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 |
600,000 IU/mL |
800,000 IU/mL |
|||
|
LVL |
HVL |
LVL |
HVL |
LVL |
HVL |
|
267/431 |
212/485 |
323/552 |
156/364 |
355/628 |
124/288 |
|
62.0 |
43.7 |
58.5 |
42.9 |
56.5 |
43.1 |
SVR rate by VL
cut-off, n (%)
#369. Response to Peginterferon Alfa-2b and Ribavirin for Chronic Hepatitis C in Patients with Body Weight >125 kg: Results from the WIN-R Trial.
I. M. Jacobson; R. Brown; B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; L. Griffel; C. Brass; W. The.
Introduction/Aim:
In WIN-R, a US study of >4900 HCV patients from community
and academic sites that prospectively compared PEG-IFN alfa-2b 1.5ug/kg/wk +
fixed dosing (FD; 800 mg/d) or weight-based dosing (WBD; 800-1400 mg/d) of
ribavirin (RBV), sustained virological response (SVR) rates were significantly
greater with WBD than FD of RBV (AASLD’05). WBD patients weighing >105-125 kg
received RBV 1400 mg/d and had SVR rates similar to other WBD patients. The
current study evaluated SVR rates among patients weighing >125 kg, for whom
data are limited, who entered the study as protocol exceptions.
Methods:
In WIN-R, patients were randomized to PEG-IFN alfa-2b
1.5ug/kg/wk (max: 150 ug/wk) + FD RBV 800 mg/d or WBD RBV: <65 kg, 800 mg/d;
65-<85kg, 1000 mg/d; 85-<105 kg, 1200 mg/d; 105-125 kg, 1400 mg/d.
Genotype 1 (G1) patients received 48 wks of therapy, and G2/3 patients were randomized
to 24 or 48 wks of therapy. All patients were monitored for 24 wks
post-treatment. HCV RNA levels were determined by PCR (Taqman/SPRI, LLQ 29
IU/ml) at wks 0, 24, 48 and 72. RBV dose reductions and discontinuation were
required for hemoglobin <10 gm/dl and <8.5 gm/dl.
Results:
In total, 51 patients >125 kg were enrolled in the trial;
28 received FD RBV (800 mg/d) and 23 received WBD RBV (1400 mg/d). SVR occurred
in 47% of patients—30% of G1 and 67% of G2/3 patients, rates nearly identical
to those for the overall study cohort. SVR rates for the 28 FD RBV patients and
the 23 WBD RBV patients were 30% and 61% overall (P=.0342); 15% and 43% in G1
(P=.1315), and 50% and 79% in G2/3 (P=.1524). Only 3/49 (6%) had nadir Hgb
<10 gm/dl and 30/50 (6%) had neutrophils <750/mm3; for the
overall study cohort (n = 4913) these percentages were 16% and 19%. Dose
reductions of PEG-IFN occurred in 9/51 (18%) patients and 10/51 (20%) had dose
reductions of RBV.
Conclusion:
• Patients with very high body weight (≥125 kg) and high BMI (mean, 41.0 kg/m2) achieved SVR rates similar to those of patients weighing <125 kg.
• Patients weighing ≥125 kg were at least as likely to achieve an SVR as patients weighing ≤125 kg with weight-based ribavirin therapy.
• Patients weighing ≥125 kg were much more likely to achieve an SVR with weight-based ribavirin than with flat-dose ribavirin.
• Low rates of anemia and neutropenia and low dose-reduction rates probably reflect lower levels of ribavirin exposure.
• These results suggest that severe obesity should not preclude consideration of antiviral therapy for patients with chronic hepatitis C.
Supported
by Schering Plough.
#370. Hepatitis C screening and treatment among drug users in Amsterdam: interim results of the inclusion procedure in the Dutch C project.
K. Lindenburg; C. Weegink; J. Schinkel; P. Jansen; M. Beld; A. Krol; G. Casteelen; G. van Santen; R. Coutinho; M. Prins.
Objective:
Although injecting drug users (IDU) are at high risk for
Hepatitis C Virus (HCV) infection, they are less likely to be treated than
other populations. We started to offer HCV testing and treatment combined with
methadone programs in a setting where active drug use is tolerated. Here, we
evaluate the inclusion procedure 1.5 year after the start of our pilot project.
Methods:
The study population comprises DU participating in the
Amsterdam Cohort Studies (ACS) in 2005. Hepatologists, methadone specialists,
cohort staff and a special project-nurse collaborate closely to provide optimal
HCV care. DU chronically infected with HCV are offered additional medical and
psychiatric screening. HCV treatment is directly observed and combined with
methadone provision.
Results:
493 DU were offered HCV screening: 60% male, 8% homeless and
median age 45 years. HCV screening was refused by 110/466 (24%). An additional
10% (49/466) was willing but lacked medical insurance, leaving 383 (78%) to be
tested. HCV antibodies were found in 224 (59%), 144 (64%) were chronically
infected. Of these, 127 (88%) returned to obtain their test result. Of 76
HIV-negative HCV-infected DU, 77 (85%) were willing to undergo additional
medical screening which was completed by 65 (84%). For 39 (60%) a final
treatment decision was made: 18 (47%) started treatment, 9 (23%) refused, for 6
(15%) treatment was not indicated based on a liver biopsy, and for 6 (15%)
there were medical and/or social contraindications. For 26 (40%) the decision
on HCV treatment initiation is pending.
8 (44%) finished treatment, 5 (28%) are still on treatment and 5 (28%)
stopped treatment--2 virological non-responders (genotype 1) and 3 from side
effects. 5 achieved SVR (genotype 2 and 3)
Among the 18 treated subjects 14/18 (78%) were active DU,
4/18 (22%) reported injecting over the last 6 months and 16/18 (89%) were on
methadone. Compliance for HCV treatment
was 98%.
Conclusions:
78% of the participants of the ACS among DU is willing to
undergo HCV screening and has medical insurance. We observed a high return rate among screened
DU and great willingness to undergo additional medical screening. Screening appears to be time-consuming, but
once DU start HCV therapy they are fully compliant. Interim end of treatment response in the
Dutch-C project are very good. These
findings suggest that active DU can successfully undergo treatment for HCV in a
multidisciplinary approach. However,
social, medical, psychiatric and abuse related problems postpone or interfere
with HCV treatment.
#371. Pegylated interferon and ribavirin in haemodialyzed
patients with chronic hepatitis C: a prospective study.
P. Deltenre; V. Canva; F. Provôt; F. Glowacki; S.
Dharancy; H. Ben Ali; A. Louvet; J. Boitard; J. Henrion; C. Noël; P. Mathurin.
Introduction:
In haemodialyzed patients, ribavirin is contraindicated due
to a high risk of hemolytic anemia related to the end-stage renal failure. HCV
eradication before kidney transplantation may be an attractive option when
considering the deleterious impact of HCV after kidney transplantation.
Aims:
1. to determine the tolerance of combinative
therapy with pegylated interferon (Pegasys) and a weekly individual schedule of
ribavirin;
2. to provide preliminary data on
virological response.
Patients and methods:
Fourteen haemodialyzed HCV patients waiting for renal
transplant were treated with combinative therapy with Pegasys and weekly dose
of ribavirin for 6 or 12 months according to genotype. Doses of ribavirin and
erythropoietin (EPO) were adjusted according to hemoglobin level (Hb) to
maintain levels up to 10 g/dl. There were 9 patients with genotype 1, 5 with
non-1 genotype. Median viral load was 962000 IU/mL (95 % CI: 146000-3610000).
Liver fibrosis was mild or moderate (≤F2) in all but 1 patient. Mean time
on dialysis was 16 years.
Results:
Median doses of Pegasys was 180µg/week (95 % CI: 135-180 µg)
and of ribavirin 800 mg/week (95 % CI: 600-1000 mg). Before initiation of
antiviral therapy, 11 out of 14 patients were already treated by EPO. After 2
months of treatment, 13 out of 14 patients received EPO. As compared to baseline,
the median increase of EPO dose was 200 % (95 % CI: 100-305%, range: 92-525%).
Median Hb levels decreased during the first 2 months of treatment from 11.9 (95
% CI: 10.2-12.8) to 10.2 g/dl(95 % CI: 8.9-11.1, p=0.03) and remained stable
throughout the period of treatment. Five patients required transfusion but only
2 of them had Hb level lower than 7 g/dl. Eleven patients completed treatment.
Treatment was withdrawn in the 3 remaining patients for severe asthenia (n=2)
and retinal hemorrhage (n=1). After 1 and 3 months of treatment, more than 2
log decrease in viral load was reached in 86% (12 out of 14 patients) and in
92% (11 out of 12 patients), respectively. End-of-treatment virological
response (ETR) was reached in 11 out of 14 patients and sustained virological
response (SVR) in 6 out of the 10 patients reaching 6 months post-treatment
follow-up.
Conclusions:
Despite a theoretical contraindication, ribavirin may be used
in haemodialyzed HCV patients, a particular high-difficult-to-treat group of patients.
This use required a weekly adaptation of ribavirin dose and 200 % increase of
EPO. This combinative therapy with an individualized schedule of ribavirin
permits to reach ETR and SVR in 79 % (11 out of 14) and 60 % (6 out of 10) of
cases, respectively. These results are similar to those observed in
non-haemodialyzed HCV patients.
#372. Economic Evaluation of Individualized versus Standard Treatment Approach for Patients with Chronic Hepatitis C Virus Genotype-1 (G1) Low Viral Load (LVL) Using Peginterferon Alpha-2b Plus Ribavirin in the United Kingdom.
S. Zeuzem; N. Naoumov; N. Tatman; L. Cragin; S.
Sorensen.
Purpose:
A 24-week course of therapy for G1 LVL patients who become
viral negative after 4 weeks of treatment with peginterferon alpha-2b +
ribavirin was recently approved by the EMEA. Clinical evidence suggests
sustained virologic response (SVR) in this population is comparable to a
48-week course of therapy. The long-term clinical and economic impacts of
shorter treatment duration are unknown. This study evaluated the
cost-effectiveness of 24-week treatment for 4-week responders + 48-week
treatment for 12-week responders (individualized strategy) vs. 48-week
treatment for both 4- and 12-week responders (standard strategy) in the context
of current UK management guidelines, which recommend 12-week non-responders
stop treatment.
Methods:
Decision analytic and Markov models for the treatment and
disease progression phases, respectively, were designed to reflect potential
clinical events for G1 LVL patients. Response at weeks 4 and 12, SVR,
discontinuation, adherence, and disease progression rates were obtained from
published literature. Clinical data were adjusted to reflect current medical
practice. Costs included drug therapy, monitoring, adverse events, and disease
progression. Resource use data were collected from published literature and
supplemented by clinical experts. Unit costs were obtained from available
Results:
The model predicted SVR rates of 70% (standard) and 68%
(individualized) based on 4- and 12-week response rates and assumptions for
discontinuation and adherence. Due to the shorter duration of therapy, the
results indicate short-term cost-savings of £52,527 per QALY for the
individualized strategy. In addition, this strategy resulted in fewer
discontinuations and adverse events as well as improved adherence. The
long-term incremental cost per QALY was £43,595 for the standard vs.
individualized strategy. Probabilistic sensitivity analysis demonstrated the model
was robust with respect to incremental costs but showed considerable
uncertainty for incremental effectiveness.
Discussion:
·
MNodleing
is a useful tool for guiding treatment decisions when head-to-head clinical
trials have not been conducted or when predicting events that extend beyond the
trial period.
·
To
our knowledge, this is the first cost-effectiveness analysis evaluating
individualized versus standard treatment strategies for HCV-1 patients with low
pre-treatment viral load.
·
Analysis
incorporates discontinuation and adherence rates and reflects current
·
Several
limitations of this analysis deserve mention:
use of small historical control group (n=38) consisting of HCV-1 LVL
patients from Manns et al, historical control group treated with suboptimal RBV
dose due to concerns about anemia at the time study was conducted, and
exclusion of relapse patients who might be re-treated.
Conclusions:
·
For
treatment of G1 LVL patients in the
·
Probabilistic
sensitivity analyse demonstrated that the model, overall, is robust.
|
|
Costs |
QALYs |
||
|
ST |
LT |
ST |
LT |
|
|
Standard |
£13,046 |
£21,679 |
1.62 |
19.56 |
|
Individualized |
£9,202 |
£18,429 |
1.69 |
19.49 |
|
Difference |
£3,844 |
£3,250 |
-0.07 |
0.07 |
Abbreviations: ST, short-term; LT,
long-term
#373. THE INTERNATIONAL AUTOIMMUNE HEPATITIS GROUP SCORING SYSTEM IN PATIENTS WITH CHRONIC HEPATITIS C AND SERUM AUTOANTIBODIES UNDERGOING INTERFERON/RIBAVIRIN THERAPY: A PROSPECTIVE VALIDATION STUDY.
V. Monti; A. Aghemo; M. G. Rumi; M. F. Donato; E.
Arosio; R. D'Ambrosio; P. Lampertico; R. Soffredini; M. Colombo.
Background:
Non organ specific autoantibodies (NOSA) circulate in
approximately 40% of patients with chronic hepatitis C virus (HCV) infection
marking a risk for autoimmunity.
Aim:
To clarify whether HCV patients with NOSA lacking a diagnosis
of Autoimmune Hepatitis (AIH) according to the International Autoimmune
Hepatitis Group (IAHG) score system can be safely and effectively treated with
interferon (IFN)/ Ribavirin (Rbv). Material and methods: All consecutive
patients with chronic hepatitis C due to genotype 1 or 4 who between 2000 and
2005 underwent IFN/Rbv therapy were studied. NOSA were looked for at baseline
by indirect immunofluorescence on cryostat 4 μ sections from rat liver,
stomach and kidney at 1:80 dilution. The antinuclear antibody (ANA) was further
characterized on Hep-2 cells. In all patients with NOSA the IAHG was
calculated.
Results:
37 patients received standard IFN and 216 received pegylated
IFN. 82 (32%) circulated NOSA: 28 had ANA, 13 ANA + smooth muscle antibodies
(SMA), 31 SMA and 10 liver-kidney microsomal antigen antibody type 1 (LKM-1).
All patients with NOSA had less or equal to 15 IAHG score (no definite AIH).
NOSA were associated with female sex (p=0.02). A sustained virological response
(SVR) was obtained in 72 (28%) patients, 34 (42%) with NOSA vs 38 (22%) without
NOSA (p=0.01). None of patients developed an autoimmune reaction following
IFN/RBV therapy. By logistic regression a SVR was associated to NOSA, absence of
cirrhosis and low basal viremia (<800.000 IU/ml).
Conclusions:
IAHG scoring system is useful for selecting patients with
genotype 1 or 4 chronic hepatitis C with NOSA who are candidable to IFN/RBV
therapy and likely to respond well to therapy.
#374. Overcoming barriers to treatment of hepatitis C in Italian drug users. The importance of a co-management model of care.
R. Brigada; M. Bonasso; G. Borroni; M. Orso; M. C.
Vivirito; G. Orofino; C. Magni; A. Cividini; G. Pennisi.
Introduction:
Despite the high prevalence of hepatitis C virus (HCV)
infection among drug users (DU) enrolled in the methadone/buprenorphine
maintenance treatment programs (MTP), only few DU are being treated with
antiviral therapy.
Methods:
No treatment guidelines are available in Italy for management
of HCV infection among DU. Thus, experts in addiction medicine, hepatologists,
psychiatrists and psychologists organized a “Working Group on HCV Infection in
DU” to implement a multidisciplinary model of care and to draft recommendations.
The model includes screening and treatment for HCV infection among DU,
counselling pre, on and post-treatment, psychiatric evaluation and enhanced
cooperation with infectious disease specialists.
Results:
We describe the results of a pilot program designed to
integrate care for HCV infection in a setting of MTP. All patients (pts)
selected at 4 MTP centres of Northern Italy were screened for HCV antibodies
and those with positive results were tested for HCV RNA. Counselling addressing
minimization of transmission and value of treatment was offered. Enrolled pts
were treated with peg interferon and ribavirin for 24 or 48 weeks, according to
genotype, blood tests were performed and virological response assessed. The 90
treated pts (78 males,12 females, mean age 36, range 22-61) were evaluated with
a depression scale. The mean duration of HCV infection was 10 years. The most
frequent genotype was 3 (45 pts; 50%) followed by genotypes 1 (28 pts; 31%), 4
(10 pts;11%) and 2 (7 pts; 8%). Forty pts (44%) received methadone and 11 (
12%) buprenorphine. Therapy was discontinued early in 11 pts (12%); in 4 pts
(4%) because of side effects and in 7 pts (8%) because of non-compliance. The
dropout rate was highest during the first 2 months of therapy. Of the 82 pts
(90%) that ended the treatment, 62 (76%) were HCV RNA negative. Ten pts (12%)
developed depression after the 2nd month of treatment and 3 pts (4%) reported
craving for drugs or alcohol. However, none of them had to stop the treatment.
The symptoms were controlled with antidepressants or changes in substitutive
treatment. Six months after the end of therapy, only one patient (1%)
experienced a relapse.
Conclusion:
Caring for pts who use illicit drugs presents challenges to the
health-care team as it requires patience, experience and understanding of the
dynamics of addiction and HCV infection. Improved provider-patient
communication, counselling, follow-up at frequent intervals and the work of a
multidisciplinary team helped to control the dropout rate and the psychiatric
side effects. Further effort is warranted to increase the proportion of DU who
initiate treatment for HCV infection.
#375. Successful hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants.
G. P. Jeffrey; G. MacQuillan; F. Chua; S. Galhenage;
J. Bull; E. Young; G. Hulse; G. O'Neil.
Introduction:
The effectiveness of HCV antiviral therapy in patients who
have undergone recent drug dependency treatment and continue to inject drugs
sporadically is presently not clear.
Methods:
Patients attending a community based drug rehabilitation and
naltrexone implant clinic from October 2002 until March 2005 were screened for
HCV infection and if positive offered further assessment and treatment with
interferon and ribavirin therapy. The first 50 patients to commence HCV therapy
and complete at least six months follow up were prospectively studied. 49
underwent liver biopsy.
Results:
ETR response (HCV PCR negative) was 34/50 (68%) and SVR 6
months post-treatment was 31/50 (62%). Viral eradication was maintained in
those 22 patients that have had 12 months or more post-treatment follow up. The
presence of F3/F4 fibrosis or previous heavy alcohol intake (>100g/day) were
associated with non response (p<0.05), however logistic regression anaylsis
found that only prior heavy alcohol intake was associated with non response. 11
(22%) patients stopped therapy early due to side effects or poor compliance.
Only two patients with an ETR re-infected due to unsafe injection practices.
One was re-treated and achieved an SVR. Of the patients achieving a 6 month
SVR, 17 of 31 patients reported no further IDU and 13 of 31 patients occasional
IDU during treatment and this was maintained after HCV treatment cessation. 46%
of patients received antidepressant and/or antipsychotic medication during
treatment.
Conclusion:
In conclusion this prospective study of HCV treatment in a
community based subcutaneous naltrexone implant clinic found antiviral therapy
resulted in a 62% SVR. This result is comparable to that reported in hospital
based clinics in non IDU patients. The side effect profile and compliance was
also similar. HCV antiviral therapy should be offered to this large and
currently under treated group.
#376. Late treatment of chronic hepatitis C in renal
transplant recipients: an open pilot study.
G. Pageaux; G. Mourad; F. Chermak; H. Audin; V.
Garrigue; S. Deleuze; D. Larrey.
Introduction:
Renal transplantation is associated with a more severe
evolution of chronic hepatitis C as compared with HCV-infected immunocompetent
patients. This results in a decrease in survival of patients and allografts.
Treatment of hepatitis C in renal transplant recipients remains a controversial
issue, since interferon therapy has been associated with a high risk of
rejection and a low efficacy. There is very few data in the literature, since
interferon is considered as contra-indicated in these patients.
Aim:
In an open pilot study, we assessed the efficacy and the
safety of late use of interferon or PEG-interferon, associated or not to
ribavirin, in renal transplant recipients with chronic hepatitis C.
Patients:
Seven kidney recipients were treated with interferon a
monotherapy (n = 1), PEG-interferon a2a or a2b monotherapy (n = 3), or
PEG-interferon a2b associated to ribavirin (n = 3). Liver biopsy was performed
before therapy and classified according to the Metavir score.
Results:
There were 6 male and 1 female, mean age 55.4 years (36-75),
mean time between transplantation and antiviral treatment 14 years (1.6-24).
The virological and histological parameters were as follows : genotype 1 (n =
2), genotype 2 (n = 3), genotype 5 (n = 2) ; the mean viral load was 830 000
UI/ml ( 140 000 - 2 500 000) ; according to the Metavir score, 1 patient was
F1, 2 patients were F2, 3 patients were F3, 1 patient was F4. Antiviral
treatment was withdrawn in 4 patients, at week 35, week 28, week 12, week 20,
respectively, for the following reasons : anemia (n = 1) , depression (n = 2),
hemolytic and uremic syndrome (n = 1). End of treatment and sustained
virological responses were observed in 4 and 2 patients, respectively. The
characteristics of the 2 patients with sustained virological response were as
follows : one male with genotype 2, viral load 1 300 000 UI/ml, Metavir score
F1 and one female with genotype 2, viral load 140 000 UI/ml, Metavir score F2.
The 2 other patients with only end of treatment response were genotype 2 and 5,
Metavir score F2 and F3. Mean baseline serum creatinine value was 171.8 µmol/l
(83-268) and end of treatment serum creatinine value was 167.7 µmol/l (74 –
275). No patient developed graft rejection.
Conclusion:
In this pilot study, interferon a or PEG interferon, associated
or not ribavirin, was used in renal transplant recipient with chronic hepatitis
C without inducing graft rejection. A significant portion of patients achieved
end of treatment and sustained virologic response.
#377. The risk of hepatocellular carcinoma and
decompensation following hepatitis C treatment with interferon based therapy.
K. Jamil; W. Cheng; L. Tarquinio; L. Adams; L.
Mollison; G. MacQuillan; B. DeBoer; M. McInerney; S. Nazareth; C. Connelly; J.
Flexman; N. Kontorinis.
Introduction:
Patients with advanced hepatic fibrosis due to hepatitis C
virus (HCV) are at high risk of hepatocellular carcinoma (HCC) and hepatic
decompensation (HD). We evaluate their incidence following interferon therapy
in patients with F3/4 fibrosis, and study the effect of SVR.
Methods:
A cohort of patients with F3-4 fibrosis (METAVIR) treated
with IFN therapy from 1995 to 2006 was identified from the HCV databases at 3
centres in WA. All patients had compensated (Childs A) liver disease. The
incidences of HD, diagnosis of HCC and mortality were recorded. Frequency of
HCC screening with U/S and AFP were assessed. Statistical methods used were:
χ2 test, Fischer’s exact test and Welch’s unpaired t-test.
Results:
135 patients (104 males & 31 females) were followed for a
median of 983 days (0-3513) Mean age was 48 years (SD 7.8). 13 had IFN
monotherapy (SVR 31%), 33 had IFN/RBV combination therapy (SVR 42%) and 87 had
PEG-IFN/RBV therapy (SVR 46%). Asian ethnicity was associated with development
of HCC (p=0.02). Incidence of HCC was 1.4%/year overall (5.1%/year in Asians,
0.7%/year in non-Asians). There was a reduction in HCC and mortality following
SVR (see table) but this was not statistically significant. There was no
difference in development of complications between F3 (7/75, 9%) and F4 (5/60,
8%) patients. Overall, 102 patients had HCC screening of which 69% was
sporadic, 28% was annual and 3% was 6 monthly. 52 are currently in a screening
schedule.
Conclusions:
HCV eradication in this high risk population may reduce the
risk of HCC and mortality. Patients with F3 fibrosis are at similar risk to F4
for HCC and decompensation and require analogous screening. Asian patients are
at greater risk of HCC from HCV-related cirrhosis. There is a need for
standardised screening methods and follow up in all patients.
|
Complication |
Asian |
Non
Asian |
p |
SVR |
No SVR |
p |
%/Yr |
|
HCC |
3/19 (16%) |
2/116 (2%) |
0.02 |
1/51 (2%) |
4/84 (5%) |
0.65 |
1.4 |
|
HD |
0/19 (0%) |
6/116 (5%) |
0.59 |
2/51 (4%) |
4/84 (5%) |
1.00 |
1.7 |
|
Death |
1/19 (5%) |
4/116 (3%) |
0.54 |
0/51 (0%) |
5/84 (6%) |
0.16 |
1.4 |
|
Total |
3/19 (16%) |
9/116 (8%) |
0.37 |
3/51 (6%) |
9/84 (11%) |
0.53 |
3.4 |
#378. Maintenance pegylated IFN given once every three weeks prevents relapse of hepatitis C virus (HCV) in decompensated cirrhosis.
V. K. Thorat.
Background & Aim:
Successful eradication of HCV results in improvement of liver
tests and liver histology, and reduction in hepatocellular carcinoma. However,
there is limited data on the impact of anti-viral therapy in patients with
advanced liver disease. In the present study, we assessed the effect of
maintenance treatment in patients with decompensated liver disease who had
relapsed after initial anti-viral therapy.
Methods:
28 patients with HCV (genotype 2/3) and Child-Pugh score of ≥7
were included in the study. Exclusionary criteria included recurrent episodes
of spontaneous bacterial peritonitis, severe encephalopathy, serious comorbid
illnesses, HIV co-infection, platelets <50,000/ mm3, white cells <2x109
liter and hemoglobin <10g/dl. All patients were treated with 1.5 MU of
interferon (INF) for 2 weeks, then 3MU of IFN for two weeks followed by
pegylated IFN alfa-2a 180 µg once a week for 20 weeks (total 24 weeks). In
addition, all patients received ribavarin 800-1200 mg/day (weight based).
Patients who became HCV –ve at week 24 were followed for one year. Those
patients who relapsed were retreated with the same regimen as above for another
24 weeks. Patients who again became HCV –ve were started on maintenance
pegylated IFN alfa-2a 180 µg once every three weeks.
Results:
Of the 28 patients, treatment was discontinued in 4 patients
due to adverse effects and 9 patients were treatment failures. The remaining 15
patients became HCV –ve initially but 13 relapsed on follow up and 12 of these
were retreated with a second course of therapy for 24 weeks. Eleven patients
became HCV –ve after the second course and of these 10 were placed on
maintenance pegylated IFN alfa-2a. One patient relapsed while on treatment, the
remaining 9 patients remained HCV free at the end of 1 year of follow up. In
these 9 patients, the mean Child-Pugh score improved from 7.3 to 6.2 after one
year of treatment, the difference was statistically not significant. All
patients tolerated the treatment well.
Conclusions:
Maintenance pegylated IFN given once every 3 weeks in
previous relapsers maintains remission in the majority (90%) of patients,
prevents disease progression, and in some patients improves the Child-Pugh
score. Our findings suggests that maintenance treatment can be given
successfully even to patients with decompensated liver disease. Further studies
are required to determine whether the observed beneficial effect is maintained
over longer duration of treatment.
#379. A Randomized Double-Blind Placebo-Controlled Trial of Paroxetine to Prevent Interferon-α-Induced Depression in Patients with Hepatitis C.
B. J. Morasco; M. A. Rifai; J. M. Loftis; D. W.
Indest; E. E. Kizer; J. K. Moles; P. Hauser.
Background & Aims:
Prior research suggests that the prophylactic use of
antidepressant medication may prevent the development of depression induced by
treatment with interferon-α (IFN-α) in patients with hepatitis C
(HCV). However, no prior studies have assessed this in a randomized
double-blind study. The aim of the present study was to determine whether
treatment with paroxetine in a sample of patients with HCV would decrease the
likelihood of developing IFN-α-induced depression.
Methods:
In a double-blind, placebo-controlled study, 33 patients with
HCV were randomized to receive paroxetine (n=14) or placebo (n=19) four weeks
prior to beginning IFN-α and ribavirin treatment for HCV. Patients were
evaluated for psychiatric symptoms prior to HCV treatment, regularly throughout
treatment, and up to six months follow-up. The primary outcome measure was the
development of major depression, as assessed by the Structured Clinical Interview
for DSM-IV. The study blind was broken for any patient who developed
IFN-α-induced depression; these patients were put into the rescue arm of
the study and treated with paroxetine in an open-label fashion.
Results:
The rate of IFN-α-induced depression in the entire
sample was 33.3%. The prophylactic use of paroxetine did not decrease the
likelihood of developing IFN-α-induced depression (35.7% in the paroxetine
group vs. 31.6% in the placebo group, p>0.10). In those patients who
developed IFN-α-induced depression and were treated in an open-label
fashion, paroxetine was effective in reducing depressive symptoms (assessed
with the Hamilton Depression Rating Scale) below the level of clinical
significance in 10 of 11 patients.
Discussion:
These results suggest that when administered
prophylactically, the use of paroxetine does not prevent the development of
IFN-α-induced depression in patients with HCV. However, when administered
in an open-label fashion, paroxetine may be beneficial in treating depression
induced by IFN-α.
#380. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in HCV patients with complete cirrhosis (Knodell score F4).
S. Bruno; P. Maisonneuve; P. J. Pockros; M. Sarracino; M. Diago; S. Zeuzem; M. Rizzetto; P. Marcellin; S. J. Hadziyannis.
Introduction:
Patients with chronic hepatitis C (CHC) with fully developed
cirrhosis have a higher risk of developing severe complications, including
hepatocellular carcinoma, than patients without cirrhosis, and thus represent a
population with a great need for HCV treatment. However, few studies have
assessed the benefits of interferon-based therapy in this population. Here we
examined the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin
(RBV) treatment in patients with cirrhosis. Predictors of sustained virological
response (SVR) in this population were also identified.
Methods:
This post-hoc analysis from a randomised, multinational,
phase III study evaluated the efficacy and tolerability of peginterferon alfa-2a
(40KD) 180 μg/week plus RBV standard-dose (1000/1200 mg/day) or low-dose
(800 mg/day) for 24 or 48 weeks [Ann Int Med 2004, 140:346]. Patients from the
study were included in this analysis if they had histologically proven
cirrhosis (Knodell score F4). Due to small patient numbers, data from all 4
treatment arms were pooled.
Results:
Of 1311 patients enrolled in the phase III study, 90 with
complete cirrhosis (Knodell score F4) were included in this analysis. Most
patients (72%) were infected with HCV genotype 1 (G1). 56 (62%) were male and
median age was 49 years (range 32-76). No patient had oesophageal varices. The
overall SVR rate was 36% (28% in G1, 70% in G2 and 46% in G3 patients). Of the
28 patients (31%) who did not complete treatment, 4 were due to laboratory
abnormalities and 24 due to other adverse events (4 severe). There were no
deaths during treatment or follow-up. Multivariate analysis showed that the
only independent predictive factors associated with SVR were G1 infection(Odds
ratio[OR]=3.2,95%CI:1.16–8.8,p<0.01) and albumin level ≥4 g/dL
(OR=4.4,95%CI:1.26–15.48,p<0.02). In G1 patients, the SVR rate was 35% in
those with albumin ≥4 g/dL but only 14% in those with albumin <4 g/dL
(NPV=86%).
Conclusions:
Overall in CHC patients with fully developed cirrhosis
(Knodell score F4), who have a high treatment need, peginterferon alfa-2a
(40KD) plus RBV was effective in over one third of patients. Although 31% of
patients needed to discontinue treatment, only a small number of serious adverse
events were observed. Pre-treatment albumin level was the strongest predictor
of SVR. This could be used to allow the identification of subjects more likely
to benefit from treatment, although this should be confirmed. Further studies
should also be performed to determine the most appropriate schedule of
treatment for these patients with difficult-to-treat disease.
#381. Effect of hepatic steatosis 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. Rodriguez-Torres; S. Govindarajan; S. Shafran; T. Morgan; B. S. Anand; K. Barange; F. Suter; A. Lin; G. Hooper; S. Zeuzem; M. Shiffman.
Introduction:
Although data suggest that steatosis contributes to
progression of liver fibrosis, its impact on anti-HCV treatment efficacy is
less clear. Lower SVR rates in GT3 pts (vs. GT2) may perhaps be related to
higher levels of steatosis (J Hep 2004;40:993). Here we evaluated the impact of
steatosis on SVR in GT2/3 pts with peginterferon alfa-2a (40KD) plus ribavirin
using the ACCELERATE database (n=1469).
Methods:
Naïve GT2/3 pts received PegIFNα-2a 180µg/wk + RBV 400mg
bid for 16 or 24wks with 24wk follow-up. Liver biopsy was performed on all pts ≤24mo
of therapy and reviewed by one central (blinded) pathologist. Effect of
steatosis on SVR was evaluated, controlling for: steatosis grade, cirrhosis,
baseline (BL) ALT, age, gender, race, bodyweight, BL HCVRNA and treatment
duration.
Results:
BL steatosis data were available for 885 pts. 614 pts (69%)
had some degree of steatosis. GT3 pts were more likely to have steatosis than
GT2 (79% vs. 59%, p<0.001) and more advanced (19% and 6%; p<0.001; Table
1). In univariate analysis, steatosis led to a significant SVR reduction in GT3
pts, but not GT2; and SVR declined with increasing severity (Table 2). However,
this relationship was not significant in the multivariate analysis (p=0.48 in
GT2; p=0.20 in GT3 pts). Pts treated for 24wks had a significantly higher SVR
(vs. 16wks), regardless of degree of steatosis. In GT3 pts, steatosis was
strongly associated with higher BL HCVRNA than no steatosis (r=0.35;
p<0.001). Steatosis effect became significant when BL HCVRNA was removed
from the logistic regression model (p=0.01).
Conclusions:
We confirm a higher prevalence of steatosis among GT3 than
GT2 pts. GT2 and GT3 pts achieved higher SVR rates with 24wks than 16wks,
regardless of the degree of steatosis. When other factors are accounted for,
steatosis did not affect SVR in either GT2 or GT3 pts suggesting that other
factors associated with steatosis may have accounted for the inverse
association seen previously.
#382. Assessment of Th1 and Th2 cytokines during antiviral therapy for HCV Mixed Cryoglobulinemia.
R. R. Meidinger; M. R. Shey; Z. K. Ballas; W. N. Schmidt.
Introduction:
Mixed Cryoglobulinemia (MC) occurs in 40-50% of patients with
chronic HCV infection. MC results from expansion of rheumatoid factor producing
B cells and formation of cryoglobulin complexes which are useful markers for
liver and extrahepatic diseases caused by chronic HCV infection. Recent
evidence has suggested that cytokines are important for development of MC, HCV
disease progression, and successful antiviral therapy for HCV. The aim of this
study was to evaluate representative Th1 and Th2 cytokine profiles in the blood
of patients with and without MC to determine changes before and after pegylated
antiviral therapy. The correlation of cytokine levels with other variables
known to be important for SVR was also compared between the two patient groups.
Methods:
Forty patients, 20 with and 20 without MC, were randomly
recruited for study. Half of the patients in each group achieved SVR while the other
half were non-responders (NR) to standard dosages of pegylated interferon and
Ribavirin. Using Bio-Plex 100 system, Th1 (IL-2, IF-γ) and Th2 (IL-10,
IL-5) cytokines were measured in patient plasma samples before and at the end
of antiviral therapy. Inter- and intra-assay variation for patient cytokine
levels was less that 5%.
Results:
Patients with MC who achieved SVR showed significant
reductions of IL-2 and IL-10 from pre to post therapy (p < 0.025 in both
cases), in contrast to SVR patients without MC who had no significant changes
in cytokine levels. NR to antiviral therapy did not show significant changes
from pre to post antiviral therapy for any cytokine level in either group.
Overall, MC was associated with significantly higher levels of IL-2 than
patients without MC (p <0.025). Assessment of host and viral factors known
to be important for SVR to antiviral therapy revealed a significant association
of IL-2 pretreatment levels with the amount of cryoglobulin (p < 0.03). No
significant association was found in either group between any cytokine level
and pre-treatment viral load. However, both Th1 cytokines showed significant
negative correlations with Metavir fibrosis scores for patients without MC (p
< 0.03) but not for patients with MC.
Conclusions:
These results reveal differences in the baseline cytokine
profiles of HCV patients with and without MC as well as changes in cytokine
levels occurring during successful antiviral therapy and progressive liver
disease. The findings support the hypothesis that enhanced levels of Th1
cytokines such as IL-2 dominate in HCV patients with MC as compared to patients
without MC thus suggesting differences in immune response and response to
therapy in the two groups.
#383. Standard and Pegylated Interferon alfa-2b plus Ribavirin as initial treatment for HCV genotype 2 chronic hepatitis: analysis of a large single center cohort.
M. Rumi; A. Aghemo; R. D'Ambrosio; G. Ronchi; S.
Gallus; M. Colombo.
Background:
Patients with chronic infection with hepatitis C virus (HCV)
genotype 2c achieve the highest rates of SVR (80%) following
Interferon/Ribavirin treatment (IFN/Rbv). In these patients phase III
registration studies showed no superiority of PegIFN alfa-2b (PegIFN) over standard
IFNalfa-2b (IFN), nor they identified any predictor of treatment failure.
Aim:
To assess the effectiveness of Rbv combination therapy with
PegIFN and IFN in genotype 2c patients and to identify predictors of non response.
Methods: All naïve patients with genotype 2c who consecutively received
weight-dosed Rbv combined with standard IFN 3MU t.i.w. and after 2001 PegIFN
1.5 mcg/Kg week.
Results:
Epidemiological and clinical characteristics were similar at
baseline in the 94 patients who received IFN/Rbv compared to the 136 receiving
PegIFN/Rbv. By intention to treat analysis (ITT), 211 (95%) had an end of
treatment response (ETR), that was maintained in 183 (SVR=80%). Drop out rates
were similar in the 2 treatment schedules (8/136 PegIFN vs 1/94 IFN, p=0.06).
According to ITT and per protocol analysis, PegIFN was not superior to IFN in
terms of SVR rates (ITT: 78% vs 82%; per protocol: 83% vs 83 %). SVR rates
obtained in cirrhotic patients were similar in the 2 treatment groups (70%
PegIFN vs 74% IFN, p=ns), however, in the PegIFN subset, higher relapse rates
were seen in patients with cirrhosis (30%) than in those with less fibrosis
(10%) (OR 3.8 C.I. 95% 1.3-11.1). SVR was independent from sex, age, BMI,
modality of infection, disease duration, disease severity, adherence to therapy
and IFN type. By unconditional multiple logistic regression analysis, treatment
failure was predicted by pre-treatment HCV-RNA >800.000 IU/mL (OR: 2.3 C.I.
95% 1.2-4.7), persistence of HCV-RNA at week 4 (OR: 6.1 C.I. 95% 2.9-12.7) and
at week 12 (OR: 13.2 C.I. 95% 5.1-34.1).
Conclusions:
Combination therapy with PegIFNalfa-2b is not superior to
standard IFNalfa-2b in the treatment of HCV-2 patients. Cirrhotic patients
receiving PegIFNalfa-2b are at increased risk of post-treatment relapse.
#384. HCV-RNA in the fourth week as a predictive factor of sustained virological response (SVR) in genotype 1 hepatitis C patients treated with Peg-Interferon-α2b(PEG-IFN-α2b)and Ribavirin.
J. Segadas-Soares; C. Villela-Nogueira; R. M. Perez; L. Nabuco; C. Brandão-Mello; H. M. Coelho.
Background:
Currently it is not yet defined if an earlier response,
defined as a negative HCV-RNA in the fourth week of treatment, could better
foresee a SVR. Objective: The aim of this study was to evaluate the HCV-RNA in
the fourth week of treatment as a predictive factor of SVR in genotype 1
hepatitis C patients treated with PEG-IFN-α2b and Ribavirin.
Methods:
A hundred and sixty seven genotype 1 hepatitis C patients who
were treated with PEG-IFN-α2b and Ribavirin and had an HCV-RNA performed
24 weeks after the end of treatment were included. An HCV-RNA at the 4th week
of treatment was performed in all patients (Amplicor Roche). The exclusion
criteria were HBV and/or HIV co-infection. Patients were treated for at least
12 weeks and if the HCV-RNA was undetectable on week 12, treatment was
continued until week 48. Those with a detectable HCV-RNA on week 12 had their
treatment canceled and were considered as non-responders. For comparative
analysis patients were categorized in two groups as follows: G1- those with an
undetectable HCV-RNA in week 4, and G2- those with a detectable HCV-RNA in the
4th week of treatment.
Results:
The mean age was 50±11yrs, 59% female. Naïve patients (n=103)
comprised 62% of the total sample. Sixty four patients have been previously
submitted to treatment with conventional IFN and Ribavirin and, among these, 22
(13%) were relapsers (R) and 42 (25%) were non-responders (NR). The HCV-RNA in
the 4th week of treatment was undetectable in 51/167 of the total sample
(31%)-G1 and among these patients, 38 (75%) had a SVR. However, among the
116/167 (69%) patients with a detectable HCV-RNA in the fourth week (G2), only
27 (23%) had a SVR (p<0.001). Among the 103 naïve patients, the SVR was
obtained in 71% from G1 and in 29% from G2 (p<0.001). Considering the
relapsers, the SVR was 92% in G1 and 40% in G2 (p=0.002). Among non-responders,
SVR was 50% in G1 and 8% in G2 (p=0.06).
Conclusion:
A negative HCV-RNA in the fourth week of treatment is an
excellent predictive factor for SVR in naïve and relapsers and should be an
important tool in genotype 1 hepatitis C treatment.
#386. Efficacy and safety of IFN treatment for the 70 year-old or over patients with chronic hepatitis C.
H. Kodama; S. Takahashi; S. Takaki; K. Yamashina; A. Hiramatsu; S. Tei; Y. Kawakami; H. Aikata; K. Chayama.
Background:
Despite the beneficial effects of IFN monotherapy or IFN and
ribavirin (IFN/Rib) combination therapy for chronic hepatitis C patients, these
treatments have several adverse events which are not tolerable, especially for
older patients. Although it used to be considered that the patients who was 60
years old or over with chronic hepatitis C should not be treated with IFN
therapy before, the mean age of the patient with chronic hepatitis C is
currently more than 60 years old in Japan.
Aim:
The aim of this study was to evaluate the efficacy and safety
of IFN monotherapy or IFN/Rib therapy for patients whose age were 70 years old
or over with chronic hepatitis C.Objective: The number of chronic hepatitis C
patients treated with IFN therapy was 360 between 2001 on January and 2004 on
September. Patients were classified into non-older group : younger than 70
years old (n=309) and older group : 70 years old or over (n=51).
Result:
The completion rate of IFN monotherapy was similar in both
non-older and older group (86% in non-older vs. 87% in older). Whereas the
completion rate of IFN/Rib therapy in older group was lower than that in
non-older group (81% in non-older vs. 62% in older, p<0.05), mainly due to
anemia. With IFN/Rib therapy, the SVR rate for the patients with genotype 1b
and high viral load was 29% in non-older group and 6% in older group, and the
SVR rate for the patients with genotype 2 or low viral load was 67% in
non-older group and 50% in older group. Whereas with IFN monotherapy, the SVR
rate for the patients with genotype 1b and high viral load was 13% in non-older
group and 17% in older group, and the SVR rate for the patients with genotype 2
or low viral load was 68% in non-older group and 63% in older group. Therefore,
based on intention to treat analysis, while SVR rate was much lower in the
older group with genotype 1b and high viral load, even with IFN/Rib therapy,
SVR rate in the older group with genotype 2 or low viral load was similar to
that in the non-older group, which reflects that there were more
discontinuation cases in older group with IFN/Rib therapy. SVR rate in the patients
with genotype 1b and high viral load was 35% in non-older group and 9% in older
group with IFN/Rib therapy, suggesting that SVR rate would be still low even
though IFN/Rib therapy was completed.
Conclusion:
Our results suggest that IFN monotherapy is effective for
older patients of 70 years old or over with genotype 2 or low viral load, and
that it is difficult to achieve SVR for older patients of 70 years old or over
with genotype 1b and high viral load.
#388. Exposure to ribavirin (RBV) predicts EVR and SVR in
patients with HCV genotype 1 infection: analysis of the Canadian Pegasys
Expanded Access Program (EAP).
V. G. Bain; S. S. Lee; K. Peltekian; E. Yoshida; M. Deschênes; M. Sherman; R. Bailey; H. Witt-Sullivan; R. Balshaw; M. Krajden.
Introduction:
Analyses of phase III trials have shown that drug exposure is
a significant predictor of SVR. We examined the relationship between exposure
to PEG-IFNα2a and RBV and the probability of EVR and SVR in patients
enrolled in the Canadian Pegasys EAP.
Methods:
This exploratory analysis was restricted to treatment-naïve
genotype 1 patients who were assigned to PEG-IFNα2a 180 µg/wk + RBV for 48
wks. In the initial phase of the EAP all patients received RBV 800 mg/d, and
1000 (≤75kg) or 1200 (>75kg) mg/d in later phases.
We considered RBV 1000/1200 mg/d to be 'optimal' (100%) in
accordance with current guidelines. Dose adjustments for AEs or lab
abnormalities were recorded, and included in a continuous measure of exposure
(%). EVR was defined as a ≥2-log drop in HCV RNA at wk12. SVR was defined
as undetectable HCV RNA (<50 IU/mL) at the end of untreated follow-up. Only
patients with known SVR status were included. The impact of baseline factors
and exposure to PEG-IFNα2a and RBV on EVR and SVR was evaluated by
multiple logistic regression analysis. Drug exposure was considered as a
continuous variable.
Results:
720 patients were included, of whom 318 (44%) and 402 (56%)
were assigned to RBV 800, 1000, and 1200 mg/d, respectively. At wk12 the mean
exposure, expressed as a percentage of the optimal dose, was 70%, 97%, and 96%
in patients assigned to ribavirin 800, 1000 and 1200 mg/day, respectively. During the first 12 wks, the mean
administered dose of PEG-IFNα2a was 94% of the planned dose.
Among patients assigned to RBV 800, 1000,and 1200 mg/d an EVR
was achieved in 73%, 80%, and 76%, respectively, and an SVR in 47%, 65%, and
58% respectively.
Significant and independent predictors of SVR included RBV
exposure (p<0.0001), baseline HCV RNA (p<0.0001), race (p<0.0001), metavir
score (p=0.0001) and age (p=0.006).
PEG-IFNα2a exposure was not associated with SVR
(p=0.818), but showed a strong trend for the prediction of EVR (p=0.051). The
failure to demonstrate an association with SVR is not surprising given the
consistently high exposure to PEG-IFNα2a.
Conclusion:
·
In
treatment-naïve HCV genotype 1 patients, ribavirin (COPEGUS) exposure from baseline
to week 12 was significantly correlated with the probability of achieving and
EVR and, especially, an SVR.
·
Exposure
to peginterferon alfa-2a (40KD) (PEGASYS) was not a statistically significant
predictor of outcomes; this may have
been due to near optimal exposure in all groups.
#389. Antiviral therapy for HCV-associated mixed cryoglobulinemia vasculitis : a long term follow-up.
D. Saadoun; M. Resche Rigon; V. Thibault; J. Piette; P. Cacoub.
Objective:
To describe the long-term follow-up of anti-hepatitis C virus
(HCV) therapy in patients with mixed cryoglobulinemia (MC).
Methods:
Monocentric study of seventy-two consecutive HCV-MC patients
who received treatment with IFNα-2b (n=32) (3 millions IU x 3/week) or
Peg-IFNα-2b (n=40) (1.5 µg/kg/week), both combined with oral ribavirin
(600 to 1,200 mg/day) for at least 6 months. Logistic regression was used to
assess factors associated with clinical remission of MC.
Results:
The mean follow-up after discontinuing antiviral therapy was
39.7 ± 24.4 months. Eight (11%) deaths were noted, primarily from cardiovascular
disease, liver disease or infection. Forty-five (62.5%) patients achieved a
complete clinical response of MC, 58% had a sustained virological response and
45.8% cleared cryoglobulin. Compared with patients treated with
IFNα-2b/ribavirin, those receiving Peg-IFNα-2b/ribavirin had a higher
sustained clinical (67.5% vs. 56.2%), virological (62.5% vs. 53.1%) and
immunological (57.5% vs. 31.2%) response, regardless of HCV genotype and viral
load. In multivariate analysis, an early virologic response [(odds ratio (OR),
3.53; 95% CI 1.18 to 10.59)] was independently associated with a complete
clinical response of MC. A glomerular filtration rate lower than 70 ml/min (OR
0.18; 95% CI 0.05 to 0.67) was negatively associated with a complete clinical response
of MC.
Conclusion:
Peg-IFNα plus ribavirin should be considered the
induction therapy for HCV-MC vasculitis. An early virological response and the
absence of renal insufficiency are the key factors of clinical response.
#390. Customizing treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in patients with HCV genotype 1 or 4 infection. Interim results of a prospective randomized trial.
P. Ferenci; H. Laferl; T. Scherzer; A. Maieron; M. Gschwantler; H. Brunner; R. Hubmann; M. Bischof; K. Staufer; C. Datz; P. Steindl-Munda; H. Kessler.
Introduction:
The rapidity and magnitude of response to therapy in GT1 and
GT4 pts is variable. Pts who have an RVR (undetectable HCVRNA at 4wks) with
peginterferon alfa plus RBV may achieve SVR after only 24wks (Hepatol
2006;43:954, J Hep 2006;44:97), while pts with no RVR may benefit from
prolonged therapy (Diago, Gastroenterol. in press). This prospective study
investigates customization of PegIFNα-2a + RBV in GT1/4 pts based on
HCVRNA level at wk4 and 12.
Methods:
Naïve GT1/4 pts were initially treated with PegIFNα-2a
180μg/wk +RBV 1000/1200 mg/d, before allocation to 1 of 4 treatments based
on HCVRNA level at wk4 and 12. At wk4, ‘super-responders’ (HCVRNA <50IU/mL)
were assigned to a further 20wks (Gp D). All other pts continued to receive
therapy until wk12 when HCVRNA was retested. Pts with an EVR (unquantifiable
[<600IU/mL] or ≥2log drop in HCVRNA) were randomized to 48wks (Gp A)
or 72 wks (Gp B) therapy. Remaining pts without an EVR were assigned to Gp C
and treated for 72wks. In Gps A–C therapy was terminated if HCVRNA remained
detectable at wk24. Due to the high number of pts with an RVR (28%; expected
15%), the target of 444pts was increased to 565 to power the study (Gp A vs
B).The study is fully recruited.
Results:
Of 401pts recruited at Jun 30 2005, 28 dropped out before
assignment. Outcomes in Gp D pts have been reported (Hepatol;44:S6). Pts in Gps
A and B had similar outcomes (Table); the lower SVR in the ITT analysis was due
to the higher no. of drop outs in the 72wk arm. Overall, relapse rates in Gps A
and B were similar (24 vs 21%). In pts with an EVR (Gps A & B), those with
HCVRNA <50IU/mL at wk12 had similar relapse rates (A,17%; B,18.5%); however,
in those with HCVRNA ≥50IU/mL at wk12, longer treatment lowered relapse
rate (A,50%; B,27%). Very few pts without an EVR (Gp C) obtained an SVR, even
with a longer duration, confirming the high NPV of an EVR.
Conclusion:
These interim results suggest that customizing duration of
therapy based on undetectable HCVRNA at wk4 and 12 is likely to be beneficial
in maximizing the probability of an SVR in GT1/4 pts.
|
|
A
(n105) |
B
(n108) |
C (n58) |
D
(n-104) |
|
BL Characteristics (± data are mean ± SD) |
||||
|
Male, n (%) |
68 (65) |
72 (67) |
39 (70) |
63 (61) |
|
Age, y |
45.3 ± 10.2 |
44.5±9.7 |
46.6 ± 10.1 |
40.8 ± 11.5 |
|
BMI, kg/m2 |
26.3±4.2 |
25.1±4.0 |
25.8±3.3 |
25.0 ± 4.4 |
|
Caucasian, n (%) |
96 (91) |
100 (93) |
55 (98) |
104 (100) |
|
HCV RNA (IU/ml x 106 |
1.64 ± 2.64 |
1.57 ± 2.24 |
1.05 ± 2.32 |
1.02 ± 2.64 |
|
HCVRNA <800000 IU/mL, n
(%) |
47 (45) |
50 (46) |
24 (43) |
71 (68) |
|
Genotype 1, n (%) |
96 (91) |
99 (92) |
48 (86) |
81 (78) |
|
F3-4, n (%) |
26 (24) |
26 (24) |
21 (36) |
21 (20) |
|
Response |
||||
|
SVR % (intent to treat) |
56.4 |
42.9 |
3.9 |
77.2 |
|
SVR %( per protocol) |
75.9 |
78.9 |
N/A |
87.9 |
|
Relapse rate |
24 |
21 |
N/A |
12 |
#391. Evaluation of fibrosis evolution using non-invasive methods according to sustained virological response in HCV patients. A pilot prospective controlled study.
V. de Ledinghen; L. Castera; J. Foucher; R. Tournan;
P. Bernard; G. Moisset; X. Moncoucy; J. Bertet; P. Couzigou.
Introduction:
FibroScan (FS) and Fibrotest (FT) are non-invasive methods
for the evaluation of fibrosis in HCV patients. The usefulness of non-invasive
methods, especially FS, for the follow-up of fibrosis in treated patients,
according to long-term virological response (LTR), is unknown. The aim of this
prospective study was to evaluate liver fibrosis evolution using FS and FT in
treated HCV compared to untreated HCV patients.
Methods:
236 consecutive patients were evaluated: 82 treated HCV
patients (43 males, age 51 ys) who undergone fibrosis evaluation (FS and FT) before
treatment and 6 months after the end of treatment and 154 untreated HCV
patients (49 males, age 54 ys) who undergone FS and FT every years.
Results:
Sustained virological response (SVR), relapse response (RR),
non response (NR) were observed in 45, 14, 23 cases, respectively. Mean values
of FS and FT at day 0 and LTR are indicated in the figure. FS and FT values
were significantly higher at day 0 in treated compared to untreated patients
(p<0.05). No statistical difference was observed between untreated patients
and SVR or RR at the end of follow-up. 87% of cirrhotic SVR had FS values <
10 kPa at the end of follow-up. Only NR had higher values of FS and FT than
untreated patients at the end of follow-up (p<0.01). Between untreated and
SVR patients, FS evolution between day 0 and LTR was significantly different
(+12% vs -14%, p=0.001). This difference was lower between untreated and RR or
NR patients (+12% vs -17% or -12%, p=0.04). For FT evolution between day 0 and
LTR, no difference was observed between untreated patients and SVR, RR or NR.
By logistic regression, only treatment was associated with regression of FS (OR
2.89, 95%CI 1.6-5.1, p<0.0001) and FT (1.83, 1.0-3.3, p=0.04).
Conclusion:
SVR and RR patients have fibrosis regression. FS seems the
best non-invasive method for the evaluation of fibrosis regression and should
be evaluated in a large controlled study.
#392. Treatment of subjects with chronic hepatitis C
infection (HCV) and end stage renal disease (ESRD) using low dose pegylated
interferon alpha 2 a (PEG-IFN) and Ribavirin (RBV).
D. Carriero; A. J. Uriel; D. T. Dieterich.
Introduction:
Up to 20% of patients (pts)with ESRD also have chronic HCV.
Tolerability of IFN and RBV in this population limits effective treatment. In
small cohort studies, sustained viral response (SVR) rates were less than 20%.
HCV is associated with poorer clinical outcomes after renal transplantation
(RT); Antiviral therapy is therefore indicated for RT candidates.
Aim:
To evaluate the efficacy and tolerability of modified dose
PEG-IFN a 2a and low dose RBV in a cohort of pre-RT candidates with HCV.
Methods:
Data was collected both retrospectively and prospectively on
15 patients with ESRD awaiting renal transplant, who had completed, or were
currently on therapy for HCV. PEG-IFN
a2a was administered once week post-dialysis.
15 patients received modified dose of 135 ug, 1 patient received full dose
(180 ug). All patients received
ribavirin 200 mg daily.
Results:
Mean age of the cohort was 50.5 yrs (25–68), 57% were male, 67%
were African-American; 12 pts were on hemodialysis and 3 on continuous
ambulatory peritoneal dialysis.
In 11 ESRD patients were secondary to diabetes or
hypertension (HTN); 2 were secondary for glomerulonephritis. 12 pts had HCV genotype (gt) 1, 2 had gt 2.
3 patients were coinfected with HIV, all were on stable
snit-retroviral therapy at baseline, with undetectable HIV RNA levels and
median absolute CD lymphocyte count of 411 cell/mm3 (range 319-620). The majority of the cohort (10/15) had
hypertension, 6 patients had a history of coronary artery disease, and four
patients had other cardiac pathology (aortic valve disease, congestive cardiac
failure, pulmonary hypertension and left ventricular hypertrophy).
Median baseline (bl) HCV-RNA level was 554,500 IU/mL (range
3380-12,100,000) 809,000 IU/ml (190,000–12,100,000), median ALT was 38 (range 7-140); AST (30
(10-265). Mean fibrosis score (out of 4)
n=11 was 2 (range 0-2). 2 patients had
cirrhsois.
11/15 (73%) of patients were on Erythropoietin (EPO) at
baseline, 4 started during therapy. All
patients on EPO at baseline required increased doses during therapy.
Seven patients (47%) required transfusion, 4 patients
required ribavirin dose reduction for anemia, 3 subsequently discontinued at
6,8, and 16 weeks respectively. No dose
reductions were required for neutropenia or thrombocytopenia.
Two patients required hospitalization and discontinuation of
therapy (1 for hip fracture, 1 for bacteremia).
One patient with cardiomyopathy died of acute CHF at week 14. One patient died at week 6 of intra-cerebral
bleed due to uncontrolled HTN.
To date 14 out of 15 patients have completed therapy. Median length of treatment was 25 weeks
(range 4-76), one subject is at week 5.
12/14 (86%) complete 12 weeks, 7/11 (44%) had an EVR. Two subjects are not year evaluable for SVR
(1 patient is HCV RNA undetectable at end of treatment, 1 subject is still on
therapy. On an ITT analysis—4/13 (31%)
achieved and SVR; 7/13 are non-responders (2 of 7 relapsed after
discontinuation of therapy).
Conclusion
·
The
majority of the cohort (85%) were able to complete 12 weeks of therapy, with
SVR being achieved in 31%.
·
Therapy
was well tolerated by over 60% of patients
·
Both
deaths during therapy were related to underlying cardiovascular disease, which
has a high prevalence in this population.
·
Well
controlled HIV should not be an exclusion to HCV therapy in patients with ESRD.
·
ESRD
should not preclude a trial of HCV therapy in carefully selected patients,
given the benefit of viral clearance prior to renal transplantation, and the
difficulties in treating HCV post transplant.
#393. A Prospective, Double-Blinded Neuropsychiatric Comparison of Pegylated Interferons Alfa-2a and Alfa-2b.
D. Sylvestre; A. Smith; L. Barrett; D. Greene.
Background:
Inter-study evidence using interferon alfa as a standard
suggests that pegylated interferons alfa-2a (PI2a) and alfa-2b (PI2b) may have
different neuropsychiatric toxicity profiles. Because of its potential importance
to the many HCV-infected patients with comorbid mental illness, we conducted a
prospective, double-blinded pilot study of PI2a vs. PI2b in patients undergoing
treatment for HCV. Endpoints included psychiatric discontinuations; initiation
and adjustment of psychiatric medications; monthly Beck Depression Inventory
(BDI) and SF-36 Quality of Life scores, and self-reported depression (D),
anxiety (A), and irritability (I).
Methods:
40 patients were randomized to treatment with ribavirin and
either PI2a or PI2b at standard dosing. Self-reported D, A, and I scored on a
0-10 scale were recorded weekly. The BDI and SF-36 were administered every 4
weeks.
Results:
39 subjects initiated treatment and 1 was discontinued due to
inadvertent unblinding. The average age was 48, 23 (57%) were male, and 27
(67%) had genotype 1. None of these measures differed between the cohorts. 15
in each cohort (75%) reported a pre-existing psychiatric diagnosis. 26 were
taking a psychiatric medication at treatment initiation, 12 (67%) in the PI2a
cohort and 14 (70%) in the PI2b cohort (p=0.55).
27 (71%) completed treatment and there were 11 (29%)
discontinuations. 4 patients had psychiatric discontinuations, 1 taking PI2a
and 3 taking PI2b (p=0.32). New psychiatric medications were initiated in 9
(50%) taking PI2a and 14 (70%) taking PI2b (p=0.18), and they were adjusted in
12 (67%) taking PI2a and 15 (75%) taking PI2b (p=0.41). BDI, SF-36, and
self-reported depression, anxiety, and irritability scores were not
statistically different at baseline, nor were there significant differences
when analyzed on a monthly basis. However, the PI2b cohort had a significantly
higher cumulative BDI score, 16.3 vs 13.1 (p=0.01), and a lower SF-36 score,
40.8 vs 48.5 (p=0.004). Additionally, those taking PI2b reported significantly
higher overall depression, 2.4 vs 2.1 (p=0.04), and anxiety, 2.8 vs 2.2 (p
<0.001), but not irritability, 2.9 vs 2.7 (p=0.32).
Conclusion:
This small but rigorous study provides the first direct evidence
that PI2a and PI2b may elicit small but measurable differences in depression,
anxiety, and quality of life during HCV treatment. It is unclear, however,
whether these will translate to meaningful differences in major
neuropsychiatric outcomes. A larger study is needed to assess the magnitude of
the differences in the psychiatric toxicity profiles of these medications and
to assess any impact on HCV outcomes.
#394. Treatment with Peginterferon alfa 2b and Ribavirin
of Chronic Hepatitis C Patients on Substitution Therapy and Outcome in the
Clinical Setting in Germany.
D. Hueppe; E. Zehnter; M. P. Manns; S. Mauss; R.
Prinzing.
Introduction:
Peginterferon (PEG-IFN alfa) and Ribavirin (RBV) are the
standard of care for hepatitis C virus (HCV) treatment. The efficacy and safety
of PEG-IFN alfa-2b and RBV was observed in
Methods:
249 active sites (117 with substitution patients) have
treated a total of 2912 HCV patients (490 on substitution and 2422 without
substitution).
Results:
The 490 substituted patients had a mean age of 35.1 years,
mean weight of 73.8 kg and 71.6% were male. 48.1% of patients were genotype 3,
42.8% were genotype 1/4/5 or 6, and 9.1% were genotype 2. 2.2% of patients
showed cirrhosis, 4.5% had a HIV co-infection, and 5.1% had a HBV co-infection.
9.0% of patients were treated in hospitals, 10.4% in BNG practices, and 80.6%
in other practices. 46.3% of patients were substituted with methadone, 13.5%
with buprenorphine, 4.1% with other agents, and in 36.1% no according
specification was present.
The majority of patients (92.7%) received PEG-IFN and RBV as
primary therapy, only 7.3% were relapse patients after IFN mono-therapy. 39.9%
received the intended PEG-IFN doses, 34.8% received lower and 25.3% higher
doses of PEG-IFN. 65.9% of patients received appropriate RBV doses.
The project is ongoing so all follow-up (FU) and end of
treatment (EOT) data for patients are not available. To date, 299 substituted
patients reached EOT and 158 the end of FU.
A normalization of ALT was seen in 71.6% of substituted
patients at EOT and 61.4% at FU compared to 72.6% at EOT and 61.9% at FU for
nonsubstituted patients. Of 158 substituted patients who completed FU, 67.7%
reached a sustained viral response (SVR), 9.5% relapsed, 8.9% were
non-responders, and 13.9% were either lost to FU or had no documentation.
Comparison of the 490 substituted with 2422 nonsubstituted
patients showed 16.9% and 19.7%, respectively, discontinued the study; reasons
for discontinuation included adverse events (3.1% vs. 4.5%), lack of efficacy
(3.9% vs 8.8%), loss to FU (2.7% vs 2.1%), patient wish (3.3% vs 1.6%,), or
other reasons (4.1% vs 2.5%, respectively).
Conclusion:
The preliminary results for the difficult-to-treat
substituted patients regarding sustained viral response and relapse rates are
very encouraging and show a high standard of treatment in
#395. Early predictors of anemia in patients with HCV
genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin 1000-1200
mg/day.
D. Jensen; N. Reau; S. J. Hadziyannis; D. Messinger;
M. W. Fried.
Introduction:
Although RBV dose adherence is critical in the treatment of
HCV genotype 1 (G1) pts, higher doses can be associated with hemolytic anemia. In
studies with peginterferon plus RBV, hematologic abnormalities were common:
hemoglobin (Hb) level <12g/dL in 52% of pts and Hb <10g/dL in 13%. Also,
RBV dose reduction was required in 22% of pts receiving combination therapy for
48wks. However, pre-treatment predictors of considerable anemia (CA; Hb
decrease ≥2.5 g/dL from baseline [BL]) were inadequate to guide
therapeutic intervention. Analysis of 59 G1 pts showed an Hb decrease ≥1.5
g/dL from BL at wk2 significantly correlated with CA at wk4. Thus, to test the
predictive value of wk-2 Hb drop, we analyzed data from 2 prospective,
randomized, phase III trials of PegIFNα-2a + RBV (NEJM,2002;347:975; Ann
Int Med,2004;140:346).
Methods:
We analyzed BL characteristics (gender, race, age,
bodyweight, BMI, fibrosis, genotype, Hb, platelets, WBC, creatinine, creatinine
clearance (CLR), wk2 Hb drop ≥1.5g/dL, and RBV and PegIFNα-2a doses)
of 555 G1 pts receiving PegIFNα-2a 180µg/wk + RBV 1–1.2g/d for 48wks, to
determine their predictability for CA at wk4 using univariate (Wald χ2
test) and multiple logistic regression analyses.
Results:
Significant factors associated with CA at wk4 in 236 pts
exhibiting a ≥2.5 g/dL decrease in Hb are listed (table). CA at wk4 was
also significantly associated with more/earlier drug dose reductions due to
anemia (p<0.0001) and lower cumulative dose of RBV (p<0.001). An SVR in
pts with CA at wk4 was only marginally reduced (47.5% vs 51.7% in pts without
CA).
Conclusions:
Important predictors of CA at wk4 included a wk2 Hb drop ≥1.5g/dL,
non-Black/Asian race, and cirrhosis. Pts with a wk2 Hb drop experienced more
dose reductions and sub-therapeutic RBV doses than those with no wk2 drop.
Early anemia intervention in pts with a wk2 Hb drop >1.5g/dL may avoid RBV
dose reduction, thereby improving the chance of achieving an SVR.
|
Factors associated with considerable
anemia at week 4 |
Univariate
|
Multivariate
|
|
|
p-value |
Odds ratio (95% CI) |
||
|
Age (10 yrs)* |
<0.001 |
ns |
– |
|
Gender (female vs. male) |
0.0426 |
ns |
– |
|
Race (Black/Asian vs. other) |
0.0046 |
0.0035 |
0.31 (0.14–0.68) |
|
Baseline Hb (1 g/dL)* |
<0.0001 |
0.0087 |
1.34 (1.08–1.66) |
|
CLR (10mL/min)* |
<0.0001 |
0.0003 |
0.82 (0.73–0.91) |
|
Cirrhosis (yes vs. no) |
0.0808 |
0.0121 |
2.06 (1.17–3.61) |
|
Wk 2 Hb drop (≥1.5 g/dL vs. other) |
<0.0001 |
<0.0001 |
23.2 (14.1–38.1) |
|
PegIFNα-2a exposure wk 1–4 (1 µg/wk/kg)* |
0.0275 |
0.0293 |
1.77 (1.06–2.95) |
*For continuous variables, the odds ratio presented relates
to a one unit change (eg the odds of having a Hb drop of ≥2.5g/dL in a
patient with a baseline Hb of 11 g/dL is 34% higher than in a patient with a Hb
of 10g/dL)
#396. Substitute opiate use in intravenous drug users
(IVDUs) does not adversely effect sustained virological response(SVR) following
treatment of chronic hepatitis C (CHC) with pegylated interferon alpha (PEG-
IFN) and ribavirin.
H. Hussaini; E. Cole; A. Flynn; J. Bergin.
Background:
Many treatment programs for CHC exclude IVDUs who currently
use intravenous or oral opiate substitution. Aims: To determine the effect of a
joint hepatology and drug team pathway on CHC SVR to treatment, in IVDUs on
concurrent opiate substitution.
Methods:
A retrospective analysis over a 4-year period of 118
treatment naïve patients:
·
Group
A with no history of IVDU (n=22),
·
Group
B with a past history of IVDU (n=30) and,
·
Group
C with substitute opiate use in IVDUs (n=66).
Patients were treated with either Peg IFN 2a/2b and ribavirin
(800-1200mg) for 6–12 months according to standard protocols. Data was analysed
on an intention to treat basis. Patients with negative hepatitis C RNA 6 months
post-therapy had a SVR. Data was stratified according to genotype (G 2-3 vs non
G 2-3) and fibrosis score (Knodell < 4 vs > 4; n=80).
Results:
The proportion of patients with genotype 2-3 was not
significantly different in Groups A (36%), B (37%) and C (53%). Group C
compared to Group A had a lower advanced (> 4) fibrosis score (18.4 vs
42.6%, p< 0.04) but not compared to group B (41.4%).
The overall and group SVR rates with stratification for
genotype and fibrosis are shown in the table below. In the entire cohort the
SVR was 53%, with a significantly higher SVR in patients with G 2-3 and less
advanced fibrosis. In Group C, SVR was also significantly greater in G 2-3
patients. However, the comparative SVRs in the three groups were similar, as
were SVR based on genotype and fibrosis score within each group. Compliance,
non-response and relapse rates were similar in all groups.
In contrast, treatment discontinuation (overall 7.6%) was
commoner in former IVDUs (n=3) and substitute opiate use IVDUs (n=4) compared
to non-IVDUs (n=1). Six-month post treatment HCV RNA data was not available in 3
former IVDUs and 4 substitute opiate users, but complete in all non-IVDUs.
Conclusions:
·
Concurrent
opiate substitution in IVDUs does not adversely affect treatment response rates
for CHC, although SVR may be underestimated in ex- and concurrent IVDUs, due to
lack of post-treatment data.
·
In
our experience, patients with opiate substitution are compliant to therapy and
should not be excluded from CHC treatment.
#397. Effectiveness of Antiviral Therapy in Patients with
Chronic Hepatitis C Treated in Daily Clinical Practice.
Goulis; S. Manolakopoulos; S. Savvidou; P. Tsekoura;
G. V. Papatheodoridis; C. Triantos; O. Anagnostou; N. Chrysanthos; K.
Thomopoulos; V. Nikolopoulou; A. Archimandritis; D. Chrysagis; D.
Tzourmakliotis; C. Arvanitakis.
Background:
Standard treatment of patients with chronic hepatitis C
consists of pegylated interferon (PegIFN) α in combination with ribavirin.
Information outside clinical practice is limited. Our aim was to determine the
efficacy and safety of PegIFN plus ribavirin in routine clinical practice.
Patients and Methods:
356 consecutive treatment-naïve hepatitis C patients from
five centers in Greece who fulfilled the following criteria age >18 years,
absence of HBV or HIV coinfection, adherence to treatment duration above 80%,
absence of other comorbid conditions were included in the study. Patients were
treated with either PegIFNα2a (n=104) or PegIFNα2b (n=251) and
ribavirin for 24 weeks (HCV genotype 2,3) and 48 weeks (HCV genotype 1,4)
respectively. Multiple logistic regression analysis was used to identify
baseline factors of SVR. The influence of age, gender, alcohol use, BMI,
infection duration, mode of transmission, baseline viral load, serum ALT,
genotype, liver histology (inflammation and fibrosis), hepatic steatosis and
type of interferon were analysed.
Results:
Demographic characteristics: 56.8% male, IV drug abuse 31.1%,
mean BMI 23.6+4 kg/m2, distribution of genotypes: GT1 46.1%, GT2 7.3%, GT3 34%
and GT4 12.6%, median HCVRNA 5.27x105 (0.02-6050x105) IU/mL, mean HAI
7.51+2.39, severe fibrosis (Ishak > 4) 15.3%, steatosis >33% 30.1%.
Sustained Virological Response (SVR) was achieved in 254/356
patients (71.3%) According to genotype: GT1 112/164 (68.3%), GT2 20/26 (77%),
GT3 105/121 (86.7%), GT4 17/45 (37.8%). Multiple logistic regression analysis
showed that cirrhosis (OR 4.88), genotype 1 or 4 (OR 3.38), age >40 (OR
2.19) and hepatic steatosis on liver biopsy (OR 2,24) were baseline factors
independently associated with a significant lower chance of SVR. Patients with
GT4 had a significant lower SVR compared to patients with GT1 (37.8 vs 68.3%,
p<0.05) although there was no difference in patient age, median infection
duration, gender, mode of transmission, BMI, alcohol consumption, baseline
viral load, treatment adherence or histological activity and stage.
Conclusion:
·
Our
results clearly show that in clinical practice patients with >80% adherence
to the current treatment regimens of PegIFN-α and ribavirin could achieve
response similar or even better to those of controlled clinical trials.
·
Hepatic
steatosis is a baseline factor independently associated with poor response to
treatment.
·
GT4
has a significant lower response rate compared to GT1 in Greek naïve chronic
hepatitis C patients.
#398. Plasma ribavirin quantification in patients with
chronic hepatitis C, genotype 1, treated with peginterferon and ribavirin.
J. SALMERON; P. Muñoz de Rueda; L. Rodriguez; J.
Candel; R. Quiles; R. Andrade; M. Diago; J. Navarro.
Background:
The ribavirin (RBV) association to peginterferon (Peg-IFN) is
very important in order to increase the rate of sustained virological response
(SVR). But one of the side effect of RBV is anemia (9% to 13%) related to HCV
therapy, that induces a dose modification and discontinuation of RBV.
Aim.
To study the relation ship between plasma RBV concentration
(RBV-C) with the anemia and SVR in patients with chronic hepatitis C (HCC),
genotype 1, treated with 180 μg Peg-IFN α-2a and 1.000-1.200 mg RBV
during 48 weeks.
Patients and Methods.
Prospective study of 62 patients with HCC. RBV-C was
determined in 52 patients during treatment in 1, 2, 3, 4, 6, 8, 10 y 12 months.
RBV-C was carried out with serum samples drawn before the morning
administration of RBV by high-performance liquid chromatography (HPLC) with
commercially available reagents. Patients were classified as sustained
virologic response (SVR) (n=28) and non responders NR (n=24).
Results.
RBV-C was between 2 and 2,5 µg/ml during treatment, but
within 2 months was higher than 2,5 µg/ml. Body weight average before treatment
was 69 kg, and at the end of treatment decreased to 63 kg (0-19 kg), with rapid
recovery after treatment (71 kg, P< 0.001). Patients with weight loss >7
kg had a higher RBV-C within 2 months period, and they had a higher hemoglobin
decrease. Hemoglobin reduction was between 0,2 and 8,6 g/dL during treatment,
and in men the reduction was higher (P=0.09). 55% of patients had a hemoglobin
decrease >2 g/dL during the first month. 48% of patients had a drop in Hb
between 3-5 g/dL, and 11% >5 g/dL. There was a negative correlation between
the RBV-C and the hemoglobin of following month (P<0.05). Also patients with
a RBV-C peack of >3 mcg/ml had a higher decrease of hemoglobin concentration
than patients with < 3mcg/mL (P=0.002). Early virological response and SVR
was not correlated with RBV-C. But patients with SVR received a higher doses of
RBV (mg/kg).
#399. Managing HCV infection in injecting drug users: a
community model.
K. Jack; M. Varnam; B. J. Thomson.
Introduction
Injecting drug use is the dominant risk factor for the
acquisition of HCV and by far the most important route for ongoing
transmission. The identification and provision of treatment to this vulnerable
population, however, remains a major challenge. Non-attendance rates of over
40% are common in hospital based HCV clinics in the
Aim:
Against this background, we have initiated a pilot study to
assess the feasibility, safety and efficacy of a nurse led HCV service for
injecting drug users based entirely in the community.
Methods:
The study focused initially on 212 clients attending a shared
care clinic in an inner city primary care facility between 31 August 2004 and 1
September 2005. 147 were male and 65 were female. All were receiving prescribed
opiates and many continued to inject. 187 of 192 offered serological testing
for HCV agreed to the procedure. No sample could be obtained from 1 patient. Of
the remaining 186, 95 (51%) were HCV antibody positive. Sixty of the 95 HCV
positive clients were positive for HCV RNA as determined by RT-PCR. All HCV PCR
positive clients were counselled and assessed for treatment according to a set
of criteria developed with the primary aim of maintaining patient safety while
on antiviral therapy. These criteria were based on pattern of drug use,
physical and mental health, social circumstances and housing. All candidates
for treatment were reviewed in the primary care clinic by a hospital
consultant.
Results:
22 of the 60 PCR positive clients were assessed as suitable
for treatment.
·
15
patients have commenced treatment with PEG-RBV
·
1
patient achieved SVR
·
6
patients completed treatment with end of treatment response
·
1
withdrew for lack of virologic response
·
1
patient withdrew because of side effects
·
1
patient withdrew for psychiatric side effect
·
5
patients still on treatment.
Attendance rates at the nurse led clinic exceeded 80%.
Conclusion
This study found a large pool of HCV infected individuals
attending a single primary care clinic, the great majority of whom would either
not have been referred to, or would not have attended, a secondary care
facility. Our results so far indicate that HCV services, including anti-viral
therapy, can be safely delivered to this high risk group on the community. Our
study may constitute a new model for the delivery of care to this important
population.
#400. Pegylated interferon plus ribavirin in chronic hepatitis C patients with liver lesions related to alcohol intake.
J. Perez Poveda; M. Trapero-Marugan; N. Syong-Hyung ;
J. Moreno-Monteagudo; M. Borque; L. Garcia-Buey; X. Salcedo-Mora; R.
Moreno-Otero.
Aims:
To establish the prevalence of lesions related to alcohol
intake (LA) in patients with CHC. To analyse the sustained virological response
(SVR) to pegylated interferon alpha (PEG-IFNα-2b) plus ribavirin. To
correlate the existance of LA with liver fibrosis and treatment response.
Patients/Methods:
We analysed liver biopsies of 62 consecutive patients (49 males,
79%) with CHC according to METAVIR score before starting antiviral combination
therapy. LA were considered when two or more items (Mallory bodies,
megamitochondries, polimorphonuclear infiltrate, steatosis, perivessel fibrosis
and siderosis) were detected. All parameters were evaluated as: 0: none, 1:
mild, 2: moderate and 3: intense. All of liver biopsies was evaluated by the
same pathologist. Viral genotype and quantitative viraemia were assessed.
Patients received PEG-IFNα-2b plus ribavirin (adjusted to weight) during
six or twelve months according to genotype. Statistics: Student's t test, U
Mann-Whitney, chi-squared and ANOVA test.
Results:
LA were detected in 54/62 patients (87%). Single parameters
appeared in liver biopsy as follows: 46/62 steatosis, 3/62 megamitochondries,
2/62 Mallory bodies, 41/62 infiltrate by polimorphonuclear cells, 42/62
perivessel fibrosis and 28/62 siderosis. Patients with LA presented higher GGT
levels than patients without LA (72 ± 51 vs 34 ± 33 U/L; p<0.05), but no
differences were found regarding viraemia (1024629 ± 916092 vs 748750 ± 415982
IU/mL; p=0.4), AST levels (74 ± 47 vs 63 ± 71 U/L; p=0.5) and ALT levels (124 ±
93 vs 121 ± 133 U/L;p=0.9). Nevertheless patients with LA show more intense
fibrosis (F3-F4) than patients without LA but with no statistical significance
(37% vs 25%; p=0.7). All patients finalised therapy and follow-up period: 54
with LA and 8 without LA. The global SVR rate was 46.8% (29/62): the SVR rate
in patients with LA was 46.3% and 50% in patients without LA.
Conclusion:
1. A high prevalence of LA in CHC
patients exists
2. LA may be associated to an increase
in hepatic fibrogenesis.
3. LA presence does not determine a
worse virological response to combination therapy.
#402. The Therapeutic Effect of Ribavirin plus Pegylated
Interferon in Chronic Hepatitis B and C.
R. Chien; C. Hu; I. Sheen; Y. Liaw; C. Yen; J. Chang.
Background/Aims:
Concurrent chronic hepatitis B virus (HBV) and hepatitis C
virus (HCV) infection appears to increase the risk of progressive liver
disease. Studies with conventional interferon-alfa and/ or ribavirin
combination in patients with HBV-HCV coinfection have been carried out. The
efficacy is not satisfactory. Therefore, we retrospectively analyze the
therapeutic effect of ribavirin plus pegylated interferon in the treatment of
chronic hepatitis B and C.
Patients:
Forty patients with chronic hepatitis B and C were enrolled.
They are filled with the following criteria: 1). age, 18-70 years; 2).
seropositive for HBsAg and antri-HCV > 6 months; 3). elevated alanine
aminotransferase (ALT) ≧ 2 times upper limit of normal twice
one month apart; 4). alcohol, autoimmune, toxic and hepatitis delta coinfection
were excluded.
Methods:
All patients received pegylated interferon alfa 2a or 2b
subcutaneous injection once weekly plus oral ribavirin 800-1200 mg daily for 24
weeks. Regularly clinical assessment, hemogram, biochemical and virological
checked up. The efficacy assessment was performed at end of 24-week treatment
(EOT) and at end of 24-week follow-up (EOF). Statistical analysis was performed
using Chi-square test, Fisher’s exact test and stepwise logistical regression
model where appropriate.
Results:
They were 65% male with a mean age of 56 years. Fifteen
percent of them were cirrhosis and 66 % were infected with HCV genotype 1b. All
patients were seropositive for HCV RNA, but only 11% were seropositive for HBV
DNA. The mean pretherapy biochemical tests levels were: ALT 133 U/L; total
bilirubin 0.9 mg/dL; albumin 4.4 gm/dL. At EOT, the ALT nomalization rate
(biochemical response, BR), HCV and HBV seroclearance (virological response;
VR) or both (complete response; CR) were 65%, 84% and 56% respectively. At EOF,
the BR, VR and CR were 67%, 50% and 44% respectively. Stepwise logistical
regression analysis showed no clinical predictor to response. However, patients
infected with HCV genotype non-1b showed superior response than those with
genotype 1b at EOF (CR, 80% vs 20%; P=0.089).
Conclusion:
Combination therapy using ribavirin plus pegylated interferon
is effective in patients with chronic hepatitis B and C, especially those with
HCV genotype non-1b. Further large scale clinical study is warranted.
#403. Improvement in immunological abnormalities in
patients with chronic hepatitis C who have a sustained virological response to
therapy.
A. A. Modi; J. Feld; R. Loomba; B. Borg; T. Heller; M.
Ghany; E. Doo; J. Liang; J. Hoofnagle.
Background:
Patients with chronic hepatitis C often have immunological
abnormalities such as elevations in serum immunoglobulin G (IgG), rheumatoid
factor (RF) and antinuclear antibody (ANA), which usually correlate with more
advanced disease. The effects of successful antiviral treatment on these abnormalities
has not been well defined.
Aim:
To evaluate the effect of interferon-based antiviral therapy
and sustained virological response (SVR) on immunological markers in chronic
hepatitis C virus (HCV) infection.
Methods:
179 patients with chronic hepatitis C treated at the Clinical
Center of the NIH were available for analysis. Patients had been treated with
either standard or pegylated interferon and ribavirin within genotype
appropriate regimens. Patients were categorized as having an SVR (HCV RNA-negative
24 wks after stopping therapy) or non-response (which included both
non-responders and relapsers). Values for RF, ANA and IgG from before and 24
weeks after stopping therapy were obtained from retrospective chart review.
Comparisons were performed using χ2 analysis.
Results:
The 179 patients were predominantly men (59%) and Caucasian
(76%) with an average age of 48 (range = 28 to 73) yrs. Genotype 1 accounted
for 71%, genotype 2 for 17%, genotype 3 for 11% and genotype 4 for 1% of cases.
Both pre- and post-treatment values for RF were available in 160, ANA in 157
and IgG in 53 patients. RF was present in 77 patients before therapy and
declined in 44% of patients with an SVR but in only 18% of non-responders
(p=0.001). Similarly, IgG levels declined in 74% of patients with an SVR but in
only 43% of non-responders (p=0.038). Finally, ANA was present in 24 patients
before treatment and declined in 14% of patients with an SVR, but in only 6% of
non-responders (p=ns).
Conclusion:
Patients with chronic hepatitis C who achieve an SVR
frequently have improvements in RF and IgG levels which may be surrogate
markers for immune activation and disease activity that decrease following
viral eradication.
#404. Pegylated Interferon alfa-2b Plus Ribavirin in
Patients With Genotype 1 Chronic Hepatitis C With a Slow Virologic Response: An
Early Enrollers Analysis of the SUCCESS Study.
M. Buti; Y. Lurie; N. Blokhina; G. Teuber; W. Halota; J. Sumskiene; Z. Vozianova; F. Wong; R. Winkler; R. Esteban.
Aim:
To assess the efficacy of 72 vs 48 weeks' therapy with
peginterferon (PEG-IFN) alfa-2b plus ribavirin (RBV) in G1, treatment-naive,
chronic hepatitis C patients who have slow virologic response.
Methods:
This is an open-label study involving treatment-naive G1
patients with hepatitis. Patients will receive PEG-IFN alfa-2b 1.5µg/kg QW +
weight-based RBV (800–1400mg/day) for 12 weeks (Fig.). HCV RNA levels at weeks
12 and 24 will determine whether patients are discontinued or assigned to 48 to
72 weeks of treatment. Patients will be followed for 24 weeks after treatment.
Early virologic response (EVR) is defined as ≥2 log decrease in HCV RNA
or undetectable HCV RNA levels at week 12. Primary endpoint is SVR 24 weeks
after therapy. HCV RNA levels are measured using TaqMan assay (LLQ, 29IU/mL) at
screening, baseline, weeks 4, 12, 24, 48, 72, and follow-up.
Results:
As of September 2006, 1033 patients have been screened and
1428 patients are enrolled at 133 sites in Europe, Canada, and Israel. Of
these, 12-3 patients have been treated until week 12, and 190 until week 24.
Most (63.3%) patients are men, white (96.2%), and have a mean age of 43 years
and a mean body weight of 76kg (range, 45–124kg).
Virologic Response
• RVR was observed in 188 (17%) of
1129 patients with available data for week 4 and EVR was observed in 726 (78%)
of 934 patients with available data for week 12 as of May 2006
• EVR was observed in 1044 (87%) of
1203 of patients with available week 12 HCV RNA data as of September 2006.
— 781 (75%) of 1044 had undetectable
levels of HCV RNA.
— 263 (25%) of 1044 had a ≥2
log10 decrease from baseline in HCV RNA levels.
• Of those with available 12- and
24-week HCV RNA data as of September 2006, 126 (66%) of 190 had a ≥2
log10 decrease from baseline in HCV RNA levels at week 12 and undetectable HCV
RNA at week 24 and were classified as slow responders
Conclusions:
Preliminary observations from SUCCESS are encouraging and
indicate that most (87%) G1 patients treated with PEG-IFN alfa-2b plus
ribavirin attain an EVR.
Upon completion of the study, data from SUCCESS may determine
whether extending duration of therapy with PEG-IFN alfa-2b plus ribavirin from
48 weeks to 72 weeks improves SVR in slow responder G1 patients.
#406. The Antiviral Efficacy of an HCV Polymerase
Inhibitor in the Chimpanzee Model: Genotypic and Phenotypic Analyses.
C. Chen; Y. He; L. Lu; B. Lim; R. L. Tripathi; A.
Roth; T. Middleton; T. Pilot-Matias; L. E. Hernandez; D. W. Beno; M. A. Long;
H. Mo; W. M. Kati; T. D. Bosse; D. P. Larson; R. Wagner; R. E. Lanford; W. E.
Kohlbrenner; D. J. Kempf; A. M. Molla.
Background:
A-837093 is a novel, potent inhibitor of HCV NS5B polymerase.
In replicon–based cell culture assays, the EC50 values of A-837093 for HCV
genotypes 1a and 1b are 11 nM and 3 nM, respectively. This compound also
demonstrates good pharmacokinetic properties, with oral bioavailability ranging
from 63-77% in rats and 90-100% in dogs.
Methods:
The antiviral efficacy of A-837093 was evaluated in
chimpanzees infected with HCV in a proof-of-concept study. The design included
oral dosing of 30 mg per kg BID for 14 days followed by a 14-day post-treatment
observation. Serum samples were withdrawn at various times throughout the study
period to determine viral load, plasma drug levels, and for clinical chemistry
analysis.
The NS5B genes were cloned into a subgenomic replicon-based
shuttle vector to evaluate their phenotypic response. Individual clones were
isolated and sequenced to compile a detailed analysis of the viral population
composition.
Results:
At day 2 of therapy, viral load reductions of 1.4 and 2.5
log10 copies/ml for 1a and 1b chimpanzees, respectively, were observed. After
this initial drop in viral load, rebound of plasma HCV RNA was observed in the
genotype 1b-infected animal while the genotype 1a-infected chimpanzee
experienced a sustained viral load reduction throughout the treatment period.
Clonal sequencing revealed the presence of several mutations associated with
resistance to A-837093, such as C316Y and G554D in samples from the genotype
1b-infected animal.
Conclusion:
These findings validate the in vivo antiviral efficacy of
benzothiadiazine HCV polymerase inhibitors. The outgrowth of resistant strains
in the genotype 1b-infected animal is consistent with in vitro studies showing
the presence of preexisting resistant mutants, and suggests that this compound
would be optimally useful in combination with other HCV antiviral agents.
#408. Mutagenic effect of ribavirin on NS5B quasispecies heterogeneity in vitro and in patients with chronic hepatitis C.
W. Hofmann; A. Polta; E. Herrmann; U. Mihm; B.
Kronenberger; T. Sonntag; V. Lohmann; B. Schoenberger; S. Zeuzem; C. Sarrazin.
Introduction:
The addition of ribavirin to (pegylated) interferon alfa has
substantially increased sustained virologic response rates in the treatment of
chronic hepatitis C. Ribavirin is suggested to act as an RNA virus mutagen thereby
reducing the viral fitness which results in lethal mutagenesis and error
catastrophe. However, data on the mutagenic effect of ribavirin in chronic
hepatitis C (CHC) are controversial.
Methods:
We studied the non structural (NS)5B quasispecies heterogeneity
(1041 base-pair fragment, mean number of clones, n=18) in HCV replicon cells
(subgenomic HuH7 replicon system, HCV-con1) treated with increasing doses of
ribavirin or, as a control, with its L-enantiomer levovirin. Furthermore, NS5B
quasispecies heterogeneity was determined from stored serum samples of 14
patients with CHC genotype 1b infection, who received ribavirin alone (n=7) or
in combination with pegylated interferon alfa (n=7), both at baseline and
during the first weeks of therapy.
Results:
Cultivation of the HCV replicon cells per se resulted in an
increase of the NS5B mutational frequency. However, ribavirin at a
concentration of 500µM, but not levovirin induced a further increase with a
maximum of 2.5 fold after 48h. In patients undergoing ribavirin monotherapy,
the total NS5B mutational frequency was higher during the first weeks of
therapy as compared to baseline (p=0.01) but only 5 out of 7 patients had an
increase when paired serum samples were analyzed (p=n.s.). Genetic complexity
(p=0.043) and the proportion of specific G-to-A transitions increased
significantly (p=0.003). Serum ribavirin concentration was positively
correlated with evolution of NS5B genetic diversity (p=0.039). In patients
receiving pegylated interferon alfa and ribavirin combination therapy a
decrease of mutational frequency (p=0.002), unchanged genetic complexity and a
lower proportion of G-to-A mutations (p=0.002), respectively, were detectable.
Conclusion:
Ribavirin, but not its clinically non effective L-enantiomer
levovirin possesses a dose-dependent mutagenic effect in HCV replicon cells. In
patients with chronic hepatitis C undergoing monotherapy, ribavirin exhibits
moderate mutagenic effect early during therapy which may escape detectability
in patients undergoing interferon alfa and ribavirin combination therapy.
#409. Infection of human hepatocyte chimeric mouse with
genetically engineered hepatitis C virus and its susceptibility to interferon.
M. Imamura; N. Hiraga; M. Tsuge; C. Noguchi; S. Takahashi;
E. Iwao; C. Tateno; M. Honda ; S. Kaneko; T. Wakita; K. Yoshizato; K. Chayama.
Purpose:
Studies of hepatitis C virus (HCV) infection and replication
in vivo have been hampered by the lack of a small animal mode with long-term
HCV infection. A mouse model of HCV has been developed using human hepatocyte
chimeric mouse and the cell line producing genotype 2a HCV has been shown to
infect this mouse. As an extension of this model, we attempted to develop an
infectious model of molecularly cloned both genotype 1a and 2a HCV RNA, and
evaluated its susceptibility to interferon (IFN)-α.
Methods:
HCV was infected to the human hepatocyte chimeric mice by
following methods. 1) intravenous inoculation of genotype 1b HCV-infected human
serum, 2) intrahepatic injection of genotype 1a molecular clone, 3) intravenous
inoculation of culture medium collected from hepatoma cell lines transfected
with genotype 2a HCV genome. The HCV-infected mice were intramuscularly
administrated with consecutive daily injection of 7000 IU/g/day of IFN-α,
and mice serum HCV RNA titer were analyzed.
Results:
The mice inoculated with HCV-infected human serum developed
measurable viremia 2 weeks after inoculation. The viremia reached a plateau 6
to 8 weeks after infection and persisted high titer of HCV RNA for more than 12
weeks. IFN-α-treatment reduced HCV RNA titer in HCV-infected mice. The
mice inoculated with in vitro generated HCV RNA also developed high level of
viremia in both genotype 1a and 2a. With 1 week-IFN-α treatment, the viral
load reduced to undetectable limit in genotype 2a-infected mouse. However, only
1 log decrease was seen in genotype 1a-infected mice.
Conclusion:
We have established a genetically engineered genotype 1a and
2a HCV-infected mice model, and the mice pronounced different susceptibility to
IFN-α. These animal models would be useful for studies of HCV virology and
resistance of HCV against IFN.
#412. Identification of human monoclonal antibodies
against HCV E1 that broadly neutralize retroviral pseudoparticles and
JFH1-based viruses.
J. Meunier; S. Takikawa; R. Russell; J. Bukh; V.
Goossens; G. Maertens; E. Depla; S. Emerson; R. Purcell.
Background:
Hepatitis C virus infection is a major cause of chronic liver
disease worldwide. Unfortunately, development of an effective vaccine has
proven to be very challenging. Passive immunoprophylaxis using monoclonal
antibodies to both glycoproteins would be an attractive alternative to prevent
or control HCV infections, but thus far, only mAbs against E2 have been shown
to neutralize.
Methods:
A large panel of mAbs against E1 or E2 was derived from mice,
chimpanzees or humans immunized with recombinant envelope proteins. In
addition, mAbs were also retrieved from HCV patients that cleared infection. In
an initial screening all mAbs were evaluated for neutralization of a genotype
1a retroviral pseudoparticle (HCVpp). Antibodies showing at least 50%
neutralization in this first assay were further characterized with respect to
neutralization of other genotype HCVpp, JFH1 HCVcc neutralization and epitope
mapping.
Results:
Out of a panel of more than 50 mAbs, only 3 monoclonal
antibodies neutralized retroviral pseudoparticles (HCVpp). The neutralization
titers of two human mAbs against E1 and one chimpanzee mAb against E2 were
determined with HCVpp representing each of the six HCV genotypes. All three
mAbs reacted against the HCVpp 1a, with neutralization titers from 1:800 to
1:3200. Surprisingly, all three mAbs also reacted strongly against HCVpp of
genotypes 4 and 5 (neutralization titers from 1:400 to 1: 3200), and almost as
well against HCVpp 6a (1:100 to 1:1600). All three mAbs reacted weakly or not
at all against HCVpp 3a and HCVpp 2a, respectively. However, all three mAbs
neutralized cell-culture grown HCVcc JFH1 (genotype 2a) by 80% to 90%.
Especially the E1 specific mAbs recognize an epitope region which has so far
not been associated with HCV entry.
Conclusion:
For the first time, E1 neutralizing mAbs were identified. The
antibodies show an unexpectedly broad and strong cross-genotype neutralization
activity. Therefore, the results of this study may contribute to the
understanding of HCV replication and may be used in novel clinical approaches
for the control of HCV infection.
#417. In vitro antiviral effects of combinations of Abbott HCV polymerase inhibitors with IFN or NS3/4A protease inhibitors.
G. Koev; T. Dekhtyar; L. Han; P. Yan; J. M. Beyer; T.
Ng; C. Lin; D. P. Larson; T. D. Bosse; H. Chen; K. F. McDaniel; L. L. Klein; R.
Wagner; W. M. Kati; D. J. Kempf; H. Mo; A. M. Molla.
Aim:
In search of an alternative to the standard IFN-RBV treatment
of HCV infection, we have discovered a series of potent inhibitors of the HCV
NS5B RNA polymerase. While monotherapy often leads to resistance development,
drug combinations have proven to deliver superior results in HIV therapy, and
are almost certain to be most effective in treatment of HCV. In this study, we
examined the short-term and long-term antiviral activity of Abbott HCV
polymerase inhibitors in combination with IFN and NS3 protease inhibitors.
Methods:
The antiviral effects of compound combinations were studied
in the HCV 1b-N replicon cell culture system. In the short-term combination
assays, serial dilutions of one compound were combined with dilutions of
another compound in a checkerboard manner. The level of HCV replication was
determined by the SEAP reporter assay 4 days after compound addition. In the
long-term combination assays, replicon cells were grown in the presence of the
compounds for 16-20 days being passaged every 4 days. Replicon RNA levels were
determined by Real-Time RT-PCR at each passage.
Results:
A-837093 and A-848837 are benzothiadiazine NS5B inhibitors
discovered at Abbott. They exhibit replicon EC50s in the 1b-N HCV replicon of 5
nM and 2 nM, respectively. A-837093 showed additive to synergistic antiviral
interactions with human IFN and the HCV protease inhibitor BILN-2061 at most
concentrations tested. Treatment with either A-837093 or BILN-2061 alone in a
long-term assay resulted in an HCV RNA drop of ~4 logs and ~3 logs,
respectively, but did not completely clear RNA in the course of the 16-day
treatment. Replicon RNA sequence analysis revealed development of specific
resistance mutations in response to A-837093 (Y448H, G554D, D559G, in NS5B) and
BILN-2061 (D168V in NS3). On the other hand, the combination treatment with the
two compounds at concentrations of 10 times their respective EC50s resulted in
a replicon RNA drop of over 7 logs, which led to undetectable HCV RNA within 12
days of treatment. Combination of A-848837 with the protease inhibitor
SCH503034 also cleared HCV replicon RNA in a long-term assay.
Conclusions:
Our results suggest that highly potent benzothiadiazine inhibitors
of HCV polymerase such as A-837093 and A-848837 have the potential to be used
in combination with different classes of HCV inhibitors for the treatment of
HCV infection.
#422. The C-terminus of the first structural domain of HCV
and GBV-C NS5A protein inhibit HIV replication in Jurkat cells.
J. Xiang; J. H. McLinden; Q. Chang; T. M. Kaufman; J.
T. Stapleton.
Introduction:
The most closely related human virus to HCV is a
nonpathogenic flavivirus initially called hepatitis G virus, but usually referred
to as GBV-C because it is not associated with acute or chronic hepatitis. HCV
and GBV-C nonstructural phosphoproteins NS5A share several properties including
a predicted N-terminal ER membrane anchoring domain, a zinc-binding domain, a
region associated with interactions with PKR and subsequent inhibition of
phosphorylation of eIF-2a, and two phosphorylation forms. Because co-infection
of primary lymphocytes with GBV-C and HIV results in inhibition of HIV
replication and because the HCV NS5A protein has pleotropic effects on cells,
we examined the effect of HCV and GBV-C NS5A on HIV replication.
Methods:
Jurkat (CD4+ T lymphocyte) cell lines were constructed that
stably expressed full-length HCV and GBV-C NS5A, or a series of HCV and GBV-C
NS5A deletion mutants. Negative control cells contained only the vector (which
expresses GFP). NS5A expression was regulated by doxycycline, and was measured
by immunoblot and immunofluorescence microscopy. HIV replication was measured
by p24 antigen release or infectivity.
Results:
HIV replication was potently and significantly inhibited in
Jurkat cell lines expressing full-length HCV and GBV-C NS5A proteins compared
to vector control cell lines (> 95% reduction p24 antigen days 4-6, > 2.5
log10 reduction in infectivity on day 6 post-infection; p< 0.01 for each).
GBV-C NS5A deletions that contained amino acids 1 to 182 inhibited HIV, whereas
C-terminal deletions expressing GBV-C aa’s 1 – 152 or regions expressing aa’s
237 – 414 did not. Mutants containing HCV structural domain I (aa’s 1 - 213)
inhibited HIV while domains II (aa’s 214 – 342) and III (aa’s 343 – 447) did
not. Comparison of HCV NS5A with the GBV-C NS5A region involved in HIV
inhibition reveals a region that is predicted to share hydrophobic and secondary
structure, despite little sequence homology. This domain is currently being
expressed in Jurkat cells to determine if it too mediates HIV inhibition in
Jurkat cells. In addition, expression of these peptides in non-lymphocyte cell
lines is underway to determine if this effect is cell-specific. In conclusion,
a region at the C-terminus of domain I of HCV and GBV-C NS5A protein inhibits
HIV replication in Jurkat cells. Further characterization and mapping of NS5A
effects on gene expression and identification of cellular proteins that
interact with this protein are underway.
Conclusions:
HCV and GBV-C NS5A proteins may lead to a novel,
cellular-based approach to inhibiting HIV replication.
#423. A comprehensive system for consistent numbering of HCV
sequences, proteins and epitopes.
C. Kuiken; C. Combet; J. Bukh; G. Deleage; M.
Mizokami; R. Richardson; E. Sablon; K. Yusim; J. Pawlotsky; P. Simmonds.
Introduction:
In October 2004, an expert meeting was convened in parallel
with the 11th Symposium on Hepatitis C and Related Viruses to resolve current
issues in HCV nomenclature and numbering. Inconsistent and inaccurate numbering
of locations in DNA and protein sequences is a problem in the HCV literature
and may become clinically problematic. A standardized numbering system will
circumvent these problems in the future. We present a simple numbering scheme
to facilitate the identification of the position number or precise location of
interest in HCV DNA or proteins.
Discussion:
The proposed numbering system was adapted from the Los Alamos
HIV database (1), with elements from the hepatitis B virus numbering system
(2). The system comprises both nucleotides and amino acid sequences and
epitopes. It uses the full length genome sequence of the H77 strain as a
reference, and includes a method for numbering insertions and deletions
relative to this reference sequence.
1. Korber B, Foley B,
Kuiken C, Pillai S, Sodroski J: Numbering Positions in HIV Relative to HXB2CG.
In: Korber BK, C.L.; Foley,B.; Hahn,B; McCutchan,F.; Mellors J.W.; Sodroski,J.,
ed. Human Retroviruses and AIDS. Los Alamos: Los Alamos National Laboratory,
1998.
2. Stuyver LJ,
Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, Schinazi RF.
Nomenclature for antiviral-resistant human hepatitis B virus mutations in the
polymerase region. Hepatology 2001;33:751-757.
#425. Rapid Decline of Hepatitis C Viral (HCV) RNA and
Very Early Virologic Responses (VEVR) Are Associated With Low Sequence
Diversity in the NS5A Region.
M. K. Jain; H. Yuan; A. Reeck; N. Attar; D. S. Carney;
M. Gale; W. M. Lee.
Background:
Early events in interferon (IFN) treatment of HCV impact
overall outcome. HCV viral kinetic studies show great variation in initial
responses thought to result from direct IFN-mediated effect on replication of
IFN-sensitive HCV quasispecies. The level of sequence diversity within the NS5A
coding region has been associated with HCV treatment outcome in some studies.
We hypothesized that lower sequence diversity in NS5A might be associated with
more rapid responses to HCV therapy.
Methods:
Ten HCV genotype 1 patients were treated with pegylated
interferon alfa 2a and ribavirin, sera collected at 0, 24, 48, and 7 days(d)
and clone analysis was performed for the entire NS5A (10 to 13 for each time
point).
Results:
Five patients had fast viral load (VL) decline [>0.8 log
at 72 hours(h)]; 5 had slow VL decline. Four of 5 of those with fast VL decline
had VEVR (bDNA neg at wk 4) compared to none of those who had a slow VL decline
(p=0.05). All 5 with fast VL decline also demonstrated EVRs at 12 wks compared
to 2 of 4 slow decliners; 1 patient in the slow decline group withdrew prior to
12 wks. Of the 5 patients with fast VL decline clinical outcomes showed: 3
SVRs, 1 relapse and 1 ETR. Of the patients with slow viral decline: 1 SVR, 2
NR, and 1 relapse. Sequence diversity at baseline was narrow (median 0.009) in
the fast viral decliners compared to a median of 0.024 in the slow viral
decliners (p=0.03). One patient with higher sequence diversity at baseline had
a fast VL decline but failed to achieve VEVR. No other patients with high
sequence diversity at baseline had a 72h rapid response or VEVR. Phylogenetic
analysis showed a closely related cluster of clones at 7d when compared with
baseline in 4/5 patients with fast VL decline. No clonal clustering was
observed in patients with slow VL decline. We observed varying degrees of
sequence diversity between the previously described ISDR/PKR binding domain and
V3 regions in most patients, suggesting that these regions are under different
selective pressures. Summary: Rapid VL decline during the initial 72h of
interferon treatment predicts a VEVR at 4 wks. Those showing VEVR had lower
sequence diversity at baseline; this group appeared to develop an even more
closely related cluster of clones connoted by changes within NS5A by 7d of
therapy than did non-VEVRs.
Conclusions:
Low sequence diversity of NS5A may be important in obtaining VEVR.
IFN therapy appears to be more effective in patients with limited diversity at
baseline and when even more closely related clones emerge. Screening for clonal
diversity at baseline and at 7 days might provide additional insights to
predict later viral responses.
#429. FIBROSIS IS ASSOCIATED WITH INSULIN RESISTANCE AND
STEATOSIS IN CHRONIC HEPATITIS C PATIENTS WITH GENOTYPE 1 AND 4 BUT NOT
GENOTYPE 3.
R. Moucari; T. Asselah; V. Paradis; H. Voitot; D.
Cazals-Hatem; M. Martinot-Peignoux; S. Maylin; M. Nicolas-Chanoine; D. Valla;
M. Vidaud; P. Bedossa; P. Marcellin.
Aim:
To assess the impact of the metabolic syndrome and insulin
resistance on steatosis and fibrosis severity according to genotype and viral
load in a cohort of patients with chronic hepatitis C.
Patients and Methods:
300 consecutive patients with chronic hepatitis C were
evaluated. Presence of the metabolic syndrome was assessed in all patients on
the day of liver biopsy. Insulin resistance was defined as HOMA >3.
Necroinflammation and fibrosis were evaluated using the METAVIR score. Severe
fibrosis was considered with fibrosis stage F2-F4. Steatosis was graded as
absent, moderate (<30%) or severe (>30%). Serum HCV RNA (Bayer's VERSANT®
HCV RNA 3.0 Assay) and genotype (sequencing) were determined for all patients.
Results:
Patients characteristics were: male sex (n=173), mean age
47.6 years, mean BMI 24.9(BMI> 28, n=60; BMI > 30, n=28). Eighty- two
patients had central obesity. Metabolic syndrome was present in 44 patients and
insulin resistance in 110 patients. Steatosis was present in 162 patients (54%)
(mild in 53, moderate in 57 and severe in 48 patients). Genotype distribution
was: 1 (n=164), 3 (n=57), 4 (n=50) and 2 (21 patients). Mean serum HCV RNA was
1.1 106 IU/ml and 117 patients had viral load>800 000 IU/ml.
In patients with genotype1and 4, insulin resistance,
steatosis and fibrosis distribution were similar and analysis of pooled data
showed:
·
Severe
Fibrosis was more frequent in patients with insulin resistance (61/84 vs. 54/127,
p<0.001) and severe steatosis (43/66 vs. 54/127, p=0.003)
·
Insulin
resistance was associated with metabolic syndrome (27/36 vs. 58/177,
p<0.001), severe steatosis (42/69 vs. 42/142, p<0.001) and severe
fibrosis (61/115 vs. 23/96, p<0.001)
·
Severe
Steatosis was associated with metabolic syndrome (21/3vs. 47/175, p<0.001),
insulin resistance (43/97 vs. 23/96, p<0.001) and severe fibrosis (45/107
vs. 26/110, p=0.004).
·
In
genotype 3 patients, severe steatosis was significantly more frequent (29/57
vs. 69/211, p=0.01) and was associated with high viral load (serum HCV RNA
>800 000 IU/ml) (12/16 vs. 13/36, p=0.01) but not with fibrosis neither with
insulin resistance. Prevalence of the metabolic syndrome as well as insulin
resistance was significantly lower compared to other genotypes.
Conclusion:
·
Fibrosis
was associated with both steatosis and insulin resistance in chronic hepatitis
C patients with genotypes 1 and 4. I
·
Steatosis
is associated with the metabolic syndrome, insulin resistance in HCV genotypes 1 and 4.
·
Steatosis
is associated with viral replication in HCV genotype 3.
#430. STEATOSIS IS ASSOCIATED WITH INTRAHEPATIC HCV RNA
LEVEL IN GENOTYPE 3 CHRONIC HEPATITIS C.
R. Moucari; S. Maylin; M. Martinot-Peignoux; T. Asselah;
H. Voitot; D. Cazals-Hatem; V. Paradis; M. Vidaud; M. Nicolas-Chanoine; D.
Valla; P. Bedossa; P. Marcellin.
Background and Aim:
In chronic hepatitis C patients, the relationship between
intrahepatic viral load and histological features is not well known. The aim of
this study was to analyze the impact of intrahepatic HCV RNA level on insulin
resistance, steatosis and fibrosis.
Patients and Methods:
Eighty six patients with absent or severe steatosis were
selected from a prospective series of 300 patients with chronic hepatitis C who
underwent a liver biopsy between September 2005 and May 2006, and had available
frozen samples (-80°C). Severe steatosis was defined as affecting more than 50%
of hepatocytes. Insulin resistance was defined as HOMA >3. Necroinflammation
and fibrosis were evaluated using METAVIR score. Serum HCV RNA (HCV RNA
Quantiplex v3.0) and genotype (sequencing) were determined for all patients.
RNA was extracted from liver biopsy (Qiagen-Rneasy Mini Kit) and HCV RNA was
quantified (Bayer’s VERSANT ® HCV RNA Quantiplex 3.0 assay).
Results:
There was no significant correlation between serum and
intrahepatic viral load (r2= 0.28). Patients with genotype 1 had significantly
higher viral load in serum (1.6 106 IU/ml vs. 0.6 106 IU/ml, p=0.003) and in
liver (7.2 106 IU/g vs. 2.4 106 IU/g, p=0.04) in comparison with patients with
other genotypes. Intrahepatic viral load was not significantly different
between patients with or without insulin resistance (4.9 106 IU/g vs. 4.0 106
IU/g, p=0.7). Intrahepatic viral load was also not different in patients with
mild or moderate fibrosis (F1-F2) compared to those with bridging fibrosis or
cirrhosis (F3-F4) (4.9 106 IU/g vs. 1.9 106 IU/g, p=0.3). In patients with
genotype 3, intrahepatic viral load was associated with severe steatosis (6.0
106 IU/g vs. 1.0 106 IU/g, p=0.01). This difference was not found in patients
with other genotypes
Conclusion:
We found no correlation between serum and intrahepatic viral
load. Genotype 1 was associated with higher serum and intrahepatic viral load
compared to other genotypes. Intrahepatic viral load was associated neither
with insulin resistance, nor with fibrosis severity. Intrahepatic viral load
was associated with severe steatosis in genotype 3.
#432. Selection And Characterization Of Hepatitis C Virus
Replicons Resistant To A Potent Polymerase Inhibitor A-837093.
L. Lu; P. Krishnan; R. Pithawalla; T. Dekhtyar; T. Ng;
W. He; T. Pilot-Matias; D. Larson; T. Bosse; R. Wagner; D. Kempf; A. Molla; H.
Mo.
Purpose:
We undertook this study to characterize the resistance
profile of A-837093, a potent HCV RNA dependent RNA polymerase (RdRp)
inhibitor.
Methods:
The anti-HCV activity of A-837093 was determined in HCV
replicon cells by the reduction of HCV RNA. HCV replicon colonies resistant to
the inhibitor were selected by treating the HCV subgenomic 1b-N replicon cells
with A-837093 at a concentration 10 times above its EC50. Genotypes of the
resistant colonies were determined by sequencing the NS5B polymerase gene.
Individual mutations were introduced into a luciferase-expressing replicon by
site-directed mutagenesis. The susceptibility of the mutants was evaluated by a
transient replication assay.
Results:
A-837093 displayed excellent activity in HCV replicon with
EC50 of 3 and 11 nM against HCV genotype 1b and 1a, respectively. Replicon
colonies selected by A-837093 exhibited substantial decreases in susceptibility
to A-837093. Genotypic analysis demonstrated that each colony contained one of
the following mutations: S368A, Y448H, G554D or D559G in the NS5B gene.
Molecular clones containing the above single mutations conferred moderate
(Y448H, 19-fold) to high-level (200-300 fold) resistance to A-837093. In
contrast, all four mutants retained susceptibility to a thiophene-2-carboxylic
acid polymerase inhibitor (Shire 2), the HCV protease inhibitor BILN2061 and
interferon. Mutant replicons showed significantly impaired fitness compared
with the wild-type replicon.
Conclusion:
This study suggests that monotherapy with the polymerase
inhibitor A-837093 may lead to the development of resistance. However, the lack
of cross-resistance may allow this agent to be used in combination with
different classes of polymerase inhibitors, protease inhibitors or interferon.
#436. Mutations in the Natural Strains of NS3 Protease
Domain of HCV in HIV/HCV Coinfected Patients Under Antiretroviral Therapy
Including or Not HIV Protease Inhibitors.
G. Morsica; S. Bagaglio; L. Alagna; C. Lodrini; G.
Gallotta; L. Galli; S. Dispinseri; A. Lazzarin; C. Uberti-Foppa.
Introduction:
HCV Protease inhibitors (HCV-PI) have been recently
identified as potential candidates for new-anti-HCV therapy. In vitro studies
have shown mutations within replicon system that confer resistance to VX-950
and SCH503034 HCV-PI.
Methods:
Mutations within NS3 protease gene were investigated by
direct sequencing in 38 HIV/HCV coinfected patients, harboring HCV genotype-1.
Nineteen of 38 patients were treated with HIV protease inhibitors (HIV-PI) at
time of samples collection whereas the remaining 19 patients received
antiretroviral therapy (ART) without HIV-PI since two years from samples
examination.
Results:
The comparison of mutations between HIV/HCV coinfected
patients and a pool of 250 sequences obtained from Genbank as control group,
showed that the presence of amino acid (aa) change at position 156, conferring
resistance to HCV-PI, was higher in HIV positive patients than in the control
group (3/38 vs 2/250; p=0.0177). HIV infected patients under ART with PI showed
a mutational profile significantly different from that detected in the control
group (3/19 vs 2/250; p=0.0028). On the contrary, HIV infected patients under
ART without PI exhibited a mutational profile similar to that detected in the
control group (0/19 vs 2/250; p=ns). An aa change A156G or A156T, was found in
3 (15.7%) HIV infected patients under ART regimen including HIV-PI and in none
of HIV infected patients under ART without HIV-PI, but the difference was not
statistically significant (p=0.2297). The aa substitution at position 170 of
NS3 was prevalently detected in HIV infected patients under ART than in the
reference group of sequences obtained from Genbank (5/38 vs 0/250;
p<0.0001). However, this aa substitution did not result differently
distributed between patients treated or not with HIV-PI (2/19 vs 3/19; p=ns).
Conclusions:
In this small cohort of HIV/HCV coinfected patients, the natural strains of the NS3 protease domain exhibited mutations that were related to resistance to HCV-PI. This finding could have implication for the treatment with HCV-PI of HIV/HCV coinfected patients with naturally selected drug-resistant variants.