61) that were treated with
standard doses of Peg IFN/RBV between 2002 and 2004 were identified.
A 1:1 control group of non-diabetes HCV patients (n=61)
matched for genotype and ethnicity treated during the same time period at the
same institution was identified. Descriptive statistics were performed to
characterize both groups. Univariate analysis was performed to compare
variables of interest. Logistic regression was performed to identify
independent factors associated with treatment failure. Safety measures included
the occurrence of any serious adverse events (SAE), early withdrawals or ALT
flares during therapy.
Results:
Patients with Diabetes had higher Body Mass Index (BMI) than
non-diabetes (32.4 + 6.0 vs 28.5 + 6.6, p=0.0009) and were more likely to have
advanced fibrosis (56% vs 28%, p=0.003). SVR was observed in 14/61 (23%) of HCV
plus diabetes patients compared to 31/61 (51%) of non-diabetes patients
(p=0.001). By univariate analysis, Diabetes (p=0.001), genotype 1 (p=0.005),
and African American ethnicity (p=0.03) were associated with lack of SVR.
Multivariate logistic regression identified Diabetes [OR=3.9, 95% CI 1.7-9.3;
p=0.001] and genotype 1 [OR=3.7, 95% CI 1.2-12.3; p=0.02] as independent
predictors of treatment failure in patients with HCV. This association remained
significant after adjusting for other relevant variables including presence of
advanced fibrosis and ethnicity. Among patients with Diabetes, SVR was higher
in patients who were on therapy with ISA (29%) compared to those who were not
on ISA (20%). However, this difference in SVR did not reach statistical
significance. The rates of serious adverse events, early discontinuation and
ALT flares were similar between HCV plus diabetes patients receiving ISA (21
patients) and HCV plus diabetes not receiving ISA (40 patients).
Conclusions:
1. Diabetes is a predictor of treatment
failure in HCV patients treated with Peg IFN/RBV.
2. Based on this limited assessment, ISA
appear to be safe when combined with Peg IFN/RBV in diabetic HCV patients and
may be associated with higher SVR.
3. Type II diabetes is associated with
more advanced fibrosis stage in HCV patients compared to those without
hepatitis C.
Topic: Experimental therapies – R1626
S. Roberts; G.
Cooksley; G. Dore; R. Robson; D. Shaw; H. Berns; M. Brandl; S. Fettner; G.
Hill; D. Ipe; K. Klumpp; M. Mannino; E. O'Mara; I. Najera; Y. Tu; C. Washington
Background and Aims:
HCV polymerase is an essential enzyme for HCV replication.
Inhibitors of the HCV polymerase enzyme are a promising class of compounds
under development for the treatment of chronic HCV infection. R1626 is a
pro-drug of the nucleoside analog R1479, developed to significantly increase
bioavailability and HCV inhibition. We carried out a multiple ascending dose
study to evaluate the safety and tolerability, pharmacokinetics and antiviral
activity of R1479 in treatment-naïve patients chronically infected with HCV
genotype 1.
Methods:
A total of 47 patients were randomized to receive one of four
dose levels of R1626 monotherapy or matching placebo for 14 days. Assessments
included safety, pharmacokinetics, antiviral activity and resistance
development. Regression analysis was conducted to evaluate the relationship
between R1479 plasma concentration, ALT and viral load decreases.
Results:
The mean HCV RNA concentrations at baseline were ≥ 6.3
log10 IU/mL in all four treatment groups. Mean (median) HCV RNA
reductions of 0.3 (0.2), 1.2 (0.8), 2.6
(2.7) and 3.7 (4.1) log10 were observed at doses of 500, 1500, 3000 and 4500 mg, bid, respectively. Sixteen of
the 35 patients who received R1626 had HCV RNA reductions >2 log10 by Day
14. Regression analysis demonstrated a good correlation between R1479 Cmax, AUC
and Cmin and viral load reduction. The mean Cmin values for the 1500, 3000 and
4500 mg bid dose groups were equal to or exceeded the IC90 as determined in the
Replicon system. Individual patient response patterns at these doses showed
consistent and time-dependent decrease in viral load. Although 6/9 patients in
the 500 mg bid group showed no decrease or rebound in viral load due to
sub-optimal drug exposure during treatment, none of these patients showed viral
resistance. In addition, time- and treatment-dependent decreases in ALT levels
were also observed, with 5/8 and 7/9 patients achieving normalized ALT levels
in the 3000 and 4500 mg bid cohorts, respectively.
Summary
·
R1626
demonstrated linear pharmacokinetics up to 4500 mg bid
·
Tehre
was a robust antiviral effect with mean viral load reductions of 1.2-27 log following 1500, 3000, and 4500 mg bid, respectively
following 14 days of monotherapy.
·
Viral
rebound during treatment was observed in three patients, all of whom received
the lowest dose of 500 mg. No viral
resistance ws observed in these patients.
·
Tolerability
was good following twice daily doses for 14 days up to 3000 mg bid.
·
Reversible
mild to moderate haematological changes were treatment-and time-related.
Conclusion
Treatment with R1626, a novel and
potent nucleoside analog targeting HCV polymerase, was well tolerated up to
3000 mg bid and significantly reduced HCV RNA in patients chronically infected
with genotype 1 when used as monotherapy.
Does-, time-, and exposure-related decreases in viral load were observed
following multiple doses of R1626, with decline observed as early as 4 hours
following the first dose. The maximum
decrease in HCV RNA levels was noted on Day 14, the last day of dosing. Importantly, no viral resistance was observed
in those patients with no decrease or rebound of viral load during
treatment. A Phase 2 study of R1626 in
combination with peginterferon alfa-2a with or without ribavirin in underway.
Topic: Current HCV Treatment - General
S. Wang; C. Huang; N.
Ravendhran; W. M. Cassidy; H. Chen; C. D. Howell
Background:
A sustained virologic response (SVR) following HCV therapy
results in durable improvements in liver histology and a decrease in hepatic
decompensation and primary liver cancer. Whether treatment confers long-term
benefit in the absence of a SVR is controversial.
Goal/Methods:
To address this question, we compared gene expression in
liver biopsies obtained at week (wk) 72 from 5 SVR (wk 48 & 72 serum HCV
RNA negative (-), 4 HCV relapsers (REL) (HCV RNA- at wk 48 & positive (+)
at wk 72), and 7 virologic nonresponders (NR) (HCV RNA+ at wk 24 & 48)
after 48 wks of initial peginterferon alfa-2a (PEG-IFN) and ribavirin therapy.
Control liver biopsies were from 12 untreated HCV genotype 1 patients. Liver
cRNA was hybridized to the Affymetrix HG-U133 plus 2 gene chip (Affymetrix,
Results:
Compared to untreated HCV controls, 457 intrahepatic genes
were down-regulated in SVR patients at wk 72. Of genes with known functions,
immune response (66;14.2 %), response to virus (15;
3.2%), response to pest, pathogen or parasite (34; 7.3%), and protein
localization and transport (34; 7.3%) were the most significant functional
classes (p < 0.0001 for each category). Seventy-seven intrahepatic genes
were down-regulated and 17 genes were up-regulated in REL patients. These genes
were associated with biopolymer metabolism [21 (22.6%); p<0.005], response
to virus [4 (4.3%); p<0.004), and protein/macromolecule metabolism [20
(21.5%); p = 0.07]. The 177 genes down-regulated in NR relative to controls
were associated with alcohol metabolism [14 (4.7%); p < 0.001], protein
localization and transport [18 (6.1%); p = 0.003), organic acid metabolism [16
(5.4%); p 0.004), and secretion [10 (3.4%); p = 0.007). Only 21 differentially
expressed genes were shared between SVR and REL groups, and 13 genes between
SVR and NR groups. In both instances, the mean fold change in gene expression
was 1.5-2.0 times greater in the SVRs. Forty-five (10%) genes down-regulated in
SVR relative to controls were associated with liver fibrosis, compared to 2
(2.1%) and 1 (< 1.0%) genes down-regulated in the REL and NR groups.
Conclusion:
SVR patients exhibit more marked
down-regulation of a greater number of intrahepatic genes families than NR and
REL including genes associated with liver fibrosis. NR and REL patients show
modest changes in a restricted set of gene families with no apparent
relationship to liver fibrosis.
Topic: Experimental therapies – Interferon-Beta
M1803. Feasibility of induction by twice-daily administration
of interferon-beta prior to the standard combination therapy using pegylated
interferon-alpha-2b plus ribavirin.
T. Nakatani ; Y.
Akashi; H. Matsuo; S. Takeyama; M. Uejima; Y. Yamane; K. Hashimoto; E. Kikuchi
Aims:
It has been reported that longer treatment with combination
therapy using pegylated interferon (IFN)-alpha-2b plus ribavirin (RIB) for
patients infected with hepatitis C virus (HCV) leads to more effective viral
eradication. However, in
Methods:
Forty patients chronically infected with genotype 1b HCV were
divided into 2 groups. Thirty-two patients underwent standard 48-week
combination therapy using 1.5 μ/kg of pegylated IFN-alpha-2b plus RIB
(600-800 mg/day depending on body weight) (group 1). Eight patients received
3MU IFN-beta twice-daily for 2 weeks followed by the standard combination
therapy described above (group 2). HCV quantity as well as its reduction
profile such as HCV negativity and rate of 2-log decrease was assessed at the
certain time point. Serum HCV-RNA was quantified using the Amplicor HCV monitor
assay (SRL,
Results:
HCV quantity of each patient was more than 100 KIU/ml,
meaning the high baseline viral load. Gender, age, HCV viral load, platelet and
ALT at baseline did not differ significantly between 2 groups. Serum HCV-RNA
(KIU/ml) at baseline, weeks 2, 4, 8, 12 and 24 was 2419±1605/2406±1253,
222±210/36±103 (P<0.05), 165±209/6±18 (P<0.05), 103±183/4±7 (P<0.05),
75±155/3±8 (P<0.05) and 90±191/0±0 (P<0.05) in group1 and group2,
respectively. HCV negativity at weeks 2, 4, 8, 12, 24 and 48 was 0%/0%, 0%/38%,
10%/56%, 29%/81%, 57%/100% and 79%/100% in group1 and group2, respectively. EVR
in group2 was over 2.5 times higher than that in group1. The reduction rate of
HCV-RNA by at least 2 logs at weeks 2, 4, 8, 12 and 24 was 25%/75%, 40%/100%,
63%/100%, 64%/100% and 83%/100% in group1 and group2, respectively. No more
significant adverse effects were observed in group2 compared with group1 during
the treatment period.
Conclusion:
When the length of combination therapy using pegylated
IFN-alpha-2b plus RIB is limited to 48 weeks, IFN-beta induction may be
feasible in achieving SVR throughout early viral clearance.
Topic: Experimental therapies – Valopicitabine
N. Gitlin; E. J.
Lawitz; T. Nguyen; Z. Younes; J. Santoro; D. McEniry; R. Chasen; J. Goff; D.
Dieterich; S. Knox; K. Kleber; J. Leone; B. Belanger; N. A. Brown; G. and the
006 Investigator
Background:
Current therapy (pegIFN/RBV) results in suboptimal virologic response
rates particularly in patients with genotype 1 (HCV-1) infection. The antiviral
activity profile of valopicitabine in combination with peg-IFN in treatment
naïve patients with HCV-1 infection is being evaluated in this ongoing Phase
IIb study.
Methods:
Key eligibility criteria: no prior treatment, compensated
disease, HCV RNA ≥5 log10 IU/mL, ALT <5 xULN. Patients were randomly
assigned to one of five treatment groups:
PegIFN alone to W4, with valopicitabine 800mg/day added in
W5; (B) valopicitabine 200mg/day + pegIFN; (C) valopicitabine ramped 400 to
800mg/day in 1st week + pegIFN; (D) valopicitabine 800 mg/day + pegIFN; and (E)
valopicitabine 800 mg/day + pegIFN. PegIFN-α2a is dosed 180 μg QW
starting Day 8 (Groups A-D) or Day 1 (Group E). Due to higher GI side effects
with the 800mg/day valopicitabine dose, a protocol amendment was implemented to
reduce the valopicitabine dose in Groups A, C, D and E to 200 or 400 mg/day.
Most patients had received at least 12 weeks of treatment at the time of the
dose reduction.
Results:
Up to W4 the rate of viral decline was valopicitabine
dose-related. By W12, 85% of patients in Group B and 88% in Groups C-E achieved
>2 log drop in HCV RNA. HCV RNA was below 600 IU/mL (Amplicor quantification
limit) in most patients by W12. Results at W24 and W36 indicate continued
antiviral efficacy in all arms, with HCV RNA non-detectable by TaqMan™ in most
patients (Table). In Group B (valopicitabine 200mg/day + pegIFN), partial data
through the end of treatment (W48) indicate maintained suppression of HCV RNA
with good tolerance of study medication. Complete W48 data (end of treatment)
will be presented.
Conclusions:
Valopicitabine 200mg/day, plus pegIFN results in HCV RNA
levels below the Amplicor PCR quantification limit in most pts by W12 and to
date shows durable suppression of viremia with satisfactory tolerance in
treatment-naïve HCV-1 patients.
|
|
Mean ↓ from Baseline |
Amplicor™ negative |
TaqMan™ negative |
||||
|
Treatment Group |
n |
Week 24 |
Week 36 |
Week 24 |
Week 36 |
Week 24 |
Week 36 |
|
A |
34 |
-4.17 |
-4.16 |
74 |
71 |
62 |
68 |
|
B |
34 |
-4.24 |
-4.14 |
71 |
68 |
68 |
68 |
|
C |
34 |
-4.24 |
-3.90 |
71 |
68 |
59 |
59 |
|
D |
36 |
-4.56 |
-4.41 |
81 |
72 |
67 |
67 |
|
E |
35 |
-3.90 |
-3.75 |
63 |
54 |
49 |
49 |
Topic: Experimental therapies - Taribavirin
M1805. Pre-Dosing Taribavirin Prior to Combination
Therapy With Pegylated Interferon Alfa-2b Versus Standard Combination
Dosing: 24-Week Interim Results Examining Safety and Viral Kinetics.
M. Palmer; R. A.
Rubin; V. K. Rustgi; D. Li; B. Murphy
Background:
Data from a phase 3 study revealed that dosing taribavirin
(TBV), a pro-drug of ribavirin, with pegylated-interferon resulted in
significantly lower rates of anemia compared to ribavirin and
pegylated-interferon but did not meet the non-inferiority standard for
efficacy. An examination of viral decay kinetics revealed the sharpest decline
during TBV therapy occurred at weeks 4 through 6, when TBV had reached
steady-state. This proof-of-concept study examined whether first-order viral
kinetics could be influenced by pre-dosing TBV to steady-state prior to the
introduction of pegylated interferon.
Methods:
This US-based, multi-center, open-label, proof-of-concept
study enrolled 23 patients in the TBV pre-dosing arm and 19 patients in the TBV
standard dosing arm. Patients were randomized to receive TBV 600mg BID either
as monotherapy for 4 weeks followed by combination therapy with pegylated
interferon alfa-2b (pre-dose arm) or administered concurrently with pegylated
interferon alfa-2b (standard dosing arm). All patients in the study were
therapy-naïve, genotype 1, high viral load, with a mean weight of 77 kg in both
arms. Log-transformed HCV-RNA change from baseline and the incidence of anemia
(hemoglobin <10 g/dL) were assessed.
Results:
See table. Anemia was seen in 0% of the
pre-dosed patients versus 5.3% in the standard dosing arm.
Conclusions:
Patients receiving 4 weeks of TBV monotherapy prior to
starting pegylated interferon had a steeper decline in HCV-RNA with no
difference in the rate of anemia. The variance in the viral decline may be a
function of both the impact of having TBV at steady state when pegylated
interferon is introduced into therapy and/or increased conversion of TBV to
ribavirin due to longer exposure. Based on this data, a larger study examining
pre-dosing of both TBV and ribavirin is warranted to assess the impact of TBV
steady-state on phase 1 viral decline.
Mean log-transformed HCV-RNA change from baseline
|
|
TBV pre-dosed (n=23) |
TBV standard dosing (n=19) |
|
CT-day 1 |
-0.34 |
0.09 |
|
CT-day 2 |
-1.40 |
-1.00 |
|
CT-week 1 |
-0.80 |
-0.27 |
|
CT-week 4 |
-1.74 |
-1.16 |
|
CT-week 8 |
-2.19 |
-1.82 |
|
CT-week 12 |
-2.45 |
-1.88 |
|
CT-week 24 |
-2.51 |
-2.09 |
Topic: Durrent HCV Therapies – Side Effects
M. Kugelmas; O. Ryan;
G. A. Spiegelman; M. Mah'Moud
Background:
Hematologic toxicity is one of the most common reasons for
dose reduction or discontinuation when treating chronic hepatitis C. In turn,
these dose reductions negatively affect the chance of achieving early virologic
response (EVR) during therapy of patients with genotype 1 chronic hepatitis C
(HCV-1).
Aims and Methods:
We are comparing standard of therapy (ST) with pegylated
interferon alfa 2b (P-IFN) plus weight-based ribavirin (RBV) in patients with
HCV-1 to an adjuvant therapy (AT) regimen where anemia is pre-emptively treated
with darbepoetin alfa (3 mcg/kg SQ Q2W starting with hemoglobin <12 g/dL or
<75% of baseline), neutropenia is pre-emptively treated with filgrastim (300
mcg SQ QW for ANC <900 mm3), and more lenient cut-off levels for
thrombocytopenia are allowed in order to try to prevent dose reductions due to
hematologic toxicity. The study is powered to show a 22% difference in SVR in
favor of the adjuvant therapy arm.
Results:
To date 106 patients with HCV-1 have received at least 12
weeks of therapy, 54 in the ST arm and 52 in the AT arm. In the ST arm, 63% are
male, 60% are heavier than 75 kg, 20% have advanced fibrosis (stage 3 or 4),
75% have high baseline viral load (> 600,000 IU) and 8 are AA. In the AT
arm, 68% are male, 76% are heavier than 75 kg, 23% have advanced fibrosis, 69%
have high baseline viral load and 10 are AA. In the ST arm, thirty-six of
fifty-four patients achieved EVR, 9 with undetectable viremia. In the AT arm,
thirty-seven of fifty-two patients achieved EVR, 15 with undetectable viremia.
Twenty-six patients in the AT arm (50%) received growth factors (20
darbepoetin, 6 filgrastim). Fourteen patients in the ST arm had dose
reductions, half reduced each drug. The hemoglobin nadir was noted around week
14-15 of therapy in both arms.
Conclusions:
We have previously shown (DDW ’06) that the use of growth
factors prevents dose reductions of P-IFN and RBV in patients receiving anti
HCV-1 therapy and maintains more physiologic hemoglobin levels. This update
shows non-statistically significant differences in EVR, but a mathematical edge
in favor of the adjuvant therapy group, both for total patients achieving EVR
(72.6% vs. 66.7%, AT vs. ST, respectively) and those who do so with
undetectable viremia (40% vs. 25%, AT vs. ST, respectively). Ongoing results of
the study will show whether use of growth factors will allow for higher
sustained viral response (SVR). Study drugs and support were provided by Amgen
Inc. (Darbepoetin and Filgrastim) and Schering Plough (Peg-Intron and Rebetol).
Topic: Current HCV Therapies - General
M1808. Metabolic Syndrome Is A Strong Predictor Of Treatment Failure In Patients
With Chronic Hepatitis C
I. Hanouneh; A. E. Feldstein;
R. Lopez; K. B. Cesario; A. A. Pillai; C. O. Zein; N. N. Zein
Background:
The metabolic syndrome (MS) is a unique pathophysiologic
condition whose underlying mechanism is related to insulin resistance. In HCV
patients undergoing therapy with Peg IFN/RBV, insulin resistance has been
linked to treatment failure.
Aims
Our Aims were to estimate the prevalence of metabolic
syndrome in HCV patients undergoing anti-viral therapy and to assess its
predictive value in treatment outcome.
Methods:
All HCV patients that were treated with Peg IFN/RBV between
2002 and 2004 and had clinical data to assess for MS were identified (n=251).
MS was defined using the ATP III criteria. Descriptive statistics were computed
for all factors. Univariate analysis was performed to compare variables of
interest. A logistic regression analysis was performed to study multivariable
associations. The final model contained gender, ethnicity, genotype, metabolic
syndrome, fibrosis, and steatosis stage.
Results:
Metabolic syndrome was present in 71/252 (28%) patients.
Metabolic syndrome was less common in Caucasian patients compared to
non-Caucasian patients [49/193 (25%) vs 22/58 (38%), p=0.063].
Overall SVR was achieved in 121/252 (48%) patients. Genotype
1 (p<0.001), non-Caucasian ethnicity (p<0.001), male gender (p=0.04),
higher fibrosis stage (p=0.03), higher BMI (p=0.013), and MS (p<0.001) were
significantly associated with lack of SVR.
Adjusting for ethnicity, genotype, gender, fibrosis, and
steatosis stage, subjects with Metabolic syndrome are
more likely to fail treatment than those without Metabolic syndrome.
Conclusion:
·
Metabolic
syndrome is frequently seen in patients with hepatitis C and associated with
steatosis and advanced fibrosis.
·
Consistent
with previous studies, genotype 1 non-Caucasian ethnicity and advanced fibrosis
are independent, predictors of poor response to pegylated interferon and
ribavirin therapy.
·
Metablic
syndrome appears to be an independent strong predictor of failure to achieve
SVR.
·
If
confirmed, metabolic syndrome could be easily incorporated into clinical
practice to identify HCV patients who are less likely to benefit from antiviral
therapy.
Topic: Disease Progression - General
M1810. Serum Leptin Concentrations In Chronic Viral Hepatitis: A Clinical Approach.
S. Manolakopoulos; S.
Bethanis; C. Liapi; P. Sklavos; F. Stripeli; A. Margeli; A. Christidou; A.
Katsanika; E. Vogiatzakis; D. Tzourmakliotis; S. Theocharis
Background&Aims:
The role of serum leptin and the relationship between leptin
and insulin resistance in patients with chronic viral hepatitis (CVH) remain
obscure. Our aim was to investigate the relationship between serum leptin
concentrations and the severity of liver disease in a cohort of subjects with HbeAg-negative
chronic hepatitis B (CHB) and hepatitis C(CHC)
Methods:
We studied 50 (36 men) consecutive patients suffering from
biopsy-proven chronic hepatitis C due to HBV(n=25) or
HCV(n=25)infection. Thirty-two (17 men) healthy volunteers served as controls.
Levels of serum leptin and insulin were determined at baseline and at the end
of the treatment.
Results:
Patients with severe fibrosis (stages 4-6)presented
higher serum leptin levels compared to those with lower fibrosis stage(7276
pg/ml vs 4395 pg/ml,p=0.01). In patients with chronic hepatitis B those with a
virologic response to lamivudine monotherapy presented lower serum leptin
levels (5334 vs 13111.5 pg/ml,p-value=0.003) than
non-responders. In genotype 1 chronic hepatitis C patients, insulin resistance
was associated with lower response rate to antiviral therapy(Graph
1).
Conclusion:
Increased leptin concentrations are associated with more
severe disease state in patients with chronic hepatitis C and represent a
negative prognostic factor for response to lamivudine monotherapy in chronic
heptitis B. In chronic hepatitis C insulin resistance influences negatively the
response to antiviral treatment in patients infected with genotype 1.
Topic: Experimental therapies - Taribavirin
M1811. Pharmacokinetic/Pharmacodynamic (PKPD) Modeling
of Hemoglobin (Hgb) in a Phase 3 Study With
Taribavirin and Ribavirin in Therapy-Naïve HCV Patients.
R. Braeckman; D.
Fisher;
Background:
Patients receiving a fixed dose of taribavirin (TBV, 600 mg
BID), an oral pro-drug of ribavirin (RBV), in two Phase 3 studies experienced
lower rates of anemia compared to standard dose ribavirin (1-1.2 g/day),
although SVR rate was lower with taribavirin.
Aim:
To develop a PKPD model to describe the dose-exposure-effect
relationship between taribavirin/ribavirin and Hgb to predict optimized
taribavirin regimens and identify predictors of anemia.
Methods:
A compartmental PK model and a
mechanistic Hgb turnover PD model were constructed and fitted to observations
from 752 (taribavirin, n=494; ribavirin, 258) patients in the VISER1 study. The
anemia model (Hgb) involves homeostasis and turnover of red blood cells (RBC).
Circulating ribavirin increases Hgb elimination due to RBC hemolysis. A
feedback mechanism driven by decreasing Hgb levels stimulates Hgb production.
The model accounts for the relationship between doses of taribavirin and ribavirin, their
respective ribavirin concentrations and the decrease of the Hgb levels versus
time. The data were fitted according to this model using the NONMEM® software (
Results:
The apparent elimination clearance (CL/F) of ribavirin was
2.3-fold larger following administration of taribavirin compared to ribavirin;
therefore, ribavirin concentrations were 2.3-fold lower with taribavirin (~15
mg/kg). Both body weight and creatinine clearance influenced ribavirin exposure
with taribavirin.
The anemia model satisfactorily fitted the Hgb data, yielding
model parameter estimates. This relationship between circulating ribavirin and
Hgb was the same in both taribavirin and ribavirin dosing groups. The ribavirin concentration
that yielded half-maximal effect of ribavirin on Hgb turnover (EC50) varied
minimally with gender: 7.2-7.6 mcg/mL (males and females, respectively). The
maximal hemolytic effect (Emax) was influenced by gender, HCV genotype, patient
age and weight.
Pharmacometric modeling based on logistic regression of
VISER1 patients with HCV genotypes non-2/3 indicates that an
ribavirin target exposure of 50 mcg×hr/mL (24-hour AUC) would lead to a SVR of
59% and anemia rate of 12%. Analysis of actual response rates by taribavirin
dose/kg in VISER1 showed an SVR rate of 52% and anemia rate of 6.5% in patients
(n=138) receiving >18 mg/kg TBV.
Conclusion:
1. Higher taribavirin doses are
predicted to increase ribavirin exposure and, in turn, SVR rate.
2. Taribavirin 32 mg/kg predicts the
same ribvavirin exposure as with standard ribavirin.
3. Taribavirin doses in the range of
20-28 mg/kg may achieve SVR comparable to rivavirin but less anemia compared to
standard doses of ribavirin,
Topic: Experimental therapies - General
M1812. In Vivo Efficacy of a Fully Human Monoclonal anti-E2
Immunoglobulin in Passive Immunoprophylaxis of HCV Infection.
A. Krishnan; K. Viker;
B. Knudsen; P. Parren; F. Beurskens; M. R. Charlton
Background:
HCV infection is the most common indication for liver
transplantation in
Specific aim:
To determine whether a fully human, high concentration mAb to
the E2 epitope of HCV that recognizes noncovalently linked E1E2 complexes and
which has demonstrated neutralizing of binding activity in vitro (Virology 249,
32–41 (1998)) can prevent HCV infection in vivo.
Methods:
Human hepatocytes, freshly harvested from resected liver
wedges were transplanted into mice transgenic for five amino acid deletion
isoform of human hepatocyte growth factor backcrossed with a SCID strain.
Animals received retrorsine (to provide a replicative advantage to transplanted
human hepatocytes) and multiple doses of CCL4 (to cause necrosis of murine
hepatocytes). Engraftment of human hepatocytes was determined by
semi-quantitative analysis of human albumin production by Western blotting.
Following maximal engraftment, mice were randomly assigned to receive either
E2-hmAb (Genmab, Utrecht, Netherlands)(100mg/kg)(n=6) or placebo (n=6) followed
by inoculation with high HCV RNA titer human serum pooled from chronically
infected patients with HCV genotypes 1a and 1b. Analysis of post-inoculation
HCV RNA was carried out in a blinded fashion on post-inoculation days 1, 8, 15,
22 and 29 using a highly sensitive real-time nucleic acid amplification assay
(Cobas Taqman, Roche Molecular Systems Inc., Branchburg, N.J).
Results:
One of six mice (17%) in the E2-hmAb group had HCV RNA
detectable postinoculation (day 8 only, 4.3 log10 IU/ml). Five of six mice
(83%) receiving placebo developed sustained levels of HCV RNA (days 8-29, range
3.5-5.7 log10 IU/ml).
Conclusions:
These data indicate that a fully human E2-mAb can provide
passive immunity against HCV infection of human hepatocytes in vivo. Further
studies are needed to determine the minimally effective concentration (EC50) of
the studied mAb prior to consideration of clinical studies.
Topic: Current HCV Therapies – Side Effects
M1813. Genome-wide analysis for genes that mediate
IFN-induced depression in HCV patients.
M. Trippler; Y. Erim;
S. Bein; G. Gerken; J. F. Schlaak
Aims and background:
Combination therapy with pegylated interferon (IFN)-alpha and
ribavirin for chronic hepatitis C can induce depressive side effects in up to
one third of patients. Therefore, this study assessed the primary
transcriptional in vivo response to IFN-alpha in HCV patients to identify
possible mechanisms that mediate IFN-induced depression.
Patients and methods:
A total of 50 Caucasian patients with histologically proven
chronic hepatitis C were treated with standard combination therapy consisting
of pegylated IFN-α2a (Pegasys, 180µg once weekly) with ribavirin (800-1200
mg daily) for 6 or 12 months. RNA was isolated (PAXgene, PreAnalytiX) from
peripheral blood which was collected 12h before and 12h after the first
injection of IFN-α. The transcriptional profile was analysed using human
genomic microarrays (Affymetrix HG U133A) and quantitative real-time RT-PCR.
Array data were normalized (RMA Express software) and fold change values were
subjected to significance analysis (SAM software) and class prediction analysis
(PAM software) to identify genes which are differentially regulated in patients
with or without IFN-induced depression.
Results:
14/50 patients (28%) developed clinically relevant
IFN-induced depression. Using class prediction analysis, the development of
depression could be predicted by 24 genes with 95% accuracy. 10 of these genes
were significantly higher expressed in patients with IFN-induced depression
compared to patients without depression. Interestingly, 4 of these genes were
previously described as being associated with recurrent major depression,
whereas the remaining genes were identified as known classical ISGs. This data
was verified by quantitative RT-PCR. Basal gene expression before IFN injection
was not significantly different in both groups of patients. Expression of these
genes is currently being assessed in patients hospitalised for severe major
depression and normal healthy controls.
Conclusions:
These data suggest a direct role of IFN response genes in generating
depression as side effect of antiviral therapy. Finally, the functional
analysis of the differentially regulated genes that were identified in this
study could lead to the discovery of novel therapeutic approaches to improve
the efficacy of and adherence to HCV therapy and, possibly, major depression.
Topic: Experimental therapies - general
Y. Haruna; A. Inoue
Introduction/Aim:
It was suggested that rectally administered interferon (IFN)
is transferred into the lymphatic system via rectal mucous membrane in animal
study. We reported that administration of low dose IFN suppository could
suppress hepatitis C virus (HCV) replication in patients with chronic hepatitis
C. In this study, we focused on examining the long-term biological effects
after the therapy.
Methods:
Fourteen patients with chronic hepatitis C participated in
the study. The IFN suppository, which was made in the Department of Pharmacy of
Results:
In 13 out of the 14 patients, viral load was decreased at
week 4. The ratio of the viral load compared with before the treatment (mean ±
S.E.) was 0.555 ± 0.102 (rang: 0.004 to 1.430) at week 4. The suppression of
viral replication was sustained during the treatment (p<0.0001), whereas the
viral load increased after the end of treatment. The 2-5 AS activity and
CD4/CD8 ratio were significantly changed during the treatment. The 2-5 AS
activity (pmol/dl, mean ± S.E.) was 87.9 ± 12.7 before and 120.8 ± 18.2 at week
8 (p=0.0076). The CD4/CD8 ratio (mean ± S.E.) was 2.67 ± 0.34 before and 2.06 ±
0.25 at week 8 (p=0.013). Platelet count (104/mm3) was increasing during the
treatment, and the increased count was sustained until 72 weeks after the end
of treatment (mean ± S.E., 16.1 ± 1.1 before and 18.8 ± 1.4 at 4 weeks after
the end of treatment). Serum albumin (g/dl) also showed increase both during
and after the treatment (4.10 ± 0.07 before and 4.27±0.09 at 4 weeks after the
end of treatment). Statistical analysis using one way repeated measure ANOVA
confirmed significant sustained increase of both platelet count and albumin
level during and after the end of treatment (p=0.0057 and p=0.0217,
respectively). No side effect was seen during and after the treatment.
Conclusion:
·
The
low dose IFN suppository treatment suppressed HCV replication with elevated 2-5
AS activity and decreased CD4/CD8 ratio. Also, both platelet count and serum
albumin level were increased after the end of treatment as well as during it.
·
The
low dose IFN suppository treatment could be indicated to patients with
thrombocytopenia or poor hepatic functional reserve (e.g. cirrhotic patients).
Topic: Experimental therapies – ITMN-191
P. Rajagopalan; S.
Misialek; L. M. Blatt; S. D. Seiwert; K. Kossen
Background:
Combination therapy for chronic hepatitis C with pegylated
interferon alfa and ribavirin (SoC) results in a Sustained Virologic Response
(SVR) rate of approximately 50%. Direct antiviral agents may improve the rate
of SVR when used in combination with SoC or in novel regimens. ITMN-191 is a
potent HCV NS3/4A protease inhibitor in clinical development. The current study
examines ITMN-191 potency and binding kinetics in biochemical assays.
Methods:
The activity of NS3/4A protease was observed using a
continuous fluorescence resonance energy transfer (FRET)-based peptide cleavage
assay under conditions that maximize sensitivity and protease stability.
Dissociation of ITMN-191 was assessed by monitoring recovery of protease
activity following rapid dilution of pre-formed NS3/4A-ITMN-191 complex.
Summary/Conclusion:
·
ITMN-191 is an extremely potent inhibitor of HCV
NS3/4A protease with a true biochemical potency of 36 pM against genotype 1b.
·
Binding
follows a two step mechanism where initial complex formation is followed by
isomerization to a more stable complex.
·
Dissociation
of ITMN-191 FROM ns3/4a is a very slow process with a t1/2 of 5
hours.
·
The
slow dissociation of ITMN-191 from NS3/4A is evidenced by persistent inhibition
in both biochemical assays and HCV replicon reduction in cell based assays.
·
These
studies may have clinical significance as bulk drug levels following Cmax may
under represent potential virologic responses.
Topic: Disease Progression – Metabolic disorders
M1819. The association of selected adipokines with hepatic
steatosis in patients with chronic hepatitis C infection.
S. Galhenage; K.
Patel; H. M. Patton; T. Walker; W. Symonds; M. F. Abdelmalek; J. G. McHutchison
Background:
It is unclear whether the ability of adipokines to modify
host lipid metabolism is associated with steatogenesis in patients with chronic
hepatitis C (CHC) infection. We thus evaluated the relationship between
adipokine levels and steatosis in patients with CHC infection.
Methods:
Liver biopsies and matched serum samples from 241 untreated
CHC patients were selected from Duke serum and tissue
repository. Biopsies were blindly evaluated for degree of steatosis by 2
pathologists with high concordance (Kappa 0.84,p<0.005).
Steatosis was recorded as % affected hepatocytes and graded:
0(0-2%),1(3-29%),2(30-59%)and 3(≥60%). HCV genotype, serum HCV RNA and
body mass index(BMI) were measured. Serum leptin,
adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1),
and tumor necrosis factor (TNF-α) were measured using conventional assays.
Comparisons between adipokines and steatosis % were made by pairwise
correlation and multivariable stepwise linear regression weighted for BMI.
Results:
Patients were mostly males (174/241, 72%), mean age 44.2 ±
7.4 yrs, genotype-1 infection (149/241, 46.9%), with steatosis present in 113
(46.9%). No significant differences were noted in BMI between genotype
1(Genotype 1) and genotype non-1(G non-1) patients (27.8 vs.27.7 kg/m2).
Mean steatosis was significantly lower in Genotype 1 compared
with Genotype non-1
(8.46% vs. 15.47%, p=0.006). No correlation of steatosis was observed with log
HCV RNA (p=0.62). For all patients, linear regression for steatosis percentage
indicated weak positive correlation with IL-6 (R2=0.16, p=0.04) and PAI-1
(R2=0.033, p=0.003) and negative correlation with adiponectin (R2 =0.015,
p=0.04).
Analysis of variance indicated differences in mean
adiponectin (p=0.01) and PAI-1(p=0.04) by fat grade. Stepwise linear regression
modeling for steatosis % weighted for BMI indicated independent negative
correlation for adiponectin, and positive correlation for IL-6 and PAI-1 (R2
=0.154, p<0.0001) for G1 infection. There was no association observed
between adipokine levels and steatosis % for G non-1 infection.
Conclusions:
Steatosis in Genotype 1 chronic hepatitis C may be associated
with adiponectin and PAI-1, indicative of the role of host metabolic factors in
steatogenesis. These associations were not apparent in genotype non-1 infection,
reflecting other pathogenetic mechanisms of steatosis e.g. virally mediated
factors in genotype 3.
|
|
Estimate |
Standard Error |
p value |
|
IL-6 |
0.022 |
0.0124 |
0.07 |
|
Adiponectin |
-7.02 x 10-8 |
3.69 x 10-8 |
0.05 |
|
PAI-1 |
0.00087 |
0.00022 |
0.0001 |
Multivariable stepwise linear regression for steatosis %
weighted for BMI in genotype 1 infected patients.
Topic: Disease Progression - General
M1820. Regulatory failure of serum prohepcidin levels
in patients with hepatitis C.
M. Nagashima; M. Kudo
Background / Aims
Elevated serum ferritin and hepatic iron concentrations are
frequently observed in chronic hepatitis C (CHC), which may be related to
hepcidin. Because the role of hepcidin in chronic hepatitis C patients remains
unknown, We aimed in this study to generate some
information about hepcidin in chronic hepatitis C.
Methods
To determine whether serum hepcidin correlates with markers
of iron status in patients with viral hepatitis, we measured serum prohepcidin
levels in patients with hepatitis C virus (HCV) and hepatitis B virus (HBV)
infection and in healthy controls.
Results
Serum prohepcidin and ferritin levels were negatively
correlated (r=-0.182, P=0.037) in HCV patients and positively correlated in HBV
patients and in healthy controls. The total iron scores in liver specimens from
HCV patients were also negatively correlated (r=-0.403, P=0.013). Serum
prohepcidin levels in patients with liver cirrhosis (LC) were significantly
lower than in patients with chronic hepatitis (CH). In both chronic hepatitis
and liver cirrhosis, serum prohepcidin levels were significantly lower in HCV
patients than in HBV patients.
Conclusion
Failure of homeostatic regulation of serum prohepcidin
concentrations may be induced by HCV infection, resulting in elevation of serum
ferritin levels, which leads to the progression of liver injury by iron
overload in chronic hepatitis C patients.
Topic: Disease progression – metabolic disorders
S. Galhenage; K.
Patel; H. M. Patton; T. Walker; W. Symonds; M. F. Abdelmalek; J. G. McHutchison
Background:
Steatosis in chronic hepatitis C (CHC) infection is
associated with both host metabolic and viral factors. The role of adipokines
in development of steatosis in chronic hepatitis C infection remains unclear.
We evaluated the relationship between several adipokines and changes in
steatosis following interferon (IFN)-based therapy for chronic hepatitis
C.
Methods:
Paired pre- and post-treatment (Rx) liver biopsies and
matched serum samples were selected from a repository. Biopsies were blindly
evaluated for steatosis and recorded as percetnqage of affected hepatocytes and graded
according to: 0(0-2%),1 (3-29%), 2
(30-59%) or 3 (≥60%). Leptin, adiponectin, interleukin-6 (IL-6),
plasminogen activator inhibitor-1 (PAI-1)and tumor
necrosis factor (TNF-α) levels were measured using conventional assays.
Treatment consisted of interferon monotherapy or combination
therapy with ribavirin. Sustained virological response (SVR) and non-response
(NR) were defined as absence at 6 months or persistence of HCV RNA
post-treatment respectively. Comparisons were by paired t-test and contingency
analysis.
Results:
The study cohort of 52 chronic hepatitis C patients (M/F
40/12), genotype 1 (29/52, 55%), had mean baseline steatosis 13.17 ±
2.33%.There was no mean difference in steatosis percentage between paired
biopsies for genotype 1(-0.89%, p=0.32)and genotype non-1
patients(-7.4%,p=0,12).
There was an association with direction of change in
steatosis grade and adipokines for TNF-α (p=0.05) and PAI-1(p=0.006). For
genotype 1, change (Δ) in steatosis percentage correlated with Δ IL-6
only (R2 =0.16, p=0.03. For genotype non-1, there was trend toward positive
correlation for Δ PAI-1 and Δ steatosis percentage (R2=0.16, p=0.06.
Mean Δ TNF-α was greater in genotype 1 patients with SVR compared to
NR with no other differences for adipokines by virologic response for genotype
1 or genotype non-1.
There were no significant differences in mean adipokine
levels before and after Rx for genotype 3 (n=12) and non-3 (n=38) and no
correlation for Δ adipokines and Δ steatosis %. Mean adipokine
differences for G3 SVR (n=5) vs G3 NR (n=7) were not significant; for non-3 NR
(n=28) vs. SVR (n=10) only TNF-α levels were significantly different(37.63 vs -157.6, p=0.007).
Conclusions:
The adipokines TNF-α, IL-6 and PAI-1 may have limited
utility in following changes in steatosis in chronic hepatitis C genotype 1
infection. Similar associations were not apparent for genotype genotype non-1
or genotype 3 related changes in steatosis or viral response.
|
|
G1 SVR |
G1 NR |
p value |
G non-1 SVR |
G non-1 NR |
p value |
|
Δ IL-6 |
-0.55 |
-1.03 |
p=0.97 |
-0.44 |
-17.69 |
p=0.42 |
|
Δ TNF-α |
-154.4 |
39.9 |
p=0.04 |
-49.97 |
-12.63 |
p=0.44 |
|
Δ Leptin |
-920.5 |
1205.6 |
p=0.73 |
917.29 |
-456.8 |
p=0.64 |
|
Δ Adiponectin |
-2 x 106 |
6.4 x 106 |
p=0.4 |
27939 |
2.2 x 106 |
p=0.67 |
|
Δ PAI-1 |
-88.9 |
-689.6 |
p=0.74 |
-1540 |
315.67 |
p=0.34 |
|
Δ Steatosis % |
0.125 |
-1.28 |
p=0.75 |
-29.57 |
2.37 |
p=0.02 |
Topic: Disease Progression – Metabolic disorders
M1823. Chronic HCV Infection causes Insulin
Resistance- A Meta-analysis.
S. Jalil; R. R.
Mummadi; G. K. Sood
Background and Aim:
Chronic Hepatitis C virus (HCV) infection is associated with
increased risk of type 2 diabetes. It has been postulated that HCV infection
promotes Insulin resistance (IR) and leads to development of diabetes.
Recently, several studies have reported the link between chronic HCV infection
and insulin resistance before the development of diabetes. These studies
however are heterogeneous in their design and outcome measures. We performed a
meta-analysis of available studies (1988 through November 2006).
Methods:
Electronic databases Medline, CINAHL and Science Citation
Index were searched. Studies with non-diabetic, non-cirrhotic chronic HCV
infected patients with a healthy control group for comparison were included for
analysis. Main outcome analysis was level of Insulin resistance as measured by
homeostasis model assessment for insulin resistance (HOMA-IR). HOMA-IR data for
HCV patients and controls were abstracted. Meta-analysis was performed using
Comprehensive Meta Analysis Software Version 2.
Results:
A total of 342 journal articles and abstracts were reviewed.
Eight studies which met the search criteria were selected. There were 951
chronic HCV patients with HOMA-IR results. The pooled data of HOMA-IR from six
studies favors insulin resistance in patients with chronic hepatitis C
infection (Std diff in means: 3.79, SE: 0.056, CI:
3.59-3.81; p= 0.001) as shown in table 1.
Conclusions:
This meta-analysis suggests that chronic HCV infection is
associated with insulin resistance when compared to healthy controls. The
insulin resistance in chronic hepatitis C patients is independent of
genotype. There is increased incidence
of steatosis in genotype 3 infection.
Topic: Disease Progression - General
M1826. Hepatitis C and End Stage Renal Disease: A Global Survey.
J. A. Ortiz; J. M.
Palma-Vargas; F. H. Wright; F. E. Membreno; S. Harrison; P. F. Foster
Introduction/Methods:
Hepatitis C virus (HCV) is an important cause of morbidity in
patients with End Stage Renal Disease (ESRD). Treatment algorhytms for these
complex patients have yet to be validated. To determine the degree of
variability in treating this patient population, we sent a 22 question survey
to over 1000 transplant professionals via the Internet. Specific topics
involved in this survey were: Pre-transplant HCV diagnosis strategies,
Pre-transplant HCV treatment modalities, Transplant strategies and
post-transplant HCV therapies and immunosupression.
Results:
There were 137 respondents as follows: 32 hepatologists, 31
nephrologists, 28 multi-organ transplant surgeons, 22 liver transplant
surgeons, 19 kidney transplant surgeons and 5 miscellaneous. Three surveys were
eliminated due to incomplete answers leaving 134 surveys for the final
analysis.
In addition to serologic viral studies, 61% of the
respondents would perform a liver biopsy for the pre-transplant HCV work-up.
Biopsy time intervals varied widely among answers and 38% of the respondents
had no established protocol. The majority of the respondents (75%) stated that
the hepatologist or gastroenterologist were involved
in the decision -making process.
Regarding pre-transplant HCV therapy, 68% of the respondents
would treat at least some of these patients with interferon. Thirty eight
percent would use ribavirin. Dosage varied widely among the respondents.
Transplant strategies included the use of HCV positive donors
for HCV positive recipients in 64% of respondents. Additionally, 4% would use
HCV positive donor organs for HCV negative recipients. Combined liver/kidney
transplantation was advocated by 50% in the asymptomatic biopsy proven
cirrhotic patient on dialysis.
Regarding post-transplant HCV therapy, 17% of the respondents
would treat kidney transplant recipients with interferon and 33% would treat
dual liver/kidney transplant recipients with interferon.
Finally, immunosupression management after kidney transplant
in this setting showed that the majority of respondents are inclined to adjust
it, however the methods varied widely.
Conclusions:
This global survey indicates that management of the HCV
patient with ESRD pre and post-transplant varies greatly depending on the
practitioner. A consensus conference is required to establish guidelines based
on organized prospective multi-center trials.
Topic: Acute –
D. Manning; M.
O'Brien; C. O'Farrelly; J. E. Hegarty
Background:
Complex host and viral factors interact to determine the
outcome of hepatitis C viral (HCV) infection. The main focus of research into
the pathogenesis of HCV has been on the adaptive immune system. Interferon
alpha, a protein with antiviral and immunomodulatory properties is a key
component of the innate immune system and is the therapeutic strategy of choice
for HCV infection.
Objective:
The objective of this study was to evaluate the production of
interferon alpha from total peripheral blood mononuclear cells (PBMCs) from
patients who had been exposed to hepatitis C from contaminated anti-D
immunoglobulin in 1977/ 8. Our hypothesis was that patients who failed to
spontaneously clear HCV may have defective interferon alpha production.
Methods:
PBMCs were isolated by density gradient centrifugation from
24 females (13 polymerase chain reaction positive) who had been exposed to
hepatitis C from a single source in 1977/ 8. PBMCs were stimulated for 24 hours
with polyinosinic acid: polycytidilic acid (poly I: C) which was transfected
into the cytoplasm with Lipofectamine 2000. Poly I: C is a synthetic double
stranded RNA which acts as a TLR3 ligand. Interferon alpha levels in the
supernatants were measured using a commercially available enzyme linked immunosorbent
assay kit (PBL Biolabs,
Results:
Interferon alpha was detected in all samples following
stimulation with poly I: C transfection. Interferon alpha was not detected in
any sample stimulated with poly I: C or Lipofectamine 2000 alone. The
interferon alpha concentrations as measured by ELISA were (results expressed as
median [interquartile range] in pg/ ml): PCR positive patients 52.9 [44.94 –
66.48], PCR negative 49.94 [45.96 – 94.43]. There was no significant difference
between these results (p = 0.77).
Conclusions:
Interferon alpha production from PBMCs in-vitro is not
defective in patients who fail to spontaneously clear HCV. A defect in the
response to interferon alpha may be responsible for persistence of viraemia in
these patients
Topic: Diseaese progression – general
M1829. Proteinuria in chronic HCV infection: a link
for chronic kidney disease (CKD)?
S. K. Satapathy; C.
Lingisetty; S. Chaudhari; S. Williams
Background/objectives:
The role of Chronic HCV infection in the etiology of chronic
kidney disease (CKD) is still a matter of debate. Proteinuria by dipstick, a
simple test in practice, is a useful and cardinal sign of underlying renal
abnormalities.
Aim:
To elucidate the impact of hepatitis
C virus (HCV) infection on the occurrence of proteinuria amongst adults.
Methods:
A retrospective chart review of the urinalysis with dipstick
for proteinuria detection was done on 568(M:F::383:185)
HCV positive patients, and were compared with 349 HCV negative (M:F::232:117)
patients matched for age, race, and sex who were seen at the GI clinic. Urine
analysis was available in 432 HCV positive patients and 284 controls.
Proteinuria was categorized into nil, intermittent or persistent.
Results:
Persistent proteinuria was noted in a significantly higher
number of patients with chronic HCV infection, [36(8.3 %) vs. 12 (4.2%),
p=0.032], although intermittent proteinuria was comparable in both groups
[73(17%) vs. 44(15.5%), p=0.619]. Proteinuria was significantly absent more
commonly in the control group compared with HCV positive group [229(80.6%) vs.
319(73.8%), p=0.036].
The difference in persistent proteinuria was found even after
excluding diabetics [22(6.6%) vs. 5(2.2%), p=0.017]. Multivariate logistic
regression analyses showed that Serum Creatinine [P <0.0001, OR=1.774; 95%
CI: 1.34-2.348] and diabetes mellitus [P=0.038, OR=0.303; 95% CI: 0.098- 0.937]
were the significant factors associated with proteinuria, followed by body
weight, HCV viral load, age, Genotype status, HIV status, hypertension, sex and
race.
Conclusion:
Proteinuria is significantly associated with chronic HCV
infection.
Logistic regression analysis of various factors predicting proteinuria
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Topic: Disease Progression – Metabolic disorders
M1831. Metabolic predictors of steatosis and fibrosis
in chronic hepatitis C(HCV).
P. K. Pandya; J. S.
Nachnani; P. Callahan; D. Reker; S. Mathur
Background:
Histologic evidence of steatosis in liver biopsies of HCV patients
is well documented. Recent evidence suggests that HCV is directly responsible
for steatosis in genotype 3 infection whereas steatosis in genotype 1 is a
consequence of metabolic derangement specifically insulin resistance (IR). The
relative contribution of associated cytokine and adipokine abnormalities on
steatosis and fibrosis remains unclear.
Aim:
To systematically characterize the
metabolic abnormalities and correlate these findings with concomitant
histologic evidence of steatosis and fibrosis.
Methods:
Demographic, anthropometric, serologic, and metabolic
parameters were studied in a cross-sectional study of treatment naïve veterans
with chronic hepatitis C. Insulin resistance was defined as a HOMA (fasting
insulin (mU/L) x fasting glucose (mmol/L)/22.5) greater than 2.5. Serum levels
of TNF-α, IL-6, adiponectin and leptin were measured using ELISA. Chronic
HCV inflammatory activity and fibrosis were determined according to the
modified hepatic activity index (HAI). Univariate analysis and multivariate
analysis were performed.
Results:
The average age, BMI, viral load, ALT and HOMA were 52.6±7.2,
28.8±5.8, 3.4x106,64.5±62.6 and 4.71±5.9 respectively.
All but two of the patients were male. Caucasians and African Americans
comprised 68.8% and 22.5% of the cohort.
The predominate genotype in the cohort was genotype
1(78.5%). 55% of the cohort was insulin resistant. Univariate analysis using
fibrosis as a dependant variable showed Waist Hip ratio > 1 (p=0.04), Race
(p=0.01), perisinusoidal fibrosis(p=0.0038), HOMA
(p=0.0001), TNF(p<0.0001), Steatosis(p=0.0086), IL-6(p< 0.0001), and BMI
(0.003) to be significant.
For steatosis, Race (p=0.02), perisinusoidal fibrosis(p=0.0015), HOMA(p < 0.0001), IL -6 (p=0.0006),
Adiponectin (p=0.01), Leptin (p=0.03) and BMI (p=0.02) were found to be
significant. Multivariate analysis using regression with steatosis as the
dependent variable identified HOMA (p=0.0007) but not leptin, adiponectin, TNF
a, IL-6, age, or BMI (p=ns) as an independent variable. For fibrosis HOMA
(p=0.03), adiponectin(p=0.048), TNF a(p=0.2), and IL-6
(p=0.009) were independently associated while age, BMI, and leptin were not.
Conclusion:
·
Insulin
resistance is common in chronic HCV.
·
HOMA
but not BMI independently predicts both steatosis and fibrosis.
·
Adiponectin,
IL-6 and TNF-α were independent predictors of fibrosis while adipokines or
cytokines were not predictive of steatosis.
·
Insulin
resistance is an independent predictor of steatosis and fibrosis.
·
Hence
therapeutic modulation of insulin sensitivity in insulin resistant HCV patients
should be further evaluated.
Topic: Disease Progression—Metabolic disorders
M1832. Lack of association between hepatitis C and
diabetes mellitus: a case-control study.
S. K. Satapathy; C.
Lingisetty; S. Chaudhari; S. Williams
Background:
Although a higher prevalence of type II diabetes mellitus
(diabetes) has been reported in patients with hepatitis C virus (HCV)
infection, the results are conflicting and even negative association has been reported.
Aim:
The aim of this study was to determine relationship of
diabetes with chronic HCV infection in a large population of HCV patients, by
comparing with an age, race, and sex matched control population. The presence
of diabetes was ascertained by using American Diabetes Association guidelines
based on fasting glucose measurement and medication history. Presence of HCV
infection was assessed by serum testing for anti-HCV antibodies.
Methods:
A total of 568(Male:Female::383:185)
anti-HCV positive patients were compared with 349 anti-HCV negative
(Male:Female::232:117) patients matched for age, sex and race who were seen in
GI clinic.
Results:
The prevalence of type II diabetes in the anti-HCV positive
group was comparable to that of the control group [105 (18.5%) vs. 56(16%),
P=0.346]. These differences did not change on sub-group analysis of the Black
patients [27(17%) vs. 17(17.3%), p=0.940], although there was a trend for
higher number of diabetics among Hispanic patients [75(21.2%) vs. 34(15.3), p=
0.078].
Multivariate logistic regression analysis revealed higher age
[p< 0.017 OR=1.037, 95% CI= 1.007– 1.069], and presence of hypertension
[p<0.0001, OR=0.214, 95% CI= 0.115–0.401] were the only significant
predictors for the presence of DM in patients with chronic HCV infection.
Gender, race, body weight, serum creatinine, HCV-genotype at baseline, IVDU,
and HIV status were not predictors.
Conclusion:
·
In
our study no significant differences were notes in regards to the prevalence of
diabetes in patients with chronic HCV and controls without chronic HCV
infection (18.5% vs. 16%, p=0.346.
·
Higher
age and presence of hypertension were the only significant predictors for the
presence of diabetes in patients with chronic HCV infection.
Logistic regression analysis of various factors predicting Diabetes Mellitus:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Topic: Diagnostic tools – non-invasive markers
M1833. Investigating the Cause of High Ast/Alt Ratio in
HCV-Induced Liver Cirrhosis.
J. Loubert; V.
Raymond; S. Selliah; M. Bilodeau
Introduction:
For more than 50 years, the enzymatic activities of serum
transaminases (aspartate-AST and alanine-ALT) have been used to evaluate liver
diseases. Mostly synthesized by hepatocytes, these enzymes are released in the
serum when the liver undergoes injury and cell death. There is good clinical
evidence that a higher ratio of AST over ALT (AS/LTr) is indicative of the
presence of underlying cirrhosis especially in HCV-infected patients: the
explanation of this feeding is unknown. In order to define the respective role
of fibrosis and HCV proteins in this observation, experiments were performed to
measure the respective activities of theses enzymes in tissue samples or
hepatocytes obtained from different experimental models.
Material and Methods:
AST and ALT activities were measured in:
1. Tissue homogenates from normal (N), HCV-infected
cirrhotic (F4-HCV) and non-HCV-infected cirrhotic (F4) human livers;
2. Cell homogenates from purified
hepatocytes isolated from N and F4-HCV livers; and
3. Cell homogenates from
hepatoma-derived parental (Huh7), sub-genomic HCV replicon-transfected (9-13)
and interferon-cured replicon (TX) cell lines.
Results:
AST levels were 140±16 IU/mg liver in homogenates from normal
livers in comparison to 106±12 IU/mg liver in F4-HCV and 115±7 IU/mg liver in
F4 livers. ALT levels were 65±10 IU/mg liver in normal livers, 32±4 IU/mg liver
in F4-HCV livers and 34±5 IU/mg liver in F4 livers. AS/LTr were significantly
higher in both F4-HCV and F4 livers in comparison to controls (3.4±0.4 and
4.0±0.4 vs 2.3±0.1; p<0.02). When AST and ALT were measured in purified
preparations of hepatocytes, AST levels were higher in cells obtained from
F4-HCV livers in comparison to normal livers (167±31 vs 100±8 IU/mg prot)
whereas ALT levels were lower (34±6 vs 49±3 IU/mg prot). This led to higher
AS/LTr in hepatocytes from F4-HCV livers (6.2±1.5 vs 2.1±0.2, p=0.01). On the
other hand, AST and ALT levels were lower in 9-13 cell line homogenates
compared to the parental Huh7 (100%±3 vs 61%±7, p=0,04).
Levels were corrected in the TX cell line.
Our data demonstrate that the tissue concentrations of AST
and ALT are affected by the presence of fibrosis, this observation being
independent of the presence of HCV infection. In hepatocytes isolated from
cirrhotic livers, AST activity is higher than in normal hepatocytes: this is
the reverse for ALT. On the other hand, HCV proteins might negatively affect
the activity of these enzymes irrespective of the presence of fibrosis.
Conclusion:
The intracellular activity of these routinely used enzymes
are significantly affected by the presence of liver fibrosis and possibly too
by HCV infection.
Topic: Disease progression – general
M1836. Prevalence of Gallstones Among Persons With Hepatitis C Virus Infection In
S. Memon; N. K.
Khatri; U. Soomro; W. Jafri; R. Ghori
Background:
Although cirrhosis is a risk factor of gallstones, a recently
published data also suggested that Chronic Hepatitis C (CHC) infection is
associated with gallstones in men in
Methods:
We included all the consecutive adults with HCV antibody
positive (patients) and HCV antibody negative (Controls) who visited our
hepatology clinic from June 2006 to October 2006. We noted the stage of
disease, weight, BMI, associated Diabetes Mellitus (DM), ethnicity and number
of children in case of women. After taking verbal consent, their HCV status
checked and Ultrasound abdomen was also done. Patients who had cholecystectomy
in past before the declaration of their HCV status were excluded.
Results:
A total of 762 participants with 467 HCV antibody positive
and 295 as control were included. There were 420 (55%) men (270 HCV antibody
positive and 150 control) and 342 (45%) women (197 HCV positive and 145 control). The prevalence of gallstones was significantly
higher (p value =0.048) in HCV antibody positive men (9.4%) than controls
(4.0%). There was no such difference noted in case of women (p value = 0.4).
The prevalence of gallstones was increased significantly with severity of liver
disease, increasing age, marital status, and residence in village.
Conclusion:
Chronic HCV infection was strongly associated with gallstones
among men but not in women in our study in
Topic: Disease progression – general
M1837. Co-infection with Cytomegalovirus in Chronic Hepatitis
C Infection.
D. Majumdar; S. D. Ryder; P. McClure
;
Background/Aims:
CMV infection is a common worldwide infection with an adult
prevalence rate of 40-95%. Although in the immune-competent host it usually
causes an asymptomatic infection, it is an important cause of graft dysfunction
following OLT (including when the underlying cause of liver damage is HCV
infection). In the non-transplant setting, progression of HCV infection is seen
with co-infection with HIV and HBV. This study examines the role of CMV
co-infection in chronic HCV infection in immune-competent hosts.
Methods:
Data were obtained from the Trent HCV database. Patients were
excluded if they had coexisting HIV or hepatitis B infection. They were
categorised as HCV RNA negative (anti HCV positive), HCV RNA positive with mild
(Ishak stage 0 and 1) and severe (Ishak stage 4, 5, 6) liver fibrosis. We
compared the CMV status among HCV RNA positive versus the negative group, and
among those with mild and severe fibrosis. We also compared CMV seropositivity
rates in responders and non-responders to PEG interferon and ribavirin
combination therapy. Serum samples were tested for CMV serostatus using
Vironostika anti-CMV III EIA kits.
Results:
153 patients were HCV RNA negative (54.2% CMV seropositive),
54 were HCV RNA positive with mild fibrosis (66.7% CMV seropositive) and 116
(67.2% CMV seropositive) had severe fibrosis. 114/165 (69%) HCV RNA positive
patients achieved SVR following combination therapy. On univariate analysis
there was no relationship between CMV seropositivity and development of severe
fibrosis or achievement of SVR. HCV RNA positive patients however had a higher
rate of CMV seropositivity (67.1%) versus HCV RNA negative patients (54.2%),
odds ratio (OR)1.72 (95% CI: 1.09 to 2.7, p=0.019, n=323). On multivariate
analysis taking into consideration confounders (age at testing, sex, risk
factors for infection, alcohol intake), age at sample testing was found to be
the only variable associated with both CMV (mean±SD, 45.4±10.2, n=197 and 42.1±10.9,
n=126 for CMV positive and negative respectively, p=0.005) and HCV RNA
positivity (mean±SD, 49.6±6.9, n=170 and 38.0±10.7, n=153 for HCV RNA positive
and negative respectively, p<0.001). On adjusting the OR for age, there was
no significant difference between the groups.
Conclusion:
CMV serostatus in the immune-competent patient with chronic
HCV infection does not have any effect on spontaneous viral clearance rates,
liver fibrosis development, or the achievement of SVR with treatment.
Topic: Disease Progession – Extrahepatic Man.
M1838. Clinical Spectrum of Chronic Hepatitis C Virus-related
Cryoglobulinemia in the
G. Lake-Bakaar;
Introduction:
Several studies have described the clinical spectrum of liver
disease in patients with chronic Hepatitis C Virus HCV-related mixed
cryoglobulinemia, HCV-C. However, the majority of these reports have been from
outside the
We have analyzed clinical data from 43 patients with
HCV-related cryoglobulinemia, presenting to a large academic referral center in
NY. The diagnosis of symptomatic HCV-related cryoglobulinemia (HCV-C) was based
on the presence of HCV RNA in plasma associated with typical lower limb
purpuric rash; inflammatory polyarthralgias; and sensory or motor peripheral
nerve disturbance.
Results:
The majority of the patients were female, aged over 50 years.
Most were genotype 1 (87%) with evidence of significant fibrosis. Reduced
levels of serum complement, C3, C4 or CH50 typified the group. Rheumatoid
factor RF, abnormal ALT and overt renal disease were present in a minority of
the patients. There was clinical evidence of autoimmune disease in
approximately 25% of patients.
Conclusion:
The association between HCV-C and advanced fibrosis or
cirrhosis of the liver is confirmed. The genotype distribution reflects that
which is predominant in our patient population. Most of our patients have
reduced levels of serum complement. This may be a better discriminate for HCV-C
than RF. The high incidence of overt autoimmune disease might reflect increased
production of cross-reacting antibodies.
Patient Characteristics
|
Topic: Disease progression – general
M.1839 Early Occult Portal Hypertension in Chronic Hepatitis C
David
S. Zimmon, Forrest Manheimer Dept of Medicine; Fred B. Smith, Sergei Aksenof,
Dept of Pathology, St. Vincent’s Hospital, New York, N.Y.
Aim/Methods
We examined 23 patients with chronic hepatitis C (HCV) for esophageal varices (EV) by upper
gastrointestinal endoscopy, for portal hypertension (PH) by wedged hepatic vein
catheterization for measurement of portal pressure (PP) and for histopathologic
grade and stage (Scheuer) by liver biopsy retrospectively by two blinded
pathologists. Initially only patients requiring transjugular liver biopsy for
contraindications to percutaneous biopsy including bleeding diathesis, morbid
obesity or thrombocytopenia were examined. Recognition of severe PH as evidence
of global progressive liver disease in the absence of EV prompted PP
measurement in subsequent chronic HCV patients. Patients with edema or ascites
were excluded.
Results
In two HCV patients right atrial pressures were 12 and 13mmHg
implying systemic hypervolemia.
In 16 patients without EV 16/23 (69%) PP was greater than
10mmHg (range 12-28, mean 19 mmHg).
In 8/23 (31%) with suspected or small (+1) EV easily missed
during endoscopy, PP ranged from 10-20 (mean14) mmHg. Small EV, easily
overlooked at endoscopy, may indicate severe PH and should be considered an
indication for hemodynamic evaluation. Endoscopy and PP measurement seek PH in
the basal fasting state when PP is at its nadir. Two of 23 liver biopsies were
inadequate for interpretation. Stage 4 (cirrhosis) was seen in 7/21 (33%).
Stage 1 (19%) or Stage 2 (28%) was present in 48% with 4/21 (19%) stage 3. Over
all PH was found in 67% before cirrhosis was apparent on liver biopsy or EV were obvious at endoscopy.
In this small number of referral (to hepatologists) biased
patients neither biopsy stage nor absence of esophageal varices excluded PH and
associated hemodynamic abnormalities including hypervolemia and high IVC
pressure. PH was recently identified in HCV as an early rejection signal after
hepatic transplantation in HCV. Conversely frank cirrhosis may be present
without EV.
Conclusion:
Our findings suggest that PH develops early in chronic HVC
and is often not detected by endoscopy or transjugular liver biopsy. This
implies a need for early hemodynamic screening to identify global progressive
disease.
Topic: Experimental therapies - general
M1840. Trial of oral n-acetylcysteine (NAC) to treat
insulin resistance in chronic hepatitis C(HCV).
P. K. Pandya;
Background:
The prevalence of insulin resistance and type 2 DM (diabetes)
is significantly higher in HCV patients compared to controls. Furthermore in
patients with HCV, insulin resistance is associated with advanced liver fibrosis
and reduced outcomes to antiviral therapy. NAC has been shown to improve
insulin resistance in recent studies, but its effect in HCV patients is not
known. Additionally, a recent study has revealed that NAC inhibited
TNF-alpha-mediated activation of NF-kappaB and improved the adverse changes in
the levels of IL-6, PAI-1 and adiponectin in adipocytes.
Aim:
To study the effect of NAC on insulin
sensitivity and adipocytokine derangements in insulin resistant patients HCV
patients.
Methods:
33 consecutive treatment naïve patients with chronic HCV and
insulin resistance as defined by HOMA > 2.5 were randomized to receive 2400
mg of NAC or no medication for 30 days. Detailed anthropometric and metabolic
parameters were studied before and after therapy. Demographic, histologic, and
metabolic parameters between patients and controls were compared with two
tailed t-test or X2 analysis. Pre and post treatment values were similarly
compared. Repeated measures analysis to test the effects between subjects and
within subjects were evaluated with repeated measure analysis using ANOVA for
the primary endpoint variable of HOMA.
Results:
15 treatment and 14 control patients completed therapy. The
demographic, metabolic, viral, and histologic parameter of control and
treatment groups were similar (p=ns). Similarly comparing pretreatment to post
treatment values in controls and NAC treated groups revealed no statistically
significant changes (Table 1). The effect of therapy on HOMA with repeated
measure analysis revealed no differences between subjects (p=0.14) or within
subject differences (p=0.96)
Conclusions:
Short term therapy with the hepatoprotective antioxidant NAC
failed to improve insulin sensitivity in insulin resistant patients with
chronic HCV. Additionally the proinflammatory cytokines and adipokines were
unchanged after therapy.
Table 1
|
Topic: Diagnostic Tools – non-invasive
M1842. Transient elastography in chronic hepatitis B
and C predicts severe fibrosis similarly.
C. Verveer; H. R. van
Buuren; P. E. Zondervan; B. E. Hansen; H. Janssen; R. J. de Knegt
Background:
Assessment of liver fibrosis is important in chronic liver
diseases. In chronic hepatitis B and C it helps to determine prognosis and
indication for therapy. Transient elastography is a novel method for
measurement of liver fibrosis. In contrast with the liver biopsy it is comfortable
and without any risk.
The Fibroscan® has been validated in large cohorts of
hepatitis C patients, but its use in hepatitis B patients is still
undetermined. We investigated whether reliability of the Fibroscan® in viral
hepatitis B and C are comparable.
Methods:
All consecutive patients undergoing a liver biopsy had an
additional Fibroscan®-measurement. Correlation between liver histology
(Metavir) and the outcome of liver elasticity (Fibroscan®, kPa) was determined.
In this cohort we studied the outcomes between both groups of elasticity
measurements and liver fibrosis stages in order to investigate comparability.
Results:
Among 68 hepatitis B patients 7 had Metavir F0, 25 F1, 21 F2,
9 F3 and 6 F4; corresponding elasticity was (mean:) F0 5.36 kPa, F1 7.69 kPa, F2 9.15 kPa, F3 13.41 kPa and F4 17.05
kPa.
Among 73 hepatitis C patients 3 had Metavir F0, 31 F1, 23 F2,
13 F3 and 3 F4; corresponding elasticity was (mean): F0 3.40 kPa, F1 6.48 kPa,
F2 7.82 kPa, F3 12.86 kPa and F4 13.73 kPa.
To determine the predictive value of the elasticity
corresponding to severe fibrosis logistic regression was performed. Graphs for
HBV and HCV were not significant different indicating comparable elasticity
measurements for predicting fibrosis in HBV or HCV.
Conclusion:
The Fibroscan® is applicable in both chronic hepatitis B and
C with a similar predictive value for liver fibrosis.
Topic: Disease Progression – Extrahepatic Man.
M1843. Associations among Susceptibility Factors for Human
Porphyria Cutanea Tarda.
S. Jalil; J. J. Grady;
K. E. Anderson
Background:
Porphyria cutanea tarda (PCT) is the most common form of
porphyria and results from an acquired deficiency of hepatic uroporphyrinogen
decarboxylase (UROD). Both familial and sporadic forms become manifest in the
presence of multiple susceptibility factors that lead to excess iron or
oxidative stress in hepatocytes. Most previous studies have addressed one or a
few such factors individually. We examined associations among multiple factors
in a large cohort of patients seen at a single medical center.
Methods:
Susceptibility factors as well as demographic and clinical
features, including smoking and diabetes, were tabulated by a retrospective chart
review for all 143 PCT patients seen at the gastroenterology clinic or General
Clinical
Results:
Patients were all adults (range 33-86, mean 52.2 yrs), and
predominantly male (66%) and Caucasian (88%). The mean age of onset of PCT was
41 ± 8.8 yrs. The most common susceptibility factors were ethanol use (in 87%),
smoking (81%), chronic hepatitis C virus (HCV) infection (69%) and HFE mutations
(51%, with 6% C282Y/C282Y and 8% C282Y/H63D). Less common were estrogen use
(24%, but in 63% of women), diabetes (8%), HIV (13%) and inherited UROD
deficiency (17 % with low erythrocyte UROD activity). More than 70% had 3 or
more susceptibility factors. A significant association was found between HCV
and ethanol use (OR: 6.3) and smoking (OR: 11.9). HCV was also associated with
HIV (OR: 4.9). Estrogen use was somewhat more common among Caucasians, and
diabetes more common with inherited UROD deficiency. Significant associations
among other factors were not found.
Conclusions:
1.
Multiple susceptibility factors are found in the great majority of
individuals patients.
2.
Susceptibility factors that related to life style and behavior, namely
ethanol (alcohol) use, smoking, HCV and HIV showed statistically significant
associations within the cohort.
3.
A significant proportion (48%) of patients had BMI >25 kg/m2 and
were at risk for steatosis, which may be another susceptibility factor.
4.
Combination of particular susceptibility of PCT.
5.
Studies of these associations in PCT in other geographic areas would be
of interest.
Topic: Diagnostic tools – non-invasive
M1844. Point of Care Non-Invasive 13C Methacetin
Breath Testing Accurately Identifies Significant Liver Inflammation and
Fibrosis: A Novel Method For
Assessing Liver Damage.
G. Lalazar; O. Pappo;
B. Müllhaupt; O. Goetze; M. Margalit
Background:
Significant liver disease may be present in a seemingly
healthy population with normal liver enzymes and minimal symptoms. The serum
ALT level may not reflect the degree of liver damage, and liver biopsy has been
the gold standard for assessment of fibrosis and inflammation. The point of
care non-invasive BreathID® continuous online 13C methacetin breath test (MBT)
reflects hepatic microsomal function (CYP1A2) and has been shown to correlate
with hepatic fibrosis.
Aim:
To assess the ability of the
BreathID® 13C MBT to differentiate patients with significant liver
inflammation and/or fibrosis from healthy controls.
Methods:
184 patients with chronic HCV infection (59 females, 125
males, mean age 45.8, BMI 24.9), who had undergone a liver biopsy within 9
months, and 81( 38 females, male 43, mean age 39.8, BMI 24) healthy controls
(no known liver disease, normal liver enzymes and ultrasound) matched for age
and sex, underwent 13C MBT following ingestion of 75mg of methacetin. Forty
three controls and 11 patients underwent the MBT at least twice to determine
test reproducibility. MBT parameters included PDR peak (percentage dose
recovered) and CPDR10, 20, 30, 60 (cumulative PDR10, 20, 30 and 60 minutes
after ingestion of methacetin, respectively). Correlations between breath test
parameters and HAI (Hepatic Activity Index) inflammation score or METAVIR
fibrosis score were evaluated. We compared MBT parameters between controls and
patients grouped by HAI and METAVIR scores.
Results:
In HCV patients, all MBT parameters correlated significantly
with inflammation and fibrosis scores (p<0.0001). MBT accurately
differentiated between controls and patients with significant periportal and
bridging inflammation (HAIa > 2), any inflammation type (total HAI ≥
4) (AUC 0.87 and 0.82, 95%CI 0.78-0.97 and 0.74-0.91; sensitivity 88% and 78%;
specificity 78% and 77%; NPV 97% and 84%; and PPV 45% and 65%, respectively),
or patients with significant fibrosis (METAVIR > 2) (AUC 0.96, 95%CI
0.92-1.00; sensitivity 96%, specificity 86%, NPV 97%, and PPV 81%). Inter-test
variability was ≤ 13% (95%CI 0.11-0.15). Results were independent of BMI
in patients and healthy controls.
Conclusions:
The point of care BreathID® continuous online 13C
MBT accurately differentiates patients with significant liver inflammation
and/or fibrosis from healthy controls. This test may prove to be a powerful
non-invasive tool for detecting occult liver dysfunction.
Topic: Current Treatment - General
M1845. Retrospective Analysis of the Effect of Taking a
Statin Along with Peginterferon and Ribavirin (PI+R) on SVR.
T. Bader; M. Madhoun;
S. Rizvi
Methods:
104 patients taking PI+R were compared to 30 patients who by
chance took triple therapy [(PI+R) plus a statin]. A modified intent to treat
approach was taken whereby if any patient had a least one data point after
starting therapy, he or she was included in the denominator.
Virtually all patients taking a statin were on simvastatin
(n=25); 2 were on lovastatin, 2 on atorvastatin and 1 on fluvastatin.
The pooled SVR rate* for the 104 patients on standard
treatment was 37%. This is the highest SVR ever reported in the medical
literature for a VA based population.
The pooled SVR rate for the triple therapy group was 63%. In
terms of HCV subgroups, the effect was statistically strongest for genotype
one, the most difficult subgroup to treat.
Conclusion:
Statins appear to be associated with a higher SVR rate of
standard PI+R therapy. This observation principally occurs on the basis of a
medium powered statin (simvastatin) in terms of the Ikeda experiment
(Hepatology 2006;44:117-125). The only patient to take
fluvastatin during the study was cured. Statins need to be studied
prospectively for their effect on hepatitis C and the outcome of treatment.
SVR Rate
|
|
No Statin |
p value |
Statin |
|
Genotype 1 |
16/65 (25) |
.014 |
11/20 |
|
Genotype |
20/26 |
.43 |
3/5 |
|
Genotype |
7/15 |
.035 |
5/5 |
|
Pooled |
37% |
.009 |
63% |
*Pooled analysis makes the population proportion 70%
genotype 1 and 30% non-genotype 1 in order to mimic the proportion of genotypes
in the
Topic: Current HCV Teatment - Pegasys
M1846. Cost-effectiveness of Early Treatment of
Chronic Hepatitis C With Peginterferon Alfa-2a (40KD) Plus Ribavirin Before
Progression to Advanced Liver Disease.
J. Hornberger; P.
Pockros; T. Chu; K. K. Patel; M. L. Shiffman
Background:
Current guidelines recommend a pegylated interferon plus
ribavirin (RBV) as treatment of choice for chronic hepatitis C (CHC). The rate
of sustained virologic response (SVR) achieved with such therapy is >80% in
pts with HCV genotypes 2 or 3 and approximately 50% in pts with genotype 1
infection. However, data from clinical studies indicate that pts with more
advanced liver disease are less likely to achieve an SVR, suggesting that
treatment should be initiated at an earlier stage of disease to optimize the
chance of cure.
Aim:
To determine the cost-effectiveness of treating mild CHC
compared with delaying treatment until liver disease progresses to a moderate
or cirrhotic stage.
Methods:
Using pooled data from two randomized trials of peginterferon
alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®), we constructed a
state-transition probability model to evaluate the cost-effectiveness of early
treatment before progression to advanced liver disease. In the model (
Results:
The model showed that early treatment with peginterferon
alfa-2a plus RBV in genotype 1 pts with mild CHC reduced the 30-y risk of
cirrhosis by 13.5% (23.7% early vs 37.2% delayed), increased mean overall
survival by 0.48 y and increased mean survival adjusted for QoL by 0.75 y.
Although the additional drug cost of early treatment with peginterferon alfa-2a
+ RBV was $9,911 vs delayed treatment, this was offset by cost savings from
reduced monitoring and treatment. Delayed treatment was predicted to require an
average of 4.0 biopsies (costing $9,178) and additional treatment of
progressive liver disease and complications of cirrhosis (costing $6,347).
Compared with delayed treatment, early treatment with peginterferon alfa-2a
plus RBV was therefore associated with cost savings of $5,443 over the lifetime
of each pt. One-way sensitivity analysis showed that age and social discount
rate were the most influential parameters in the model.
Conclusions:
Early treatment with peginterferon alfa-2a (40KD) (PEGASYS®)
plus RBV (COPEGUS®) in pts with HCV genotype 1 infection is projected to reduce
the risk of cirrhosis, increase life expectancy, and cost less than monitoring
and subsequent delayed treatment of more advanced disease.
Topic: Current Treatment - Pegasys
M1849. Herbal and Milk Thistle Use in the HALT-C Trial of
Advanced Chronic Hepatitis C.
L. B. Seeff; T. M.
Curto; G. Szabo; G. T. Everson; H. L. Bonkovsky
Background & Aims:
The HALT-C (Hepatitis C Antiviral Long-Term Treatment against
Cirrhosis) Trial involves persons with chronic hepatitis C (CHC) and biopsy
evidence of marked fibrosis or cirrhosis who had failed previous antiviral
therapy. Enrollees initially received lead-in treatment with peginterferon
alfa-2a and ribavirin. Non-responders were then randomized to 3.5 years reduced
dose peginterferon or no treatment.
Herbals, used for centuries in
Our aim was to determine whether these patients, treated with
standard therapies at least once in the past and willing to be re-treated again
long-term, nevertheless used herbal supplements, primarily milk thistle (MT),
and whether MT affected symptoms, quality of life (QOL) and biochemical and
virological features of HCV infection.
Methods:
Baseline evaluation prior to the 24-week lead-in included
history, physical examination, biochemical and virologic assessment, and liver
biopsy. Patients also completed baseline questionnaires on prior and current
use of over-the-counter supplements and herbal preparations.
Results:
Among 1145 enrollees, 641 (56%) never used herbals, 235 (21%)
used them in the past only, and 269 (23%) were using them at enrolment. 0f the 64 herbs used Silymarin was taken by
195 person (72%). 772 (67%) never used
Silymarin. 178 (16%) used it in the
past, and 195 (17%) using it at baseline.
The baseline use of all herbals and of Silymarin varied widely among the
10 different centers. Baseline data from
the 10 participating centers revealed variable Silymarin use, being most
frequent in
Although univariate analyses identified that Silymarin users
had significantly fewer symptoms and better quality of life indices than
non-users, most of these differences became non-significant after adjusting the
analyses using relevant covariates.
There were no association between the use of Silymarin and lowered
levels of HCV RNA.
Conclusions:
·
Approximately
15% of persons with chronic hepatitis C, previous non-responders to orthodox
antiviral therapy and now willing to enrol in a long-term treatment trial with
peginterferon, nevertheless used Silymarin at study entry—men more frequently
than women, and Non-Hispanic Whites more frequently than African Americans and
Hispanics.
·
In
this survey of self-motivated users of herbal Silymarin was not associated with
lower levels of ALT or HCV RNA.
·
Only
a prospective, randomized, controlled study using standardized formulation of
Silymarin will determine this product has any value for hepatitis C. Such a study is currently in progress.
Topic: Pegasys
M1850. Differences between genotype 1 patients with SVR or
relapse after treatment for chronic hepatitis C (CHC) with peginterferon
alfa-2a (40kd) (PEG) and ribavirin (RBV).
E. Zehnter; S. Mauss;
K. Boeker; L. Thomas; S. Racky; W. Schmidt; R. Ullrich; I. Sbrijer; R. Heyne;
A. Schober; C. John; K. Hey; B. Bokemeyer; B. Kallinowski; B. Moeller; S. Pape;
U. Alshuth; D. Hueppe
Introduction:
Although treatment with pegylated interferon and ribavirin
have increased the SVR substantially there is still a relapse rate after
end-of-treatment response about 20-30%. It is unknown whether there are defined
parameters at baseline or in the course of treatment, which are deciding for
relapse.
Methods:
The Association of German independent Gastroenterologists
(bng) together with Roche is conducting a nationwide observational study to
determine the quality of treatment for CHC in routine clinical practice. Until
May 2006 data of 4377 patients in different phases of treatment with PEG and
RBV were recorded. From 648 pts with Genotype 1 compete data with regard to EOT
and SVR were available.
Results:
517/648 pts (75.6%) with EOT achieved an SVR, so 24.4% had a
relapse.
Demographic data for 167 relapsers (REL) vs 517 pts with SVR
(SVR) were: mean age REL 46.8 y, SVR 41.81y, whereas female relapsers were 51.9
yrs old, 58.7%/56.3% male, BMI 25.8/24.7 kg/m2, mean duration of infection:
14.5y/11.0 y, source of infection (>1 answer possible): transfusion 24.0%/20.7%,
iv drug abuse 27.0%/38.1%, medical action 11.4%/12.6%, unknown 30.5%/24.8%,
concomitant diseases 56.3%/50.9%. 39.9% of REL pts had low viral load at
baseline (cut-off of 400,000 IU/ml)
in contrast to 55.2% of SVR pts. No differences between REL and SVR was seen in
the calculated cumulative dose of PEG (95.9%/96.3%) or in treatment duration
(47.7 weeks), but 28.0% REL got less than 80% of the cumulative RBV-dose
compared to 20.8% pts with SVR. AE rate was 57.5% in REL and 51.3% in SVR. One
third of pts was checked for HCV-RNA in week 4: only 10.8% of REL achieved RVR
against 25.8% of SVR pts. The difference in EVR (>=2-log10 drop in HCV RNA
or HCV RNA undetectable at week 12) was smaller: 91.6% vs 96.6%
Conclusion:
1. Concerning baseline predictive values
besides age and duration of infection there were no differences in host related
parameters.
2. Differences were given in the
cumulative dose of ribavirin and virus determined factors like viral load and decay
in viral load over treatment time.
3. The latter leads to assumption, that
a decline in relapse rate is achievable through optimization of treatment
duration.
Topic: Pegasys
T. Scherzer; K.
Staufer; P. Steindl-Munda; H. Holzmann; P. Ferenci
Background:
In genotype 1/4 chronic hepatitis C patients previous studies
have demonstrated that the rapidity of viral response allows individualisation
of therapy (24 weeks to 72 weeks). We evaluated the rapid virological response
at week 2 and 4 in patients with genotype 2/3 to predict the response to
combination therapy.
Methods:
In 84 treatment-naive genotype 2/3 chronic hepatitis C
patients (15 genotype 2, 69 genotype 3a, f: 34, m:55; mean age: 37.8a) treated
in our centre in a multicenter prospective, randomized, controlled trial
evaluating 180µg peginterferon alfa-2a (PEGASYS®, Roche, Basel, CH) combined
with ribavirin (COPEGUS®,Roche, Basel, CH) 400 or 800mg/d for 24 weeks (Ferenci
et al, EASL 2006), viral response was evaluated by qualitative and quantitative
PCR (COBAS® AMPLICOR, Roche-Diagnostics, Pleasanton, USA, detection limit
<50IU/ml) after 2 and 4 weeks of therapy.
Results:
Of the 84 patients 78 completed
treatment and follow-up. In 28 patients (36%) HCV-RNA became undetectable at week 2 and in
further 39 patients (50%) at week 4. Thus 67 patients had undetectable HCV
after 4 weeks, 8 patients cleared HCV between week 4 and 24. The rapidity of
viral response was independent of the mean (±SD) baseline viral load
(HCV-RNA-negative at week 2: 3.1±4.0 MIU/ml; at week 4: 3.3±4.5;
HCV-RNA-positive at week 4: 2.9±4.0).
Seventy five had an end-of-treatment (EOT) response, 60
achieved a sustained virologic response (SVR) and 15 relapsed. Relapse rates
were similar among week 2 and 4 virological responders (14.3% vs. 13,4%), but were higher in patients with detectable virus at
week 4 (47%). SVR rates were identical among the HCV-RNA-negative patients at
week 2 (86%; PPV 0.857, NPV 0.28) and those becoming negative at week 4 (77%;
PPV 0.853, NPV 0.533).
The overall predictive performance of an HCV-RNA test with a
detection limit of 50IU/ml was more accurate at week 4 (PPV 0.855, NPV 0.85,
sensitivity 0.883). There was no difference between week 2 and 4 virological
response rates, EOT and SVR for the different doses of ribavirin.
Conclusions:
HCV-RNA should be tested after 4 weeks of therapy. 86% of
virologic responders at week 4 achieved an SVR. Measuring viral load at earlier
time points adds no further information. SVR in patients treated with 400 or
800mg of ribavirin were identical. Reduction of treatment durations in rapid
virologic responders should be prospectively studied.
Topic: Current HCV therapies – general
M1852. Role Of
Hmg-Coa Reductase Therapy In Hepatitis C (HCV) Treatment Outcomes.
V. Singh; E. J. Carey;
M. Rudraraju; M. J. Rosati; C. A. Grumeretz; V. Balan; H. E. Vargas
Background:
Approximately 3 million people have ongoing HCV infection in
the
Aims:
To determine the difference in HCV
treatment outcomes and potential toxicity (heralded by Liver Injury Tests (LIT)
elevations) in patients on concomitant statin therapy at the initiation of
therapy for HCV.
Methods and Patients:
We performed a case control study based on 298 patients who
underwent treatment with PEG-IFN and ribavirin combination from January 2000
until September 2006. Of these, 17 (5.7%) were on a statin at the initiation of
HCV treatment, predominantly for management of dyslipidemia.
Two groups of patients were identified:
·
Group 1 included all patients treated with
PEG-INF and ribavirin therapy and treated with a statin for any duration of
time after the initiation of antiviral therapy (N = 17) and
·
Group 2 consisted of HCV patients undergoing
PEG-INF and ribavirin therapy who never received a statin, matched for age, sex
and genotype (N = 34).
The two groups were compared in terms of virological response
to treatment, with attention to Early Virological Response (EVR), End of
Treatment Response (ETR) and Sustained Virological Response (SVR) and LITs
before and after treatment.
Results:
Group 1 had improved ETR rates (100% versus 78.2%, p= 0.05)
and SVR rates (82.3% versus 53.1%, p=0.05) compared to Group 2. SVR was defined
as persistence of undetectable HCV RNA at 24 weeks after completion of
treatment. The difference in EVR among both groups was not statistically
significant (82.3 % versus 58.8%, p=0.10). The LIT in both groups improved with
treatment without any evidence of hepatotoxicity. Mean AST, ALT and Alkaline
Phosphatase decreased significantly from initiation to end of treatment as
expected. The mean LIT of both groups did not differ from each other
significantly both before and after treatment.
Conclusions:
1. Patients undergoing antiviral therapy
for HCV treatment who receive concomitant statin therapy have improved ETR and
SVR.
2. Statins may play a role in improving
treatment outcomes of hepatitis C and this influence should be studied
prospectively.
3. Statins do not appear to be harmful
in this setting and should not be viewed as absolutely contraindicated in
patients undergoing hepatitis C treatment.
Topic: Disease Progression – Extrahepatic Man.
M1853. Outcomes of pegylated interferon and ribavirin therapy
for HCV patients with cryoglobulinemia as compared to patients without
cryoglobulinemia.
S. Ali; R. R. Meidinger;
Z. Kayali; K. E. Brown; M. D. Voigt; D. R. LaBrecque; W. N. Schmidt
Introduction:
Mixed cryoglobulinemia occurs in 40-50% of patients with
chronic HCV infection. Cryoglobulins (CGs) have been associated with increased
risk of cirrhosis and extrahepatic complications of chronic HCV infection.
Although earlier studies reported the efficacy of interferon monotherapy for
patients with CGs no large study has compared viral response rates
prospectively in patients with and without CGs after treatment with
peginterferon and ribavirin. The aim of our study was to determine whether the
response of patients with CGs to peginterferon and ribavarin differs from that
of patients without CG. We also wished to determine whether CGs affected other
variables known to be important for treatment outcome.
Methods:
167 HCV treatment-naïve patients were recruited prior to
initiation of standard dosages of peginterferon-α and ribavirin. Serum CGs were measured prior to therapy. Patients were treated for 24 (genotypes 2, 3)
or 48 weeks (genotype 1). At 6 month follow-up, patients were classified as
sustained virological responders (SVR), non-responders (NR) or
responders/relapsers (RR) according to established criteria.
Results:
51 patients (31%) were CG positive, and 116 patients (69%)
were CG negative. There were no differences in age, sex, or genotype
distributions between the two groups.
·
There
was no difference in the percentages of SVR, NR or RR in either group.
·
There
was a significant increased percentage of CG+ who discontinued anti therapy
early.
·
There
were no differences in response between the groups when stratified according to
age, sex, or pathological findings.
·
A
higher percentage of CG positive patients with high viral loads achieved SVR
than CG negative patients.
·
A
higher percentage of CG negative genotype 1 patients achieved SVR than CG
positive patients.
For multivariate analysis, a logit model for viral response
was used with the independent variable CG positive and each covariate fitted
individually. Initial testing showed
that being CG positive or CG negative did not alter the covariate model main
effect. The only significant covariate
effect on viral response was genotype.
Covariables tested in the model were gender, viral load, activity , steatosis, age, RF and ALT.
Conclusions
·
The
presence of CG did not affect the overall percentages of SVR, RR and NR
profiles in HCV positive patients.
·
A
higher percentage of patients with CG who achieved SVR had high viral load than
patients without CG who achieved SVR.
·
Patients
with CG were statistically more likely to discontinue therapy early or be lost
to follow-up.
·
Multivariate
analysis showed no difference in the effect of covariates on the responses to
CG positive and CG negative patients.
Topic: Current Treatment - Pegasys
M1854. Treatment Duration and Histological Response to
Peginterferon Alfa-2a/Ribavirin.
P. Pockros; P. Martin;
F. M. Hamzeh; E. Lentz; A. Lok
Background:
Current treatment practice in HCV, aimed at achieving SVR, is
to discontinue treatment in patients with detectable serum HCV RNA at 24 weeks.
Although histologic improvement is associated with SVR, patients treated with
peginterferon alfa-2a/ribavirin have shown improvement in inflammation without
SVR. Longer treatment duration may enhance histologic improvement regardless of
SVR. We have compared histologic responses in HCV genotype 1 patients treated
for 24 or 48 weeks.
Methods:
All HCV genotype 1-infected patients (n= 211) with paired
biopsies prior to and 24 weeks after the end of treatment from two registration
trials of peginterferon alfa-2a/ribavirin were included. Metavir score was used
to stage fibrosis (0-4) and to grade activity (0-3). Improvement was defined as
decrease of ≥1 stage or ≥1 grade and worsening as increase of ≥1
stage or ≥1 grade. Statistical evaluations were performed using the
Cochran-Mantel-Haenszel Test stratified by ribavirin dose (800 or 1000/1200
mg/d).
Results:
Improvement in activity and/or fibrosis score was observed in
93 (86%) of 108 patients who achieved SVR, and in 45 (44%) of 103 patients who
did not (p<.001). Among the latter, a higher percentage of those treated for
48 weeks had improvement in activity or fibrosis than those treated for 24
weeks (p=0.049). A similar trend, favoring longer treatment for patients
without SVR, was observed when analyzing patients with histologic worsening.
Among patients who achieved SVR, there was no difference in histologic
improvement between those treated for 24 and 48 weeks.
Conclusion:
·
Among
patients chronically infected with HCV genotype 1, those who achieved SVR after
treatment with peginterferon alfa-2a plus ribavirin were more likely to have
histologic improvement than those who did not.
·
Among
patients who achieved SVR, the proportion with histologic improvement was
similar in groups treated for 24 or 48 weeks, regardless of ribavirin dose.
·
Among
patients who did not achieve SVR, 9 of 72 (13%) treated for 48 weeks but none
of 31 treated for 24 weeks (O=.054) had improvement in fibrosis stage. The percentage of patients with either
inflammation or fibrosis
improvement was significantly (P=.044) better for those who were
treated for 48 than for 24 weeks, after controlling for ribavirin dose.
·
These
findings suggest that longer treatment duration may be necessary for fibrosis
improvement in patients without SVR.
·
Fifty
of 72 (69%) and 18 of 31 (58%) patients without SVR were relapsers in the 48-
and 24-week treatment arms, respectively. Although the numbers were small, the
trend favoring 48 weeks in histologic outcome was similar in relapsers and
nonresponders.
·
The
numbers in this retrospective analysis were small. The hypothesis generated from this study,
that a longer duration of treatment may be beneficial for histologic outcome
should be tested in a larger clinical trial.
Histologic
improvement in relation to SVR and treatment duration
|
SVR
|
Treatment
Duration (wk) |
N
|
≥1
grade |
≥1
stage |
≥1
grade or ≥1 stage improved |
|||
|
x (%) |
p-value |
x (%) |
p-value |
x (%) |
p-value |
|||
|
Yes |
24 |
15 |
14 (93%) |
.26 |
1 (7%) |
.69 |
14 (93%) |
.38 |
|
48 |
93 |
76 (82%) |
14 (15%) |
79 (85%) |
||||
|
No |
24 |
31 |
9 (29%) |
.23 |
0 |
.05 |
9 (29%) |
.05 |
|
48 |
72 |
30 (42% |
9 (13%) |
36 (50%) |
||||
Topic: Current HCV Therapies - General
D. Friedman; S.
Rashdan; C. D. Levine; J. Weinstein; R. H. Ghalib
Background:
The primary goal of HCV treatment is an SVR determined by a
negative HCV RNA at 24 weeks after discontinuation of therapy. One report on
early relapse rate in patients treated with standard IFN or Peg IFN monotherapy
noted only 2% of patients became HCV RNA positive between 12 and 24 weeks after
discontinuation of therapy. No data has been reported on early relapse rates
following response to Peg IFN plus ribavirin therapy. Therefore this study was
designed to assess the predictive value of the 12 week follow-up viral load in
determining SVR.
Methods:
This was a cohort study of HCV patients treated from 2003 to
present. All patients who were HCV RNA undetected (<29 IU/mL) at the end of
treatment with viral counts done at follow-up week 12 and 24 were included.
Results:
154 patients qualified for inclusion (89 men, 65 women). Age
range was 18-79 (mean 48.7 ± 8.8). Race distribution was White 119 (77%), Black
12 (8%), Hispanic 16 (10%), and other 7 (5%). Fibrosis was stage 0-1 in 23,
stage 2 in 38, stage 3 in 35, and stage 4 in 44 patients. Genotype distribution
was 87 (56%) with 1, 43 (28%) with 2, 18 (12%) with 3, 4 (3%) with other.
Duration of treatment in genotype 1 was 44-72 weeks (mean 49.1 ± 4.9) and
genotype 2/3 was 12-60 weeks (mean 27.1 ± 11.6). This was the first treatment
in 114 (74%) patients, 16 (10%) were relapser and 22 (14%) were nonresponders.
Treatment was with Peg IFN alfa-2a in 58 (38%), Peg IFN alfa-2b in 70 (45%),
and CIFN in 26 (17%). In predicting SVR (Table 1), the follow-up week 12 viral count had a sensitivity of 99%, specificity of 94%, PPV of
97%, and NPV of 98%. Follow-up 12 week viral count did not predict the SVR
status in 4 patients all of whom had cirrhosis and were in their first
treatment course. One patient positive at follow-up week 12 (HCV RNA 9000
IU/mL) later achieved an SVR. The accuracy of prediction in cirrhotics was
sensitivity 95%, specificity 88%, PPV 86%, and NPV 95%.
Conclusions:
A follow-up week 12 viral count is useful in predicting
attainment of SVR and is 100% accurate in patients without cirrhosis. In this
sample, 9% of patients with cirrhosis were misclassified by the follow-up week
12 viral count. Use of an earlier viral count in patients without cirrhosis
would allow earlier retreatment for those with relapse and allow earlier
confirmation of successful treatment.
Table 1: Post Treatment HCV Viral Counts in Patients with EOT Response
|
|||||||||||||||||||||
Topic: Current Treatment - Pegasys
U. Meyer; E. Zehnter;
S. Mauss; K. Boeker; T. Lutz; S. Racky; W. Schmidt; R. Ullrich; I. Sbrijer; R.
Heyne; A. Schober; C. John; K. Hey; B. Bokemeyer; B. Kallinowski; B. Moeller;
S. Pape; U. Alshuth; D. Hueppe
Introduction:
In the
Methods:
The Association of German independent Gastroenterologists
(bng) in cooperation with
Results:
1529 pts (13.1%) of the cohort were > 60 yrs. Of them 382
(25.0%) received treatment with PEG plus RBV. Demographic data of treated pts
were: mean age 65.2 y, 43.5% male, BMI 26.1 kg/m2, severe fibrosis
or cirrhosis (F3/F4, Desmet-Scheuer) 30.9%, GFR <90 ml/min/1.73m2
26.5%, concomitant diseases 65.7%, most frequently heart disease (52.6%),
diabetes (16.7%) and diseases of the joints (10.8%), Caucasian 96.2%, mean
duration of infection: 18.1y, source of infection (>1 answer possible):
transfusion 35.6%, iv drug abuse 0.8%, medical action 16.5%, unknown 42.7%.
Genotypes: 1(85.6%), 2(8.9%), 3(3.1%),
Conclusion:
·
Comparing
data of patients > 60 yrs with other usually studied populations reveal that
due to poorer conditions at the beginning of treatment therapy has to be discontinued
very often especially for poor tolerability.
·
In
this group of patients another more careful action is necessary to prevent the
escalation of adverse events leading to discontinuation.
Topic: HIV/HCV Coinfection
B. S. Zingman; H.
Morales; F. Rodriguez; K. Freeman; T. Portzline; R. Cruz; L. Aliaga; R. Yanes;
J. Shuter
Background:
A multidisciplinary HIV/Hepatitis C (HCV) Co-Infection
Program was established in 2003 at the
Methods:
This is a prospective evaluation. Standard treatment
durations and dosing of pegylated interferon/ribavirin by HCV genotype (geno)
were used. All treated patients are included including those retreated for
failure. EVR=>1 log drop in HCV RNA at 12 wks; ETR=undetectable HCV RNA at
completion of planned treatment; SVR=undetectable HCV RNA >6 months after
ETR.
All analyses are ITT with censoring of: those on treatment
<12 weeks could not be designated as EVR; EVRs who moved are unevaluable for
ETR; ETRs who moved or are <6 months after ETR (“pending”) are unevaluable
for SVR. Overall SVR Rates = %ETR x %SVR.
Results:
As of
The Overall SVR Rates of the Program compare favorably to a
27% SVR rate (14% geno 1, 73% other genos) in Chung NEJM 2004; a 40% SVR rate
(29% geno 1, 62% genos 2/3) in Torriani [APRICOT] NEJM 2004; and a 27% SVR rate
(17% genos 1/4, 44% genos
Conclusions:
·
The
Montefiore HIV/HCV Co-Infection Program’s multidisciplinary approach
demonstrates outcomes comparable to major
·
The
Program’s results are especially notable given its inner-city population and
inclusion of some with previous treatment failure.
·
The
data suggest that this model, if widely replicated, could improve HCV treatment
outcomes among co-infected patients.
|
|
All Evaluable |
Evaluable Geno 1 |
Evaluable Geno |
|
EVR |
71/102 (70%) |
46/77(60%) |
25/25 (100%) |
|
ETR |
36/75 (48%) |
19/57 (33%) |
17/18 (94%) |
|
SVR |
20/31 (65%) |
8/18 (44%) |
12/13 (92%) |
|
Overall SVR Rate |
31% (95% CI 23-41%) |
15% (95% CI 8-25%) |
87% (95% CI 69-97%) |
Topic: Current HCV treatment – General
C. D. Abrasley; K.
Lavu; G. K. Sood; W. D. Johnson; M. Azzouz
Background:
Antiviral therapy for chronic hepatitis C (HCV) is associated
with ischemic cardiac morbidity including interferon associated toxicity and
hypoperfusion related to anemia. Cardiac screening using stress testing is a
routine practice prior to therapy in patients with risk factors considering
that cardiac ischemia is a treatment exclusion criterion. Limited data exists
on the validity of such practice and impact on treatment outcome and cost
effectiveness.
Methods:
A retrospective review of patients with HCV enrolled through
our VA liver clinic 2002-2005 was performed. Data on 103 patients was analyzed
including demographics, cardiac risk factors, and results of stress testing
when applicable. Patients with cardiac
risk factors (age, hypertension, diabetes, family history, hyperlipidemia,
tobacco use, abnormal EKG) underwent stress testing (exercise or nuclear)
unless a recent heart catherization was done. Patients with abnormal stress
test underwent further cardiac evaluation. Cardiac events including angina
pectoris or myocardial infarction that occurred during or after therapy were
analyzed.
Results:
A total of 103 patients, 52 blacks and 51 whites were
included in this review with mean age of 50.3 ± 0.56. The mean BMI was 32.4 ±
3.84 with 52% having hypertension, 16% diabetes, 33% a family history of
coronary artery disease (CAD), 27% hyperlipidemia, 64% tobacco use, and 19%
having abnormal EKG. Three patients had stable documented CAD and received
antiviral therapy without cardiac events. A total of 66 patients had
pretreatment stress testing (exercise or nuclear) with 14 (21%) abnormal
results. Cardiology evaluated all 14 patients and performed cardiac
catherization on 11, and recommended medical therapy on 3. Only 1 of 11
catherizations was found to be abnormal with non-critical CAD. All patients
received antiviral therapy and no cardiac events occurred during treatment.
Three patients had Acute Coronary Syndrome (ACS) 8 weeks to 2
years following therapy. All three patients were in the group with normal
cardiac stress tests and none in the group with abnormal or no stress test.
Thus, 3/52 negative stress test patients had ACS compared to 0/14 positive
stress test patients.
Conclusions:
Although the potential for adverse cardiac events exist for
patients with HCV receiving antiviral therapy; the routine practice of
pretreatment cardiac stress test in patients with cardiac risk factors may not
be warranted as it did not impact cardiac outcome and added to the cost of
therapy in our sample. A larger sample with prospective analysis is needed to
support our conclusion
Topic: Current HCV Treatment- general
S. Rashdan; D.
Friedman; C. D. Levine; J. Weinstein; R. H. Ghalib
Background:
Response to current treatment for HCV has been defined by
viral decrease at set times of 12 and 24 weeks of treatment. Previous studies
have shown that genotype 1 patients with undetectable virus at week 4 of therapy
(RVR) are more likely to achieve an SVR. The primary aim of this study was to
determine the predictive value of the RVR for SVR in HCV genotype 2/3 patients
treated with Peg/RBV.
Methods:
This retrospective cohort study evaluated HCV genotype 2/3 patients
treated between 2003 and 2006 at the Liver Institute at Methodist Dallas who
had week 4 viral counts available. Nine patients were excluded for ESRD,
coinfection with HIV, liver transplantation, and unavailable follow-up data.
Results:
The sample included 56 patients [39 genotype 2 (70%) and 17
genotype 3 (30%)]. There were 30 females (54%) and 26 males (46%) with a mean
age of 47.8 ± 10.1 years.
The sample was predominately Caucasian (44, 79%) with 3 African
Americans (5%), 7 Hispanics (13%) and 2 Asians (4%).
Mean BMI was 27.9 ± 5.4 with 22 (39%) having stage 3-4 on
biopsy. Ten patients had received prior treatment. Patients were treated with
Peg alfa-2a (26, 46%), Peg alfa-2b (24, 43%) and CIFN (6, 11%) and 38 (68%)
received weight based ribavirin dosing. Viral responses by time points were:
77% RVR (n=43; 33/39 genotype 2 and 10/17 genotype 3); 98% EVR (n=55; 38/39
genotype 2 and 17/17 genotype 3); 70% SVR (n=39; 29/39 genotype 2 and 10/17
genotype 3). In patients who were EOT negative, the relapse rate was higher in
the genotype 3 patients (38%) vs. genotype 2 (22%). Of the 43 patients with
RVR, 34 (79%) achieved SVR compared to 5 (38%) of the 13 patients without RVR
(p<.009; total sample PPV=79% and NPV=62%; genotype 2 PPV=79% and NPV 50%;
genotype 3 PPV=80% and NPV=71%).
The association of other factors for SVR was tested in a
logistic regression that identified fibrosis (S0-2 vs. S3-4), prior treatment,
and ribavirin dose reduction (any reduction vs. none) as significant variables
(-2 log likelihood 35.8; model Chi-square 18.9, df=3,
p<.0001)
Conclusions:
Analysis of HCV response in these genotype 2/3 patients
revealed that those with an RVR were significantly more likely to achieve SVR.
Other factors that were significantly associated with SVR were the stage of
fibrosis, failing prior therapy, and any ribavirin dose reduction during
treatment. No significant relationship was found for IFN drug, weight based
ribavirin dosing, gender, BMI, genotype 2 vs. 3, or interferon dose reduction.
Further investigation is indicated to determine treatment variations that may
improve SVR in patients who do not achieve RVR.
Topic: Current HCV Therapies – general
K. Ishii; K. Higami;
K. Matsumaru; N. Takamura; H. Nagai; Y. Sumino; K. Miki
Background/Aim:
Age is well known to have influence on the efficacy of IFN
therapy. We previously reported that the type 1 IFN receptor 2 (IFNAR-2)
expression by leukocyte subsets, including lymphocytes (Ly), monocytes (Mo),
and granulocytes (Gr), showed changes during IFN therapy in chronic hepatitis C
(CHC) patients. The present study was performed to investigate IFNAR-2
expression by leukocyte subsets in aging patients with CHC during IFN therapy.
Patients and Methods:
Thirty-five adults with biopsy-proven CHC (M/F: 22/13, an age
between 21 and 71 years, a baseline serum HCV-RNA level quantified by RT-PCR
between 0.5 and 730 KIU, and infection with HCV genotype 2a or 2b) were
studied. Seven patients were treated with IFN-alpha alone (5-6MU), 15 patients
with consensus IFN (12-18MU) alone, or 13 with IFN-alpha 2b (6MU) plus
ribavirin (400-800 mg/day). All IFNs were administered daily for 2 weeks,
followed by the same dose thrice weekly for 22 weeks. Patients were divided
into 2 groups according their ages; a young group: 21 patients aged < 56
years (median age: 45; range: 28-56 years), and an old group: 14 patients aged
> 57 years (median age: 64; range: 59-71 years). Blood samples were
collected on days 0, 3, 7, and 14 of treatment. IFNAR-2 expression was
determined by calculating the mean fluorescence intensity (MFI) after staining
with an anti-IFNAR-2 antibody. Qualitative RT-PCR was tested at multiple times
during and after treatment. When qualitative RT-PCR was negative at 24 weeks
after the end of therapy, patient was defined as a sustained viral response
(SVR). When that was positive, patient was defined as a non-SVR.
Results:
The baseline MFI of Ly, Mo, and Gr showed no significant
differences between the 2 groups. The MFI of Mo increased to reach a peak on
day 3 and thereafter decreased gradually in both groups. The MFI of Mo at days 3,
7, and 14 was significantly higher than at baseline in the young group, but
that was significantly higher only at day 3 than at baseline in the old group.
The MFI of Gr was decreased gradually in both groups, but only showing
significant change in the young group. Negativity for serum qualitative HCV-RNA
was seen in 17 (81%) patients from the young group and in 11 (79%) patients
from the old group at week 2, and in 20 (95%) and in 12 (85%) patients at week
4, respectively. Finally, the SVR was obtained in 19 (90%) patients from the
young group and in 12 (85%) patients from the old group.
Conclusions:
Aging may blunt IFNAR-2 expression by Mo during an early
phase of treatment, which
may be related to response to IFN and an early HCV clearance.
However, aging did not affect SVR rate in CHC patients infected with genotype
2a or 2b. So those patients should be
considered for treatment regardless of their age.
Topic: Current HCV Therapies – Pegasys
H. L. Bonkovsky; A.
Tice; R. G. Yapp; H. C. Bodenheimer; A. Monto; S. Rossi; M. S. Sulkowski
Background:
Treatment compliance is a challenge in treating patients with
chronic hepatitis C (CHC) on methadone maintenance. To determine if direct
observed therapy (DOT) enhances compliance relative to self administration
(SA), a prospective, open label, multicenter, randomized pilot study of the
safety, feasibility and tolerability of peginterferon alfa-2a/ribavirin
treatment was performed in patients in methadone maintenance programs not
previously treated for CHC.
Methods:
Patients were randomized 1:1 to directly observed therapy or
self administration. Directly observed therapy patients were seen every week
for 48 weeks at methadone clinics, whereas self administration patients were
seen per assessment schedule and only at the investigative sites. Patients infected
with HCV genotype 1 were treated for 48 wks with peginterferon alfa-2a (180
μg/wk) plus ribavirin (1000/1200 mg/d), whereas patients infected with HCV
genotypes 2 and 3 were treated for 24 wks with peginterferon alfa-2a (180
μg/wk) plus ribavirin (800 mg/d).
Results:
Patients randomized to the two groups were well matched for
sex, age, race/ethnicity, baseline serum [HCV RNA], body mass index (BMI), and
HCV genotypes.
The Table shows SVR rates by group and HCV genotype. Stepwise logistic regression analysis, using
as factors treatment (SA vs DOT), gender, age (≤40 vs >40 yrs), genotype (1 vs 2,3), race (Caucasian vs
other), baseline [HCV RNA] (≤800,000 vs >800,000 IU/mL), and ALT (≤90
vs >90 U/L), showed that DOT treatment was the only significant predictor of
SVR (OR 4.3, 95% CI 1.06-17.3, P=.042) and Caucasian race (OR 10.8, 95% CI
1.13-104, P=.039). Based on defined
efficacy stopping rules, 77% (37/48) completed the prescribed length of
therapy. Two directly observed therapy and 3 self administered patients were
withdrawn for adverse events, while 6 and 9, respectively, were withdrawn for
non-safety reasons. The most common adverse events in both groups were fatigue,
nausea, depression, and headache.
Conclusion:
·
Patients
in methadone maintenance programs can be treated safely and successfully with
peginterferon alfa-2a plus ribavirin for chronic hepatitis C while continuing
methadone treatment.
·
Overall
SVR rates and rates of patient dropout, discontinuance, and dose adjustments
similar to other studies in methadone maintenance patients.
·
The
DOT group had a higher SVR rate than the SA group.
·
The
DOT group also had lower postbaseline BDI-II scores than the SA group
o
Occurrence
of higher SVR and lower postbaseline BDI-II score in the DOT group (may or may
not indicate correlation).
o
Need
to condu7ct trials in larger number of patients.
o
Treatment
with peginterfeorn alfa-2a once weekly, at the methadone maintenance clinic, is
an efficient way to administer both medications at the same time.
These findings suggest that peginterferon alfa-2a/ribavirin
can be used safely and successfully to treat CHC patients on methadone
maintenance. Moreover, there may be a benefit of directly observed therapy in
this challenging population. Further studies are warranted.
|
|
%
SVR (n/N) |
||
|
HCV Genotype |
All Patients (N=48) |
DOT Group (n=24) |
SA Group (n=24) |
|
All |
44% (21/48) |
54% (13/24) |
33% (8/24) |
|
1 |
31% (9/29) |
23% (3/13) |
38% (6/16) |
|
2,3 |
63% (12/19) |
91% (10/11) |
25% (2/8) |
Topic: Current HCV Treatment – Side Effects
M. Palmer
Background:
Adherence to pegylated interferon (PIFN) plus ribavirin (RBV)
has been shown to be a crucial factor in achieving early virologic response
(EVR) and subsequently sustained virologic response (SVR) in patients with hepatitis
C (HCV). Studies have shown that adherence to RBV, especially in the first 12
wks of therapy, may be more important than adherence to PIFN. In the HIV
patient population, fewer pills required/day results in better adherence,
improved results, and improved QOL. RibaPak
(RBP) is a 400 mg and/or 600 mg RBV tablet that requires up to 66% fewer
tablets than RBV (200mg).
This study was undertaken to determine if simplifying the
dosing regimen of RBV has an impact on adherence, AEs and QOL in HCV patients
on combination therapy.
Methods:
From May - Nov 2006, 107 patients were identified who were on
treatment with RBP and PIFN. 92 patients met the following requirements: RBP
for ≥12 wks and complete data for comparison. Pts. were divided into 3
groups:
·
Group
A (n= 22): Treatment experienced (n=8 relapsed, n= 5 nonresponder, n=9 early
termination due to AEs or noncompliance) with PIFN plus RBV,
·
Group
B (n= 49): Treatment naïve -pts switched to RBP after ≥12 wks RBV, and
·
Group
C (n=21): Treatment naïve pts on RBP for ≥12 wks. Groups A and B were evaluated q4 wks X ≥ 12 wks for: AEs, adherence,
drug preference and QOL. Group C was evaluated for adherence.
·
Group
D (n=21): Control group – consecutive matched Naive patients on ≥ weeks on PINFN plus RBV.
Results:
·
Group
A: 7 pts reported less AEs (nausea, dyspepsia, loss of appetite (LOA) and/or
weight loss) on RBP. 27 missed RBV vs 3 missed RBP in the 1st 12 weeks of
respective therapies. 15 pts preferred RBP due to simplification of regimen or
diminished AEs. 7 pts found no difference in treatment regimens. 14 pts
reported improved QOL on RBP.
·
Group
B: 17 pts reported less AEs. 11 missed RBV vs 0 RBP. 40 preferred RBP/9 no
difference. 37 improved QOL.
·
Group
C: 1 missed RBP; 5 missed ribavirin.
Conclusions:
·
In
all 3 groups there is a trend toward:
o
Diminished
AE’s mostly GI, in patients taking BRP
o
Improved
QOL in patients taking RBP
o
Improved
adherence in patients, taking RBP
o
Less
concomitant medication use
o
Patient
preference for RBP
Topic: Current HCV Therapies – side effects
M1863. Prevalence and Risk Factors of Thyroid Disease
in Patients Treated For Hepatitis C Virus.
H. Wiesinger; J. Amar;
H. Chaun; R. A. Enns; L. Halparin; B. McDougall; S. Whittaker; A. S. Ramji
Introduction:
An increased incidence of thyroid disease in patients with
hepatitis C treated with interferon-α monotherapy or combination with
ribavarin for has been described. However predictive factors for developing
thyroid complications in this population is not well described, particularly
when using pegylated interferon in combination with ribavirin.
Objective:
To determine the prevalence and predictive factors of thyroid
disease in patients with hepatitis C treated with combination pegylated
interferon/ribavirin compared to those treated with an
interferon-α/ribavarin combination.
Methods:
A retrospective analysis of all hepatitis C patients treated
with combination pegylated interferon-α2b and ribavirin or
interferon-α/ribavarin from 1995 to 2005 at a tertiary care centre was
conducted. Patients were separated into two groups: (a) those with no thyroid
abnormalities during therapy; and (b) patients with a change from normal to
abnormal TSH levels, or those requiring treatment for either hyper- or
hypothyroidism. The two groups were compared for predictive factors including:
demographics, HCV genotype, stage of disease, and therapy type.
Results:
Of 137 patients, 26 (19%) developed abnormal TSH during their
treatment. Eight of these patients required treatment for either hyper- or
hypothyroidism. Twenty two of 26 patients (85%) developed thyroid abnormalities
within the first 24 weeks of treatment, with 38% occurring in the first 12
weeks. Females were affected more than males (31.6% vs 14.1%, respectively,
p=0.02). Thyroid dysfunction occurred more frequently in patients treated with
pegylated interferon than those treated with a non-pegylated formulation (27.1%
vs 12.8%, respectively, p=0.035). Genotype, biopsy stage and response to
treatment were not predictive of thyroid abnormalities.
Conclusions:
Thyroid function abnormalities are more common in patients
treated with pegylated interferon/ribavirin than in those with
interferon/ribavirin, and more prevalent early in treatment course. This may be due to the sustained serum
concentration of pegylated interferon.
Thyroid function testing should be done at baseline and frequently
throughout treatment. TSH abnormalities
should be investigated and treated accordingly.
Topic: Current HCV Therapies – General
M1864. Predictors of Treatment Among Patients With Chronic Hepatitis C Virus Infection.
F. Kanwal; T. Hoang;
B. M. Spiegel; S. Eisen; A. Gifford; S. M. Asch
Background:
Chronic infection with hepatitis C virus (HCV) is a prevalent
and expensive condition affecting 1.3% of the
Methods:
Using administrative and clinical data from 5 VA Medical
Centers in
Results:
6,686 (46.8%) of 14,275 HCV patients met our a-priori
criteria for treament “eligibility.” Of these, 3,226 (48%) were seen by a
specialists, of whom 697 (10.5%) received treatment. Treatment rates varied
from 3% to 15% across the 5 facilities. Significant predictors of treatment
receipt included lower patient age (β=-0.03, p<0.0001), presence of
cirrhosis (β=1.15, p<0.0001), lower ALT (β=-0.152, p<0.0001),
higher hemoglobin (β=0.26, p<0.0001), and lower platelet count
(β=-0.002, p=.01). In addition, treatment rates were 3 times higher among
providers who treated >20 patients per year versus providers with lower
annual treatment numbers. Patients seen at the facilities with the lower
treatment rate were 18% less likely to receive treatment compared to those seen
at the facilities with a higher treatment rate.
Conclusions:
HCV patients who are younger, have cirrhosis, and are seen by
more experienced providers at facilities with high treatment rates appear more
likely to receive treatment. These data suggest that although patient
characteristics are important predictors of treatment in HCV, most of the
variation in treatment rates is explained by system-level factors. These
potentially modifiable system-level factors are high-yield targets for future
quality improvement initiatives in HCV.
Topic: Current HCV Treatment – General
M1866. Antiviral Completion Rates and Sustained Viral
Response in Hepatitis C Patients with- versus without- Pre-existing Major
Depressive Disorder.
P. Hauser
Objective:
To determine and compare antiviral completion and sustained
virologic response (SVR) rates between hepatitis C (HCV) patients with- versus
those without pre-existing major depressive disorder (MDD). As HCV patients
with MDD are often excluded from antiviral therapy because of the presumed risk
of worsening depressive symptoms secondary to interferon our objective was to
examine the validity of this assumption.
Methods:
We conducted a retrospective chart review of all patients
treated for HCV at the Portland VA Medical Center who signed informed consent
allowing collection and analysis of clinical data from electronic medical
records. We collected data on genotype, pre-treatment psychiatric diagnosis and
antidepressant use, antiviral therapy, side effects, emergency room (ER) visits
and in-patient hospitalizations during treatment, as well as completion and
SVR. Patients were divided into two groups- MDD (patients who had a pre-
antiviral treatment diagnosis of MDD and were taking antidepressant medication
at least 3 months prior to starting antiviral treatment), and controls (no MDD-
patients who did not have a pre-antiviral treatment diagnosis of MDD and had
been antidepressant free for at least 3 months prior to starting antiviral
treatment).
Results:
Relative to the control group, the MDD group had a similar
percent of patients that were genotype 1. There was no significant difference
between groups in the percent of patients who had ER visits (MDD- 9/30 or 30%
versus controls- 4/25 or 16%) or required in-patient hospitalization (MDD- 2/30
or 7% versus controls- 2/25 or 8%). Only one MDD patient had an ER visit for
psychiatric reasons and no MDD patients attempted suicide. Side effects and
reasons for discontinuation of antiviral treatment were not different between
groups. Also there were no differences between groups in antiviral treatment
completion rates (MDD- 18/30 or 60% versus controls - 17/25 or 68%) or SVR
(MDD- 15/30 or 50% versus controls - 13/25 or 52%).
Conclusions:
The results of our retrospective chart review suggest that
patients with pre-antiviral treatment MDD on antidepressants are no more likely
than patients without MDD to have side effects or adverse events during
antiviral treatment. Furthermore, patients with MDD have similar completion and
SVR rates. Our results suggest that patients with MDD can be safely and
effectively treated with antiviral therapy using an integrated care model
involving mental health care providers.
Topic: Current HCV Therapies – Disease Progression
M1867. Change of Serum Cholesterol Fractions In Patients With Chronic Hepatitis C After Sustained
Viral Response To Ifn Therapy
K. Ishii; N. Takamura;
K. Higami; K. Matsumaru; T. Ikehara; H. NAGAI; M. Watanabe; Y. Sumino; K. Miki
Background/Aim:
Chronic hepatitis C virus infection (HCV) is suggested to
have relationship with host lipid metabolism. Several IFN regimens are active
against chronic hepatitis hepatitis C (CHC). The goal of this study was to
clarify change of host lipid metabolism in patients with sustained viral
response (SVR) by several IFN therapy regimens.
Patients and Methods:
Thirty-six adult patients with biopsy-proven CHC were studied. The enrollment criteria included an age between 33 and 69 (median: 58 )years, baseline serum HCV-RNA quantified by RT-PCR (Amplicor version 2; Roche) between 33 and more than 850 (median: 456) KIU, infection with HCV serotype (S) 1 (genotype 1a or 1b) or 2 (genotype 2a or 2b), and elevated ALT for at least 6 months. Patients (M/F: 26/10; S1/S2: 27/9) were treated with IFN-alpha, consensus IFN, or pegylated IFN-alpha 2a alone, or with IFN-alpha 2b or pegylated IFN-alpha 2b in combination with ribavirin. Quantitative HCV-RNA was tested at multiple times during and after treatment. When quantitative HCV-RNA was negative at least 24 weeks after the end of therapy, patient was defined as a sustained viral response (SVR). When that was positive, patient was defined as a non-response (NR). Body weight (BW) was measured before, at the end of therapy, and at least 24 weeks after the end of therapy (judge point). Serum total c