Tuesday Posters (11/15/2005)– HCV Treatment – 8:00AM – 6:30PM
Abstract ID: 64900
Category: JO7: HCV:
Treatment
Are there differences in sustained virological response (SVR)rates in patients with HCV genotype 2 or 3 infection and persistently ‘normal’ ALT activity undergoing treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®)?
a. alberti, University of
Padova, Padova, Italy, R. Reindollar, Carolina Center for Liver Disease,
Charlotte, NC, M. Romero-Gomez, Hospital Universitario de Valme, Seville,
Spain, D. Prati, Ospedale “A. Manzoni”, Lecco, Lecco, Italy, P. Couzigoue,
Hepato Gastroenterology Department Hautleveque, Pessac, France, S. Zeuzem,
Saarland University Hospaital, Homberg, Germany
In patients with chronic hepatitis C and persistently
‘normal’ ALT levels, Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin
(COPEGUS) produced SVR rates of 72% and 78% after 24 and 48 weeks of treatment,
respectively, in patients infected with HCV genotype 2/3 (Zeuzem et al,
Gastroenterology 2004; 127:1724). However, as some studies have shown different
outcomes in genotype 2 and 3 patients, we examined, separately, SVR rates in
patients infected with HCV genotypes 2 and 3 patients who were enrolled in this
large, randomized international study.
Methods
Patients infected with chronic HCV genotype 2 or 3 and with
ALT levels ≤30IU/L on ≥3 occasions over 18 months were randomized
to receive 24 or 48 weeks treatment with peginterferon alfa-2a (40KD)
180μg/week plus low-dose ribavirin (800mg/day). All patients were
monitored for 72 weeks. The primary endpoint was SVR, determined by qualitative
PCR (HCV RNA <50 IU/mL COBAS AMPLICOR® HCV Test, v2.0), after 24 weeks
untreated follow-up. In this ITT analysis, differences in efficacy between HCV
genotype (2 vs 3) and duration of treatment (24 vs 48 weeks) were assessed by
Cochran–Mantel–Haenszel test, stratified by geographical region. SVR rates were
also analysed after stratification by HCV RNA (> and ≤800,000 IU/mL;
HVL vs LVL).
Results
In the 117 patients who were randomized to 24 or 48 weeks
treatment, SVR rates were similar in genotype 2 and 3 patients (77% vs 71%
respectively, p=0.135; odds ratio [OR, stratified by treatment] = 0.49 [95% CI
= 0.18–1.29]). SVR rates between the two treatment groups were similar in
patients infected with genotype 2 and 3 (Table). The number of patients with
genotype 3 infection and HVL was too low to allow evaluation.
Conclusion
Overall, in patients
with persistently ‘normal’ ALT levels, similar outcomes were seen in patients
with HCV genotypes 2 and 3 following treatment with peginterferon alfa-2a
(40KD) (PEGASYS®) plus ribavirin (COPEGUS®). Thus, the conclusions based on the
combined genotype 2/3 data are valid when outcome data from patients infected
with the two genotypes are considered separately.
Abstract ID: 65103
Category: JO7: HCV:
Treatment
PEGYLATED INTERFERON PLUS RIBAVIRIN VERSUS NON-PEGYLATED INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C – A COCHRANE SYSTEMATIC REVIEW.
M. Simin, The CHBGroup,
Dept. 7102, H:S Rigshospitalet, DK-2100 Copenhagen, Copenhagen, Denmark, J.
Brok, The CHBGroup, Dept. 7102, H:S Rigshospitalet, DK- 2100 Copenhagen,
Copenhagen, Denmark, D. Stimac, Departement of Gastroenterology, Clinical
Hospital Center of Rijeka, Rijeka, Croatia, C. Gluud, The CHBGroup, Dept. 7102,
H:S Rigshospitalet, DK-2100 Copenhagen, Copenhagen, Denmark, L. Gluud, The
CHBGroup, Dept. 7102, H:S Rigshospitalet, DK-2100, Copenhagen, Copenhagen,
Denmark
Aim:
We aimed to assess the beneficial and harmful effects of pegylated
interferon plus ribavirin versus non-pegylated interferon plus ribavirin in
patients with chronic hepatitis C.
Material and methods:
We identified randomised clinical trials through The Cochrane
Library, MEDLINE, EMBASE, LILACS, and SCI EXPANDED until May 2005. Outcomes
were reported as relative risks (RR) or weighted mean differences (WMD) both
with 95% confidence interval (CI) based on random effects meta-analyses. Rare
events were estimated by Peto odds ratio (OR).
Results:
We included 17 randomised clinical trials with 5184
participants. Pegylated interferon plus ribavirin had significantly beneficial
effect on sustained virological response (RR 0.80, 95% CI 0.73 to 0.88)
compared with non-pegylated interferon plus ribavirin. There were no significant
differences between the two interventions regarding liver-related morbidity
plus all-cause mortality (OR 1.22, 95% CI 0.33 to 4.51), histological
inflammation (RR 0.54, 95% CI 0.24 to 1.23), histological fibrosis (RR 1.05,
95% CI 0.87 to 1.27), or post-treatment quality of life (WMD 0.20, 95% CI -1.96
to 2.36). Pegylated interferon plus ribavirin was associated with significantly
lower quality of life during treatment (WMD 1.50, 95% CI 0.32 to 2.68) and
increase of adverse events: neutropenia (RR 1.96, 95% CI 1.32 to 2.90),
thrombocytopenia (RR 2.05, 95% CI 1.15 to 3.68), arthralgia (RR 1.19, 95% CI
1.05 to 1.35), and injection-site reaction (RR 1.85, 95% CI 1.36 to 2.53).
Conclusion:
Pegylated interferon plus ribavirin significantly increase
the proportion of patients with sustained virological response, but also the
risk of adverse events. We recorded no convincing evidence that pegylated
interferon plus ribavirin reduces mortality or liver-related morbidity.
Abstract ID: 65347
Category: JO7: HCV:
Treatment
Early Viral Kinetics in Patients with Chronic Hepatitis C and End Stage Renal Disease During Therapy with Peginterferon alfa-2a.
G. A. Lutchman, National
Institutes of Health, Bethesda, MD, A. Neumann, National Institutes of Health,
Bethesda, MD, M. Ghany, National Institutes of Health, Bethesda, MD, T. Heller,
National Institutes of Health, Bethesda, MD, B. Borg, National Institutes of
Health, Bethesda, MD, J. J. Feld, National Institutes of Health, Bethesda, MD,
R. Loomba, National Institutes of Health, Bethesda, MD, Y. Park, National
Institutes of Health, Bethesda, MD, T. Liang, National Institutes of Health,
Bethesda, MD, J. Hoofnagle, National Institutes of Health, Bethesda, MD
Background:
Chronic hepatitis C (HCV) infection is common in patients
with end stage renal disease (ESRD), particularly those on hemodialysis.
Initial reports suggest a lower sustained virological response (SVR) to
pegylated interferon (PEG) and ribavirin therapy and a greater incidence of
side effects. It is unclear if the poor response to therapy is due to lack of
efficacy of interferon or to inadequate dosing due to intolerance.
Aim:
To compare the early viral kinetics to PEG alfa-2a
mono-therapy in patients with HCV genotype 1 infection with and without ESRD.
Methods:
Patients with HCV infection with normal renal function were
randomized to PEG alfa-2a and ribavirin (1000-1200 mg/day) (Group A) or
monotherapy with PEG alfa-2a (Group B) for 4 weeks after which both groups
received combination therapy for another 44 weeks. Patients with ESRD (CrCl
<10 ml/min) and HCV infection (Group C) were treated with PEG alfa-2a for 4
weeks after which ribavirin was added in low escalating doses. The current
analysis is focused on the analysis of viral kinetics in the first 4 weeks of
therapy in the two groups (B and C) receiving PEG á-2a monotherapy. Blood
samples were taken at baseline, 12, 24, 48, 72 hrs and at weeks 1, 2, 3 and 4.
HCV RNA was measured using Cobas Amplicor (LD < 50 IU/ml).
Results:
Viral kinetic analyses were available on 24 patients in Group
B (9 men, 2 African Americans) and 7 in Group C (7 men, 4 African American).
Patients with ESRD had significantly lower ALT (35±16 vs. 95±81 IU/L,
p<0.01) but had similar baseline viral levels (6.1 vs. 6.3 log) and similar
histological findings of necroinflammation and fibrosis on liver biopsy.
Patients with renal disease had a lower maximal 1st phase decline (0.52 vs.
0.87 log IU/ml), greater viral rebound (0.37 vs. 0.27 log IU/ml) and lower
overall viral decline during the first week (0.16 vs. 0.60 log IU/ml), but none
of these differences reached statistical significance. However patients with
ESRD had a significantly slower 2nd phase decline (-0.11 vs. -0.25 log/ wk,
p=0.05) compared to patients without ESRD. In addition, 7/7 patients with ESRD
had a 2nd phase decline less than 0.3 log/wk, which was predictive of non-SVR
in previous studies, while this was true for 13/24 (54%) of patients without
ESRD (p<0.05, Fishers Exact).
Conclusions:
Patients with chronic HCV infection and ESRD appear to have a
significantly slower 2nd phase viral decline during PEG alfa-2a mono-therapy
than those with normal renal function. Although this may partially account for
poorer treatment responses, these findings need to be confirmed in a larger
cohort.
Abstract ID: 66167
Category: JO7: HCV:
Treatment
Persistence with Hepatitis C Therapy in the Department of Veterans Affairs (VA).
S. Usman Iqbal, Boston
University School of Public Health, Boston, MA, F. Cunningham, Hines VA
Hospital, Hines, IL, A. Lee, Boston University School of Public Health, Boston,
MA, D. R. Miller, Boston University School of Public Health, Boston, MA, A. W.
Law, Roche Laboratories, Nutley, NJ, L. Kazis, Boston University School of Public
Health, Boston, MA
Background:
Two forms of combination therapies, peginterferon alfa-2a
with ribavirin (PEG-IFN a-2A/RIB) and peginterferon alfa-2b with ribavirin
(PEG-IFN a-2B/RIB), are currently used for the treatment of hepatitis C
infection (HCV). However, limited data are available on patient persistence
with prescribed therapies.
Objectives:
To evaluate and compare treatment persistence with PEG-IFN
a-2A/RIB and PEGIFN a-2B/RIB.
Methods:
We conducted a retrospective analysis of 5,611 VA patients >
18 years of age who were newly-diagnosed with HCV mono-infection. Patients who
received their first prescription of either combination therapy between October
2003 and September 2004 were included in the study. Using pharmacy data,
persistence was defined as the period from the date of the first peginterferon
prescription filled to the date of discontinuation. Persistence was estimated
using the Kaplan-Meier method. Likelihood ratio test of equality over strata
was performed to detect any differences in persistence between the treatment
groups.
Results:
During the study period, 57.8% patients received PEG-IFN
a-2A/RIB and 42.2% on PEG-IFN a-2B/RIB. The treatment groups were similar in
regards to age, gender, and race distribution. The median duration of therapy
was 5.4 months (95% CI: 5.2 to 5.5) for PEG-IFN a-2A/RIB and 4.6 months (4.4 to
4.8) for PEG-IFN a-2B/RIB. Treatment-specific persistence and 95% CI at 12, 24,
36, and 48 weeks since treatment initiation are shown in the table. Likelihood
ratio test of equality in persistence between treatment groups yielded
Chi-square=26.4, with p<0.0001.
Conclusion:
Persistence with PEG-IFN a-2A/RIB therapy was significantly
greater than with PEG-IFN a-2B/RIB in VA patients diagnosed with HCV. These
results may have implications for the clinical management of HCV patients and
treatment outcomes.
Abstract ID: 66294
Category: JO7: HCV:
Treatment
Hepatic steatosis in patients with HIV-HCV co-infection enrolled in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT): Clinical characteristics and response to treatment.
m. Rodriguez-Torres, Fundación de Investigación de Diego, Santurce, PR, R.
SOLA, LIVER SECTION. HOSPITAL DEL MAR, BARCELONA, Spain, N. Clumeck, CHU
Saint-Pierre, Brussels, Belgium, E. Lissen, Virgen del Rocio University
Hospital, Seville, Spain, H. Sette Jr., Instituto de Infectologia Emilio Ribas,
São Paulo , Brazil, P. Buggisch, Universitaetsklinikum Hamburg-Eppendorf,
Hamburg, Germany, J. DePamphilis, -, Nutley, NJ, D. Dieterich, The Mount Sinai
Medical Center, New York , NY
Peginterferon alfa-2a (40KD) (PEGASYS®) + RBV (COPEGUS®)
produced higher SVR rates (40 vs 20 and 12%, respectively, p<0.001) and
histological response rates (57 vs 39 and 41%, respectively, p ≤ 0.04) than
peginterferon alfa-2a (40KD) monotherapy or IFN/RBV in APRICOT. Hepatic
steatosis in co-infection is not well studied. We analyzed data from pts with
paired biopsies in APRICOT to identify factors associated with steatosis at
baseline, the impact of baseline steatosis on the probability of an SVR, and
the impact of viral eradication on steatosis.
Methods
Co-infected pts were randomized to peginterferon alfa-2a
(40KD) 180 μg/wk + RBV 800 mg/d or placebo, or IFN 3MIU 3x/wk + RBV x48 wks.
Biopsies were obtained 15 months before enrollment (BL) in
all pts and at end of follow-up in pts at some centers. A central study
pathologist evaluated pre and post-treatment biopsies in blinded fashion.
Steatosis was defined as >5% of hepatocytes with fatty changes per low power
field. SVR was defined as undetectable serum HCV RNA (<50 IU/mL) at wk 24 of
untreated follow-up (wk72).
Results
Paired biopsies were submitted for 283/860 pts overall, 65 of
whom had steatosis at baseline. At BL, pts with steatosis were more likely to
have genotype (GT) 3 infection (p<0.0001), a histological diagnosis of
bridging fibrosis/cirrhosis (p=0.0311), higher HCV RNA (p=0.0132), elevated
serum triglycerides (p=0.0132), abnormally high random blood glucose levels (p=0.0097),
and higher ALT quotients (p=0.0067) than pts without steatosis. Overall 26/65
(40%) of pts with and 73/218 (33%) of pts without steatosis at BL had SVRs. In
those treated with peginterferon alfa-2a (40KD) + RBV 12/21 (57%) of pts with
and 38/69 (55%) of pts without steatosis at BL had SVRs. Achievement of an SVR
in the overall population of pts with paired biopsies and in those treated with
peginterferon alfa-2a (40KD) + RBV (21/90 had steatosis at BL) was associated
with a significantly lower incidence of steatosis at wk 72 (vs BL; Table).
Conclusion
Hepatic steatosis is associated with GT3 infection in
co-infected pts. The presence of steatosis does not appear to reduce the
overall probability of achieving an SVR. Viral eradication with peginterferon
alfa-2a (40KD) + RBV is associated with a reduced incidence of hepatic
steatosis in co-infected pts.
Abstract ID: 67086
Category: JO7: HCV:
Treatment
Early ribavirin improves sustained virological responses in acute HCV infection in HIV positive individuals.
M. Danta, Centre for
Hepatology, London, United Kingdom (Great Britain), J. Turner, Centre for
Sexual Health and HIV Research, London, United Kingdom (Great Britain), R.
Johnson, Centre for Sexual Health and HIV Research, London, R. Lascar, Centre
for Sexual Health and HIV Research, London, United Kingdom (Great Britain), M.
Johnson, Department of HIV medicine, London, United Kingdom (Great Britain), G.
Dusheiko, Centre for Hepatology, London, United Kingdom (Great Britain), I.
Williams, Centre for Sexual Health and HIV Research, London, United Kingdom
(Great Britain), R. Gilson, Centre for Sexual Health and HIV Research, London,
United Kingdom (Great Britain), S. Bhagani, Department of HIV medicine, London,
United Kingdom (Great Britain)
Aims:
To describe the virological outcomes of two different
treatment strategies for acute HCV infection in HIV infected individuals.
Method:
Acute HCV was defined by seroconversion to anti-HCV within
six months of a negative result and/or a positive HCV RNA. HIV-positive
individuals presenting with acute HCV infection at two centres were offered
treatment, but with different standard regimens. At centre 1 (early ribavirin)
all individuals persistently positive for HCV RNA by RT-PCR 12 weeks after
presentation were offered pegylated interferon alpha-2b (1.5 μg/kg) and
ribavirin (>10.6 mg/kg) for 48 weeks. At centre 2 (delayed ribavirin)
individuals were offered immediate treatment with pegylated interferon alpha-2a
or -2b for 24 weeks. Ribavirin (800mg/d) was then added if individuals were
still positive for HCV RNA at week 12.
Results:
Baseline characteristics were similar in individuals at
centre 1 (n=24) and centre 2 (n=15); mean age (35.7 vs 36.3 years), mean CD4
count (583 vs 515 cells/mcl), on HAART (58% vs 47%), HCV genotype 1/4 (83% vs
87%), mean HCV viral load (6.4x106 IU/ml at both) and baseline mean ALT (177 vs
362 IU/ml). The mean time to treatment from diagnosis was 15.2 weeks (centre 1)
and 6.4 weeks (centre 2). Sustained virological responses (SVR) were available
in 26 patients. SVR were significantly better using initial combination
pegylated interferon plus ribavirin compared to delayed ribavirin (61% (centre
1) vs. 23% (centre 2), p<0.001). The median duration of treatment was 34
weeks (centre 1) and 25 weeks (centre 2). Side effects were similar between the
two centres. The mean fall in haemoglobin was not different between the regimes
(2.7 g/dl (centre 1) vs. 2.6 g/dl (centre 2), p=ns). HIV parameters were not
significantly impacted with treatment.
Conclusions:
The optimal treatment schedule for acute HCV in HIV
co-infection is not known but our experience suggests that pegylated interferon
alone has poor efficacy. In contrast to acute HCV mono-infection, ribavirin in
the first 12 weeks significantly improves the long-term virological outcomes in
HIV-infected patients with acute HCV. Despite the majority of patients having
HCV genotypes 1/4, SVRs of 61% were achieved with combination pegylated
interferon and ribavirin.
Abstract ID: 67172
Category: JO7: HCV:
Treatment
CYTOKINE RESPONSE IN CHRONIC HEPATITIS C (CHC) PATIENTS TREATED WITH PEGYLATED INTERFERON PLUS RIBAVIRIN.
M. Trapero Marugán, Liver Unit. Hospital Universitario de La Princesa,
Madrid, Spain, Madrid, Spain, R. Moreno-Otero, Liver Unit. Hospital
Universitario de La Princesa, Madrid, Spain, L. Garcia-Buey, Liver Unit.
Hospital Universitario de La Princesa, Madrid, Spain, J. Moreno-Monteagudo,
Liver Unit. Hospital Universitario de La Princesa, Madrid, M. Vitón, Immunology
Service. Hospitla Universitario de La Princesa, Madrid, Spain, C. Muñoz,
Immunology Service. Hospital Universitario de La Princesa, Madrid, Spain, M.
Borque, Molecular Biology Unit. Hospital Universitario de La Princesa, Madrid,
Spain, X. Salcedo-Mora, Liver Unit. Hospital
Universitario de La Princesa, Madrid, Spain
AIMS:
1) To compare the cytokine profiles in peripheral blood
mononuclear cells (PBMCs) from patients with CHC and healthy controls. 2) To
analyse the cytokine profiles in CHC patients during combination therapy. 3) To
correlate the cytokine production with sustained virological response (SVR).
METHODS:
A total of 44 caucasian genotype 1 naive patients with CHC
received PEG-IFNa2a (weekly) plus RBV (1-1.2 g/day) for 48 weeks. Besides, 16
healthy controls were studied. The intracitoplasmic expression of IL-4, IFNg
and TNFa, and surface CD4 and CD8 markers from PBMCs, both resting and
stimulated, were measured using flow cytometry. SVR was defined as HCV-RNA
negativity after 6 months follow-up. Statistics: Student´s t test, c2 test and
ANOVA test, logistic regression.
RESULTS:
All 44 patients (mean age 45.2±8.1 years) finished follow-up.
Healthy controls presented a higher percentage of CD8 T cell than CHC patients
(22.1±7 vs 16.9 ±10; p<0.004), higher expression of IFNg by CD4 resting T
cells (0.03±0.02 vs 0.87 ±1.3; p<0.02), higher expression of TNFa by CD8
(29.8±17.3 vs 19.5±17.3; p<0.05) and CD4 stimulated T cells (36.3±9.9 vs
26.7±22.3; p<0.02) and lower intracitplasmic expression of IL-4 by CD4 T cells
(1.3±0.7 vs 2.7±2.9;p<0.01). During treatment, IL-4, IFNg and TNFa levels
fell progressively in all patients. After follow-up, 26 patients had SVR
(59.1%), 13 relapsed (29.5%) and 5 were non-responders (11.4%). At the first
month during treatment, expression of TNFa by CD4 T cells was higher in
patients with a SVR than in NR (36.46±24.9 vs 17.2±20.7; p<0.01). At the
third month, the percentage of CD4 T cells was lower in patients with a SVR
(34±16 vs 44±15.3; p<0.04), stimulated-IL-4 expression by CD4 T cells was
lower in patients with SVR (1.9±4.2 vs 3.9±4.2; p<0.05) and TNFa expression
by CD4 T cells was higher in patients with a SVR (48.8 ±20.9 vs 31.2 ±23;
p<0.01). At the end of treatment, expression of IFNg by CD8 stimulated T
cells was higher in SVR (17.3±14 vs 10±8.5; p<0.04) as well as the
expression of IFNg by CD4 stimulated T cells (10.7±8.2 vs 5.9 ±5.5; p<0.03).
After a multivariate analysis, predictive factors of a SVR were: percentage of
CD4 T cells and expression of TNFa by CD4 stimulated T cells at first month of
treatment, expression of IFNg by CD4 T cells at third month of treatment, and
expression of TNFa and IFNg by CD8 stimulated T cells, AST and ALT levels and
hemoglobin.
CONCLUSIONS:
IFNg and TNFa expression by CD4 and CD8 T cells (cytokine
response type 1) during antiviral treatment is associated with SVR suggesting
the replication control and later clearance of HCV.
Abstract ID: 67356
Category: JO7: HCV:
Treatment
PEG-IFN alpha 2b (1.5 mcg/kg/wk) + rib (800-1400 mg daily) is significantly more effective than PEG-IFN alpha 2b (1.0 mcg/kg/wk) + rib (800-1400 mg daily) in men with GT 1 and women with GT 2/3: Final results of a prospective, randomized, controlled trial.
S. L. Flamm, Northwestern
University Medical School, Chicago, IL, J. Goldman, Gastroenterology Assoc.,
Hazel Crest, IL, J. Cahan, Consultants in Gastroenterology, Munster, IN, G.
Nelligan, Rockford Clinic, Rockford, IL, D. Chua, Summit Digestive and Liver
Disease, Oakbrook Terrace, IL, B. Shapiro, Northwest Healthcare, Hoffman
Estates, IL, M. Bawani, Gastroenterologists, Ltd., Libertyville, IL, R. Yapp,
Digestive Health Services, SC, Downers Grove, IL, E. Jurkovic, Digestive
Disease Consultants, Kankakee, IL, R. Brown, Columbia University Medical
Center, New York, NY, S. Skahen, Northwestern University Medical School,
Chicago, IL, T. Jackson, Northwestern University Medical School, Chicago, IL
Background:
PEG-IFNa2b (1.5 mcg/kg/wk) + ribavirin (800mg/d) is effective
for pts with chronic hepatitis C virus (HCV). The medications have many side
effects and frequently require dose reduction or discontinuation. PEG-IFNa2b
(1.0 mcg/kg/wk) monotherapy data yield equivalent SVR in comparison to PEG-IFNa
2b (1.5 mcg/kg/wk) monotherapy. SVR and tolerability of PEG-IFNa2b (1.0 mcg/kg/wk)
+ ribavirin are unknown.
Aim:
We sought to determine the efficacy and tolerability of
PEG-IFNa2b [1.0 mcg/kg/wk vs 1.5 mcg/kg/wk] in combination with ribavirin to
determine if lower dose PEG-IFN a 2b is equally effective as the standard dose.
Methods: Pts with HCV (+ HCV RNA) were evaluated within the context of a
prospective, randomized, controlled, multi-center trial comparing PEG-IFNa2b
(1.0 mcg/kg/wk) [LD] + riba(800-1400mg/d) vs. PEG-IFNa2b (1.5 mcg/kg/wk) [SD] +
riba(800-1400mg/d). Demographic, serological (ALT), virologic (HCV RNA level
and genotype) and histological data were obtained. Meds. were given for 24 wks
(HCV GT 2/3) or 48 wks (HCV GT 1). Tolerability (side effect profile and d/c
rate) was determined. SVR data are reported.
Results:
312 pts were randomized; 281 received meds. (133 in SD and
148 in LD) and are included in the analysis. There were significantly more men
(p=0.01) and GT 2/3 (p=0.01) in the LD grp. Mild and advanced fibrosis were
evenly distributed between the grps. There was a strong trend for better
overall SVR in the SD 70/133 (53%) vs LD 65/147 (44%). There was also a strong
trend for better SVR in GT 1 SD 47/104 (45%) vs. LD 34/99 (34%). In men, SVR in
GT1 was significantly better in SD 30/62 (48%) vs LD 14/50 (28%),p=0.05. In
women, SVR in GT1 was similar SD 17/42 (40%) vs LD 20/49(40%). There was also a
strong trend for better overall SVR in GT2/3 SD 23/29 (79%) vs. LD 31/48 (65%).
In men, SVR in GT2/3 was equivalent SD 15/20 (75%) vs LD 19/24 (79%). In women,
SVR in GT 2/3 was significantly better in SD 8/9 (89%) vs LD 12/24
(50%),p=0.05). There was a strong trend to benefit with SD with 10-15% > SVR
in mild and advanced fibrosis grps. There were no significant differences in
tolerability (9% d/c rate in both SD and LD and 20% PEG dose reduction in SD vs
10% in LD), p=NS.
Conclusions:
1)Standard dose PEG-IFNa2b + riba was significantly more
efficacious in men with GT 1 and women with GT 2/3 compared to LD. 2)There was a
strong consistent trend to SVR benefit in ALL treatment sub-grps including GT
1l, GT 2/3, men, women, mild and advanced fibrosis. 3)There were low d/c and
dose reduction rates in both groups. 4)The results of the large prospective
trial comparing SD and LD PEG-IFNa2b regimens are awaited to confirm these
findings.
Abstract ID: 67749
Category: JO7: HCV:
Treatment
Treatment outcomes to combination therapy in patients with HCV genotype 6.
M. Nguyen, Stanford
University Medical Center, Pacific Health Foundation, Palo Alto, CA, H. Trinh,
Pacific Health Foundation, San Jose, CA, R. T. Garcia, Pacific Health
Foundation, San Jose, CA, K. Hoda, Pacific Health Foundation, San Jose, CA, E.
Keeffe, Stanford University Medical Center, Palo Alto, CA
PURPOSE:
The prevalence of HCV infection in Southeast Asia is
approximately 6%. HCV genotype 6 and its subtypes (also known as genotype 7, 8,
and 9) are found in 30- 35% of this population. However, little is known
regarding the natural history as well as response to antiviral therapy in this
large patient population with HCV genotype 6.
METHODS:
To examine treatment response to antiviral therapy in
patients with HCV genotype 6, we performed a retrospective review of all
patients who were evaluated and started on treatment with either interferon 3MU
tiw + ribavirin 800 mg/d (IFN+RBV) or pegylated IFN (1.5mcg/kg for PEG IFN-á2b
and 180 mcg for PEG IFN- á2a weekly) and RBV 1000-1200 mg/d (PEG IFN+RBV)
between 1/2001 and 12/2003 at a single U.S. center. Primary end point was overall
SVR in all treated patients, and analysis was intention-to-treat. Student
t-test and chi-square statistics were used to compare various clinical
variables between the 2 treatment groups. Multivariate analysis was used to
identify potential predictors of SVR.
RESULTS:
A total of 81 patients were identified (39 with genotype 6,
6a, 6b; 37 with genotype 7, 7a, 7b; and 5 with genotype 8, 8a, 8b). Mean age
was 57±10, 73% were male, 17% had known cirrhosis, 12% had previous treatment
with IFN monotherapy Forty patients (49%) received IFN+RBV and 41 (51%)
received PEG IFN+RBV. Treatment completion rate was 77% for the IFN+RBV group
and 78% for PEG IFN+RBV. Sixty-three (78%) patients were treated with a 24-week
course and 18 (22%) with a 48-week course. There were no statistically
significant differences in age, sex, SVR or treatment duration between the 2
treatment groups. Overall SVR was 51%. SVR was 48% for patients treated with
24-week course and 65% in the 48-week group (p=0.21). On multivariate analysis,
only treatment completion is an independent predictor of a SVR (OR=9.1,
p=0.02).
CONCLUSIONS:
In this Southeast Asian population with HCV genotype 6 and a
treatment completion rate of 78%, overall SVR to combination therapy was 51%.
There is a trend for higher SVR (65%) in those treated for 48 weeks as compared
to the 24-week group (48%) but this difference did not reach statistical
significance. Therefore, until further data from large, prospective studies are
available, patients with genotype 6 who are candidates for therapy should be
offered a 48-week course of therapy.
Abstract ID: 67872
Category: JO7: HCV:
Treatment
Modeling Ribavirin Pharmacokinetics in HIV-1/HCV-Coinfected Patients Predicts Higher Intracellular Ribavirin Concentration in Sustained Viral Responders.
H. Dahari, Los Alamos
National Laboratory, Los Alamos, NM, R. M. Ribeiro, Los Alamos National
Laboratory, Los Alamos, NM, M. Zeremski, Weill Medical college of Cornell
University, New York, NY, T. Licholai, Weill Medical college of Cornell
University, New York, NY, I. Haller, Weill Medical college of Cornell
University, New York, NY, A. S. Perelson, Los Alamos national Laboratory, Los
Alamos, NM, A. H. Talal, Weill Medical college of Cornell University, New York,
NY
Background:
In hepatitis C virus infection, ribavirin (RBV) has recently
been proposed to act as a viral mutagen that increases second phase HCV RNA
decay in patients who exhibit low interferon effectiveness. The
pharmacokinetics of pegylated interferon (PEGIFN) and RBV have not been
evaluated simultaneously. We sought to evaluate any association between RBV and
pegylated IFN -2b pharmacokinetics, and its influence on the
outcome of treatment.
Methods:
Twenty-four IFN naïve, HIV/HCV-co-infected patients received
PEGIFN (1.5 g/kg) once weekly plus daily ribavirin (1.0 g or 1.2 g)
for up to 48 weeks. Blood samples were frequently obtained during the first 16
days of treatment and monthly thereafter. Plasma samples were assayed for RBV
using high performance liquid chromatography and for PEG-IFN using a validated
electrochemiluminescence-based assay. A one-compartment pharmacokinetics model
(OPK) was used to fit each patient’s longitudinal PEG-IFN plasma concentration,
whereas a two-compartment model (TPK), which accounts for RBV in plasma and in
cells, was needed to fit the RBV plasma concentration. Statistical significance
was determined using nonparametric methods and Spearman rank correlations.
Results:
Six patients (25%) had a sustained virological response
(SVR). Baseline HCV RNA titers (5.3 vs. 6.4 log cp/ml, p<0.006) and RBV
area-under-the-curve (AUC) in plasma during the first three days of therapy
were significantly lower in SVR than non-SVR (AUC [0, 72 hr] 1.56 vs. 2.8 mg/ml
hr, p<0.03). A significant inverse correlation was found between RBV AUC [0,
72 hr] and PEG-IFN AUC [0, 72 hr] (r=-0.6, p<0.007). Although PEG-IFN
pharmacokinetic parameters were similar in SVR and non-SVR patients,
preliminary fits indicate that the mean RBV transport rate constant from the
cellular compartment into plasma was significantly lower in SVR (3.6 x 10-3 vs.
2.8 x 10-2 hr-1, p<0.008). Thus, the predicted mean steady-state
concentration in the cellular compartment was significantly higher in SVR than
in non-SVR (1.35 vs. 0.522 g/ml, p<0.01).
Conclusions:
Our model suggests that cellular RBV transport is enhanced
early in treatment in SVR patients as predicted by the increased mean
steady-state cellular concentration in SVR patients, by the lower plasma RBV
concentration during the first three days, and by a lower RBV transport rate
from the cellular compartment into plasma.
Consequently, differential RBV transport early in treatment, eventually
leading to higher RBV accumulation in the cellular compartment, may differentiate
SVR from non-SVR patients.
Abstract ID: 61871
Category: JO7: HCV:
Treatment
Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to prior therapy with either interferon alfa and ribavirin or pegylated interferon and ribavirin.
K. Chen, Chicago Medical
School, North Chicago, IL, P. Seraphin, Loyola University medical Center,
Maywood, IL, L. Murphy, Loyola University Medical Center, maywood, IL, N. Shah,
Loyola Univ. Medical Center, Maywood, IL
Background:
Current standard therapy for HCV based on pegylated
interferon (Peg IFN) and weight-based ribavirin (RBV) results in approximately
50% of patients achieving a sustained viral response (SVR). There are no approved
treatment alternatives for patients who fail to respond to Peg IFN + RBV. We
reviewed our experience with the use of consensus interferon (IFN alfacon-1)
and RBV in these nonresponder (NR) patients.
Methods:
All patients were treated initially with IFN alfa-2a or Peg
IFN + RBV. Those who failed to clear HCV RNA and were classified as NR were
then retreated with IFN alfacon-1 + weight-based RBV (800 mg-1200 mg/day) for
at least 48 weeks. Pretreatment liver biopsy, HCV genotype, viral load and
usual demographics were collected for all subjects. Patients on IFN alfacon-1 +
RBV retreatment were allowed to use growth factors to continue with their
treatment as needed. IFN alfacon-1 was given to all patients at a starting dose
of 15 mcg/daily with weight based RBV. Doses were adjusted as necessary for
hematological side effects.
Results (table):
79 patients were screened and 76 patients were treated with
IFN alfacon-1 and RBV (65% Caucasian, 16% African American, 4% Hispanic, 15%
other); 49 male and 27 female; age ranged from 20-76 years (Mean. 61 (80%) had
HCV genotype 1; 36 (47%) had Metavir fibrosis F3/F4. At the end of treatment
(week 48), 55 (72%) patients were HCV RNA negative. At week 72, 38 (50%)
achieved an SVR. One patient on treatment underwent liver transplantation and
stopped treatment. At that time, his viral load had dropped to 1,830 copies/mL.
RESULTS
|
|
Week 48 (end of treatment) |
Week 72 (SVR) |
|
HCV RNA negative |
55 (72%) |
38 (50%) |
Conclusions:
These data suggest that IFN alfacon-1 and weight-based RBV
are a potential alternative in Peg IFN plus RBV NR HCV patients. In addition,
NR patients with advanced disease (F3/F4) tolerated this therapy well and
should be candidates for retreatment with IFN alfacon-1 and RBV. Further study
is warranted to confirm these findings.
Abstract ID: 62587
Category: JO7: HCV:
Treatment
Peginterferon-a 2b and Ribavirin Treatment in Patients with Hepatitis C Virus-Related Systemic Vasculitis.
d. saadoun, Department of
internal medicine, Pitie-salpetriere Hospital, Paris, Fr, paris, France, n.
limal, service de médecine interne, paris, France, d. sene, service de medicine
interne, paris, France, O. lidove, service de médecine interne, paris, France,
J. Piette, service de médecine interne, paris, France, P. Cacoub, service de
médecine interne, paris, France
Objective:
Type II mixed cryoglobulinemia (MC) is a systemic vasculitis
usually associated with hepatitis C virus (HCV) which may involve the skin, kidneys,
and nervous system. Molecular evidence of antigen-driven B-cell proliferation
is definitively provided in HCV-associated type II MC, and HCV appears as the
key trigger. The present trial was established to investigate the efficacy of
Pegylated-interferon-a (PegIFN-a) with ribavirin in patients with HCV-MC
vasculitis.
Methods:
Nine consecutive HCV-MC patients received PegIFN a-2b (1.5
μg/kg/week) plus oral ribavirin (800 to 1200 mg/day) for at least 6
months. The response to treatment was analysed by comparing clinical,
immunologic, and virologic parameters at the initial evaluation and during
followup.
Results:
The mean duration of Peg-IFN a and ribavirin was 13.5 ± 2.8
months. After a mean follow-up of 18.7 months after stopping treatment, all nine
patients are alive. Seven patients (77%) had a sustained virologic response and
were complete clinical responders. Serum cryoglobulin disappeared in 5/9 (55%)
and complement levels normalized in 77% of patients. One patient had a partial
virological response with a complete clinical response. A clinical relapse of
MC vasculitis occured in another patient associated with reappearance of HCV
RNA. Treatment was well tolerated and no side side effects required
discontinuation of therapy.
Conclusion:
Treatment with PegIFN a-2b and ribavirin can achieve a
complete clinical response in most patients with HCV-MC vasculitis. Complete
clinical response correlates with the eradication of HCV and requires a shorter
period than that previously reported with IFNa and ribavirin.
Abstract ID: 62599
Category: JO7: HCV:
Treatment
Efficacy of PEG-IFN alfa-2b vs. PEG-IFN alfa-2a + ribavirin regimens in treatment naïve chronic HCV patients: A cumulative meta-analysis of retrospective data from 6 clinic sites.
HCV Meta-Analysis Working
Group, MetaWorks Inc., Medford, MA, P. L. Almasio, University of Palermo,
Palermo, Italy, L. Cavalletto, University of Padova, Padova, Italy, L.
Chemello, University of Padova, Padova, Italy, A. Craxi, University of Palermo,
Palermo, Italy, K. Fahrbach, MetaWorks Inc., Medford, MA, D. Frame, MetaWorks
Inc., Medford, MA, C. Y. Ling, MetaWorks Inc., Medford, MA, S. Mauss, Center
for HIV and Hepatogastroenterology, Duesseldorf, Germany, F. F. Poordad, Center
for Liver Disease and Transplantation, Cedars-Sinai, Los Angeles, CA, S. D.
Ross, MetaWorks Inc., Medford, MA, N. N. Zein, The Cleveland Clinic Foundation,
Cleveland, OH, S. Herrine, Thomas Jefferson University, Philadelphia, PA, C.
Trepo, Hôpital Hotel Dieu, LYON Cedex 02, France
Objective:
To elucidate differences in effectiveness of weight-based
(alfa-2b) and fixed dose (alfa-2a) pegylated interferons + ribavirin
(PEG-IFN+RIB) treatment regimens in treatment-naïve chronic HCV patients in
settings outside of clinical trials.
Methods:
European and US clinical investigators identified primarily
through independent congress abstracts and collecting data under relevant
institutional ethical guidelines were recruited to contribute de-identified
data for meta-analysis. Eligible patients were treatment-naïve adults with
chronic HCV (G1, G2, or G3), receiving PEGIFN + RIB, consecutively treated
since 1/2001. Patients in clinical trials, with HIV or HBV co-infection, or
decompensated liver disease were excluded. The primary efficacy measure was
sustained viral response (SVR), i.e., absence of detectable HCV RNA 6 months
after end of treatment response (EOTR). Data were meta-analyzed using a
hierarchical generalized linear model (HGLM) to control for patient- and
site-level variation, and an adjusted odds ratio (OR) was calculated for the
difference between PEG-IFNs. Patient selection criteria and analytic methods
were determined prospectively by an expert panel. Prognostic impact of
treatment regimen, weight, site, baseline ALT quotient, age, gender, and race
were assessed.
Results:
Six sites (2 US, 2 Germany, 2 Italy) contributed data,
totaling 824 patients (61% male, 94% Caucasian, mean age 46, mean weight 76
kg). The two groups were comparable in terms of baseline characteristics and
RIB dosing (mean 957 mg for PEGIFN alfa-2b, 987 mg PEG-IFN alfa-2a). SVR in G1
patients was significantly (p=0.017) higher for PEG-IFN alfa-2b vs. PEG-IFN
alfa-2a.
Table 1. SVR by drug and genotype
Higher SVR rates were also achieved with PEG-IFN alfa-2b for G2
and G3 patients, though this difference was not significant. Between-site
heterogeneity was apparent in G2 and G3, but not G1, analyses.
Conclusion:
Treatment with PEG-IFN alfa-2b has an advantage relative to
PEG-IFN alfa-2a in the achievement of SVR in treatment-naïve adults with
chronic HCV, G1. Additional clinic sites are being identified through the
literature to validate observations from this initial analysis. Further
analyses will evaluate secondary endpoints of early response, EOTR, and relapse,
as well as incorporating additional patient covariates into the HGLM model.
Abstract ID: 63531
Category: JO7: HCV:
Treatment
Erythropoietin Increases Platelets Count During Antiviral Therapy With Interferon and Ribavirin for Chronic Hepatitis C Virus Infection.
U. Borate, Albert Einstein
Medical Center, Philadelphia, PA, K. Rothstein, Albert Einstein Medical Center,
Pghiladelphia, PA, V. Araya, Albert Einstein Medical Center, Philadelphia, PA,
S. J. Munoz, Albert Einstein Medical Center, Philadelphia, PA
Erythropoietin (EPO) is now often used to treat
ribavirin-induced anemia in patients with chronic hepatitis C (HCV) virus
infection, hoping to neutralize a reduced probability of SVR caused by
anemia-related dose reductions. As a growth factor, EPO may also stimulate
platelet production. Indeed recombinant human EPO stimulates platelet
production in mice and rats, and EPO administration has been reported to
increase platelets counts in patients on dialysis and on chemotherapy.
AIM:
To determine whether HCV patients on anti-viral therapy and
receiving EPO exhibit a change in platelet counts.
METHODS:
A careful retrospective analysis of platelet counts of HCV
patients on antiviral therapy at a liver center. Platelet counts were evaluated
just prior to start of EPO (baseline), and then at week 2, and months 1, 2, 3,
4,5 and 6 into therapy with pegylated interferon and ribavirin. Patients
received adjuvant EPO (40,000 U/ wk) for severe anemia associated with
ribavirin therapy. Controls: patients on antiviral therapy who did not receive
adjuvant EPO due to only mild anemia on antiviral therapy, matched for baseline
platelet count, presence of cirrhosis, age, race, sex and HCV genotype. We
excluded patients who received EPO for less than a month, had irregular follow
up, or had concomitant disease or medications known to influence platelet
counts.
RESULTS:
40 patients were studied: 20 received adjuvant EPO and 20
served as controls. 5 % had established cirrhosis. Age, gender, genotype and
ethnicity were similar between groups. Predictably, patients on EPO exhibited
an increase in haemoglobin (2.1±0.3gm/dl), but also showed an increase in
platelet count as early as 2 weeks into EPO therapy. In contrast, platelet
count did not change appreciably in controls. The increase in platelet count
associated with adjuvant EPO became more pronounced and significant at 1, 2 and
3 months into therapy (PC: + 42,500, + 40,000 and + 47,500 per cc respectively;
p=0.03,0.04, 0.04).
CONCLUSIONS:
Adjuvant use of erythropoietin is associated not only with
increased hemoglobin but also with increased platelets counts in patients on
antiviral therapy with interferon and ribavarin for chronic HCV infection. The
extent of EPO effect on platelet counts was a rise between 30,000 to 47,500/cc.
It would appear that adjuvant EPO may contribute to maintaining optimal doses
of antiviral therapy by supporting both, hemoglobin and platelet levels. The
effect of EPO on the latter may be particularly beneficial in cirrhotic
patients who are often thrombocytopenic prior to the start of antiviral
therapy. These observations warrant further characterization by prospective
studies.
Abstract ID: 65190
Category: JO7: HCV:
Treatment
Impact of baseline hepatitis C virus (HCV) RNA and genotype on the efficacy of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in patients with compensated cirrhosis/bridging fibrosis.
P. Marcellin, Hopital
Beaujon, Clichy, France, S. Roberts, The Alfred Hospital, Melbourne, Australia,
A. Alberti, DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, PADOVA, Italy, c.
trepo, Hopital Hotel Dieu, Lyon, France, S. Zeuzem, Saarland University
Hospital, Homburg, Germany, H. Sette Jr., Instituto de Infectologia Emilio
Ribas, São Paulo , Brazil, J. T. Brouwer, Reiner de Graaf Hospital Group,
Delft, Netherlands, A. Horta-Vale, Clinica DMI, Portugal, Portugal, E. Gane,
Middlemore Hospital, Auckland, New Zealand
Introduction
We have shown that peginterferon alfa-2a (40KD) (PEGASYS) plus
ribavirin (COPEGUS) is superior to conventional interferon plus ribavirin in
patients with cirrhosis/bridging fibrosis, with SVR rates of up to 37% (vs 25%;
A531, AASLD 2004). We have now determined if this superiority is consistent
when baseline HCV RNA level and genotype are considered.
Methods
Interferon-naïve adults with quantifiable HCV RNA, elevated
serum ALT, and compensated liver disease who had been enrolled in two phase III
trials were analysed. Patients received peginterferon alfa-2a (40KD) 180 mg/wk
plus either low-dose (800 mg/day) or standard-dose (1000/1200 mg/day) ribavirin
for 24 or 48 wks. SVR (HCV RNA <50 IU/mL COBAS AMPLICOR® HCV Test, v2.0
during wks 12–24 of followup) rates of each of the four peginterferon alfa-2a
(40KD) plus ribavirin regimens were compared with conventional interferon
alfa-2b 3 MIU tiw plus ribavirin 1000/1200 mg/day for 48 wks (one of the arms
in one study). Combined data (all four Peginterferon alfa-2a (40KD) plus
ribavirin regimens) were also analysed. Differences in efficacy were assessed
by Cochran–Mantel–Haenszel test stratified by genotype (1 vs non-1) and HCV RNA
(> vs ≤800,000 IU/mL; HVL vs LVL).
Results
·
A total of 2181 patients were randomized
to combination treatment and received at least one dose of study medication in
the two trials. Of these, 431 (19.8%)
had compensated cirrhosis/bridging and were included in this analysis.
·
Compared with all patients enrolled
in the two trials, patients with compensated cirrhosis/bridging fibrosis tended
to be older (47 vs. 43 years) and were more likely to be male (73% vs. 67%).
·
The overall SVR rate in all
patients with compensated cirrhosis/bridging fibrosis who received 48 weeks’
treatment with peginterferon alpha-2a (40KD) plus ribavirin 1000/1200 mg/day
was 48%, compared with 33% in patients treated with conventional interferon
alfa-2b plus ribavirin 1000/1200 mg/day (p=0.00106). The higher SVR rate in patients with
compensated cirrhosis/bridging fibrosis receiving peginterferon alfa-2a (40KD)
plus ribavirin when the analysis was restricted to genotype 1 patients (37% vs.
25%, p=0.1500), or patients with HCV genotype 2/3 69% vs. 48%, p=0.1026), or
when patients were stratified according to baseline HCV RNA level.
·
SVR rates in genotype 1 patients
with compensated cirrhosis/bridging fibrosis receiving peginterferon alfa-2a
(40KD) plus ribavirin 1000/1200 mg/day for 48 weeks (the recommended treatment
regime) and conventional interferon alfa-2b plus ribavirin 1000/1200 mg/day for
48 weeks.
o Genotype 1 patients with a baseline HCV RNA level ≤ 800,000 IU/mL
had a higher SVR rate than those with a baseline HCV RNA level >800,000
IU/mL in both treatment groups.
o SVR rates were consistently better in genotype 1 patients receiving
peginterferon alfa-2a (40KD) plus ribavirin vs. conventional interferon alfa-2b
plus ribavirin, irrespective of HCV RNA level.
o SVR rates in HCV genotype 2/3 patients with a baseline HCV RNA level ≤
800,000 IU/mL receiving the various peginerferon alfa-2a (40KD) plus ribavirin
treatment regimens ranged from 57-100%.
o SVR rates in HCV genotype 2/3 patients with a baseline HCV RNA level
>800,000 IU/mL receiving the various peginterferon alfa-2a (40KD) plus
ribavirin treatment regimens ranged from 58-71%. However, the number of genotype 2/3 patients
receiving low-dose ribavirin for 48 weeks was small.
o Overall, 5/7 (71%) HCV genotype 2 patients with compensated
cirrhosis/bridging fibrosis achieved an SVR following treatment with peginterferon
alfa-2a (40KD) plus the recommended dose of ribavirin (800 mg/day) for the
recommended duration (24 weeks). This
included 3/5 (60%) patients with a baseline HCV RNA level > 800,000 IU/mL.
o Similarly, 10/13 (77%) HCV genotype 3 patients with compensated
cirrhosis/bridging fibrosis receiving peginterferon alfa-2a (40KD) plus
ribavirin 800 mg/day for 24 weeks achieved an SVR, including 9/12 (75%nt)
patients with baseline HCV RNA level >800,000 IU/mL.
o Only three patients with compensated cirrhosis/bridging fibrosis infected
with HCV genotype 2/3 receiving peginterferon alfa-2a (40KD) plus ribavirin 800
mg/day for 4 weeks had a baseline HCV RNA level ≤ 800,000 IU/mL; all of
these patients achieved an SVR.
o Genotype (genotype 1 vs. non-genotype), baseline HCV RNA (≤
8000,000 IU/mL) and enrolment at a US center were the only significant baseline
predictors of an SVR in the overall patient population with compensated
cirrhosis/bridging fibrosis.
o In genotype 1 patients, treatment duration, HCV RNA level, ALT quotient,
bodyweight, and age were significant predictors of an SVR.
Conclusion
o In HCV genotype 1 patients with compensated cirrhosis/bridging fibrosis,
the recommended treatment regimen of peginterferon alfa-2a (40KD) (PEGASYS)
plus ribavirin (COPEGUS) 1000/1200 mg/day for 48 weeks produced an overall SVR
rate of 37%, while HCV genotype 2 and 3 with compensated cirrhosis/bridging
fibrosis, the recommended regimen of peginterferon alfa-2a (40KD) plus
ribavirin 800 mg/day for 24 weeks produced SVR rates of 71% and 77%
respectively.
o In genotype 1 and 2/3 patients with compensated cirrhosis/bridging
fibrosis treated with peginterferon alfa-2a (40KD) plus ribavirin, SVR rates
were higher in patients with low compared to high HCV RNA levels, although very
few patients with genotype 2/3 infection had low baseline HCV RNA levels.
o These data confirm that current treatment recommendations for patients
with chronic hepatitis C can be applied in patients with compensated
cirrhosis/bridging fibrosis.
o HCV genotype and baseline HCV RNA level were significant and independent
predictors of an SVR in patients with compensated cirrhosis/bridging fibrosis.
Abstract ID: 65965
Category: JO7: HCV:
Treatment
The increase of von Willebrand factor as a new predictor of response to combination antiviral therapy in patients with chronic hepatitis C.
M. Homoncik, Dep. of
Internal medicine IV, Div. of Gastroenterol. and Hepatol.,
Vienna, Austria, E.
Formann, Int. Med IV, Vienna, Austria, W. Sieghart, Dep. of
Internal medicine IV, Div.
of Gastroenterol. and Hepatol., Vienna, Austria, P. Ferenci,
Dep. of Internal Medicine
IV, Div. of Gastroenterol. and Hepatol., Vienna, Austria, A.
Gangl, Dep. of Internal
medicine IV, Div. of Gastroenterol. and Hepatol., Vienna,
Austria, M.
Peck-Radosavljevic, Dep. of Internal medicine IV, Div. of Gastroenterol.
and Hepatol., Vienna,
Austria
Background:
Von Willebrand factor (vWF) is an acute phase protein which
increases during combination antiviral therapy. There is no method up to date
to differentiate between sustained virological responders and relapsers during
the therapy of hepatitis C. The aim of this study was to investigate if the vWF
can predict sustained virological response during antiviral combination
therapy.
Methods:
Eighty two consecutive patients with chronic hepatitis C were
included. Patients with genotype 1 or 4 (n=51) received 180 μg PEG-IFN-á2a
1/week and 1000-1200 mg ribavirin daily over a period of 48 weeks. Patients
with genotype 2 or 3 (n=31) received 180 μg PEG-IFN-á2a 1/week and 800 mg
ribavirin daily over a period of 24 weeks. vWF-Ag levels were measured before,
during, and 6 months after the combination therapy. Data are presented as mean
± 95% confidence intervals (CI).
Results:
50 patients were sustained virological responders (SVR), 23
were relapsers and 9 non-responders. Baseline vWF was mean 194% (164-222%) and
was not different between the 3 groups. vWF increased to a maximum of 267 %
already after 4 weeks of the therapy (p<0,05). The vWF was higher in relapsers
than in SVR starting with week 4 of therapy and the greatest difference was
noted on week 24 of therapy: mean 301% (95% CI: 257-346 vs. 237% (95% CI:
215-259%), p<0,01). Accordingly, 6 months after the end of therapy vWF was
higher in relapsers than in SVR (186 %; CI: 147-224 vs. 142%; CI: 125-157
p=0,05).
Conclusion:
The increase in vWF during combination antiviral therapy is
significantly higher in patients who will relapse as in patients who will be
SVR. This can be explained by systemic inflammation induced by hepatitis C
virus. Further studies in larger patients groups are needed to investigate a
predictive value of vWF on SVR.
Abstract ID: 66081
Category: JO7: HCV:
Treatment
ALTERATIONS OF LEPTIN LEVELS DURING IFN-á TREATMENT IN PATIENTS WITH CHRONIC VIRAL HEPATITIS B AND C: Evidence of an IFN-á-mediated suppression of leptin production.
C. Liaskos, Research Lab
of Internal Medicine, Medical School, Larissa, Greece, T. A. Zografos, Research
Lab of Internal Medicine, Medical School,, Larissa, Greece, E. Togousidis,
Research Lab of Internal Medicine, Medical School, Larissa, Greece, K. Zachou,
Research Laboratory of Internal Medicine, Medical School, Larissa, Greece, N.
Gatselis, Research Lab of Internal Medicine, Medical School, Larissa, Greece,
E. Rigopoulou, Academic Liver Unit, Medical School, University of Thessaly,
Larissa, Greece, A. Germenis, Laboratory of Immunology and Histocompatibility,
Larissa, Greece, G. N. Dalekos, Academic Liver Unit & Research Lab of
Internal Medicine, Medical, Larissa, Greece
Background/Aims:
Serum leptin levels in chronic hepatitis C (CHC) patients
have been reported to be different than normal and in many cases associated
with characteristics of liver histology. The aim of this study was to determine
leptin levels in serial samples from patients with chronic hepatitis B (CHB)
and CHC treated with interferon-alpha (IFN-á) and to evaluate whether there is
(are) any association(s) between leptin levels and patients’ characteristics.
METHODS:
Sera from 63 CHB and 42 CHC patients were investigated at
four timepoints (before, during treatment with IFN-á, end of treatment and end
of follow-up) for the presence of leptin using an
enzyme-linked-immunosorbent-assay. The control groups consisted of 36 patients with
autoimmune liver diseases and 44 healthy, all matched for body mass index with
CHB and CHC patients.
RESULTS:
Leptin levels before IFN-á administration were significantly
higher in both CHB and CHC groups compared to healthy (p<0.004) and disease
controls (p=0.0001). During the course of IFN-á a significant reduction of
serum leptin levels was found in both CHB and CHC groups (p=0.0001) while at
the end of follow-up leptin levels did not differ compared to both control
groups. Biochemical or virological response to treatment was not associated
with the leptin reduction in both viral groups.
CONCLUSIONS:
This study provides for the first time convinced evidence of
a standard kinetic profile of serum leptin levels in CHB and CHC patients
treated with IFN-á. Actually, leptin levels reduced significantly at the end of
IFN-á treatment and remain sustained at low levels up to the end of follow-up.
As the clearance of the viruses was not associated with the alterations of
leptin levels, we suggest IFN-á as a potential direct inhibitor of leptin
production.
Abstract ID: 66690
Category: JO7: HCV:
Treatment
Randomized Trial of Pegylated Interferon for the Treatment of Acute HCV in Seattle Injection Drug Users.
C. Wang, University of
Washington, Seattle, WA, L. Cook, Fred Hutchinson Cancer Research Center,
Seattle, WA, M. Krows, University of Washington, Seattle, WA, K. Ng, Fred
Hutchinson Cancer Research Center, Seattle, WA, E. Hough, Public Health Seattle
& King County, Seattle, WA, H. Thiede, Public Health Seattle And King
County, Seattle, WA, E. Krantz, University of Washington, Seattle, WA, K.
Jerome, University of Washington, Seattle, WA, A. Bagabag, Fred Hutchinson
Cancer Research Center, Seattle, WA, H. Hagan, Center for Drug Use and HIV
Research, New York, NY, L. Corey, University of Washington, Seattle, WA, A.
Wald, University of Washington, Seattle, WA
OBJECTIVE:
To determine the efficacy of pegylated interferon for the treatment of acute hepatitis C infection in injection drug users (IDU)
METHODS:
Subjects were recruited from longitudinal studies of IDU in Seattle. Acute hepatitis C was defined by seroconversion to anti-HCV positive within 6 months of screening in a previously seronegative IDU. Subjects with acute hepatitis C with detectable serum HCV and no contraindications to pegylated interferon (PEG) therapy were randomized to receive 6 months of PEG or to 6 months of observation. Study endpoints were lack of detection of hepatitis C virus (HCV) measured 6 months after treatment discontinuation or after 6 months of observation. Reinfection was assessed by comparing the HCV genotype present in baseline and subsequent serum samples. HCV genotype was determined using the Abbott HCV Genotype ASR assay.
RESULTS:
9 subjects have been randomized to treatment and 12 to control. In the treatment and control arms, 5 of 9 subjects (55%) and 8 of 12 subjects (67%) had genotype 1 infection, respectively. Age, gender, and baseline viral load did not differ between the two groups. For the 4 treatment subjects reaching the study endpoint, 3 achieved an SVR and 1 subject was a nonresponder. For the 7 control subjects reaching the study endpoint, 1 subject naturally cleared virus and 6 have developed chronic HCV. Two treatment subjects and 1 control subject who are still in follow-up became reinfected by a different HCV genotype after initially achieving undetectable serum HCV levels. Thus, a total of 3 reinfections have occurred in this study (Figure 1).
CONCLUSIONS:
In a randomized trial of PEG for acute HCV in IDU, PEG resulted in SVR in 3 of 4 subjects (75%) completing treatment and follow-up. In untreated controls, 6 of 7 subjects have developed chronic infection (86%). The reinfection rate in this trial is higher than reported in published studies, with 3 of 21 (14%) of subjects becoming reinfected within 6 months of viral clearance.
Abstract ID: 66739
Category: JO7: HCV:
Treatment
Pharmacodynamic effects of pegylated interferon-alpha2b differentiate sustained virologic responders from nonresponders in hepatitis C virus/human immunodeficiency virus coinfected patients.
R. M. Ribeiro, Los Alamos National Laboratory, Los Alamos, NM, A. . Talal, Weill Medical College of Cornell University, New
York, NY, K. . Powers, Los Alamos National Laboratory, Los Alamos, NM, M.
Grace, Schering-Plough Research Institute, Union, NJ, C. Cullen,
Schering-Plough Research Institute, Union, NJ, M. Hussain, Schering-Plough
Research Institute, Union, NJ, A. S. Perelson, Los Alamos National Laboratory,
Los Alamos, NM
Background & Aims:
Pegylated interferon alpha (PEG-IFN) has become standard
therapy for hepatitis C virus (HCV) infection. However, the weekly dosage of
this product leads to waxing and waning concentrations of PEG-IFN during the
dosing interval. We sought to evaluate whether PEG-IFN alpha pharmacokinetics
and pharmacodynamics may partially account for differences in treatment
outcome.
Methods:
Twenty-four IFN naïve, HCV and human immunodeficiency virus-1
(HIV-1) co-infected patients received PEG-IFN alpha-2b (1.5 μg/kg)
once weekly plus daily ribavirin (13 mg/kg) for up to 48 weeks. Blood samples
were obtained frequently after the first three PEG-IFN doses. HCV RNA levels
were determined using a real-time reverse transcriptase polymerase chain
reaction assay, and PEG-IFN alpha concentrations were measured using a
validated, electrochemiluminescence-based assay. HCV kinetic models
incorporating pharmacokinetic and pharmacodynamic parameters, to account for
changing drug effectiveness between doses, were developed to model changes in
HCV RNA under treatment.
Results:
Six patients (25%) were sustained viral responders (SVR) and
the rest were nonresponders (NR) – in this group we include two patients that
showed an end of treatment response. We found significant pharmacodynamic
differences between SVR and NR patients. The PEG-IFN alpha-2b concentration
that decreases HCV production by 50% (EC50) was lower in SVR (0.17 vs. 0.33
μg/L, p=0.05). In addition, both the average effectiveness and the
ratio between average PEG-IFN concentration and EC50 were significantly
increased in SVR, after the first (0.84 vs. 0.55, p=0.005; 13 vs. 2.0, p=0.01,
respectively) and second doses (0.85 vs. 0.58, p=0.032; 17 vs. 2.5, p=0.02,
respectively). Baseline log10 HCV RNA levels were significantly lower (5.2 vs.
6.4 log10, p=0.003) and second phase viral decay (delta) was significantly
faster (0.52 vs. 0.18 /day, p=0.015) in SVR than in NR.
Conclusions:
Pharmacodynamic measurements, namely the EC50 and the ratio
between average PEG-IFN concentration and EC50, are different in SVR and NR
co-infected patients. In contrast, pharmacokinetic measurements do not differ
between SVR and NR patients. Thus, a successful treatment response does not
appear to be due to different serum PEG-IFN alpha2b concentrations, rather it
appears to depend on patient or virus response to similar concentrations of
PEG-IFN. Because of waning PEG-IFN alpha effectiveness between doses, models
that incorporate pharmacokinetics maybe more accurate then models that assume
constant efficacy when evaluating HCV kinetics in patients treated with PEG-IFN
alpha-2b.
Abstract ID: 67281
Category: JO7: HCV:
Treatment
Safety and efficacy of 24-week course of pegylated interferon-Ą2a and ribavirin for the treatment of acute HCV infection in HIV positive patients.
S. Dominguez, Hopital
Pitie Salpetriere, Service des Maladie Infectieuses, Paris, France, J. Ghosn,
Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, France, M.
Valantin, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris,
France, A. Schruniger, Hopital Pitie Salpetriere, Service de Virologie, Paris,
France, P. Bonnard, Service des Maladies Infectieuses, Hopital Tenon, Paris,
France, V. Thibault, Hopital Pitie Salpetriere, Service de Virologie, Paris, T.
Poynard, Hopital Pitie Salpetriere, Service d'Hépatologie, Paris, France, C.
Katlama, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, Y.
Benhamou, Hopital Pitie Salpetriere, Service d'Hépatologie, Paris, France
Background:
Treatment of acute hepatitis C (HCV) in HIV-infected patients
have been poorly addressed.
Objective:
To evaluate the efficacy and tolerability of a 24-week course
of of Pegylated interferon a2a (PEG-IFNa2a) and ribavirin (RBV) for the
treatment of acute HCV infection in HIV positive patients (pts).
Methods:
HIV-positive pts with acute HCV infection defined by simultaneous
ALT elevation, documented HCV seroconversion to anti-HCV positive antibody (Ab)
and positive qualitative HCV RNA (Cobas Amplicor HCV 2.0, lower limit of
detection of 50 UI/ml) were included in a prospective open study. In order to
document more precisely time of HCV infection, HCV Ab and HCV RNA were
retrospectively performed on stored serum samples available in the 12 months
before diagnosis.Pts with detectable HCV RNA (> 50 UI/L) at least 12 weeks
after diagnosis were treated with PEG IFN a2a (180 μg/week) and RBV (800
mg/day) for 24 weeks. Patients were followed every 4 weeks during the
pretherapeutic and treatment periods. Sustain virological response (SVR) was
defined by a negative qualitative HCV RNA 24 weeks after the end of treatment
(EOT).
Results:
A total of 25 consecutive homosexual men were included.
Unprotected sex intercourse was the only identified risk factor of HCV
contamination in all pts with a concomittent active syphilis in 7 pts. At
baseline 24 patients were on HAART, 21 pts had HIV RNA <200 copies/mL and a
median CD4 count of 451/mm3. HCV genotypes(GT) distribution was: GT1 =7 , GT3
=7 and GT4 =11 . Only one pt with GT3 had a spontaneous negativation of serum
HCV RNA at week 3 and remained HCV RNA negative untill 48 weeks. Of the
remaining 24 pts, 5 refused anti-HCV therapy and 19 pts started anti-HCV
therapy. Median HCV RNA at treatment initiation was 1096 KUI/ml (range
101-4373), median ALT was 311(range 82-1271), median time from diagnosis to
treatment initiation was 13 weeks. Of the 14 patients who achieved the 24 weeks
post-therapeutic period, 10 had a SVR (71%). All of the patients with SVR
became HCV RNA negative by week 12 of therapy. One pt (GT 1)achieved HCV RNA
negativation and relapsed 12 weeks after EOT. Treatment is still ongoing in 5
pts. There was no safety issue in all treated pts. There was no substantial
changes in HIV RNA and in CD4 count 24 weeks after EOT.
Conclusion:
Treatment of acute hepatitis C with pegylated interferon
(180μg/w) and RBV (800 mg/d) for 24 weeks lead to a high SVR rates in HIV
infected patients. Early recognition and treatment of acute HCV infection is
mandatory in HIV population to prevent chronic evolution because of the poor
efficacy of anti HCV therapy in chronic HCV infection.
Abstract ID: 67720
Category: JO7: HCV:
Treatment