Saturday Poster Sessions, October 28, 2006
HCV: Pathogenesis
#271. Immunization with Hepatitis C Virus-Like Particles Induces Partial Protection against Hepatitis C Virus Infection in Chimpanzees.
G. A. Elmowalid; M. Qiao ; S. Jeong ; B. Borg; T.
Baumert; R. Sapp; K. Murthy; Z. Hu; J. Liang.
Introduction:
Recombinant hepatitis C virus-like particles (HCV-LP)
containing HCV structural proteins (core, E1, and E2) produced in insect cells
resemble the putative HCV virions and are capable of inducing strong and broad
humoral and cellular immune responses in mice and baboons.
Aim:
Here we present evidence on the immunogenicity and induction
of protective immunity by HCV-LP in chimpanzees.
Methods:
Two groups of two chimpanzees each were immunized with HCV-LP
or HCV-LP + adjuvant ASO1B (a lipid-based adjuvant from GSK).
Results:
After four immunizations over an eight-month period, all
animals developed strong HCV-specific cellular immune response including
IFN-γ+CD4+ and IFN-γ+CD8+ T-cell and proliferative lymphocyte
responses against core, E1 and E2. The immunogenicity of HCV-LP was not
enhanced by the adjuvant. The chimpanzees in both groups were challenged with
100 CID 50 of HCV CG1B inoculum. Upon challenge with HCV, one chimpanzee
developed transient viremia with low HCV RNA titers (~104 copies/ml) in the
third and fourth weeks post-challenge. The three other chimpanzees became
infected with higher levels of viremia (up to 10 5 copies/ml) but their viral
levels became unquantifiable ( 600 copies/ml) ten to twelve weeks
post-challenge. After HCV challenge, all four chimpanzees demonstrated a
significant increase in both peripheral IFN-γ+ and IL-2+ T-cell and
proliferative responses as well as the presence of intrahepatic T-cell response
against the HCV structural proteins. The T-cell responses against various nonstructural
proteins also became detectable within 3 weeks after infection. These T-cell
responses coincided with the fall in HCV RNA level. Previously, three other
naïve chimpanzees have been challenged with the same HCV inoculum at lower
CID50 (3-10). One cleared the infection and two developed persistent infection
with viremia in the range of 105-6 copies/ml.
Conclusion:
Our results suggest that HCV-LP immunization induces strong HCV-specific cellular immune responses and confers partial protection against HCV challenge in the chimpanzee model.
#277. Mouse Model for HCV Pathogenesis.
R. Witek; J. R. Bess; J. Dong; J. S. Elyar; C. Liu.
Introduction:
Hepatitis C virus (HCV) infection is a major health threat in
the world. An estimated 170 million people are infected with the virus.
Although it has been postulated that the host immune system plays a role in
pathogenesis, the interaction of the virus and the host immune system remains
obscure. One major obstacle to HCV investigations is the lack of a robust small
animal model. Considering the vast amount of knowledge on mouse immune system,
availability of a reliable murine model for HCV undoubtedly has a great
advantage.
Aim:
The current research tests the feasibility of developing an
animal model to study HCV immunopathogenesis.
Methods:
The experimental design utilized repopulation of mouse
(Balb/cJ) livers with an HCV positive CG1b cell line (hepatocytes derived from
Balb/cJ mouse) following partial hepatectomy (PHx) and monocrotaline (MCT)
pre-treatment. MCT blocks endogenous hepatocyte proliferation, thus providing a
proliferative advantage to the transplanted cells. Since the mice used in the
experiment are immune competent, the effects of the immune system on HCV
positive hepatocytes and their effects on liver pathology was systemically
investigated by performing histological stainings and molecular analysis by
RT-PCR.
Results:
In the first part of the experiment, HCV positive CG1b cell
line was established by stably transfecting immortalized male BNL murine
hepatocyte cell line with HCV-ribozyme based expression plasmid pEHr/Neo
containing full-length HCV RNA genome. The RT-PCR analysis of the BNL-CG1b cell
line reveals high expression of HCV RNA, and Western Blot shows expression of
NS5a proteins. In the second part of the experiment, transplantation of
BNL-CG1b cells led to liver repopulation in BALB/cJ mice verified by SRY
analysis at 30 days post transplantation. H&E examination of liver tissue
revealed increasing levels of inflammation and fibrosis progressing with time
post transplantation (30, 60, and 90 days). However, SRY was not detected at 60
and 90 days.
Conclusion:
The results presented in the current study support the
feasibility of creating a small animal model for HCV pathogenicity utilizing
BNL-CG1b cell transplantation to MCT/PHx treated animals. The inflammation,
lymphocytic infiltration and liver fibrosis observed in the experimental mice
conform to liver pathology observed in patients with chronic HCV. It is
possible that transplanted BNL-CG1b cells are invoking CD8+ CTL response (day
30) that led to the initial clearance of HCV producing cells (day 60).
The presented animal model offers an innovative approach to
investigate HCV immunology and will be used for future studies to elucidate
mechanisms of HCV liver immunopathogenesis.
#282. Persistence of hepatitis C virus (HCV) in chimpanzees is associated with a loss of intrahepatic T cell function during the late acute phase.
H. Watanabe; M. E. Major.
Background:
Infection with HCV frequently leads to chronic hepatitis and
cirrhosis and is associated with hepatocellular carcinoma. The liver is the
primary site of viral replication therefore we undertook a detailed
intrahepatic study of the dynamics of T-cells, apoptosis, and gene expression
during the acute phase of HCV infection in chimpanzees.
Methods:
We examined sequential liver biopsies from chimpanzees that
developed persistent infection or spontaneously cleared the virus and
correlated this data with viral kinetics and clinical signs of hepatitis.
Studies used formalin-fixed biopsies and RNA extracted from frozen liver
tissue. T cell infiltration was assessed in liver sections using antibodies
specific for CD4 or CD8 and H&E staining. Apoptosis was assessed using a
TUNEL assay and M30 antigen staining. Real-time PCR was used to assess mRNA
levels for specific response genes.
Results:
Several features were common to all animals regardless of
disease outcome. Using histological analyses we observed increased intrahepatic
T-cell infiltration (5-10-fold above baseline) in both groups of animals with
CD8+ T-cells representing the major population throughout infection. In some
cases the onset of T-cell infiltration was early (2 weeks post infection) but
in all animals the appearance of immune T cells was associated with liver
apoptosis and mild ALT elevations. In all animals apoptosis (5-20% of liver
cells) occurred prior to the ALT peak with no direct correlation between
maximal apoptosis and peak ALT. Major differences associated with outcome were
observed during the late acute phase. Liver biopsies from cleared animals
showed an increased frequency of apoptosis, relative to persistently infected
animals, which correlated with increased intrahepatic CD8+ T cell frequency
(8-10-fold above baseline) in this group. Up to 20% of the infiltrating T cells
observed during the late acute phase in the cleared animals stained positive
for perforin expression whereas only 1-2% of liver infiltrating T cells in the
persistently infected groups at this same time point were perforin positive.
Conclusions:
These data support the hypothesis that although both groups
of animals mount immune responses during the acute phase these are not
maintained in frequency or efficacy in animals that develop persistent
infections. There is ongoing intrahepatic immune control of replication in the
animals that clear virus but there is a reduction in both the numbers of T
cells infiltrating the liver during the late acute phase in animals that develop
persistent infections and significantly fewer of these cells are functional in
clearing the virus by inducing apoptosis.
#292. Altered Hepatic Metabolic Function in Patients with Chronic Hepatitis C is Associated with Obesity, Insulin Resistance, or Hepatic Steatosis, Independent of Cirrhosis: Results from the HALT-C Trial.
G. T. Everson; C. C. Kulig; M. L. Shiffman; R. K.
Sterling; T. R. Morgan; J. C. Hoefs; T. M. Curto; J. E. Everhart; D. Wagner.
Introduction:
Hepatic dysfunction in patients with chronic hepatitis C
(CHC) could be related to metabolic effects of obesity, insulin resistance
(IR), or hepatic steatosis, or underlying cirrhosis. In our study, we used
multiple quantitative tests (QLFTs) and controlled for cirrhosis, to define
associations of obesity, IR, and hepatic steatosis with altered hepatic
function.
Patients and Methods:
All patients (N=285) were enrolled in the Hepatitis C
Antiviral Long-Term Treatment to Prevent Cirrhosis (HALT-C) Trial. Patients had
either bridging fibrosis (Ishak fibrosis score 3 or 4) or compensated cirrhosis
(Ishak fibrosis score 5 or 6, 40%), 92% were infected with genotype 1, and all
had failed prior treatment with interferon or interferon/ribavirin. Test
compounds were given intravenously (lidocaine, 0.5mg/kg, galactose, 30g,
[24-13C]cholate, 20mg, technetium sulfur colloid, 5mCi) and orally (antipyrine,
500mg, caffeine 300mg, [1-13C]methionine, 200 mg, [2,2,4,4-2H]cholate, 40mg).
Caffeine elimination (Cf kelim), antipyrine elimination (AP kelim) and
clearance (AP Cl), and MEGX formation quantified microsomal function.
Methionine breath test (MBT) quantified mitochondrial function. Galactose
elimination capacity (GEC) assessed cytosolic metabolism and blood flow.
Clearance of orally administered cholate (CA Cloral), cholate shunt (CA Shunt),
and perfused hepatic mass (PHM) measured by SPECT liver-spleen scan assessed
portal inflow and shunt. Body mass index (BMI), insulin resistance (homeostasis
model assessment (HOMA) = {[Glucose, mmol/L] x [Insulin, µU/ml]} / 22.5), and
hepatic steatosis (graded 0, 1, 2, 3 by panel of HALT-C pathologists) were the
independent variables.
Results:
Relationships between QLFTs and quartiles of BMI or HOMA, or
grades of steatosis, were analyzed by ANOVA with a test for trend. BMI
quartiles were associated inversely with MBT (P=0.03) and GEC (P<0.0001).
HOMA quartiles were associated inversely with AP kelim (P<0.0001), AP Cl
(P=0.03), MBT (P=0.0007), GEC (P=0.0001), PHM (P=0.0002), CA Cloral (P=0.002),
and directly with CA Shunt (P=0.006). Hepatic steatosis was associated
inversely with both AP Cl (P=0.05) and MBT (P=0.0006). After controlling for
cirrhosis, the remaining significant relationships were BMI with GEC
(P<0.0001), HOMA with GEC (P=0.04) and AP kelim (P=0.0004), and hepatic
steatosis with AP Cl (P=0.02) and MBT (P=0.02).
Conclusion:
Altered hepatic metabolic function in patients with CHC is
associated with obesity and insulin resistance, independent of cirrhosis. Hepatic
steatosis, but not obesity or insulin resistance, is associated with impaired
hepatic mitochondrial function.
#295. The Role of Hepatitis C Genotype 3 Core Protein Domain 3 in Intrahepatic Steatosis.
R. Jhaveri; J. G. McHutchison; K. Patel; A. Diehl.
Background:
Steatosis is a common histological finding and a poor
prognostic indicator in patients with Hepatitis C virus (HCV) infection. The
etiology of steatosis is multifactorial, but appears to be closely correlated
with unknown viral factors in HCV genotype 3 infected patients. We previously
identified novel amino acid polymorphisms at residues 182/186 within domain 3
of HCV Core protein that correlate with intrahepatic steatosis in a well
characterized group of HCV genotype 3a infected patients. The combination of
leucine-isoleucine (LI) and phenylalanine-valine (FV) at these positions
correlated with steatosis while phenylalanine-isoleucine (FI) correlated with
the absence of steatosis. In this project, we expressed these patient derived clones
and corresponding mutants to examine if lipid accumulation occurred in cultured
liver cell lines.
Methods:
We transfected human and rat liver cell lines with steatosis
and non-steatosis associated HCV genotype 3a Core clones. Transfected cells
were then stained using a combined immunofluorescence and oil red o protocol.
Cells were analyzed using MetaMorph software that quantified the amount of oil
red o in cells expressing HCV Core protein.
Results:
Expression of all the HCV Core isolates led to increased
intracellular lipid compared to controls in 5H cells at transfection efficiency
of 5%. Expression of a steatosis-associated clone (FV) led to significantly
more intracellular lipid in transfected cells when compared with a
non-steatosis clone (FI) (11.4%±6.7% vs. 7.8%±3.3%; p=0.02). Expression of a
mutant designed to reverse the steatosis phenotype (FV to FI) resulted in a 27%
decrease in the amount of intracellular lipid compared to the parent clone
(11.4%±6.7% vs. 8.3%±4.8%; p=0.03). Mutation of another steatosis-associated
clone (LI to FI) resulted in a 37% decrease in intracellular lipid compared to
its parent clone (p=0.01).
Conclusions:
We have verified the importance of specific amino acids
within domain 3 of HCV Core protein genotype 3a in altering host lipid
metabolism and/or trafficking. Future work will attempt to identify the
mechanisms involved.
Sample image of HCV Core expression and Oil Red
staining.
#308. The Hepatitis C Virus Core Protein of Genotypes 1B and 3A Down-Regulate Insulin Receptor Substrate 1 via Genotype-Specific Mechanisms.
V. Pazienza; S. Clément; P. Pugnale; S. Conzelmann; M.
Foti; A. Mangia; F. Negro.
Background/Aims:
Both molecular and clinical evidence support a link between
the hepatitis C virus (HCV) infection and insulin resistance. We examined the
in vitro interaction between the HCV core protein of genotypes 1b and 3a with
the insulin signalling pathway.
Methods:
We measured the levels of insulin receptor substrate 1 (IRS-1),
IRS-2 and other factors involved in the insulin signal transduction in human
hepatoma cells (Huh-7) transiently expressing the HCV core protein of genotypes
3a or 1b by different molecular biology and immunofluorescence techniques.
Results:
IRS-1 (but not IRS-2) protein level was significantly reduced
in Huh-7 expressing the core protein of both genotype 3a (P= 0.0067) and 1b (P=
0.04) as compared to cells transfected with the empty pIRES2-EGFP vector. IRS-1
degradation was associated with an increased phosphorylation at Ser636/639.
However, whereas the core protein of genotype 3a promoted IRS-1 degradation by
upregulating the suppressor of cytokine signal 7 (SOCS-7) and the
downregulation of peroxisome proliferator-activated receptor γ (PPARγ),
the downregulation of IRS-1 by the core protein of genotype 1b proceeded
through the activation of the mammalian target of rapamycin (mTOR). These
findings were confirmed by using specific inhibitors (siRNAs for SOCS-7,
rapamycin for mTOR) or agonists (rosiglitazone for PPARγ).
Conclusions:
Despite the little sequence divergence of the HCV core
proteins of genotypes 3a and 1b, the two proteins seem to interfere with the in
vitro insulin signaling using genotype-specific mechanisms. This, coupled with
mounting clinical evidence, suggests an evolutionary advantage for HCV to
maintain an insulin resistant state.
#310. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C.
J. M. Pestka; M. B. Zeisel; P. Schürmann; B. Bartosch;
F. Cosset; A. H. Patel; H. Meisel; J. Baumert; S. Viazov; K. Rispeter; H. E.
Blum; M. Roggendorf; T. F. Baumert.
Background and aim:
In contrast to a detailed understanding of antiviral cellular
immune responses, the impact of neutralizing antibodies for resolution of acute
hepatitis C is poorly defined. The analysis of neutralizing responses has been
hampered by the fact that patient cohorts as well as HCV strains are usually
heterogeneous and that clinical data from acute-phase and long-term follow-up
after infection are not easily available.
Methods:
Using an infectious retroviral HCV pseudo-particle model
system, we studied a cohort of women accidentally exposed to the same HCV
strain of known sequence.
Results:
In this single-source outbreak of hepatitis C virus infection
in East Germany 1978-1979, viral clearance was associated with a rapid
induction of neutralizing antibodies in the early phase of infection.
Neutralizing antibodies decreased or disappeared following recovery from HCV
infection. In contrast, chronic HCV infection was characterized by absent or
low-titer neutralizing antibodies in the early phase of infection and
persistence of infection despite the induction of cross-neutralizing antibodies
in the late phase of infection.
Conclusions:
These data indicate that rapid induction of neutralizing
antibodies during the early phase of infection may play an important role for
control of viral infection and contribute to HCV clearance. This finding may
have important implications for understanding of the pathogenesis of HCV
infection and the development of novel preventive and therapeutic antiviral
strategies.
#313. Insulin Resistance and Liver Fibrosis in Virus C Chronic Hepatitis and in Nonalcoholic Fatty Liver Disease.
G. Svegliati-Baroni; E. Bugianesi; E. Peruzzi; F.
Ridolfi; F. Tarsetti; F. Ancarani; E. Petrelli; E. Brunelli; M. Lo Cascio; M.
Rizzetto; G. Marchesini; A. Benedetti.
Background:
Insulin resistance, the hallmark of nonalcoholic fatty liver
disease (NAFLD), is also frequently found in patients with chronic HCV
hepatitis (CHC), and has been associated with histological liver damage
(steatosis and fibrosis).
Aims:
To examine the relationship between histological findings and
biochemical parameters of insulin resistance in CHC and NAFLD patients.
Methods:
We assessed the degree of basal insulin resistance (by the
homeostasis model assessment, HOMA-R) and post-load insulin sensitivity (by the
oral glucose insulin sensitivity index, OGIS) in 90 patients with CHC (23
genotype 3) and in 90 pair-matched patients with NAFLD. Basal and post-load
insulin resistance were defined as HOMA-R ≥ 2.7 and OGIS ≤ 9.8
ml/kg*min, respectively corresponding to the upper and lower quartile of a control
population. Steatosis was scored according to Brunt in both groups, fibrosis
according to Brunt in NAFLD and to Ishak in CHC.
Results:
Severe steatosis (grade 3) was associated with HOMA-R (OR
4.42; CI 1.16-16.85; P=0.029) in NAFLD and with HOMA-R (OR 14.87; CI
1.17-89.70; P=0.038) and OGIS (OR 7.43; CI 1.25-44.07; P0.027) in genotype
non-3 CHC, but not in genotype 3. After adjustment for age, gender and BMI, in
NAFLD severe fibrosis ( stage 3-4) was predicted by elevated aminotransferases,
fasting hyperglycemia, basal and post-load insulin resistance and steatosis at
univariate analysis, but only by OGIS ≤ 9.8 (0.56; 0.35 – 0.91; P =
0.019) at multivariate analysis. In CHC, OGIS ≤ 9.8 (OR 9.43; CI
1.43-62.13; P=0.020) was the sole independent predictor of severe (stage 4-6)
fibrosis. When split according to genotype, post-load insulin resistance was
associated with severe fibrosis only in genotype non-3 patients.
Conclusions:
Post-load insulin resistance (OGIS ≤ 9.8 ml/kg*min) is
an independent predictor of severe fibrosis in NAFLD and genotype non-3 CHC and
represents a useful tool to select patients who may benefit of
insulin-sensitizing therapy.
#317. Inhibition of Hepatitis C viral (HCV) replication by in-vivo dimerization of STAT1.
X. Li; H. Zhu; M. Butera; D. R. Nelson; C. Liu.
Background:
It is known that type I interferons (IFN) induce
intracellular antiviral state via the JAK-STAT signaling pathway. Dimerization
of STAT1, STAT2, and STAT3 are key steps in this pathway. However, the precise
role for each individual STAT in antiviral defense is not completely defined.
Aim:
The goal of this study is to determine the role of STAT1
homodimers in the establishment of intracellular antiviral activity.
Methods:
To create an inducible STAT1 dimerization system, STAT 1 open
reading frame is fused with estrogen receptor (ER) domain, resulting in
STAT1-ER fusion expression construct. The fusion protein dimerization is
inducible by estrogen analog (4-HT). The construct was then transfected into
HCV replicon cell line, FL-Neo. Various doses of 4-HT were incubated with the
cells and the STAT1-ER dimerization was monitored by Western blot analysis
using an anti-STAT1 antibody. The target genes of the STAT1 dimers were
examined by cDNA microarray analysis and real-time RT-PCR assay. The effect of
STAT1 homodimers on HCV replication was determined by HCV-specific real-time
RT-PCR assay.
Results:
The STAT1-ER fusion protein formed homodimers with 4-HT stimulation.
The amount of dimers is positively correlated with the doses of 4-HT. By
transfection assay, the formation of STAT1 homodimers substantially inhibited
HCV full-length RNA in correlation with the formation of homodimers indicating
the establishment of antiviral activity in the replicon cells. The dimmers also
induced many interferon-stimulated genes (ISGs) in human hepatoma cells.
Conclusions:
We have established an inducible and cytokine-independent STAT1
activation system. This system would provide a valuable tool to understand the
molecular events triggering the intracellular anti-HCV activity in liver cells.
The system would also allow us to identify STAT1-specific target genes.
#318. Hepatitis C virus is present in CD4+ T cells of chronically infected patients impairing their IFN-g production.
A. Perrella; A. D'Antonio; C. Esposito; D. Vergani; S.
Grattacaso; C. Sbreglia; L. Atripladi; A. Di Spirito; D. Guarnaccia; O.
Perrella.
Background/Aim:
HCV, a hepatotropic RNA virus responsible for frequent
evolution to chronic hepatitis, impairs IFN- gamma production by T helper 1
lymphocytes (Tsai T et al. Hepatology
1999). HCV has been recently shown to infect B cells, monocytes and dendritic
cells. We aimed to investigate whether HCV also infects CD4+ T lymphocytes,
replicates in them, and influences IFN-gamma production.
Methods:
We enrolled 20 patients with histologically proven (Grade 10,
Stage 2) chronic hepatitis C (CHC) (Group A) and 10 healthy blood donors as
controls (Group B). We measured HCV-RNA by real-time PCR (Amplicore Roche 2.5
qualitative and quantitative system; cut off 50 IU/mL and 600 IU/mL
respectively) in PBMC and CD4+ T cells (Dynal CD4+ separation kit; purity ≥90%)
before, after 6-day stimulation with HCV (Core and NS3) and Influenza A (InfMp)
peptides (2mcg/mL each), and after a further 2-days stimulation with PMA and
ionomicin. IFN-gamma production by CD4+ T cells was assessed by an ELISpot
assay (PMA and Ionomicin stimulation).
Results:
PBMC and CD4+ T cells from CHC patients were positive for
HCV-RNA by qualitative assay before stimulation with HCV peptides, while
healthy donors were negative. After 6-day stimulation, HCV-RNA was detectable
by both qualitative and quantitative assay (752 +/- 46 IU/mL) in CD4+ T cells
exposed to HCV peptides but not in those exposed to InfMp peptides. HCV-RNA
levels in CD4 cells increased to 1856 +/- 125 IU/mL after further stimulation
with PMA ionomicin, these cells showing a reduced IFN-gamma production compared
to CD4+ T cells stimulated with InfMp viral peptide (188 +/- 82 vs 322 +/- 128
SFC - U Mann Whitney p < 0.01)
Conclusion:
These preliminary results show that in patients with CHC, the
virus is present and replicates in CD4+ T cells impairing their IFN-gamma
production. This impairment may promote chronic evolution of the infection.
#330. Treatment of Cirrhotic Patients with HCV Referred for Liver Transplantation Using an Escalating Dose Regimen of Pegylated Interferon Alpha-2a and Ribavirin.
H. Massoumi; H. Elsiesy; B. Peterson; V. Khaitova; E.
Norkus; P. Grewal; L. Liu; P. Martin; P. Lopez; N. Bach; T. Schiano.
Introduction:
The rapid progression to cirrhosis and poor tolerability of
interferon post liver transplant (LT) have necessitated the consideration of
treating HCV with PEG-IFN and ribavirin in cirrhotic pts. At the Mount Sinai
Medical Center, we have initiated a protocol using PEG in pts seen in the
transplant office. The aim of our study was to assess the safety and efficacy
of this treatment.
Method:
90 cirrhotic pts were prospectively treated from 2/03 to
4/06. Exclusion criteria included co-infection with HBV or HIV or renal
insufficiency. We used an escalating dose regimen starting with 90 mcg of
PEG-IFN alpha-2a and 400 mg of ribavirin and advanced to 180 mcg and 800-1200
mg respectively over a period of 8 weeks. Hematopoietic growth factors were
started if hemoglobin was <12 or ANC was <750. Treatment was stopped if
platelet count was <20,000. Pt demographics, comorbidities, BMIs, lab
values, MELD and Child’s scores, CT liver volumes, complications and outcomes
were recorded.
Results:
Mean age was 55.3 ± 6.9 years, 69% males, and 53% whites 23% Hispanics,
16% African Americans. 34% had a history of prior treatment with IFN. 76% had
genotype 1 or 4. Mean Child’s score was 6.7 ± 2 and mean MELD 11.2 ± 3.7. 18%
of pts needed dose reduction, 30% stopped treatment due to adverse effects, 11%
had hepatic decompensation, 7% died and 14% underwent LT. Epoetin or
darbepoetin was used in 58% and filgrastim in 31% of pts. End of treatment
response (ETR) was seen in 65% of pts. During a mean follow up period of 9.6
months, 40% of responders had virological relapse; 4/32 pts followed for >
6months after therapy had SVR.
Pts who stopped PEG had significantly smaller liver volumes
(1366 ± 279 vs 1738 ± 561) (p=0.005). Child’s score (p=0.002) and MELD (p=0.03)
were strongly predictive for discontinuation of PEG; Child’s score appearing to
be a stronger predictive factor than MELD. Rate of serious complications was
22% in Child’s class A, 53% in class B and 100% in class C(p<0.0005);
Child’s C pts had a 15 fold increase risk for hepatic decompensation or death.
Every 1 g/dl lower baseline serum albumin below 4.8 predicted a 96% higher risk
of hepatic decompensation or death. No pt had significant bleeding related to
low platelet count (mean platelet count 74 ± 52×1000; range of 18-346×1000).
Conclusion:
Using an escalating dose regimen of PEG-IFN alpha-2a and
ribavirin and aggressive use of hematopoietic growth factors, we achieved a 65%
ETR in cirrhotic pts. These results were tempered by 14% risk of hepatic
decompensation or death and significant relapse rate. Serum albumin and Child’s
score were predictive of hepatic decompensation or death.
#331. Identification of candidate genes that mediate depressive side effects of pegylated IFN-αlpha 2a in patients with chronic hepatitis C.
M. Trippler; Y. Erim; S. Bein; G. Gerken; J. F.
Schlaak.
Aims and background:
Combination therapy with pegylated interferon (IFN)-alpha
plus ribavirin has been shown to be the most effective treatment for chronic
hepatitis C (HCV). One of the most common side effects is IFN-induced severe
depression, which can impair quality of life, reduce treatment adherence and
even lead to suicide. This study assessed the primary transcriptional response
to IFN-alpha-2a plus ribavirin in HCV patients to identify possible candidate
genes that mediate the depressive side effects of IFN-α.
Patients and methods:
A total of 18 Caucasian patients with histologically proven
chronic hepatitis C were treated with standard combination therapy consisting
of pegylated IFN-α2a (Pegasys, 180µg once weekly) for 12 months (HCV
genotype 1, n=14) or 6 months (HCV genotype 2/3, n=1/3) in combination with
ribavirin (800-1200 mg daily). 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 changes were
calculated from before and after IFN injection. Fold change values were
subjected to significance analysis (SAM software) and class prediction analysis
(PAM software). The patients were investigated using the Mini-DIPS, a
semi-structured interview, which facilitates relevant diagnostic criteria
according to the four axis of the DSM-IV. Furthermore depression scores were
evaluated with psychometric instruments, Beck`s Depression Inventory and
Hospital Anxiety and Depression Scale.
Results:
8 patients were non-responders (NR) to therapy while 10
patients had a sustained virological response (SVR). 8/18 patients suffered
from IFN-induced depression. Using class prediction analysis, the development
of an IFN-induced depression could be predicted by 24 genes with 95% accuracy.
9 genes were significantly higher expressed in patients with IFN-induced
depression compared to patients without depression. 6 of these genes were
identified as typical interferon response genes. Interestingly, 3 of these 9
genes were previously described as being associated with recurrent major
depression.
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 drug targets to improve the
efficacy of and adherence to HCV therapy.
#332. The Nonstructural 5A (NS5A) Protein of Hepatitis C Virus Genotype 1b Does Not Contain an “Interferon Sensitivity Determining Region”.
R. Brillet; F. Penin; C. Hezode; P. Chouteau; D.
Dhumeaux; J. Pawlotsky.
Introduction:
Various explanations have been forwarded for differences in IFN-alpha-based treatment outcomes. Together with a number of host parameters and disease characteristics, virus-related factors play an important role in the likelihood of permanent viral clearance after therapy. The nonstructural protein 5A (NS5A) of HCV has been suggested to contain an “interferon sensitivity determining region“ (ISDR). If NS5A indeed contains an ISDR, the latter would be expected to impact mainly on the initial viral decline, meaning that the degree of viral decline on day 1 should be associated with qualitative or quantitative differences in NS5A functions and, thus, in the amino acid sequences that subtend these functions.
Aim:
This hypothesis was tested by studying patients receiving their first injection of standard IFN alpha, the IFN molecule with the most rapid initial antiviral effect.
Results:
We studied whether the degree of viral decline on day 1 is associated with differences in amino acid sequences that subtend NS5A protein functions in 16 patients receiving their first IFN injection (11 responders, 5 nonresponders). Phylogenetic analyses of the full-length protein and of particular functional domains showed no relationship between the baseline protein sequence and the antiviral response. We analyzed nonstructural protein 5A quasispecies sequences amino acid by amino acid, and studied the physicochemical properties of the proteins. The sequences showed no differences in the number of mutations in the putative ISDR relative to the prototype HCV-J sequence between responders and nonresponders, or according to IFN antiviral efficacy. No relationship was found between antiviral efficacy at 24 hours and the baseline sequence of any region of the protein. Amino acid changes were observed in a few cases at 24 hours in both responders and nonresponders, but no consistent pattern of amino acid shifts was observed, ruling out the possibility that IFN administration selected “IFN-resistant“ variants.
Conclusion:
Our findings show that there is no “interferon sensitivity determining region” in the NS5A protein of HCV genotype 1, and that the NS5A sequence does not influence the capacity of IFN to block viral replication. They do not rule out a role of NS5A in subsequent viral clearance, through effects unrelated to IFN resistance.
#335. Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (RBV)(COPEGUS®) in patients with “difficult-to-cure” characteristics.
M. Fried; D. Jensen; M. Rodriguez-Torres; L. Nyberg;
A. Biscegli; T. Morgan; P. Pockros; A. Lin; L. Cupelli; D. Nelson.
Introduction:
Patients with HCV genotype 1 (G1) and high viral load (HVL)
have historically been considered “difficult-to-cure” with response rates
<50%. High bodyweight also negatively impacts SVR for all interferon-based
therapies, although to a lesser degree. Thus, G1 pts with HVL and above average
bodyweight represent a subgroup (≈20% of total population) for which
improved treatment strategies are needed.
Aim:
The aim of this study was to determine if intensification of
treatment using higher, fixed doses of PegIFNα-2a and RBV in patients with
these treatment-resistant characteristics provide increased benefit with
manageable risk.
Methods:
In this prospective, controlled pilot study, treatment-naïve
HCV G1 adults with HCVRNA >800,000IU/mL and bodyweight >85kg were
randomized to 48wks of either PegIFNα-2a 180 or 270µg/wk + either 1200 or
1600mg/d RBV. SVR=undetectable (<50IU/mL) HCVRNA at 24wks post-therapy.
Results (Table):
188 pts, from the United States, were randomized and
treated—follow-up is available for 143 (76%); ≈18% of pts in each arm had
bridging fibrosis/cirrhosis. Similar end-of-treatment response rates were seen
in the 3 test arms; however the SVR rate was highest (47% vs 28%) with the most
intensive regimen: PegIFNα-2a 270µg/wk + RBV 1600mg/d, compared to standard
dosing. Improved SVR was driven by a lower relapse rate (40% vs 19%). Compared
to standard dosing, this regimen was associated with an increased incidence of
some hematological laboratory abnormalities, dose modifications for labs and
AEs and premature withdrawals for AEs.
Conclusions:
In pts with treatment-resistant characteristics (G1, HVL and
bodyweight >85kg), higher fixed doses of both PegIFNα-2a (40KD)
(270µg/wk) and RBV (1600 mg/d) led to a substantial increase in SVR rate (19%
more than standard dosing) but with some negative safety trends. The benefit of
an increased SVR rate with higher fixed doses of PegIFNα-2a (40KD) and RBV
should outweigh the increased potential for adverse events/lab abnormalities.
These results provide the rationale for future studies attempting to optimize
treatment response using higher doses of PegIFNα-2a and RBV and suggest
opportunities to further improve benefit/risk in patients with unfavorable
treatment characteristics.
|
|
PegIFNα-2a
(40KD) 180 µg/wk + |
PegIFNα-2a
(40KD) 270 µg/wk + |
||
|
RBV 1200 mg/d |
RBV 1600 mg/d |
RBV 1200 mg/d |
RBV 1600 mg/d |
|
|
Mean age, yrs |
47 |
50 |
47 |
49 |
|
Virological response, % (ITT) |
48 46 |
38 57 |
53 55 |
51 55 |
|
Relapse (%) |
40 |
42 |
46 |
19 |
|
Serious adverse events (%) |
9 |
13 |
13 |
11 |
|
Lab abnormalities (n, %) |
7(15) |
7(15) |
4(9) |
11(23) |
|
Dose modifications for adverse events or
lab abnormalities (%) |
20 |
26 |
17 |
28 |
|
Withdrawals due to safety reasons (%) |
13 |
6 |
17 |
23 |
#337. Clinical, biochemical, virologic and histologic outcomes of chronic hepatitis C following sustained virologic response (SVR) to HCV therapy: a prospective 5 year cohort study.
A. M. Di Bisceglie; S. L. George; K. L. Mihindukulasuriya; J. Hoffmann; B. R. Bacon.
Background:
Little is known about long-term outcomes in chronic hepatitis
C following SVR. We determined the 5 year clinical, biochemical, virologic, and
histologic outcome in 150 adults with chronic hepatitis C achieving SVR
following antiviral therapy.
Methods:
Patients with SVR were enrolled 6 to 12 mos after completion
of therapy. Subjects were seen initially and then annually to monitor clinical
outcome, serum aminotransferases and HCV RNA. Those with initial stage >2
fibrosis were re-biopsied in year 4 or 5; data on other follow-up liver
biopsies was also collected. Serum HCV RNA was assessed by PCR at every visit
and by Transcription-Mediated Amplification (TMA, Bayer) on the latest
available sample. The grade and stage of hepatitis C were assessed using the
Scheuer scoring system.
Results:
76 patients (50%) were female, 148 were Caucasian (98%) and
their mean age at entry was 49 years. Initial HCV genotypes were 1 (44%), 2
(28.6%), 3 (20.4%), 4 (1.3%) and unknown (16.6%). 86% received standard
interferon alfa-2b with ribavirin, 4% pegylated interferon and ribavirin while
treatment for the remainder was not recorded. 115 patients (77%) have been
followed for at least 4 years. During this time, 2 developed HCC requiring OLT
(both were cirrhotic) and another died of unknown causes. No other
liver-related clinical outcomes were noted. Only 1 patient had transiently
detectable HCV RNA by PCR, not accompanied by a rise in ALT. Serum from 8 of
146 patients (5.4%) was repeatedly reactive for HCV RNA by TMA a mean of 4
years after completion of treatment; serum ALT was normal in all 8 (mean 22,
range 11-28). Among 40 subjects with pre-treatment liver biopsies available for
review who underwent repeat liver biopsy, both the mean stage (2.3 vs 1.2,
p<0.001) and mean grade (2.6 vs 1.5, p<0.001) of hepatitis improved
significantly. The stage of fibrosis among 34 patients with stage 2 or greater
improved in 27 (79%), remained unchanged in 7 (21%) and worsened in none (see
table). Paired biopsies were available from 2 of the 8 TMA-positive patients.
The grade and stage improved substantially in one (from G 3, S 4 initially to G
1, S 1) while in the other it was unchanged (G 2, S 1).
Conclusions:
Individuals with chronic hepatitis C who achieve SVR are at
very low risk for virologic relapse, have continued improvement of liver
histology over 5 years but may remain at risk of HCC if cirrhosis persists.
|
Stage Pre |
No. |
Stage of Fibrosis
Post |
|||
|
Stage 4 |
Stage 3 |
Stage 2 |
Stage 1 |
||
|
4 |
7 |
2 |
2 |
1 |
2 |
|
3 |
14 |
0 |
1 |
3 |
10 |
|
2 |
13 |
0 |
0 |
4 |
9 |
|
1 |
6 |
0 |
0 |
1 |
5 |
#338. Pegylated interferon alfa 2 b + ribavirin are equally efficacious and well tolerated in patients >65 years old in comparison to other age groups: Subanalysis of a randomized, controlled study (WIN-R Trial).
S. L. Flamm; I. M. Jacobson; R. Brown; B. Freilich; N.
Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; J. Harvey; L. H.
Griffel; C. A. Brass.
Background:
Peg interferon α (IFN) + ribavirin are the standard of
care for chronic HCV. There is reluctance to administer anti-viral medications
to older populations due to a fear of side effects and possible decreased
efficacy. Limited data is available on pts. age >65 due to ineligibility for
clinical trials. The role of age in determining response to IFN-based
anti-viral therapy for chronic HCV has not been clearly defined.
Aim:
To determine if age is an independent predictor of sustained
virological response (SVR) or medication tolerability within a randomized,
controlled clinical trial of treatment-naïve pts. with HCV. Patient age grps
studied: 18-25 yrs., n=69; 26-35 yrs., n=350; 36-45 yrs., n=1866; 46-55 yrs.,
n=2200; 56-65 yrs., n=368; and >65 yrs., n=55.
Methods:
A retrospective review of the multi-center WIN-R trial
database was undertaken. Pts. were randomized to receive PEG IFNα 2b
(1.5μg/kg/wk) + either ribavirin 800 mg/d or ribavirin 800mg-1400mg/d
based on body wt. Pts. with HCV GT1/4 received 48 wks of therapy while pts with
HCV GT 2/3 were randomized to 24 or 48 wks of therapy. 4913 pts. received at
least 1 dose of medication and are included in this analysis. Although pts. age
>65 yrs. were ineligible, 55 such pts. were enrolled as protocol exceptions.
Logistic regression analyses of SVR comparing two age categories were
performed. The potential influence of demographic variables on SVR was
evaluated using the chi square test (two-way frequency table).
Results:
The overall SVR was 44%. SVR rates for the groups were: 18-25
yrs. = 57%, 26-35 yrs. = 41%, 36-45 yrs. = 45%, 46-55 yrs. = 432%, 56-65 yrs. =
41% and for >65 yrs. SVR = 46%. There was no difference in SVR in any other
patient. age groups including patients. age >65 yrs. There were no differences
in serious adverse events between all age groups. Patinets age 26-35 yrs.,
36-45 yrs. and 46-55 yrs. had fewer adverse events than those in the 56-65 yrs.
and the >65 yrs. age groups. Treatment discontinuations were significantly
higher among the 26-35 yrs. group when compared to two groups but there was no
difference in the treatment discontinuations in the >65 yrs. group compared
with any other.
Conclusions:
Patients 18 to 25 years of age had the highest SVR rate (57%)
among the 6 age groups.
• The SVR rate in patients older than
65 years (46%) was similar to the SVR rates observed in younger age groups
(41%-57%).
• Although elderly patients tended to
experience more AEs, the rate of SAEs was similar in all groups, and the
incidence
of treatment discontinuation in
elderly patients was similar to or less than that of younger patients.
• Data from this subanalysis of the
WIN-R trial strongly suggest that patients should not be denied antiviral
therapy based on age alone.
#339. A prospective, multicenter, observational study on compliance with viral hepatitis C treatments (CHEOBS study).
P. Cacoub; D. Ouzan; P. Melin; J. Lang; M. Rotily; T. Fontanges; P. Marcellin; M. Chousterman.
Objective:
The CHEOBS study is a French multicenter, prospective,
observational study designed to analyse the factors related to compliance with
the combination treatment with Peginterferon α-2b (PegIFN) and Ribavirin
(RBV) in patients with chronic hepatitis C virus (HCV) infection. Main results
in patients (pts) with a genotype 2 or 3 infection are presented.
Patients and methods:
From Jan 2003 to Dec 2004, 702 out of 2,000 pts included were
infected with a genotype 2 or 3 virus among which 641 pts had sufficient data
to be analyzed: 356 pts (group 1) received an educational program to optimize
the tolerance and the efficacy of HCV treatment whereas 285 pts (group 2) had
no specific formation. Baseline characteristics, impact of the educational
program on compliance and sustained virological response (SVR=6 months after
stopping therapy) were assessed.
Results:
The mean age was 45±11 years, 59% were male, 17% were
unemployed and 8% had poor socio-economic conditions. Pts were excessive
alcohol consumers (>50g/d; 167, 26%), smokers (336, 53%), drug abusers
(current [28, 4%], past [312, 49%]), had past depression (169, 26%) and/or current
psychiatric disorders (150, 24%). HCV viral load was >800,000 IU for 163 pts
(38%) and genotype was 2 (189, 30%) or 3 (452, 70%). A high stage of fibrosis
was frequent; Metavir F2–F3 (201, 43%), cirrhosis (65, 14%). Co-morbidities
included HIV co-infection (27, 4%), HBV co-infection (8, 1%), or other chronic
diseases (147, 23%). HCV treatment naïve pts were 81% (520), 19% had
pre-treatment once (93) or several times (27). Pts of group 1 had more
frequently a past depression (30% vs 22%), current psychiatric disorders (27%
vs 20%) and a current drug use (6% vs 2%)(p<0.05). The compliance at month 6
of treatment and the SVR in two groups are shown in the Table.
Conclusion:
·
This
is the first prospective study that evaluated “real-life” treatment adherence
in patients with genotype 2 and 3 chronic hepatitis C.
·
In
this real-life, community-based setting, patients with genotype 2 and 3 chronic
hepatitis C who received therapeutic education had:
o
Significantly
greater adherence to peg-IFN alfa-2b plus ribavirin combination therapy because
of increased adherence to ribavirin therapy
o
Significantly
higher SVR rates and a decreased rate of relapse.
|
|
Group 1 |
Group 2 |
p |
|
Duration of treatment, weeks |
29.7 ± 14.0 |
28.3 ± 12.7 |
NS |
|
Early withdrawal (<20 weeks), % |
11.8 |
14.4 |
NS |
|
PegIFN, µg/kg/w* |
1.4 ± 0.3 |
1.3 ± 0.3 |
.015 |
|
≥28 RBV pills, %** |
69.0 |
52.2 |
.001 |
|
Compliance with PegIFN + RBV, % |
59.6 |
44.8 |
.006 |
|
Sustained responders, % |
89.4 |
80.6 |
.017 |
|
Non responders, % |
4.8 |
4.9 |
NS |
|
Relapsers, % |
5.8 |
14.6 |
NS |
*during the last 4
weeks; **during the last 7 days
#340. Utility of virological response at weeks 4 and 12 in the prediction of SVR rates in genotype 2/3 patients treated with peginterferon alfa-2a (40KD) plus ribavirin: findings from ACCELERATE.
M. Shiffman; S. Pappas; B. Bacon; E. Godofsky; D. Nelson; H. Harley; M. Diago; A. Lin; G. Hooper; S. Zeuzem.
Introduction:
ACCELERATE, a prospective, randomized trial in 1469 GT2 or 3
pts shows that, overall, 24wks of PegIFNα-2a plus RBV is superior to 16wks
(Table), confirming the recommended treatment duration. Utilizing this dataset,
we determined on-treatment predictability of a wk4 and 12 response, to assess
their clinical utility in the management of GT2 and 3 pts.
Methods
Methods In ACCELERATE, naïve GT2/3 pts received
PegIFNα-2a 180µg/wk + RBV 800mg/d for 16 or 24wks. Predictability of a
response at wk4 (RVR; undetectable HCVRNA [<50IU/mL]) and at wk12 (EVR;
undetectable or unquantifiable HCVRNA or ≥2log10 drop) to forecast an SVR
(undetectable HCVRNA after 24wks follow-up) was determined in the standard
population (pts without any major protocol deviations).
Results
·
Demographic
and disease characteristics for the intent-to-treat patient population
(n=1463). Overall, patients who received
16 and 24 weeks’ treatment were well matched with regard to demographic and
clinical characteristics and the distribution of HCV genotype 2 and 3
infection.
Virologic response at week 4 (RVR)
and 12 (EVR)
·
An
RVR was achieved by 68% and 65% of patients in the 16- and 24-week arms,
respectively.
·
An
EVR as achieved by 99% and 97% of patients in the 16- and 24-week arms
respectively
o
Of
those patients who achieved an EVR, 95% and 94% respectively, had undetectable
HCV RNA at week 12
o
The
absence of an EVR was highly predictive of not achieveing an SVR (94%). However, very few patients (1.9%) did not
achieve an EVR.
Predictive value of RVR
·
The
achievement of an RVR was strongly predictive of achieving an SVR after both 16
and 24 weeks of treatment.
o
Patients
with an RVR who received 16 weeks of treatment had a high rate of SVR (82%).
o
Patients
with an RVR who received 24 weeks of treatment achieved a rate of SVR that was
8% higher than that in patients who received 16 weeks (90%; p=0.0001).
·
In
patients who achieved an RVR, those with a low viral load (≤ 400,000
IU/mL) had a higher probability of achieving an SVR (≥90%), irrespective
of treatment duration.
·
In
patients without an RVR, 24 weeks of treatment was superior to 16 weeks overall
(p<0.001) and for each genotype and baseline HCV RNA level.
Conclusion:
As almost every GT2/3 pt treated with PegIFNα-2a + RBV
had undetectable HCVRNA by wk12, the clinical utility of a 12wk response was
minimal. In contrast, a wk-4 RVR was important. GT2 and 3 pts with an RVR had a
similarly high chance of achieving SVR with 24wks. However, GT2/3 pts without
an RVR had low response rates – these pts should not be considered
‘easy-to-cure’ and would likely benefit from more intensive therapy. Detectable
vs. undetectable HCV RNA at wk4 should be utilized to guide treatment decisions
in GT2/3 pts.
#341. Evaluation of fibrosis regression using non-invasive methods in very long-term follow-up of HCV responder patients.
V. de Ledinghen; J. Foucher; L. Castera; P. Bernard;
M. Salzmann; G. Moisset; W. Merrouche; P. Couzigou.
Background & aim:
Liver stiffness measurement using FibroScan and Fibrotest are
non-invasive methods for fibrosis evaluation in HCV patients. The aim of this
longitudinal study was to evaluate liver fibrosis using FibroScan and Fibrotest
in very long-term HCV responder patients compared to (1) fibrosis stage before
treatment, and (2) a control group of patients without fibrosis (liver biopsy
F0).
Methods:
A total of 88 very long-term HCV responder patients (42
males, mean age 56 ± 11 years) who undergone fibrosis evaluation using
non-invasive methods more than one year after the end of HCV treatment (mean
time between the end of treatment and fibrosis evaluation: 3.8 ± 2.1 years,
range: 2-13 years) were studied. 85 of these patients had a liver biopsy before
treatment. This group was compared to a control group of 72 patients (33 males,
mean age 49 ± 15 years) who undergone non-invasive evaluation of fibrosis at
the time of liver biopsy with a F0 Metavir fibrosis score.
Results:
Before treatment, according to liver biopsy, liver fibrosis
was F0F1 in 19%, F2 in 43%, F3 in 19% and F4 in 19% cases. At the end of very
long-term follow-up, according to published FibroScan and Fibrotest cutoffs for
fibrosis stages, fibrosis was F0F1 in 82% and 71%, F2 in 2% and 9%, F3 in 8%
and 8%, F4 in 8% and 12%, respectively. Using FibroScan and Fibrotest, fibrosis
regression was observed in 95% and 78% of patients with F2 fibrosis at liver
biopsy before treatment, 87% and 75% of F3 patients. In the group of cirrhotic
patients before treatment (according to liver biopsy), fibrosis regression was
observed using FibroScan and Fibrotest in 68% and 53% of patients,
respectively. No statistical difference was observed between HCV responders and
the control group for liver fibrosis. Indeed, in HCV responders and F0
patients, mean values of FibroScan and Fibrotest were 7.2 ± 6.0 and 5.8 ± 3.7
kPa (NS), 0.36 ± 0.24 and 0.32 ± 0.24 (NS), respectively.
Conclusion:
More than 80% of very long-term HCV responder patients have
no or mild fibrosis. Moreover, more than 50% of cirrhotic patients before
treatment have fibrosis < F4 at the end of very long term follow-up. These
results confirm that complete regression of fibrosis is observed in very
long-term HCV responders. FibroScan and Fibrotest are sensitive and reliable
tools for non invasive evaluation of liver fibrosis and monitoring of
histological response after antiviral treatment in HCV patients.
#342. Effect of drug exposure on sustained virological response (SVR) in patients with chronic hepatitis C virus genotype 2 or 3 treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for 16 or 24 weeks.
M. Shiffman; S. Pappas; S. Greenbloom; R. Sola; L.
Nyberg; J. Bronowicki; D. Crawford; A. Lin; G. Hooper; S. Zeuzem.
Introduction:
Previous studies have demonstrated that exposure to both
peginterferon and ribavirin (RBV) impacts SVR in HCV genotype 1 pts. The aim of
the present study was to examine the effect of cumulative drug exposure on SVR
in genotype 2 (GT2) and GT3 pts enrolled in ACCELERATE, a large prospective
randomized trial (n=1469) which compared peginterferon alfa-2a (40KD) 180 µg/wk
plus RBV 800 mg/d for 16 or 24 wks. The primary results of this study
demonstrated that SVR was significantly greater with 24 wks of treatment [EASL
2006;A734].
Methods:
Complete data was available in 1373 pts. The cumulative
exposure to PEG-IFNα-2a and RBV on the probability of SVR was assessed,
while simultaneously controlling for other potential predictors (age, gender, race,
bodyweight, cirrhosis, genotype, baseline ALT and HCVRNA) using logistic
regression models. PEG-IFNα-2a dose was expressed as a multiple of the
standard 180µg dose; RBV was expressed as mean daily dose.
Results:
Cumulative PEG-IFNα-2a dose, mean daily RBV dose,
genotype, baseline HCVRNA, cirrhosis status, age and baseline ALT significantly
and independently predicted SVR (Table). SVR increased stepwise with increasing
cumulative PEG-IFNα-2a duration regardless of RBV dose. In patients with mean
RBV dose of <8.4 mg/kg/d (lowest quartile of RBV exposure), SVR increased
from 42% in pts who received ≤16 PEG-IFNα-2a doses to 67% in pts
with ≥17 PEG-IFNα-2a doses. In patients with RBV exposure of ≥11.5
mg/kg per day (top quartile of RBV exposure), SVR was 77% and 87% in pts
receiving ≤16 and ≥17 PEG-IFNα-2a doses respectively.
Conclusion:
Total exposure to both PEG-IFNα-2a and RBV affected SVR
in pts with GT2 and GT3 independent of other factors. The highest SVR (87%) was
observed in pts who received the longest duration of therapy and the highest
mean dose of RBV based upon body weight. Since all pts in this trial received
an 800 mg/d fixed dose of RBV; the reduction in RBV exposure was a function of
increasing body weight. Whether increasing RBV exposure in heavier GT2 and GT3
pts will improve SVR remains uncertain.
|
#343. Improved Virologic Response Rates With Treatment Extension To 72 Weeks Of Peginterferon Alfa-2B Plus Weight-Based Ribavirin In A Difficult-To-Treat Population Of Genotype 1-Infected Slow Responders.
B. Pearlman; C. Ehleben; S. Saifee.
Introduction:
In genotype 1-infected HCV patients, the duration of
interferon-based therapy is a critical determinant of achieving sustained
virologic response(SVR). Slow virologic responders may benefit from an extended
treatment course; improved SVR and relapse rates were demonstrated when therapy
was extended from 48 weeks to 72 weeks (Gastroenterol 130:1357, 2006). However,
previous studies utilized suboptimal doses of ribavirin for genotype 1
infection (800 mg daily). Furthermore, it is unclear if treatment extension could
benefit more treatment-resistant patients like African-Americans. We sought to
determine if treatment extension could improve response rates in a
difficult-to-treat population of slow responders using weight-based ribavirin
dosing.
Methods:
86 treatment-naïve, chronically-infected HCV patients with
elevated ALT and genotype 1 were enrolled in this single center study. Patients
were treated with 1.5 mcg/kg/week of peginterferon alfa-2b and 800-1,400 mg/day
of ribavirin, dosed according to weight. All patients examined were
slow-responders to therapy, defined by achieving at least a 2-log decrement in
HCV RNA from baseline value, yet, having detectable HCV RNA at 12 weeks (PCR,
TaqMan, Roche, detection limit 10 IU/ml). Patients were randomized 1:1 to continue
treatment to complete a total of 48 or 72 weeks. HCV RNA was rechecked at week
24, at the end of treatment, and at the end of a 24 week treatment-free
follow-up interval.
Results:
Demographic, biochemical and virologic baseline
characteristics were not statistically different between groups. Overall, 48%
of patients were African-American; 79% had high viral load; 24% had F3/4
fibrosis, and 31% had a body mass index of 30 or above. All patients had
undetectable HCV RNA at 24 weeks of therapy. Dose reductions and treatment
discontinuations for adverse events or laboratory abnormalities were similar
between groups. The end-of-treatment response rates were significantly higher
in the 72-week group compared to those in the 48-week group (54% versus 33%, respectively;
p=0.04). Relapse rates were 28% in the 72 week treatment group compared to 46%
in the 48 week treatment group (p=ns). Overall, the rate of SVR was superior in
patients treated for 72 weeks versus 48 weeks (39% versus 18%, respectively;
p=0.03).
Conclusions:
Extending the treatment duration from 48 weeks to 72 weeks in genotype-1 infected patients with slow virologic response to peginterferon alfa-2b and weight-based ribavirin significantly improves SVR rates. Treatment extension does not seem to increase the rate of dose reduction or therapy discontinuation. Results need to be confirmed in larger studies.
#344. Efficacy and tolerability of citalopram in interferon-induced depression: a randomized, placebo-controlled double-blind study on the antidepressant treatment in HCV patients with antiviral therapy.
M. R. Kraus; A. Schaefer; M. Scheurlen.
Background and Aims:
Interferon (IFN) - induced depression represents a major
complication in the antiviral treatment of chronic hepatitis C virus (HCV)
infection. According to several studies, selective serotonin reuptake
inhibitors (SSRIs) appear to be useful in the treatment and prevention of
cytokine-induced depressive symptoms. However, efficacy and tolerability of
SSRIs - given only after the onset of IFN-associated depression - have not been
demonstrated in a placebo-controlled study setting.
Methods
In a randomized and placebo-controlled single-center study,
we included a total of 100 HCV outpatients with chronic hepatitis C infection
and antiviral combination therapy (peginterferon alfa-2b and ribavirin).
Before, during, and after interferon therapy, depression was monitored using
the Hospital Anxiety and Depression Scale (HADS). When showing clinically
relevant on-treatment depression scores (HADS ≥ 9), patients were
randomly assigned to either placebo or citalopram (SSRI, 20 mg daily)
treatment. Moreover, this patient subgroup underwent close psychometric
follow-up (1, 2, and 4 weeks after the depression event). Rescue-medication
(citalopram, 20 mg daily) was started in the case of exacerbation of depressive
symptoms.
Results
Of 28 patients with clinically relevant depression scores
during IFN therapy, 14 received placebo and 1 received verum. In five patients
with exacerbating depressive symptoms, rescue-medication had to be initiated,
leading to a significant relief of IFN-induced depression (P = 0.008).
Unblinding revealed that all of the 5 patients had been allocated to the
placebo condition. Analysis of variance (2-way ANOVA: time x treatment
condition) demonstrated a statistically significant decline in HADS scores in
verum patients within 4 weeks (P < 0.001). Depression scores did not
decrease significantly over time in the placebo subgroup (n=14) and remained
markedly higher than in citalopram-treated patients (main effect therapy: P =
0.032). All patients receiving citalopram medication were able to continue and
terminate IFN combination therapy as scheduled.
Conclusions:
Our findings clearly demonstrate that citalopram treatment is
both well tolerable and highly effective in the treatment of IFN-induced
depressive symptoms. The results from our placebo-controlled study imply that
antidepressant treatment is safe when initiated after the onset of clinically
relevant depressive symptoms. A general
SSRI prophylaxis can not be recommended because this strategy would require
subjecting the majority of patients, who will not develop depression, to
potential adverse events and for no benefit.
#345. HCV Treatment Response Rates in an Incarcerated
Population-Influence of Race, Compliance and Pegylated Interferon.
W. Cassidy; A. Windham; R. Horswell.
Background:
Reportedly, incarcerated African Americans (AA) chronically
infected with HCV who are treated with interferon and ribavirin (INF/RIB) have
treatment response rates similar to non-African Americans (non-AA). This raises
the possibility that elimination of racial differences in quality of care,
access to medicine, control of co-morbidities & compliance with INF/RIB therapy
eliminates differences in treatment response rates between AA and non-AA. To
assess, we examined a quality assurance database used to monitor care given to
inmates in the Louisiana Department of Corrections. Unique to this population
is directly observed therapy with treatment discontinuation if an inmate is
non-compliant. There is minimal use of alcohol and non-prescribed drugs.
Methods:
Information on genotype (GT) 1 infected patients from the
aforementioned database was examined. Response to therapy was defined as
undetectable viral load on the most recent HCV viral load test, at least 12
weeks after starting therapy. The sample was accrued over 5 years and includes
equal numbers treated with non pegylated interferon (P-INF) + RIB & P-INF +
RIB. Response rates were compared between AA and non-AA patients after
adjustment for covariates, including biopsy stage and grade (Metavir), age, GT
1a vs 1b & use or non-use of P-INF. No gender adjustment was made, as the
sample was 99% male. A statistical model based on propensity score methods was
used to compare adjusted odds ratios.
Results:
250 patients were included. 144 (70%) were AA. There were no
statistical differences between AA & non-AA patients in age, GT 1a vs 1b,
grade, stage, & fraction receiving P-INF. The first row of the table shows
the raw response rates by racial group, as well as adjusted odds ratio (AA vs
non-AA.) The 2nd & 3rd rows show results separately for those who did &
did not receive P-INF.
Conclusion:
Overall, there is a significant difference in response rates
between AA & non-AA even in the prison setting with directly observed
therapy. Use of P-INF increased positive response in both AA & non AA.
Among those receiving P-INF, the AA vs non-AA difference is not statistically
significant. This could be due to the disappearance of racial response
differences with use of P-INF, but may stem from insufficient power to detect a
racial difference in response among those receiving P-INF.
Treatment
Response by Race (N)
|
|
AA |
Non AA |
Odds
ratio |
|
Total sample (250) |
39% |
63% |
0.37(0.001) |
|
Non P INF/RIB (108) |
16% |
46% |
0.19(0.001) |
|
P INF/RIB (142) |
58% |
73% |
0.64(0.395) |
#346. Evaluation of the efficacy of an 18 week short treatment duration in HCV type 1 infected patients based upon early viral kinetics: an approach to recognise “super-responders”.
T. Berg; V. Weich; G. Teuber; H. Klinker; B. Möller;
J. Rasenack; H. Hinrichsen; G. Pape; U. Spengler; P. Buggisch; H. Balk; M.
Zankel; C. Sarrazin; S. Zeuzem.
Introduction:
A number of ongoing studies in patients with HCV infection
have been recently concerned with the evaluation of the optimal dose and
duration of pegylated IFN and ribavirin. In a multicenter randomized controlled
study, HCV type 1-infected patients received an individualized treatment
duration from 18 up to 48 weeks tailored according to early viral kinetics.
Aim:
The aim of the present analysis was to find out whether there
are conditions which allow a reduction of the treatment duration to 18 weeks.
Study design:
433 patients have been randomized to receive either 1.5 ug/kg
body weight PEG-IFNa-2b per week plus 800-1400 mg ribavirin daily for 48 weeks
(n=225, group A) or an individualized tailored treatment duration ranging
between 18 to 48 weeks (n=208, group B). In the latter group treatment duration
was calculated by the time required to become for the first time HCV-RNA
negative as defined by bDNA assay (detection limit 615 IU/mL) multiplied by the
factor 6. Patients being found to be HCV-RNA negative by this test were
subjected to another test, the highly sensitive TMA assay (detection limit
<5.3 IU/mL).
Results:
When HCV RNA levels were quantified at baseline and weekly
using the bDNA assay it turned out that 45 out of the 208 group B patients
became already negative by week 3 and therefore received only 18 weeks of
therapy. SVR rates in these rapid responders were 62% (28/45) and consequently
significant lower than in the control group A rapid responders being treated
for 48 weeks (87%; 48/58). Furthermore group B patients with a baseline viral
load (VL) ≤800.000 IU/mL had significantly higher SVR rates (76%; 25/33)
than patients with a VL >800.000 IU/mL (31%; 4/13). When applying the TMA
assays 31 of the 45 patients became HCV RNA negative (<5.3 IU/mL) within the
first 5 treatment weeks. SVR rates after 18 weeks of treatment in these TMA
negative patients were 81% (25/31) but reached 95% in those with low baseline
viremia (≤800.000 IU/mL; 21 out of 22 patients) and only 44% in those
with high VL at baseline (>800.000 IU/mL; 4 out of 9 patients). In contrast
patients being still positive with the sensitive TMA assay at week 5 hardly had
any change to achieve SVR when treated for 18 weeks (29%; 4 out of 14
patients).
Conclusion:
This analysis underlines the importance to determine viral
kinetics at an early phase during treatment using quite sensitive HCV RNA
assays. By that means a subgroup of HCV genotype 1 infected rapid responder
patients (“super-responders”) may be identified (around 10% of the total
population) which can achieve a SVR above 90% within a treatment duration of 18
weeks.
#347. Fatigue in Patients with Hepatitis C and Non-Viral Chronic Liver Disease.
F. Barakat; M. D. Carlson; D. L. Oliver; K. Edwards; N. Karlen; R. Hilsabeck; W. Perry; T. I. Hassanein.
Introduction:
Fatigue is a common complaint in patients with Chronic Liver
Disease (CLD) and may cause impaired quality of life. Numerous studies have
described fatigue in patients with hepatitis C (HCV) and non-viral liver
disease such as Primary Biliary Cirrhosis (PBC); however, comparisons between
etiologies have not yet been conducted. The goal of this study was to evaluate
self-reported fatigue in patients with HCV versus Non-Viral CLD.
Methods:
Patients completed a set of questionnaires including the
Fatigue Severity Scale (FSS). The FSS is a 9-item questionnaire designed to
assess the impact of self-reported fatigue on daily functioning. The measure is
scored on a 7-point Likert-type scale resulting in an average fatigue score
(range 1-7). Our group defined impairment as an average score > 2 standard
deviations above published reports of normal healthy adults (2.3±0.7). Liver
disease etiology, histology, and history of psychiatric disease were also
collected.
Results:
313 subjects completed the FSS questionnaire between 1999 and
2004. After excluding patients with HCV/HIV and those on antiviral therapy, 227
patients were included in this analysis. The mean age was 49±8 years, 55% were
male, and 62% were Caucasian. 52% showed evidence of cirrhosis, and 85 (40%)
reported a history of psychiatric disease.
Etiology of CLD was HCV in 180 patients and Non-Viral CLD in 47 patients
(i.e., ETOH, NASH, AIH, PBC, PSC, Cryptogenic). Demographic and FSS scores for
both groups are reported in Table 1. Overall, 68% of patients reported
significant fatigue (Mean FSS score = 4.7±1.8). There was a significant
difference in FSS scores between the HCV and Non-Viral CLD groups (p=0.013).
There was no significant difference in FSS scores between patients with
cirrhosis (4.7±1.8) versus no-cirrhosis (4.6±1.9) (p=0.87). Patients reporting
a history of psychiatric disease had significantly greater FSS scores than
patients without psychiatric history (5.4±1.4 & 4.3±1.9, respectively;
p<0.001).
Conclusions:
·
68%
of patients with chronic liver disease, regardless of etiology, reported
significant fatigue (mean FSS score 4.7 ± 1.8)
·
Patients
with HCV reported significantly higher fatigue scores than in patients with
non-viral chronic liver disease
·
Patients
with chronic liver disease and psychiatric report significant fatigue
irrespective of liver disease etiology
|
|
HCV |
Non-viral CLD |
p-value |
|
Age |
49 ± 8 |
48 ± 14 |
0.60 |
|
Education |
13 ± 3 |
12 ± 4 |
0.81 |
|
% Male |
55% |
53% |
0.82 |
|
% Caucasian |
61% |
47% |
0.09 |
|
% Cirrhosis |
52% |
81% |
0.002 |
|
% Psych History |
40% |
32% |
0.31 |
|
FSS Score |
4.8 ± 1.8 |
4.1 ± 1.7 |
0.013 |
#348. Progression of Fibrosis and Interferon Treatment in Liver Transplant Recipients with Hepatitis C Infection.
S. Habib; C. H. Chang; J. Ahmad; D. Sass; T. Shaw-Stiffel; A. J. Demetris; M. De Vera; P. Fontes; A. Marcos; O. S. Shaikh.
Introduction:
Hepatitis C in the liver allograft recipient has an
aggressive course. A significant proportion of such recipients develop graft
fibrosis and cirrhosis within five years of transplantation. Treatment efficacy
with standard or pegylated interferon and ribavirin is also suboptimal compared
to the immunocompetent individuals. However, the effect of such therapy on
graft fibrosis remains unknown.
Objectives:
To determine the efficacy of interferon based therapies in
liver transplant recipients with recurrent hepatitis C, and to determine the
effect of interferon treatment on progression of graft fibrosis.
Methods:
We retrospectively analyzed 864 hepatitis C patients, who
underwent liver transplantation at Thomas E Starzl Transplantation Institute,
University of Pittsburgh between January 1992 and April 2006. Three hundred and
twenty two patients received either interferon (all kinds) monotherapy,
combination therapy or ribavirin monotherapy. The primary end point was stage
of fibrosis (4-6) on last available liver biopsy.
Results:
Both treated and untreated groups were similar in clinical
characteristics at the time of transplantation, and their post transplant
course was also similar. In treatment group 78% received prednisone based
immunosuppression as compared to 71% in no treatment group. 58% of patients in
treatment group had HCV RNA >1 million units/ml after transplantation. Only
those variables were included in multi-variable, which were significant on
uni-variable analysis. Treatment was categorized in multiple ways and AIC
statistics was used to select best multivariable analysis. Patients were
categorized into four groups; no treatment (n=525), <24 weeks of treatment
(n=78), 25-48 weeks of treatment (n=68) and >48 weeks of treatment (176).
Patient’s age, AST at 6 months, AST/ALT ratio of >1 at 6 month of
transplantation, warm ischemia time of >one hour, cumulative prednisone
>1000 mg and treatment status are multi-variably associated with the
progression of fibrosis . Patients, who received treatment for <24 weeks has
significantly decreased chances of progression of fibrosis to stage 4-6 (HR
0.45,p=<.005) regardless of viral response. Further analysis will be
performed regarding progression of fibrosis in patients, who achieved sustained
viral response.
Conclusion:
Among liver transplant recipients with recurrent hepatitis C,
treatment with any interferon with or without ribavirin significantly reduces
fibrosis progression to stage 4 and above regardless of viral response. Long
term treatment >48 weeks did not show any benefit on progression of
fibrosis. Further prospective trials are indicated to confirm these findings.
#349. Prospective Analysis of Sustained Virologic Response (SVR) to Peg-interferon (PEG IFN) Alfa-2b and Ribavirin Treatment in Asian and Hispanic Patients with Chronic Hepatitis C: Results from the WIN-R Trial.
B. Freilich; K. Hu; I. Jacobson; R. Brown; N. Afdhal;
P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; E. Godofsky; R. Strauss; D.
Bernstein; S. Flamm; N. Bala; V. Araya; L. Griffel; C. Brass.
Background:
Retrospective data suggest a higher SVR in Asian patients
(APs), but a lower SVR in Hispanic patients (HPs) than in Caucasian patients
(CPs) to interferon (IFN) and ribavirin (RBV) treatment for chronic hepatitis C
(CHC). Prospective studies are needed to determine SVR in APs and HPs with CHC
treated with PEG IFN and RBV. Aim: To evaluate the rates of SVR to PEG IFN alfa-2b
and RBV in APs and HPs with CHC enrolled in the WIN-R trial, a large U.S.
multicenter study comparing RBV in a fixed dose (FD) vs. a weight based dose
(WBD) combined with PEG IFN alfa-2b.
Methods:
Patients with CHC were randomized to PEG IFN alfa-2b 1.5
µg/kg once weekly combined with RBV 800 mg (FD) or RBV 800-1,400 mg WBD.
Treatment was for 48 weeks with 24 weeks follow-up. The SVR was based on
intent-to-treat (ITT) and defined as undetectable HCV RNA by central
quantitative TaqMan assay (LLD is <29 IU/ml or 100 copies/ml-Schering-Plough
Research Institute) 24 weeks post-treatment. Dose reductions of RBV were
required for hemoglobin (Hgb) < 10 g/dL and discontinuation for Hgb <
8.5. Erythropoietin was permitted concomitant with RBV dose reduction for Hgb
< 10.
Results:
5,519 patients were randomized in this trial.
Between-Group Analysis
• Overall SVR rates.
— Among patients receiving WBD
ribavirin, the SVR rates were lower in Hispanic patients (32% vs 47% for
Caucasian patients, P = .0013 and 32% vs 66% for Asian patients, P = .00008).
There was no significant difference in SVR rates between Caucasian patients and
Asian patients receiving WBD ribavirin.
— Among patients receiving FD
ribavirin, the SVR rates among Asian patients were not significantly different
than those among Caucasian or Hispanic patients. However, SVR rates were lower
among Hispanic patients (35% vs 44% for Caucasian patients, P = .0410 and 35%
vs 39% for Asian patients, P = .6299).
• SVR rates by genotype.
— Among patients with G1 receiving
WBD or FD ribavirin, there was no significant difference between patients of
different ethnic origin.
— Similar results were observed among
patients of different ethnic origin with G2/3 receiving WBD or FD ribavirin.
— SVR rates were lower among Hispanic
patients.
·
SVR Rates by Baseline Characteristics
— SVR rates were lower in patients
with high baseline viral load (>600,000 IU/mL).
— Among Asian patients, WBD ribavirin
(P = .037) and G2/3 (P = .017) were significantly associated with improved SVR
rates.
— Among Hispanic patients, G2/3 (P
< .0001) and baseline METAVIR fibrosis stage F0-F2 (P = .038) were
significantly associated with higher SVR rates.
— Among Caucasian patients, high
baseline viral load (P< .0001) and G1 were significantly associated with
lower SVR rates.
Conclusions:
Hispanic patients with chronic hepatitis C represent a
particularly treatment-resistant population. Additional studies are required to
identify factors that will improve SVR rates in this ethnic group.
• Overall WBD ribavirin is more effective than FD ribavirin.
• Asian patients achieve overall SVR rates than are at least
equivalent to those observed among Caucasian patients.
— WBD ribavirin is more effective among
Asian patients, especially among G2/3
— Additional studies among a greater
number of Asian patients are required to confirm results observed in this
study.
This study was supported by
Schering-Plough Corp.
#350. Definition of a pre-treatment viral load cut-off for an optimized prediction of treatment outcome in patients with genotype 1 infection receiving either 48 or 72 weeks of peginterferon alfa-2a plus ribavirin.
T. Berg; M. von Wagner; H. Hinrichsen; T. Heintges; P.
Buggisch; T. Goeser; J. Rasenack; G. Pape; W. Schmidt; B. Kallinowski; H.
Klinker; U. Spengler; U. Alshuth; S. Zeuzem.
Introduction:
Viral load (VL) has become an important predictor for
treatment outcome in patients with chronic hepatitis C virus (HCV) infection
but its determination becomes also relevant with respect to the
individualization of treatment duration. Thus while in previous studies a HCV
RNA cut-off of 800.000 IU/ml has been proposed to define high and low
pre-treatment VL recent observations imply that this cut off is not sensitive enough
to govern critically individual treatment strategies. In the present
exploratory analysis we now identified a baseline HCV RNA cut-off level that
obviously can predict most effectively sustained virologic response (SVR) as
well as relapse rates. The population investigated were treatment-naive, HCV
genotype 1 patients (n=455) receiving peginterferon alfa-2a (180µg/week) plus
ribavirin (800 mg/day) for either 48 (n=230) or 72 weeks (n=225) during the
course of a phase III, randomized, clinical trial.
Results:
Based on the ROC analyses, the baseline level which most
effectively differentiated between a high and low probability of SVR in the
total population was 400,000 IU/ml with a sensitivity and specificity of 0.43 and
0.78. It could be shown that the SVR rate in patients with VL ≤400,000
IU/ml was 70%, as compared to 46% in patients with baseline VL >400,000
IU/ml (p<0.0001). In contrast choosing the 800,000 IU/mL VL cut-off, SVRs
were 58% and 45% in patients with low and high VL (p=0.007). Furthermore
analyzing the 72 weeks treated patients only the 400.000 IU/mL VL cut-off was
predictive for SVR (66% vs. 48% in low vs. high VL, p=0.01), but not the
800.000 IU/mL cut off (57% vs. 48% in low vs. high VL, p=0.2). Also in
predicting virologic relapses the 400,000 IU/mL pre-treatment VL cut-off proved
to be superior to the 800.000 IU/mL cut-off. Thus we could show in the 72 weeks
treatment group that the virologic relapse rates were statistically highly
different when comparing the baseline VL ≤400,000 vs. >400,000 IU/mL
(6% vs. 29% in low vs. high VL;p=0.001). These clear differences disappeared
when a baseline cut-off of 800,000 IU/mL was used (17% vs. 29% in patients with
low and high VL; p=0.11). In the 48 week group the relapse rates with respect
to low vs. high VL cut-off of 400,000 or 800,000 IU/mL were 15% vs. 36%
(p=0.004) or 24% vs. 36% (p=0.08), respectively.
Conclusion:
This analysis shows that a baseline HCV RNA level of
approximately 400,000 IU/mL has the highest statistical power to predict SVR as
well as relapse rates in HCV type 1-infected patients treated for either 48 or
72 weeks with peginterferon-alpha-2a plus ribavirin. Use of this cut-off point
will allow treatment optimization in genotype 1 patients.
#351. Treatment with peg-interferon and ribavirin therapy in dialysis patients with chronic hepatitis C.
A. C. Tan; R. A. de Vries; R. Adang; S. Konings; N. Cnossen; S. W. Schalm; R. van Leusen.
Background and aims:
In hemodialysis patients, it is advisable to eliminate HCV
before transplantation as reactivation after kidney transplantation and
decreased survival has been described. Standard therapy consists of pegylated
interferon (PEG-IFN) with ribavirin for 48 weeks in genotype 1/4 and for 24 weeks
in genotype 2/3. Sustained response (negative HCV-RNA 6 months after treatment)
is reached in 50 – 80 %. Ribavirin is discouraged in renal insufficiency due to
accumulation and severe (hemolytic) anemia. We studied the effectiveness of low
doses of ribavirin, titrated by measuring serum levels and hemoglobin (Hb),
combined with PEG-IFN-alfa 2a (40kd).
Methods:
7 caucasian patients on chronic hemodialysis participated in
the study; 4 patients with genotype 1b, 1 with 4c/d, 1 with 2a, and 1 with 3a.
Ribavirin was started at a low dose of 200 mg each other day. Subsequent dose
changes were based on Hb and ribavirin serum level monitoring (target range 1.5
– 2.5 mg/ml). PEG-IFN-alfa 2a was given in a dose of 135 microgram weekly.
Treatment was continued for 48 weeks in genotype 1 and 4, and for 24 weeks in
genotype 2 and 3.
Results:
In 5 patients the ribavirin dose was increased to a max of
200 mg each day. In the other 2 the dose was kept at 200 mg each other day.The
PEG-IFN dose was reduced to 90 microgr/week in one patient.Despite an increase
of the weekly erythropoietin dose a max of 2 red cell transfusions was given to
4 patients. HCV-RNA showed an end-of -treatment response in all
patients.Sustained response was accomplished in 5 of them.There were no serious
adverse events.
Conclusion:
Using PEG-IFN alfa 2a (40 kd) and ribavirin, dosed using
serum levels, a sustained response was accomplished in 5 out of 7 chronic
hemodialysis patients. An acceptable Hb-level could be maintained by an
increase of the erythropoetin dose in all and a max of 2 blood donations in 4
patients. The treatment was tolerated quite well. This result is well-matched
with the result in normal kidney function. Keeping the ribavirin levels in the
therapeutic range contributes to the tolerability and safety of the treatment.
#352. IL-10 levels during treatment with PegIFN-alpha 2b and Ribavirin in patients with Chronic Hepatitis C of different genotypic constitution.
K. Kaligeros; N. Margetis; E. Vergopoulos; V. Arseniou; D. Tsakalia; M. Kokkinou; E. Karkantzos; M. Demonakou; M. Agioutantis.
Aim:
The aim of this study was to demonstrate if IL-10 levels vary
in relation to hepatitis C genotypes (1, 4-2,3) and to identify their
correlation with a better response to the treatment of genotypes 2 and 3.
Methods:
80 patients with chronic hepatitis C, with at least 6 months
abstinence from treatment, without any comorbidities (42 men, 38 women, average
age 40) were divided into Group A: 36 patients genotype 1,4 and Group B: 44
patients genotype 2,3. There were no differences in sex and age between the
groups. Eleven subjects free of hepatitis C served as control.
All patients had liver biopsy and viral load was measured by Roche
Cobas Amplicor. They received pegylated interferon a-2b 1.5 ug/kg and ribavirin
800-1200 mg/d. The IL-10 levels were measured using Elisa Biosource
immunoenzymatic method before treatment and at 8 and 24 weeks during treatment.
Results:
Before treatment, the IL-10 levels showed no considerable
differences between the groups with no correlation to the viral load, degree of
hepatic fibrosis or the transaminases levels. (Group A: average value 30 pg/ml,
Group B: average value 25 pg/ml). The average value of IL-10 levels in the
control group was 1.5 pg/ml.
At 8 weeks during treatment the average values of IL-10 were
20 pg/ml in group A and 8 pg/ml in group B and at 24 weeks 15 pg/ml and 8 pg/ml
respectively. SVR in group A was 51% and 89% in group B.
Conclusions:
The rapid decline of IL-10 levels in group B compared to
group A seems to boost the antiviral action of Th1 cytokines
(interferon-γ, IL-2, IL-12, TNF-a) which in turn, cause an early increase
of longer duration in CD4 and CD8 lymphocytes activity.
This may result in a more prolonged response to therapy in
patients with chronic hepatitis C genotypes 2 and 3 compared to genotypes 1 and
4.
#353. Efficacy And Safety Of Peginterferon Alfa-2a Administrated Every Five Days In Combination With Ribavirin In HCV Genotype 1-Infected Patients With Severe Fibrosis Not Responding To Weekly Administrations Of Peginterferon In Combination With Ribavirin.
C. Hezode; M. Bouvier-Alias; F. Roudot-Thoraval; E. Zafrani; D. Dhumeaux; A. Mallat; J. Pawlotsky.
Introduction:
Weekly administration of pegylated interferon (PEG-IFN) alfa
in combination with ribavirin is the standard therapy for chronic hepatitis C.
Failure of this combination to clear infection is frequent in patients with HCV
genotype 1. Viral kinetics studies have suggested that a rebound of viral
replication often occurs at the end of each week, i.e. before the new PEG-IFN
injection. This rebound could be responsible for treatment failures and could
theoretically be prevented by more frequent PEG-IFN administrations.
Methods:
We tested the hypothesis in 3 male and 4 female patients,
mean age 54.0 + 10.1 years, with HCV genotype 1 with severe fibrosis (F3,
METAVIR), who did not clear infection after weekly administrations of PEG-IFN
alfa-2b in combination with ribavirin. All patients were retreated by PEG-IFN
alfa-2a, 180 µg administered every 5 days for 12 weeks, followed by 180 µg/week
for an additional 36 weeks, combined with ribavirin (1,000 mg/day < 75 kg
and 1,200 mg/day > 75 kg) for 48 weeks.
Results:
An early virological response (> 2 log HCV RNA drop at
week 12) and an end-of-treatment virological response (HCV RNA < 50 IU/ml)
were observed in 6 out of the 7 patients. As shown in the Table, the mean HCV
RNA decline at week 12 was significantly more pronounced during the second
treatment (frequent PEG-IFN administration) than during the first one (weekly
PEG-IFN administration): 3.66 ± 1.35 log IU/ml versus 0.70 ± 0.46 log IU/ml,
respectively. Overall, 4 patients achieved a sustained virological response, 2
patients relapsed and 1 patient did not respond to therapy.
Tolerance was similar to previous reports with weekly
administrations of PEG-IFN combined with ribavirin. No dose interruptions or
treatment discontinuations were needed due to adverse events or laboratory
abnormalities.
Conclusion:
In conclusion, more frequent administrations of PEG-IFN alfa
in combination with ribavirin induce a sustained virological response in a
substantial proportion of patients with HCV genotype 1 infection and severe fibrosis
who did not respond to prior standard PEG-IFN-ribavirin combination.
Prospective, randomized controlled studies are now needed to confirm the
interest and evaluate the global results of frequent PEG-IFN injections in
difficult-to-treat patients with chronic hepatitis C.
|
Patients |
First treatment |
First treatment |
First treatment |
Second treatment |
Second treatment |
Second treatment |
|
1 |
6.34 |
5.08 |
1.26 |
6.42 |
<1.70 |
≥4.72 |
|
2 |
5.67 |
5.44 |
0.23 |
5.65 |
3.62 |
2.03 |
|
3 |
5.40 |
4.32 |
1.08 |
5.89 |
<1.70 |
≥4.19 |
|
4 |
6.42 |
6.25 |
0.17 |
6.27 |
> 1.70 |
≥3.48 |
|
5 |
5.96 |
4.80 |
1.16 |
6.25 |
<1.70 |
≥4.5 |
|
6 |
5.39 |
4.92 |
0.47 |
5.31 |
<1.70 |
≥3.61 |
|
7 |
6.41 |
5.91 |
0.50 |
6.75 |
5.15 |
1.59 |
#354. Transient elastography (Fibroscan©) in chronic hepatitis c. Will it modify the assessment and the follow-up of treated patients?
F. Serejo; R. Marinho; A. Costa; J. Velosa; A. Fernandes; M. Carneiro de Moura.
Aims:
To evaluate the interest of hepatic elastography for the
assessment and monitoring of histological response in chronic HCV patients
submitted to antiviral therapy, comparing with a control group.
Methods:
25 normal individuals and 158 chronic hepatitis C patients
with liver biopsy (less then 3 years) were included, 69 treated with Peginterferon+
ribavirin (SVR- 30; Relapsers (RR)- 7; NR- 32). Histological activity index
(HAI) was graded according Knodell / Peter Scheuer: 47 patients F3/4; 111
patients F0/2. Liver stiffness was measured using Fibroscan©, median in 25
controls= 4.5 Kpa (3.30 – 5.69) and was correlated with clinical and
laboratorial data including serum aminoterminal propeptide of procollagen type
III (PIIIP RIA 25 controls= 0.4 ± 0.2 U/L).
Results:
A significant correlation was found between liver stiffness
and HAI (p< 0.003). Median liver stiffness was 12.55 Kpa (9.10 - 16.24):
F0,1 - 4,92 kPa (4,21-6,17) vs F2,3,4 - 6,81 kPa (5,14-15,95), P =0,006; F0,1,2
- 5.90 kPa (4,85 – 7,25) vs F3/F4 – 12,55 kPa (9,10-16,24), P =0,001. Median
liver stiffness for detection of cirrhosis: 13.75 KPa (11.44-27.05), p=0.001.
Optimal stiffness cut-off values for fibrosis stage assessment were determined
by ROC curve analysis in 60 patients with concomitant liver biopsy specimens
that contain more then 10 portal tracts. Optimized cutoff: F≥ 2 - 5,43
(AUC- 0,79; Se- 0,78; sp- 0,67; PPV- 0,98; PNV- 0,25); F≥3 – 8,18 (AUC-
0,96; se- 0,95; sp- 0,93; PPV- 0,87; PNV- 0,97); F4- 10,08 (AUC- 0,98; se-
0,93; sp- 0,93; PPV- 0,82; PNV- 0,98). The cut-off level of PIIIP for exclusion
cirrhosis was 0.65 U/ml (se- 83%; sp- 60%; NPP= 96%). A significant correlation
of liver stiffness was seen with age (p= 0.009), cholesterol (p= 0.04),
triglycerides (p= 0.04), HOMA (p< 0.03), GGT (p= 0.006), AST (p< 0,0005);
ALT (p< 0,0005) and PIIIP (p< 0.001). After therapy, median Liver
stiffness in SVR was 5.13 Kpa (4.27-6.05), lower then in NR- 8.02 Kpa (
5.78-22.06), p< 0.0005 and similar to the control group-4.5 Kpa (3.30 –
5.69)
Conclusions:
These preliminary results suggest that Fibroscan® is able to
differenciate the different stages of fibrosis and correlates with other
parameters of progressive liver fibrosis (age, GGT, HOMA, PIIIP). In sustained
virological response values were similar to those observed in controls.
Fibroscan may become a useful and reliable method for the non invasive
follow-up of treated HCV patients. Evaluation of the early response to
antiviral therapy (1 and 3 months) in patients with genotype 1 should be
investigated.
(The authors would like to thanks Dr Vasco Lança and Mauro
Conde for statistical analysis).
#356. Development of HCC in Patients who Achieve SVR to IFN-Based Therapies is Associated with Cirrhosis and Prior HBV Exposure.
M. J. Tong; S. Tu; J. Chen; L. M. Blatt.
Introduction:
The long term benefit of IFN-alpha + ribavirin therapy in
chronic Hepatitis C patients who achieve an SVR is largely unknown however;
previous studies have reported evolution of hepatocellular carcinoma (HCC) in
some patients.
Methods:
To assess clinical benefit of SVR in our community practice,
we examined 236 patients with SVR following standard IFN, standard IFN +
ribavirin or Peg-IFN + ribavirin therapy. Patients were assessed for HCV RNA
and development of cirrhosis and HCC during follow-up. The mean follow-up time
was 46.96 ± 2.5 months. All but one patient (99.57%) remained HCV RNA negative
throughout the follow-up. At baseline 40% of patients were HCV Genotype 1, mean
HCV RNA was 5.94 ± 0.8 log10 copies/mL, 46 (20%) patients had cirrhosis and 42
(37%) were anti-HBc and/or anti-HBe positive (all patients were HBV DNA negative).
Results:
During follow-up, no patient developed cirrhosis however 9
patients with cirrhosis (4%) developed HCC and 2 patients (0.8%)with cirrhosis
developed liver failure and required liver transplant. Univariate analysis of
variables significantly associated with HCC revealed lower mean serum albumin
and platelet counts, prior HBV exposure (anti-HBc and/or anti-HBe +), presence
of cirrhosis prior to therapy and HCV genotype 1 as significant (p<0.05 for
all observations). Multivariate analysis revealed anti-HBc and/or anti-HBe
positivity and cirrhosis as independent predictors of HCC (anti-HBc and/or
anti-HBe + OR 12.5 (1.9-248) cirrhosis at baseline OR 13 (2.5-99) p<0.05 for
all observations).
Conclusion:
·
Chronic
hepatitis C patients who achieve SVR may still be at risk for development of
HCC.
·
Patients
with prior exposure to HBV and cirrhosis prior to obtaining an SVR are 12.5 and
13 times more likely to develop HCC, respectively, compared with patients
without these risk factors.
·
Patients
with these risk factors should be monitored closely for development of HCC even
if they achieve an SVR following therapy.
·
Further
study is warranted.
#357. Homeostasis Model Assessment (HOMA) as a Measurement
of Insulin Resistance is Related to Race, Stage, Grade, Body Mass Index but not
to Virologic Response to Treatment.
W. Cassidy; B. Yoffe; J. Phillips; J. McCone; R. Muhumuza; N. Bailey; E. Britton; A. Lambert; R. Horswell.
Goal:
Increasing insulin resistance (IR) is thought to lessen
immunologic response. This is an interim analysis of a study looking at the
influence of IR upon virologic response rates seen in chronic hepatitis C
infected patients treated with pegylated interferon alfa 2b (P-INF) &
weight-based ribavirin (RIB).
Methods:
Data accumulated as part of a multicenter trial that examined
the relationship between HOMA score, other clinical factors & response to P-INF/RIB
therapy. Of the 400 patients, 395 enrolled. Of that number, 241 were genotype
(GT) 1 patients with at least week 12 data. IR was assessed using HOMA score
calculated as (fasting glucose (mg/dl) / 18.5) x (fasting insulin level/22.5).
HOMA & viral load were measured at baseline, weeks 12, 24, 48, 72 or 24
weeks after last dose in a 12 week responder with early discontinuation.
Biopsies were performed within 2 years of beginning therapy. An instrumental
variables statistical model was used to assess the marginal relationship of
HOMA on viral response after adjusting for other covariates, including African
American race (AA) vs. non-AA, age, gender, biopsy grade & stage (Metavir),
body mass index (BMI) & baseline viral load. As most patients do not yet
have week 72 data, response to therapy (dependent variable in the model) was
defined as an undetectable viral load at the latest available test (for those
with viral load tests at 24 weeks or longer) or a 2+ log decline in viral load
from baseline to week 12 for those with only week 12 follow-up viral loads
available.
Results:
The unadjusted HOMA relationship to viral response was not
statistically significant (p = 0.349) & the adjusted HOMA effect was even
less (p = 0.788). HOMA scores are related to covariates that appear to assess
burden of HCV-related liver disease. For example, there is a monotonic
relationship between stage & HOMA (p < 0.001). This relationship appears
to hold for AA & non-AA regardless of BMI. HOMA is also independently
related to BMI (p < 0.001).
Conclusion:
These results suggest that HOMA score (& IR) are
influenced by degree of HCV-related liver damage and also by BMI, but HOMA was
not found to be related to virologic suppression after adjusting for other
factors related to treatment success.
Relationship
of mean HOMA score and Stage
|
|
All
Patients |
AA |
Non AA |
BMI≤27
|
BMI>27
|
|
Stage 0 |
2.07 |
3.66 |
1.83 |
2.09 |
2.05 |
|
Stage 1 |
2.47 |
2.46 |
2.47 |
2.02 |
2.85 |
|
Stage 2 |
3.06 |
3.52 |
2.90 |
2.44 |
3.46 |
|
Stage 3 |
3.43 |
3.50 |
3.34 |
2.45 |
4.40 |
|
Stage 4 |
3.97 |
4.43 |
3.67 |
3.05 |
4.54 |
|
Total |
2.97 |
3.48 |
2.75 |
2.35 |
3.47 |
#358. An Interim Analysis of the Canadian POWeR Program (Peginterferon alfa-2b Prospective Optimal Weight-Based Dosing Response): Consistent SVR Rates Across All Weight Categories.
P. Marotta; S. V. Feinman; C. Ghent; L. Scully; M.
Varenbut; J. Daiter; H. Witt-Sullivan; J. Robert; R. J. Bailey; B. Romanowski;
J. Farley; N. Abadir.
Introduction:
• Pegylated interferon (PEG-IFN)
alfa–based therapy in combination with ribavirin (RBV) is the current gold
standard of treatment for patients with chronic hepatitis C.
• Numerous studies have shown an
inverse relationship between body weight and virologic response when PEG-IFN
alfa alone or in combination with RBV are administered as flat doses.1-3
• A recent study showed that a
weight-based approach to PEG-IFN alfa and RBV dosing may improve treatment
outcomes in patients with higher body weight without compromising the responses
of patients with lower body weight.
• The WIN-R study, a large
community-based trial conducted in the United States, showed a significantly
improved response in patients receiving weight-based PEG-IFN alfa-2b
(PegIntron®) in combination with weight-based RBV compared with those who
received flat RBV dosing.5 Response rates were consistent across all weight
categories.
Aim:
The Pegetron Prospective Optimal Weight-Based Dosing Response
program (POWeR) is a large, open-label, mixed community- and academic-based
clinical outcomes program that evaluates the impact of baseline
viral and patient factors on sustained virologic response
(SVR) in patients with chronic hepatitis C who received treatment with
weight-based PEG-IFN alfa-2b and weight-based RBV.
Methods:
Study Design
• Open-label, prospective, community-
and academic-based therapeutic outcomes study conducted in treatment-naive
patients with chronic hepatitis C.
• Patients were enrolled at 138
academic and community clinics across Canada between December 2002 and August
2005.
• Patients were treated, followed up,
and managed according to current treatment guidelines and standard of care at
each site, with no study-related intervention beyond collection of data.
Patients
• At baseline the following patient
characteristics were recorded:
— Body weight: <50 kg, 50 to
<64 kg, 64 to <75 kg, 75 to <85 kg, ≥85 kg.
— Hepatitis C virus (HCV) genotype
(G): G1, G2, G3, or other.
— Extent of fibrosis (METAVIR score
F0-F4 determined by liver biopsy).
• PEG-IFN alfa-2b (1.5 μg/kg/wk)
plus weight-based RBV (800-1200 mg/d) was given according to standard of care
(for 24 weeks in G2/3 patients and for up to 48 weeks in G1 patients).6,7 Early
in the program, a week 12 virologic assessment was introduced as a standard of
care in G1 patients. G1 patients who did not have undetectable HCV RNA or at
least a 2 log10 drop from baseline viral load by week 12 were generally
discontinued from treatment.
Efficacy Assessments
• Two separate analyses were
conducted to determine response:
— Outcomes analysis: Patients with
completed and queried case report forms, including those who discontinued for
any reason, including nonresponse. In this analysis, patients who had
detectable
HCV RNA at end of treatment (EOT) and
for whom no SVR data were available were considered nonresponders.
— Completer analysis: Study
population for whom both final EOT and SVR data were available.
• EOT response was defined as
undetectable HCV RNA (<50 IU/mL) after completion of therapy.
• SVR was defined as undetectable
serum HCV RNA (<50 IU/mL) 24 weeks after EOT.
Baseline Demographics
• A total of 2194 patients were
enrolled in POWeR.
• Patient demographics were similar
in both analyses (Table 1). Most patients had HCV G1 (~60%); 58% of these
patients had high viral load at baseline (defined as >600,000 IU/mL or >2
million copies/mL
according to the local laboratory).
• A sizable proportion of patients
had severe fibrosis or cirrhosis (F3-F4, ~37%) and approximately 60% of
patients enrolled
Overall Virologic
Response and Discontinuation
• SVR was attained in 64% of patients
in the completer analysis and in 55% of patients in the outcomes analysis.
• 459 (25%) of 1820 patients included
in the outcomes analysis discontinued treatment prematurely (ie, did not
receive a full 24 or 48 weeks of treatment) and were nonresponders in the
analysis.
SVR by Body Weight and
Degree of Fibrosis
• Chi-square analysis was performed
comparing the lowest SVR weight class (75-85 kg) to the mean of the other
weight categories. Consistent with data previously reported there was no
statistically significant difference in SVR rates across patient weight
categories (P = .17) in either analysis.
• SVR rates decreased with increasing
levels of hepatic fibrosis. In the patients with available biopsy data, there
was an inverse relationship between SVR rates and baseline fibrosis stage. SVR
rates (completers
and outcomes analysis) were highest
in patients with F0-F1
SVR by Genotype
• Response rates for G1 patients were
52% and 42% in completer and outcomes analyses, respectively.
• G2 patients exhibited the highest
SVR rates (87% and 80%, respectively).
• Response rates in G3 patients were
80% and 72%, respectively.
Relapse rates
• Recognizing the limitations of an
interim analysis, relapse rates were calculated using the same patients for
whom both EOT and SVR data are available as of September 2006 (best-case
scenario).
— When PEG-IFN alfa-2b and RBV both
were dosed by weight, the overall relapse rate was low (11%).
— When stratified by genotype,
relapse rates were higher in G1 patients (16%) than in G2 and G3 patients (7%
each).
Conclusion:
In this large,
population-based study, treatment-naive patients with chronic hepatitis C were
enrolled to receive weight-based PEG-IFN alfa-2b (1.5 μg/kg/wk) plus
weight-based RBV (800-1200 mg/d).
— Patients did not conform to any
inclusion/exclusion criteria and were managed by individual physicians by
standard of care only.
— At baseline, more than one third of
patients had advanced fibrosis (35%, >F3) and 58% of G1patients had high
viral load.
• Even with these poor prognostic
characteristics, interim results of the POWeR study revealed excellent SVR
rates. Importantly, the SVR rates were consistent across all weight categories.
• Patients with G2 chronic hepatitis
C had the highest SVR rates, followed by patients with G3 and G1.
• Further analysis is required to
complete the program and report SVR in all patients enrolled. More accurate
relapse rates will then be defined.
|
Weight, kg (n = 1476) |
<50 |
50-<64
|
64-<75
|
75-<85
|
>85 |
|
SVR (%) |
57 |
56 |
54 |
52 |
56 |
|
Patients
(number) |
54 |
291 |
394 |
449 |
621 |
#359. Therapy A la Carte Is More Cost-Effective Than Standard Combination Therapy For Naive Patients With Chronic Hepatitis C.
M. Buti; M. A. Casado; R. Esteban.
Purpose:
Monitoring rapid virological response (RVR; undetectable HCV
RNA at week 4) and early virological response (EVR; undetectable HCV RNA at
week 12) rates are important tools that can be used to tailor duration of
peginterferon and ribavirin therapy in patients, limiting side effects and
costs. The purpose of this study was to analyze the financial impact of therapy
a la carte (TALC) compared with standard combination therapy (SCT) for a
population of treatment-naive patients infected by genotype 1 (G1, 74%), 2, and
3 (G2/3, 26%) from the perspective of the Spanish Health Care System.
Methods:
A budgetary impact model was constructed using a
decision-tree analysis to compare (a) SCT: peginterferon alfa-2b and
weight-based ribavirin for 24 weeks (G2/3) or 48 weeks (G1) with a 12-week
stopping rule for non-EVR and (b) TALC: the same therapy dosage but different
duration depending on RVR and HCV genotype: G1 and RVR, 24 weeks of therapy; G1
and no RVR, 48 weeks; G2/3 and RVR, 12 weeks; G2/3 and no RVR, 24 weeks. SVR
results and costs were assumed from published studies.
Results:
·
STC
and TALC strategies both resulted in similar SVR rates.
o
50%
of patients receiving SCT and 55% of those receiving TALC
·
Total
costs were higher with SCT than with TALC
o
Total
costs were $301,527,236 for SCT and $226,318,631 for TALC
o
Overall,
TALC would save $301,527,235 for SCT and $226,318,631 for TALC
·
Cost
per patient who achieved an SVR was lower with TALC than with SCT
o
Cost
per patient who achieved an SVR was $22,657 for SCT and $15,662 for TALC
o
TALC
would result in saving of $6995 per patient who achieved an SVR, corresponding
to $31% savings per SVR
o
Cost
savings per patient who achieved an SVR are greater in patients with G1 than in
patients with G2/3 ($10,125 vs. $2657).
Conclusions:
·
RVR
is an important predictor of treatment outcome in patients receiving PEG-IFN
alfa-2b plus RBV.
·
Healthcare
costs associated with the treatment of chronic hepatitis C can be reduced by
monitoring RVR to determine treatment duration.
·
TALC
represents an effective approach for minimizing the healthcare costs associated
with treatment of chronic hepatitis C without compromising SVR rates.
|
|
SCT |
TALC |
Difference |
|
Overall SVR (%) |
50 |
55 |
–5 |
|
SVR G1 (%) |
41 |
46 |
–5 |
|
SVR G2/3 (%) Cost |
76 |
79 |
-3 |
|
Overall Cost (US$) |
|
|
|
|
100 pts |
1,160,624 |
972,623 |
188,001 |
|
74 G1 pts |
939,133 |
799,933 |
139,200 |
|
26 G2/3 pts |
221,491 |
172,690 |
48,801 |
|
Cost/patient with SVR (US$) |
21,509 |
16,863 |
4,646 |
|
G1 pts |
30,217 |
21,522 |
8,695 |
|
G2/3 pts |
9,681 |
8,420 |
1,261 |
#361. Re-infection following successful treatment for Hepatitis C virus Infection with either alpha interferon or pegylated interferon/ribavirin combination therapy.
J. D. Farley; Y. Al-Khafaji; T. Mikami; W. Shum; T. A. Farley.
Background:
Until recently, there has been much reluctance to treat
hepatitis C virus (HCV) infection in illicit intravenous drug users (IVDU) who
now account for most of the chronic and new infections in Canada. One of the
reasons advanced for not treating, has been because of the likelihood of
re-infection. However, current treatment recommendations do not routinely
monitor these individuals after sustained virologic response (SVR): following
the end of treatment (EOT).
Objective:
To access the likelihood of re-infection in individuals who
were successfully treated with either alpha interferon or pegylated interferon
/ ribavirin combination therapy.
Method:
We reviewed the medical charts of all the patients who were
treated for and became re-infected with HCV.
173 pateints were identified as followed up for a range of six month to
four years. We assumed that re-infection
happened halfway between the date of the last negative test result and the date
of the first subsequent positive test result for HCV.
Results:
We identified eight (7) IVDUs, who became re-infected with
HCV after SVR. There were all former
IVDUs. Four likely resulted from IVDU,
two from tattoos and one from blood splash (during a fight). On an average, reinfection occurred 43.23
weeks after checking for SVR.
Conclusion:
·
We
have documented seven cases of re-infection of HCV in former intravenous drug
users following successful treatment for their chronic HCV.
·
We
feel that re-infection may be a more frequent occurrence than is currently
reported.
·
Current
protocols do not usually emphasize any type of counselling (or monitor and
following-up) after SVR/EOT.
·
We
believe that patients (especially IDUs) should be counselled before, during and
after treatments about the possibility of re-infection. Counseling should include risk factors such
as tattooing, sexual and direct blood contact.
There should also be ongoing monitoring and follow-up of these patients
for more than six months post treatment (probably a minimum of two to four
years) to reinforce harm reduction.
#362. Title: A Meta – Analysis of HCV Treatment in HIV Co – infected Patients.
A. Bonder; B. B. Shah; J. B. Wong.
Background and Aims:
Treatment of HCV/HIV co-infected patients has been associated
with high rates of intolerance and low response rates. The aim of this study
was to assess the efficacy of combination therapy with peginterferon plus
ribavirin (PegIFN+RBV) versus interferon plus ribavirin (IFN+RBV) in
co–infected patients.
Methods:
We performed a systematic review of MEDLINE from 1966-2006.
Sustained virological response (SVR) was pooled using the DerSimonian and Laird
random effects model. Subgroup analyses of SVR by study population
characteristics were explored.
Results:
13 trials: 6 randomized controlled trials (RCT) = 7
Non-RCT
|
|
RCT (n=1216) |
Non-RCT (n=216) |
|
Age (mean, range) |
38 (33.45) |
35 (25-47) |
|
Men (mean, range) |
79% (43-100%) |
75% (64-95%) |
|
HAART (mean, range) |
86% (68-100%) |
90 (70-100%) |
RCT Results:
|
|
IFN+RBV SVR (95% CI) |
PEG+RBV Risk Difference (95% CI) |
|
Intention to Treat (n=1216) |
16% (12-22%) |
16% (0.036-31%) |
|
Treatment Completers (n=853) |
33% (27-83%) |
16% (0.36-31%) |
|
|
IFN+RBV (95% CI) |
PEG+RBV Risk Difference (95% CI) |
|
Early Viral Response (2 trials, n=957) |
33% (27-83%) |
20% (-0.04-44%) |
|
RCT |
IFN+RBV N=599 |
PEG+RBV Risk Difference (95% CI) n=617 |
|
Adverse Events* |
13% (11-16%) |
2.3% (-1.5-6.2%) |
|
Withdrawals
Adverse effects
Insufficient response Decline continuation |
13% (11-16%) 4.6% (3.0-7.0%) 2% (4.2 -8.8%) |
2.3 (-1.5-6.2%) 3.2% (-7.4-1.1%) 1.9% (-4.8-8.8%) |
Most
common: flu-like illness, depression and
haematological complications
|
|
SVR (95% CI) |
|
|
|
IFN+RBV 4 studies (n=89) |
PEG+RBV 3 studies, n=127 |
|
Non-RCTs |
33% (20-49%) |
38% (20-59%) |
Conclusions:
·
Compared
with IFN+RBV, PegIFN+RBV significantly improves SVR in HCV/HIV co-infected
patients.
·
The
largest benefit occurs in men, CD4>500, HCV RNA>1 million and patients
who do not drink.
·
Close
psychiatric and hematological monitoring may improve response rates further.
#363. Therapeutic Efficacy of 24 Weeks’ Antiviral Treatment in Addicted Patients on Methadone Maintenance Therapy Who Have Chronic Hepatitis C, Genotype 1, With Low Baseline Viremia.
M. Simonova; K. Katzarov; D. Takov; N. Tomov; D. Z.
Aleksieva; G. N. Vasilev; E. Belokonski; N. Vladov.
Introduction:
Despite the high prevalence of HCV, there are few data about
its treatment in injection drug users. Methadone maintenance therapy (MMT) is
currently the most effective pharmacological treatment for chronic heroin
addiction. It dramatically reduces recidivism and assists the majority of those
taking it to achieve medical, psychological, and psychosocial stability. This
study aimed to assess the therapeutic efficacy of 24-week combination therapy
with pegylated interferon alfa 2b and ribavirin in addicted patients on
methadone maintenance therapy who had chronic hepatitis C, genotype 1, low
baseline viremia.
Patients and Methods:
Of 150 addicted patients on MMT with naive G1 low viral load
chronic HCV infection, aged 17-36 years and screened for the study, 68
fulfilled the enrollment criteria: ALT >1.5 ULN, baseline HCV RNA < 600
000 IU/ml (Amplicor® HCV test; Roche), genotype 1, naive to interferon,
HBV/HIV-negative, methadone dose up to 150 mg/daily. Liver biopsies were
performed in all patients and assessed by METAVIR. Early virological response
was measured quantitatively at week 12, end-of- treatment (ETR) and sustained
virologic response (SVR) was measured qualitatively at 24 weeks and 24 weeks
after treatment, respectively. Patients were treated with pegylated interferon
alfa 2b 1.5 μg/kg/weekly and ribavirin 800-1200 mg/daily according to body
weight for 24 weeks.
Results:
63 patients completed full treatment and follow-up duration
periods. ETR was observed in 49/63 patients (78%) and SVR was observed in 42/63
patients (67%). 51/63 patients (81%) who had RNA HCV <600 IU/ml at week 12
achieved SVR and no initial non-responder at week 12 achieved SVR. Dose
reductions for adverse events were required in 14/68 (20%) patients, mainly on
methadone dose higher than 100 mg/daily. Discontinuation of the therapy was
observed in 5/68 patients (7%) – 2 SAE and 3 for noncompliance to treatment
regiment.
Conclusion:
Twenty-four weeks of treatment with pegylated interferon alfa
2b 1.5 μg/kg/weekly and Ribavirin 800-1200 mg/daily appears to be an
acceptable regimen for the addicted patients on MMT with chronic hepatitis C,
genotype 1, low baseline viremia.
#364. PREDICTORS OF RELAPSE AND OF SUSTAINED VIROLOGIC RESPONSE IN PATIENTS WITH HCV GENOTYPE 3 WITH AND WITHOUT HIV CO-INFECTION: BASIS FOR AN “A LA CARTE” TREATMENT.
M. Puoti; E. Minola; B. Zanini; G. Quinzan; A.
Spinetti; S. Zaltron; L. Biasi; M. Antonini; M. Airoldi; C. Baiguera; P.
Pagani; K. Prestini; F. Zacchi; P. Nasta; O. Fracassetti; S. Fredy; G. Carosi.
Aim:
In order to optimise anti-HCV treatment in patients with HCV
G3 infection we analysed data of all consecutive HCV G3 infected patients with
and without HIV coinfection who underwent anti HCV treatment in 2 infectious
diseases departments with pegylated interferons (Pegasys 180 mcg/w or Pegintron
1-1.5 mcg/w) in combination with weight adjusted ribavirin (10,6-15 mg/Kg/day)
from 2001 to 2005. Logistic regression analysis has been used for multivariate
analysis.
Results:
Three hundred and twelve patients have been studied: age was
> 40 years in 31%, 25% were female, 72% were previous IDU, 40% HIV
coinfected, 38% with METAVIR F3-F4, 49% with HCVRNA > 600.000 IU/mL, 32%
with ALT > 3x UNL. Median treatment duration was 17.5 weeks in HIV -
patients (IQR 14-26) and 27 weeks in HIV+patients (IQR 22-28). Treatment was
stopped prematurely in 18% for adverse events and in 20% voluntarily Seventy
percent showed SVR; 13% of 256 patients with End Of Treatment Response (EOTR)
treated for at least 8 weeks after HCVRNA clearance relapsed : 3% of HIV- and
38% of HIV+(p<0.0001) Logistic regression analysis showed that SVR was
independently and significantly associated with: HIV co-infection (AOR 0.21 95%
CI 0.10-0.46) and with 4 baseline characteristics: HCVRNA > 600.000 IU/mL at
baseline (AOR 0.45 95% CI 0.20-0.47), advanced fibrosis (AOR 0.39 95% CI
0.18-0.93), ALT > 3 x UNL (AOR 0.35 95% CI 0.16-0.76), female gender (AOR
2.79 95% CI 1.01-7.16). HCVRNA clearance at 4 weeks was also independently
associated with SVR (AOR 4.49 95%CI 2.49-8.10). In patients with EOTR treated
for at least 8 weeks after HCVRNA clearance relapse was significantly
associated with HIV infection (AOR 18.92 95%CI 5.99-79.80), clearance of HCVRNA
for <20 consecutive weeks during treatment (AOR 0.11 95% CI 0.04-0.25) and
at least 2 predictors of poor response (PPR) at baseline ( AOR 5.06 AOR
1.42-17.99). Only 14% of 29 patients with >2 PPR treated for < 20 weeks
after HCVRNA clearance relapsed (p<0.01 vs. other subgroups). In patients
with HIV infection treated for < 20 weeks after HCVRNA clearance relapse was
observed in 37% of those with <2 PPR and in 52% of those with >2 PPR
(p>0.05). In HIV+ treated for > 20 weeks after HCVRNA clearance relapse
was observed in 16% of those with >2 PPR but in none of those with <2 PPR
(p= 0.02).
Conclusion:
Our data suggest that anti HCV treatment should be conducted
for 8-16 weeks after HCVRNA clearance in HIV- without more than 1 PPR (male
gender, high baseline HCVRNA, advanced fibrosis and ALT > 3 x UNL) , for 20
weeks after HCVRNA clearance in HIV- with 2 or more PPR, in all HIV+ for at
least 20 weeks after HCVRNA clearance .
#365. The PRESCO trial: impact of higher ribavirin doses
and longer duration of therapy with peginterferon alfa-2a plus ribavirin in
HIV-infected patients with chronic hepatitis C.
M. Nunez; J. Garcia-Samaniego; M. Romero; J. Portu; P.
Barreiro; L. Bonet; M. Cordero; M. Gonzalez; P. Lopez-Serrano; V. Soriano.
Background:
The treatment of chronic HCV infection has become a priority
in HIV+ patients, given the faster progression to end-stage liver disease in
the coinfected population. Poorer response in this group of patients compared
to HCV-monoinfected individuals has been reported.
Methods:
In a prospective, multicenter, open, comparative trial,
HCV/HIV-coinfected patients with elevated ALT who had not previously been
exposed to interferon were treated with pegylated interferon alfa-2a (180 mcg
per week) plus ribavirin (1,000 mg daily if body weight <75 Kg; 1,200 mg
daily if >75 kg). Patients with HCV genotypes 1 and 4 (61%) were treated for
48 or 72 weeks, while patients with HCV genotypes 2 and 3 (39%) were treated
for 24 or 48 weeks. Patients without early virological response discontinued
therapy at 12-24 weeks.
Results:
Out of 389 patients included in the trial, 137(61%) were infected
by HCV-1/4 and 67% had high HCV RNA levels. Treatment was prematurely
discontinued in 46%, due to: virologic failure 17%, serious adverse events 7%,
voluntary withdrawal or lost-to-follow-up 22%. In an intent-to-treat analysis,
sustained virological response (SVR) was achieved in 49.6% patients,
significantly more frequently in patients infected with HCV-2/3 (72.4%) than 1
(35.6%) and 4 (32.6%). No significant differences in SVR were observed when
comparing short and extended treatment arms. Relapses according to length of
therapy and HCV genotype are displayed in the table. Infection with HCV-2/3,
lower baseline HCV-RNA, and negative serum HCV RNA at week 12 were independent
predictors of SVR in the multivariate analysis.
Conclusion:
Nearly half of HIV/HCV-coinfected patients treated with RBV
1,000-1,200 mg/daily plus pegylated interferon alfa-2a 180 mcg per week
achieved SVR. Response was twice higher in HCV-2/3 than HCV-1/4 carriers. The
use of higher doses of ribavirin rather than extended duration of therapy seems
to account for the good results obtained in this study.
Relapses
according to length of therapy and HCV genotype
|
Treatment |
HCV-1/4 |
HCV-2/3 |
All* |
|
Short |
(35.9%) |
(21.0%) |
(28.9%) |
|
Extended |
(27.3%) |
(17.8%) |
(21.3%) |
|
All** |
(33.6%) |
(19.7%) |
(26.3%) |
#366. Barriers to Treatment of Hepatitis C Virus in Human Immunodeficiency Virus Infected Patients in the Real Life: Modifications in Two Large Surveys between 2004 and 2006.
P. Cacoub; P. Halfon; E. Rosenthal; G. Pialoux; Y. Benhamou; C. Perronne; S. Pol.
Aim:
To analyse the barriers to HCV treatment in HIV-HCV
co-infected patients and their evolution between 2004 and 2006 in France.
Patients and Methods:
Three hundred and eighty HIV-HCV co-infected patients were
prospectively included by 71 physicians, specialists in the care of HIV
infected patients during the period November 22 to 29, 2004 (2004 survey =
Prospecth1), whereas in the second phase of the study 58 physicians included
416 patients seen from April 3 to 10, 2006 (2006 survey = Prospecth2). A
standard data collection form was used.
Results:
Demographic characteristics were similar in the 2004 and 2006
surveys: male gender (71%), mean age (42 vs. 44 years), transmission via
injection drug use (77% vs. 82%). Patients had more often undetectable HIV
viral load (70% vs. 63%) and negative HCV RNA (24% vs. 12%) in 2006 than in
2004, with a similar distribution of HCV genotypes (genotype 1 or 4 in 65%).
Patient management has changed between 2004 and 2006. Liver biopsy was done
less frequently in 2006 (38% vs. 56%) while 24% had had a non invasive liver
damage assessment. The rate of previous treatment for HCV infection was higher
in 2006 than in 2004 (51% vs. 26%). Main reasons for the non treatment of HCV
have changed between 2004 and 2006: HCV treatment deemed questionable (55% vs.
44%), no liver biopsy (34% vs. 18%), contraindication to treatment (30% vs. 26%),
physician conviction of poor patient compliance (30% vs. 20%), and patient
refusal (16% vs. 21%). In both surveys, patients having received HCV treatment
compared to those who had never received any were more commonly of European
origin, had better control of HIV infection, were followed by a hepatologist
more often, were less frequently infected by a genotype 4, and had had a liver
damage assessment more often. In the 2006 survey treated versus non treated
patients were less frequently alcohol consumers (31% vs. 40%), particularly for
high consumption > 50 g/d (6% vs. 23%) and more commonly receiving
antiretroviral treatment with NRTI plus boosted PI (72% vs. 61%)(p<0.05).
Conclusion:
Following the 2005 European Consensus Conference, the care of
HIV-HCV co-infected patients have changed significantly in "the real
life" in France. Compared to 2004, more patients in 2006 have received HCV
treatment (HCV treatment deeming less questionable), patients had more liver
damage assessment, treatment was less contraindicated, while physicians’
conviction of poor patient compliance was lower. These results underline the
importance of continuing efforts to educate physicians and patients to increase
the access of HIV-HCV co-infected patients to HCV treatment.
#367. Contraction of HCV-Specific CD4+ T cell Responses in
Patients Undergoing Antiviral Therapy Irrespective of Race and Virologic
Outcome.
J. R. Burton; J. Klarquist; K. Im; S. Smyk-Pearson; L.
Golden-Mason; H. R. Rosen.
Introduction:
Individuals who spontaneously clear HCV infection have
vigorous HCV-specific cellular immune responses, whereas persistent infection
is associated with weak responses. The effect of antiviral treatment on
cellular immunity is not clearly defined. We examined the effect of antiviral
therapy on HCV- and CMV-specific immunity according to race and viral outcome.
Methods:
Virahep-C is a multicenter NIH funded study of response to up
to 48 weeks of peg-IFN and ribavirin in 205 Caucasian and 196 African American
naïve, genotype 1 patients. Therapy was stopped in patients with detectable HCV
RNA after 24 weeks of therapy. Primary end-point was sustained virologic
response (SVR) defined as undetectable HCV RNA at 24 weeks after completing
therapy. CD4+ T cell responses were quantified by IFN-γ enzyme linked
immunospot (ELISPOT) assays in a subset of 60 patients selected to be evenly
distributed by race and viral kinetic groups at baseline, treatment week (TW)
8, 24 and 48 and 24 weeks after stopping therapy (FU24). Briefly, 2.5x105
peripheral blood mononuclear cells (PBMCs) were incubated with HCV core (aa
1-115), E2 (383-715), NS3 (1007-1534), NS4 (1569-1931), NS5 (2054-2995), and
both positive (CMV, PHA/SEB) and negative (SDS/SOD) control antigens for 40
hours with IL-2. Non-parametric Wilcoxon or Kruskal-Wallis signed rank tests
were used for paired comparisons at each study time point. A random
coefficients model was used to examine the longitudinal pattern of CD4+ T cell
responses over time.
Results:
Overall, there were significant decreases from baseline at
TW8 (median difference 38.7 ELISPOTS/2.5x105 PBMCs, p<0.0001; 85% decrease
from baseline) that remained below baseline throughout therapy, not returning
to baseline responses at FU24 (median difference 27.2 ELISPOTS/2.5x105 PBMCs,
p=0.007; 40% decrease from baseline). These decreases were comparable across
the different groups in terms of race, viral kinetics and SVR status. Though
not statistically significant, there was a trend for higher median total
IFN-γ ELISPOTs at follow-up in patients with HCV relapse after therapy
(n=9) compared to patients with SVR (n=28) (92.3 vs. 34.2 total median
ELISPOTs/2.5x105 PBMCs; p=0.076). Responses directed against CMV were
relatively preserved during antiviral therapy.
Conclusions:
Combination antiviral therapy results in contraction of
immune responses specifically directed against HCV. These decreases in the
memory population are independent of race and virologic outcome.
This study is funded
by the NIDDK through a cooperative agreement with partial support from Roche
Laboratories Inc. through a CRADA with the NIH.
#368. Better prediction of SVR in patients with HCV genotype 1 (G1) with peginterferon alfa-2a (PEGASYS) plus ribavirin: Improving differentiation between low (LVL) and high baseline viral load (HVL).
E. Zehnter; S. Mauss; C. John; R. Heyne; B. Moller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; U. Alshuth; D. Hueppe.
Introduction:
Recently, baseline VL has become an important predictive
factor in the development of a treatment algorithm in pts with G1; however, it
is unclear whether the cut-off should be 600,000 or 800,000 IU/mL HCV RNA. Both
were derived historically from 2 x 106 cps/mL using different conversion
factors for the PCR assay used. In an analysis of predictive factors using data
from a German observational study (DDW 2006, abs #219003), developed by the
Association of German Independent Gastroenterologists (bng) and Roche Pharma
AG, categorized baseline VL (800,000 IU/mL cut-off) was not significant in uni-
or multivariate analyses. Therefore, this analysis investigated the optimal VL
cut-off for SVR prediction.
Methods:
Analyses included 916 naive patients with G1 who received
treatment with peginterferon alfa-2a + ribavirin for 48 weeks according to current
guidelines and for whom complete relevant data was recorded. The influence of
logarithmic VL on SVR was estimated as a continuous variable in univariate
logistic regression (ULR) and by analyzing the receiver operating
characteristic curve (ROC). The optimized cut-off was then compared to both
existing cut-offs using multivariate logistic regression (MLR) analysis.
Results:
In ULR, continuous VL was a strong predictor of SVR
(p<.0001; OR=0.79; CI: 0.69–0.89), but the effect of VL was non-linear. The ROC-plot
revealed a cut-off level of VL of 5.6 log10 IU/mL (~400,000 IU/mL). According
to this result, the predictability of baseline VL using a cut-off level of
400,000 IU/mL, 600,000 or 800,000 IU/mL was compared by MLR. Of the three,
400,000 IU/mL best predicted SVR (p<.0001; OR=0.48; CI:0.37–0.63). Using
this cut-off, 62.0% of patients with LVL and 43.7% with HVL had an SVR. SVR
rates according to VL cut-off are shown in the table. While in pts with LVL,
SVR rate increased with decreasing cut-off, in pts with HVL, the SVR rate was
43% regardless of cut-off, i.e. pts with VL >400,000 IU/mL had low SVR rates
similar to pts with VL>800,000/mL and belong in the same VL category.
Conclusion:
The well-accepted former cut-off of 2 x 106 copies/mL was statistically optimized for treatment with standard interferon. In the era of pegylated interferon, this cut-off is not the best way to differentiate between LVL and HVL with regard to likelihood of SVR. These data suggest that to use VL as a reliable predictor of successful treatment outcome, the optimized cut-off of 400,000 IU/mL should be used.
|
400,000 IU/mL |