S. Kamal, Q. He, A. Al Tawil, K. Khalifa,
S. Hakam, W.
Saleh, M. Omar, J. Rasenack, M.
Koziel, M. Madwar
Background
The role, onset
and duration of peginterferon treatment have not been evaluated in acute
hepatitis C.
Objective
To assess
the efficacy, safety, onset and duration of peginterferon alfa (PEG IFN) in acute hepatitis C.
Methods
In this intent
to treat study patients with acute HCV genotypes 1 and 4 (n=98) were enrolled
and prospectively followed. Patients were screened for 8 weeks after
seroconversion or first positive PCR. Fifteen subjects refused treatment but
were followed through the study. Patients without spontaneous recovery were
randomized to begin PEG IFN-alpha monotherapy at wks 8, 12, 20 respectively for
either 12 or 24 weeks. A subset of subjects who failed to achieve a virologic
response after 12 wks of treatment continued therapy for additional 12 wks.
Results
Five
untreated subjects had spontaneous recovery and another 4 subjects scheduled to
start treatment at weeks 12 or 20 resolved spontaneously before therapy. 79
subjects with persistent viremia were randomized to 3 groups (Table). The end
of treatment response was 94% and the overall SVR was 82%. The SVR was better
for genotype 4 compared to genotype 1. Earlier treatment (week 8 or 12) was
associated with higher SVR particularly in genotype 1. Twelve week therapy was
sufficient for genotype 4 while higher SVR rates in genotype 1 patients were
achieved with 24 wks treatment (86%). Peginterferon alfa-2b monotherapy was
well tolerated and associated with significant improvement in the quality of
life.
Conclusion
Peginterferon
alfa-2b monotherapy improves sustained virologic response for acute hepatitis C
virus with genotype 1 and 4 infection. Earlier treatment leads to increased
virologic response. HCV genotype 1 may
require longer treatment duration.
S. Pol, F. Carrat, F.
Bani-Sadr, E. Rosenthal, F. Lunel, P.
Morand, D. Salmon, G. Pialoux, P.
Cacoub, C. Perronne ANRS
HC02-RIBAVIC Group
Background
Hepatitis
C may be severe in HIV-infected subjects evidencing the need to treat.
Aim
To compare
the safety and efficacy of the standard (IFNa2b: 3 MIU x3/w, n=207) (INF group)
to the pegylated (PEG-IFNa2b: 1.5 mg/kg x1/w, n=205) interferon (PEG group)
both combined with ribavirin (800mg/d, approx. 12 mg/kg/d) during 48 weeks.
Methods
A
randomized, multicenter, parallel-group, open-label trial. Inclusion criteria
were: HCV-RNA positive and abnormal liver histology, CD4>200, stable
HIV-RNA, off or stable HAART.
Results
The 412
patients (40 y, 74%M, 79% IVDU) were given HAART in 82%. Mean CD4 cell count was
514 ± 229/ml, HIV RNA<400 in 66% (mean HIV load in others: 3.7±0.7 logs).
The mean pre-treatment Metavir score was A 1.8±0.7, F 2.3 ± 1.0 and 39% of pts
had F3-F4 of which 17% had sustained normal ALT. Baseline variables were not
different between groups. Treatment discontinuation occurred in 167 pts (42%)
(86 IFN & 81 PEG) and severe adverse events in 127 (31%) (64 IFN & 63
PEG), including 6 mitochondriopathies. SVR was achieved in 20% of IFN pts vs
27% of PEG pts (p=0.047). In those who did not discontinue treatment,
virological response rates were at W4 (12 vs 20%), W12 (34 vs 41%), W24 (41 vs
54%), (W48: 34 vs 52%) and W72 (6 vs 35%), respectively. Virologic response at
W12 predicted SVR with 87% Positive Predictive Value and its absence had a 99% Negative
Predictive Value. SVR varied with genotypes 1 or 4 (11%) vs 3 or others (43%),
but not with the Metavir score or the adjusted ribavirin dose.
Response-associated pretreatment characteristics included genotypes other than
1 or 4 (OR=5.9), no protease-inhibitor therapy (OR=2.0), age = 40 years
(OR=1.9) and elevated ALT (OR=1.8). Necro-inflammation significantly decreased
in the PEG pts (-0.20 vs 0.02, p=0.0008). Fibrosis stabilized in virological
responders and worsened in non responders. Steatosis improved significantly in
patients infected by genotype 3 who had a SVR (p= 0.017).
Conclusion
In HIV-HCV
coinfected pts, the combination of pegylated IFNa2b and ribavirin is associated
with a superior HCV virologic response than standard combination with a quite
similar adverse-event profile.
K. Wursthorn, P. Buggisch, B.
Zoellner, M. Zankel, C. Fischer, S.
Xiong, C. Brosgart, G. Currie, J. Petersen
Background
HBV
targeted antiviral therapy with adefovir dipivoxil (ADV) results in a significant
reduction of intrahepatic HBV cccDNA, serum HBsAg, and serum HBV DNA
(Werle-Lapostolle, Gastroenterology 2004). Pegylated interferon alfa (Peg IFN)
improves serological outcome in HBeAg positive and HBeAg negative patients
(Lau, AASLD 2004; Marcellin, New Engl J Med 2004).
Aim
The aim of
this study was to determine the virological and serological outcome in patients
with chronic Hepatitis B treated with combination therapy of Peg IFN alfa 2b
and ADV.
Methods
26
patients with chronic Hepatitis B were included in a single center open label
pilot study. Patients received a 48 week course of antiviral combination
therapy with 12kDa pegylated interferon alfa 2b 1.5µg/kg bw qw and ADV 10mg qd.
23/26 patients were analyzed at the time of abstract submission, final data
will be available as of December 2004.
Intrahepatocellular cccDNA, serum HBsAg, and serum HBV DNA was
quantified as described previously (Werle-Lapostolle, Gastroenterology 2004).
Baseline characteristics:
Median age, years 33
Male 14
Caucasian 21
Asian
5
HBeAg + 15
HBeAg – 11
HBV DNA, PCR 5
x 106
(log10 copies/ml, median)
ALT (xULN, median) 3,1
Results
At week 48, compared to week 0:
cccDNA reduction (median, paired biopsies)
-2.2log
Serum HBsAg titer reduction (median) -44%
Serum HBV DNA reduction (median) -4.7log
Serum HBV DNA <100 copies/ml 12/23(52%)
(LLoD, LightCycler, Roche)
HBeAg loss 7/13
(54%)
HBeAg seroconversion 5/13
(38%)
HBsAg seroconversion 4/23
(17%)
ALT normalisation 10/23
(43%)
ALT improvement 19/23
(83%)
METAVIR histology score improved 13/21
(62%)
Conclusion
Administration
of 48 weeks of Peg IFN alfa 2b and adefovir dipivoxil resulted in a strong
suppression of cccDNA, high rates of HBsAg seroconversion, HBeAg seroconversion
and loss, respectively. Combination therapy was safe and well tolerated. No
unexpected adverse events were reported. All patients are continuing in study
on additional 96 weeks of ADV monotherapy followed by a third liver biopsy.
N. Afdhal, M. Rodriguez-Torres, E. Lawitz, E.
Godofsky, G. Chao, B. Fielman, S.
Knox, N. Brown
Background
Only
40-50% of HCV-1 infected hepatitis C patients respond to pegylated interferon
(peg-IFNα) plus ribavirin therapy. NM283
is a novel nucleoside analog that as monotherapy reduced serum HCV RNA by a
mean 1.2 log10 (94%) in a recent 15-day trial in HCV-1 patients, most of whom
had previously failed antiviral therapy for HCV infection. NM107, the parent compound of NM283, and
interferon alfa exhibit synergistic antiviral effects against BVDV models in
vitro, prompting the current investigation of
NM283 combined with peg-IFNα in treatment naďve patients with
chronic hepatitis C.
Methods
A
multicenter, open-label phase IIa trial is evaluating whether NM283 plus
peg-IFNα-2b has enhanced antiviral activity compared to NM283 alone in
HCV-1 infected patients. Key entry
criteria are: HCV RNA >5 log10 IU/mL,
ALT <5 xULN, compensated liver disease, treatment naďve. Eligible patients are randomized 2:3 to NM283
or peg-IFNα + NM283 (combinationRx).
NM283 is dosed orally QD for 24 weeks in both groups, escalating to 800
mg/day over the first week and then continuing at that dose. The group
randomized to combinationRx receives peg-IFNα-2b (1.0 μg/kg weekly)
starting on Day 8.
Results
Presently
19 of 30 planned patients (age 22-65, 68% males) are enrolled and have received
10 or 12 weeks of treatment. Tolerance
of both treatments has been satisfactory.
Mean HCV RNA reductions (log10 IU/mL) from baseline to the last patient
visit are 1.0 for the NM283 monotherapy group and 3.2 for the combinationRx
group. Eleven of twelve combinationRx
patients treated for at least 10 weeks have had substantial HCV RNA reductions
(range 1.2-6.2 log10), and 8 of 12 patients have achieved >2 log10 decrease
in HCV RNA, which has been associated with sustained response to current
standard Rx. Presently 4 patients are PCR-negative (<10 IU/mL). 12-week early virological response data will
be presented at the meeting.
Conclusions
NM283
combined with peg-IFNα shows consistent, rapid and marked anti-HCV
activity in patients with HCV-1 infection, a historically difficult-to-treat
group. Initial EVR rates with
combinationRx are encouraging and support continued investigation of NM283 and
NM283 + peg-IFNα, which may offer improved efficacy and tolerability for
patients with HCV-1 infection.
M. Curry, A. Cardenas, N.H. Afdhal
Introduction
The
COPILOT clinical trial is evaluating maintenance therapy with PEG-Intron
0.5mcg/kg weekly versus colchicine (COLC) 0.6mg twice daily in 600 patients
with HCV and advanced fibrosis who have failed prior interferon treatment.
Clinical endpoints include death, liver failure, transplantation, variceal
bleeding and liver cancer. The 2 year evaluation suggested an improved event
free survival in patients on PEG compared to colchicine (Hepatology
2004;40;239A). We evaluated the role of portal hypertension (PHTN) on the
clinical outcomes of maintenance therapy and the role of maintenance PEG-Intron
on portal pressure.
Patients/Methods
537
patients are enrolled in the trial to date; 267 COLC and 270 PEG. 83% of
patients in each group have cirrhosis and 40% have PHTN defined by varices or
gastropathy. Endoscopy is performed every 2 years for development of new
varices. A substudy evaluated portal pressure using HVPG measurements prior to
PEG and after 24 weeks of PEG in 5 patients with varices who were not on B
blockers. Clinical endpoints were evaluated in patients with and without PHTN.
Results
132
patients have had repeat endoscopy at 2 years and new varices were seen in 11
of 66 patients on COLC versus 5 of 66 patients on PEG (p =ns). All 5 patients
had baseline elevated HVPG ( Mean 15mmHg) and all had a reduction in HVPG after
24 weeks on PEG ( Mean 6 mmHg; overall HVPG reduction 41%,mean reduction in
HVPG 7mmHg). Primary event rate for patients with PHTN was 13.5% per year on
COLC and 5.5% per year on PEG (p < 0.004). Primary event rate without PHTN
was 3% in each treatment group.Variceal bleeding over 2 years occurred in 11
patients on COLC (9%) and 1 patient on PEG (1%). Ascites and liver failure was
also more common in COLC (n = 20) compared to the group on PEG (n=13).
Conclusion
Maintenance
PEG therapy may retard varices development, reduces portal pressure and
prevents variceal bleeding and complications of PHTN compared to COLC. Clinical
endpoints are more common in patients with PHTN. PEG should be considered in
patients with cirrhosis who fail interferon and ribavirin therapy
T. Poynard, E. Schiff, R.
Terg, F. Goncales, M. Diago, J.
Reichen, R. Moreno, P. Bedossa, M.
Burroughs, J. Albrecht
Introduction
EPIC3 is a
large, prospective, controlled trial designed to understand 1) the efficacy of
treatment with PR for 48 weeks in previous treatment failures to
interferon-alfa and ribavirin therapy (I/R) and 2) for non-responders (NR) to
PR, to determine the efficacy of PEG-Intron 0.5 microgram/kg/week compared to
no treatment in either delaying progression of hepatic fibrosis or preventing
end stage liver disease in cirrhotics.
Aim
The SVR
rate in a similar population (HALT-C) retreated with peg-interferon alfa-2a
plus ribavirin was low (12%). This led us to examine the SVR to PR in the first
575 patients in EPIC3. Additionally, we evaluated the ability of EVR (>2
log10 decrease or undetectable HCV-RNA at week 12) to predict the likelihood of
achieving SVR (undetectable HCV-RNA at follow up [FU] week 12 or 24).
Methods
HCV NRs or
those that had relapsed after previous treatment with I/R received PEG-Intron
1.5 microgram/kg subcutaneously once weekly plus Rebetol 800-1400 mg/day WBD
for up to 48 weeks. All patients had pre-treatment biopsies scored by a single
reviewer using METAVIR criteria. Plasma HCV-RNA was determined at weeks 12, 24
and 48 of therapy and FU 12 and 24 using a quantitative Taq-Man assay (SPRI;
sensitivity 29 IU/mL). Genotype was determined by sequencing PCR product.
Results
Of the
first 575 patients enrolled in the combination therapy trial, 21% achieved SVR.
Of those who attained EVR, 38% achieved SVR: 61% of those HCV-RNA (-) at week
12 achieved SVR, but only 5% of those who attained EVR with detectable viral
load. SVR was higher in genotype 2/3 patients (54%) compared to genotype 1
patients (16%) and greater in previous relapsers (39%) compared to NRs (15%).
SVR was higher in F2/3 (27%) patients compared to F4 patients (14%). NRs and relapsers
who were HCV(-) at week 12 were equally likely to achieve an SVR (61% vs. 59%).
SVR was higher in G2/3 than G1 NRs (47% vs. 12%) and relapsers (58% vs. 29%).
Conclusions
Retreatment
with PEG-Intron plus weight based Rebetol achieves SVR in a substantial
proportion of I/R treatment failures who are HCV-RNA (-) at treatment week 12.
J.A. Carrion, M. García-Retortillo, M. Navasa, A.
Rimola, J.C. García-Valdecasas, X. Forns1
Introduction
Recurrence
of hepatitis C after liver transplantation (LT) is a major problem in
transplant programs.
Aim
The aim of
this prospective study was to assess the efficacy and safety of antiviral therapy
in liver transplant recipients with chronic hepatitis C.
Methods/patients
Fifty-two
patients with chronic hepatitis C (diagnosed by liver biopsy after a minimum of
6 months following LT) were randomized to receive:
Group A-
pegylated interferon alfa-2b (1,5 µg/Kg/w) and ribavirin (800-1000 mg/d) for 48
weeks;
Group B-
no treatment. Patients with severe HCV recurrence (Group C: bridging fibrosis
or necrosis, cholestatic hepatitis) were treated as group A.
Efficacy was
evaluated 6 months after treatment discontinuation and was defined as
persistent HCV-RNA negativization (SVR). All patients underwent a liver biopsy
6 months after treatment discontinuation. The baseline characteristics of the
52 patients were: age 57 years, 36 (69%) males, 45 (87 %) infected with
genotype 1b, viral load (VL) 3.5x106 IU/ml, significant liver fibrosis (F≥2)
15 (29%).
Results
From the
37 patients with complete follow-up, 5/12 (42%) of group A, 0/10 of group B and
4/15 (27%) of group C achieved SVR (p < 0.05). An early virological response (EVR: decrease in VL > 2 log10 at week 4
of treatment) occurred in 7 (78%) of 9 patients with SVR versus 3 (17%) of 18
non-responders (p=0.004). Although preliminary data do not demonstrate
significant histological improvement in patients achieving SVR, disease
progression leading to graft loss occurred only in non-responders from group C
(6 of 11, 55%). Severe adverse events were frequent in treated patients:
neutropenia and anemia requiring stimulating factors in 11 (41%) and 22 (81%),
respectively, depression in 2 (7%) and rejection in 2 (7%). Interferon or
ribavirin dose reductions were necessary in 10 (37%) and 21(78%) cases,
respectively and definitive treatment interruption in 11 (41%).
Conclusion
In
conclusion, in liver transplant recipients with chronic hepatitis C antiviral
treatment is effective in one third of
patients. However, tolerance is poor and severe adverse events are very
frequent. Therefore, treatment should be recommended only in patients with
severe HCV recurrence or in those with histological evidence of disease
progression.
J.C. Duclos Vallee, C. Feray, E. Teicher, D.
Vittecoq, A.M. Roque Afonso, M. Gigou, E.
Dussaix,M. Sebagh, C. Guettier, D.
Azoulay, R. Adam, P. Ichai, F.
Saliba, B. Roche, D. Castaing, H.
Bismuth, D. Samuel
Background.
The
recurrence of HCV infection after liver transplantation (LT) in HIV-HCV
co-infected patients could be more severe and may affect the prognosis after
LT.
Aim
We compare in a single center, the survival and the
severity after LT- recurrence of HCV in
co-infected and mono-infected consecutive patients.
Patients
9 patients
(76 males) receiving a first liver graft for HCV-related liver disease (37 for
hepatocellular carcinoma) between June 1998 and October 2004 were included.
Among them, 23 were HIV positive, had HAART-controlled HIV and more than 150
cells/mm3 of CD4 before LT. Post LT liver biopsies were available in all
patients with more than 6-months of survival and during the second year in 55
patients. Sex and age of donor and recipient, hepatocellular carcinoma, HCV
genotypes, type of transplantation, (living donor, domino) were studied
variables.
Results
Co-infected
patients were younger than mono-infected patients (41y± 11 vs 55 ± 8;
p<0.001) and received more dominos (10/23 (43%) vs 9/76 (12%)) or livers
from living donors (5/23 vs 11/76). 5/23 (27%) co-infected patients died:
severe HCV recurrence and mitochondrial toxicity (n=2), acute pancreatitis
(n=1), cerebral hemorrhage (n=1) and pancreatic adenocarcinoma (n=1). 10/76
(13%) mono-infected patients died of different causes: recurrent cirrhosis
(n=3), recurrent hepatocellular carcinoma (n=1), sepsis (n=4) and cardiovascular
causes (n=2). One- and 2-year survivals were 82% and 68% in co-infected
patients and 95% and 87% in mono-infected patients (log-rank=0.10). Pegylated
interferon alpha 2-b and ribavirin was administrated in 14/23 co-infected and
in 16/76 mono-infected patients with a virological response in 4/14 and 10/16.
In co-infected patients, the 6-month, HCV viral load was higher (6.8±0.4 log vs
6.0 ±1; p=0.03) and the score of fibrosis more severe (F ? 3 in 4/13 (31%) vs
4/42 (9%); p=0.02). Conclusions. LT in HIV-HCV co-infected patients is a
legitimate indication. However, recurrence of hepatitis C is more severe and
combined interferon and ribavirin-based therapies possibly less efficient in
co-infected than in mono-infected patients. While waiting for new drugs against
HCV, avoidance of drug toxicity, intensive and prolonged anti-HCV therapies are
mandatory to improve the long-term result of this new and challenging
indication of LT.
N. Elhajj, N. Kontorinis, C. Stanca, K. Agarwal, I. Fiel, E.
Eggleton, C. Barton, T. Schiano
Background/Aim
Due to the
immunomodulatory effects of interferon, there is concern that treatment of
recurrent HCV post liver transplantation (LT) may precipitate acute cellular
rejection (ACR), as with kidney transplantation. The aim of this study was to
assess ACR risk with Peg-IFN and RBV.
Methods
Patients
with recurrent HCV post LT treated with either Peg-IFNalfa 2a or 2b, in
combination with RBV (Peg-RBV) for > 6 months were compared to untreated HCV patients for development of
moderate or severe ACR. Subjects were matched for age, sex, year of LT and
immunosuppression. ACR episodes were treated with solumedrol bolus and
augmentation of primary immunosuppression. Liver biopsies were graded (Banff
criteria) by a blinded pathologist.
Results
65 post LT
HCV patients treated with Peg-RBV were matched with 65 HCV untreated controls.
Age, follow up and immunosuppression between 2 groups were equal. In each group
immunosuppression was tacrolimus (52), cyclosporin (12) and rapamycin (1). 8
were also on mycophenolate or azathioprine. Overall, including the
pre-treatment period, there were 37 episodes of ACR in 26 patients in the
Peg-RBV group vs 31 episodes in 24 patients in the controls (p = 0.38). During
Peg-RBV therapy there were 13 episodes of ACR in the Peg-RBV group vs 9 in the
controls (p = 0.48). 33% with rejection on Peg-RBV had a prior history of
rejection. Highest risk of rejection occurred in the early post LT period with
33 episodes of ACR in 30 patients in the first 6 months. ACR did not influence
virological response (OTR); 3 patients with ACR achieved OTR vs 6 patients
without an episode of ACR (p = 0.49). 3 had recurrent ACR on therapy and
required OKT3; of these 2/3 developed chronic rejection and graft loss.
Conclusions
Peg-RBV
does not increase the risk of ACR post LT. The early post-transplant period has
the highest risk of ACR and patients undergoing therapy during this period
should be closely monitored. ACR treatment does not influence virological
response. Following a single episode of ACR it appears safe to continue PEG-RBV
therapy, however recurrent bouts of ACR may be a risk for graft failure.
S. Martini, B. Lavezzo,
S. Saettone, A. Franchello, A. Smedile, D. Cocchis, V.
Ghisetti, E. David, M. Salizzoni, M.
Rizzetto
Introduction
After LT recurrent chronic hepatitis C develops in many
patients (pts).
Aim
We evaluated effectiveness, safety and tolerance of combination
therapy (CT: Peg-IFN alfa2b + Rb) in LT with recurrent hepatitis C.
Methods
86 pts after LT, mean age 53 ys, M/F 68/18, genotype 1-4
82,6%, with histological recurrence HCV chronic hepatitis, mean grading 6/18
(2-16), mean staging 2/6 (1-4), were treated
with Peg-IFN alfa2b 1 mcg/kg/week
plus Rb 800 mg/die for 12 months (mo). 45 pts were naďves, 41 pts were relapser
or non responder (NR) to previous conventional IFN + Rb therapy. The median
delay between LT and first antiviral
therapy was 12 mo (2-114). We evaluated virological response (qualitative
HCV-RNA negative) at the end of
treatment (ETVR) and at 24 weeks of follow-up (SVR).
Results
Table 1 shows results.
Conclusions
49% of naive pts achieved ETVR and 33% SVR with CT. 17% of retreated
pts maintained SVR. Response was satisfactory in genotype 2-3 and still
disappointing in genotype 1-4. In these difficult to treat pts, full dosage
maintainement and duration of therapy are important. Tolerance is poor and
severe side effects are frequent.
F.P. Picciotto, A. Galeota Lanza, M. De Luca, G.
Tritto, F. Lampasi, G.G. Di Costanzo, M.T. Tartaglione, L. Addario,
W. Utech, M.
Macrě, G. Marino Marsilia, A. Ascione
Background
HCV reinfection
is almost universal in patients receiving liver transplantation (LT) for end
stage liver disease due to HCV. In about one third of cases, progressive liver
damage, rapid decompensation and death develop. To date, peg-interferon +
ribavirin is considered the treatment of choice in this setting, even if
results are disappointing.
Aim
To analyze
in a prospective study the efficacy of PEG-Interferon alpha-2b + ribavirin
(PEG-IFN+RBV) in HCV-reinfected patients (pts) after LT.
Methods
On 123
cases of HCV reinfection after LT consecutively observed in our centre during
the last 4 years, 61 pts (M/F = 48/13; mean age 47±6 ys, range 41-65) were
eligible for treatment and received PEG-IFN-alpha2b (1 µg/Kg/bw) and ribavirin
(10 mg/Kg/bw) for 6 or 12 months, according to genotype. Genotype was 1b in 53
pts and 2 in 8. All but 3 underwent liver biopsy; the grade of fibrosis was
F3-F4 (Metavir score) in 28 pts. Immunosuppression: cyclosporine (23 pts),
tacrolimus (29) as single drug; plus micophenolate in 9.
Results
Fiftytwo/61
pts completed the scheduled treatment, although doses had to be reduced in
almost all pts, and 9/61 pts dropped out for side effects. According to
intention-to-treat (ITT) analysis, 40 pts were considered as non responders
(NR). End of treatment response (ETR) was obtained in 21/61 pts (34%). 17/61
pts (28%) achieved a SVR while 4 relapsed. Genotype 2 was the only
statistically significant predictor of SVR (p<.001). A two-fold risk of
non-response (not statistically significant) was observed in pts with viral
load >2M IU/ml. Neither fibrosis nor immunosuppressive regimen correlated
with SVR. Four pts (all non responders) died because of end stage liver
disease, one because of HCC recurrence. All of them were off antiviral therapy.
Conclusion
Only 28%
of HCV-reinfected patients after LT, treated with PEG-IFN+RBV, achieved a SVR.
Genotype 2 was the only predictive factor of SVR, while fibrosis and viral load
did not play a significant role. Therefore, in this setting, antiviral therapy
is less effective compared to non-LT patients, but relapse rate is similar to
that observed in immunocompetent pts.
M.R. Mas, I. Tasci, N. Mas, S.A. Vural, S.
Deveci, B. Comert, C. Akay, A.T.
Isik, E. Ozkomur, E. Cinar, Y.
Ates, G. Alcigir, M. Bozdayi
Introuction
Liver fibrosis
is characterized by overproduction and diminished degradation of matrix
proteins in the sinusoids. Hepatic stellate cells (HSCs) are the main source of
excessive collagen synthesis. Oxidative stress (OS) has an important role in
fibrogenesis. HSC apoptosis has been proposed to be involved in spontaneous
recovery (SR) of liver fibrosis.
Aim/Methods/Patients
We studied
individual and combined effects of peginterferonα2b (PegIFNα2b), and
a potent antioxidant taurine on experimental liver fibrosis. Sixty male
Sprague-Dawley rats were injected SC with CCl4 for 12 weeks to induce liver
fibrosis. After induction of fibrosis the rats were divided into four groups.
Group I (n=15) was left for SR. Group II was treated with PegIFNα2b
1.5mg/kg/week, Group III with taurine 1200 mg/kg/day, and Group IV with the
combination of these two regimens. All the rats were killed after four weeks of
treatment and histopathological fibrosis scores, αSMA(+) HSC counts,
apoptotic HSCs and hepatocytes, and OS parameters were determined.
Results
PegIFNα2b
and taurine equally improved fibrosis. Fibrosis scores were reduced
significantly in Groups II, III and IV when compared to Group I (p<0.05).
αSMA(+) cell counts were reduced in Groups II, III and IV when compared to
Group I (p<0.001). Number of αSMA(+) cells in Groups II and III were
similar. Group IV αSMA(+) cell counts were lower than Group III
(p<0.03). PegIFNα2b did not affect hepatocyte apoptosis. Taurine alone
and in combination induced hepatocyte apoptosis significantly (p<0.03,
p<0.001, respectively). Effects of PegIFNα2b and taurine on hepatocyte
apoptosis were similar. HSC apoptosis increased significantly in Groups II, III
and IV when compared to Group I (p<0.002, p<0.03, p<0.001, respectively).
HSC apoptosis significantly increased in Group IV in comparison with
PegIFNα2b and taurine treatments (p<0.02, p<0.001, respectively).
There was no difference between apoptotic HSC counts in Groups II and III
(p>0.05). Tissue SOD, MDA, and GSHPx levels improved significantly only in
Group III. In conclusion, PegIFNα2b and taurine both improved experimental
liver fibrosis.
Conclusion
Induction
of HSC apoptosis and thereby accelerating SR may be potential approaches in
treatment of liver fibrosis. Although the mechanisms of action are different,
combination of the two agents seems to have no significant benefit.
M. Calvino, J.R. Larrubia1,, T. Parra, E.
Sanz de Villalobos, F. González, C. Perna, J.
Pérez de Hornedo, A. Bienvenido
Background
CCR5
receptor plays an important role in Tc1 cells migration into inflamatory sites.
During HCV infection is essential a right HCV specific CD8 T cells migration
into the infected liver to control the virus. So, a possible way of viral
escape could be to impair CCR5 receptor expression on CD8 T cells.
Objectives
1) To
quantify CD8+/CCR5+ T cells frequency from peripheral blood and liver in
chronic hepatitis C (CHC+), other chronic hepatitis (CHC-) and healthy controls
(HC).
2) To
analyse the role of anti-viral treatment (PEG-interferon a2b and ribavirin) in
CCR5 expression on CD8 T cells from peripheral blood.
Also it
has been analysed, as internal control, CCR3 and CXCR3 expression in the different
groups.
Methods
Peripheral
blood (PBMC) and intrahepatic (IHMC) mononuclear cells from 18 CHC+ patients
and 4 CHC- patients and PBMC from 5 HC were obtained. Moreover, in ten CHC+
patients PBMC at different time-points during treatment were analysed.
Mononuclear cells were marked with anti-CD8, anti-CCR5, anti-CCR3 and
anti-CXCR3 antibodies and analysed by flow-cytometry. Data are presented as the
median frequency of CD8+/CCR5+ T cells out of total CD8+ T cells plus the
interquartile range (IQR). Comparison among groups were done by Mann-Whitney U,
Kruskall Wallis and Wilcoxon tests.
Results
Frequency
of CD8+/CCR5+ T cells in CHC+ was higher in liver (60.5%: IQR 46) than in
peripheral blood (12.5%: IQR 7) (p<0.01). CCR5 expression on CD8 T cells was
higher in PBMC from CHC+ than in HC (5.2%: IQR 4.8) but lower than in CHC-
(24%: IQR 7) (P<0.05). CD8+/CXCR3+ T cells frequency was higher in CHC+
(50%: IQR 24) than in HC (32%: IQR 14) (p<0.05). CD8+/CCR3+ T cells were not
detected in any group. Mean frequency of CD8+/CCR5+ T cells increased in 80% of
CHC+ patients during anti-viral treatment (17%: IQR 11) (p<0.01), but
neither CCR3 nor CXCR3 were modified.
Conclusions
1) CCR5
expression by T cells allows its intrahepatic sequestration in CHC+.
2) HCV
infection reduces CCR5 expression on CD8 T cells in comparison to other chronic
hepatitis. 3) Anti-viral treatment could improve CCR5 expression on CD8 T cells
in CHC+.
S. Kamal, Q. He, C. Graham, W. Saleh, A. Al Tawil, S.
Hakam, K. El Sayed, J. Rasenack, M.
Koziel
Background
Pegylated interferon
alfa (PEG IFN alpfa) improves sustained virological response rates in chronic
hepatitis C and is associated with histological improvement but the biologic
basis for this effect on the liver not been defined. The (HCV)-specific CD4+ and CD8+T cell responses are critical to
achieving a sustained virologic response to in interferon therapy however the
patterns and kinetics of intrahepatic T-cell responses in during PEG IFN alpha
therapy have not been described. This prospective study assessed the intrahepatic
(HCV)-specific CD4+ and CD8+T cell
responses before and after PEG IFN alpha treatment and correlated the pattern
of these responses to changes in liver histology.
Methods
This
prospective longitudinal study compared the HCV specific intrahepatic and
peripheral CD4+ and CD8+ T cell responses and cytokines (ELISpot) before and
after treatment with peginterferon alpha-2b/ribavirin therapy in 40 subjects.
The findings were correlated to the liver histology (Ishak score) and fibrosis
progression rate/year.
Results
The
sustained virological response (SVR) was achieved in 26/40 subjects (65%)
treated with PEG IFNalpha/ribavirin combination therapy. Histological
improvement was detected in all sustained virologic responders, relapsers (n=5)
and 3/9 non-responders. At baseline, week narrowly focused intrahepatic
HCV-specific CD4+ Th1 responses were detected in 13/40 while Cd8+ responses
could be detected in 9/40 subjects. At the end of follow-up, multispecifc CD4+
Th1 responses were detected in all sustained responders, relapsers and 2
non-reponders. CD8+ T-cell response was detected in the livers of 18/40
patients. The intrahepatic HCV-specific CD4+ and CD8+ T cell responses were
significantly related to a histological improvment.
Conclusion
This
prospective analysis indicates that peginterferon alpa-2b therapy induces histological improvement which is associated
with development of multispecific, HCV-specific CD4+ Th1 responses and
detection of HCV specific CD8+ T cells in the liver that could be related to
several parameters of a favorable outcome of chronic C hepatitis.
M. Trippler, S. Bein, K. Koop, G.
Gerken, J.F. Schlaak
Aims and background
The
mechanism of action of interferon-alpha (IFN-α) which is used
therapeutically to suppress replication of the Hepatitis C Virus (HCV) in
chronically infected patients is still unclear.
Methods
To
identify target genes that mediate the anti-HCV effect of IFN-α in vivo 24
HCV patients were treated with a standard therapy (PEG-IFNα-2b +
ribavirin). 12h before and 12h after the first injection of IFN peripheral
blood cells were assayed for the expression of IFN-inducible genes (ISGs) using
DNA microarrays and quantitative real-time RT-PCR. HCV-RNA levels were
determined 12h before and 36h after IFN injection to assess the immediate
antiviral effect of IFN. The gene expression profiles were correlated with
clinical and virological parameters.
Results
A total of
approximately 770 ISGs could be identified in this cohort of patients of which 175
genes were consistently induced in all patients. 25 candidate genes could be
identified that were significantly lower induced in patients with low (<1,5
log) antiviral response compared to patients with good (>1,5 log) antiviral
response. 8 of those could be confirmed using real-time RT-PCR. No gene could
be identified with significantly higher induction in patients with low
antiviral response.
Conclusions
In
conclusion, we could identify candidate genes that may mediate the immediate
antiviral effects of IFN-α in patients treated for chronic hepatitis
C.
H.J.
Flink, D.
Sprengers, B.E. Hansen, E. Verhey, M.
van Zonneveld, R.A. de Man, S.W. Schalm, H.L.A
Janssen
Background and aims
Flares of
liver inflammation are a well-known phenomenon during treatment with interferon
and after stopping lamivudine given for chronic hepatitis B. Although flares
are thought to represent immune-mediated clearance, little is known about the
effect of flares on response to antiviral treatment.
Aim
In this
study we investigated the timing and characteristics of flares, and assessed
the relation to treatment response (i.e. serum HBeAg loss at end of follow-up).
Methods
A total of
266 patients, participating in a global randomized controlled study were
assigned to 52 weeks of 100μg Peg-interferon alpha-2b weekly combined
with, either daily 100mg lamivudine (combination therapy) or placebo
(mono-therapy). The follow-up lasted 26 weeks. Flare was defined as 3-fold
increase in alanine aminotransaminase (ALT) compared to baseline.
Results
Sixty-seven
patients (25%) exhibited a total of 75 flares, with 38 (51%) flares in the
combination-therapy and 37 (49%) in the mono-therapy group. Overall, 30% of
patients with and 38% of patients without a flare responded to therapy (p =
0.25). In 24 patients (36%) the flare was followed by a decrease of HBV DNA of
at least 1 log, referred to as host-induced flare. In 25 (38%) patients the
flare was preceded by an increase of at least 1 log HBV DNA, referred to as
virus-induced flare. In 17 (26%) patients the flare did not meet one of these
criteria, and was classified as indeterminate. Of patients with host-induced
flare 58% responded, whereas only 20% of patients with virus-induced flares
responded, p = 0.008. Multivariate logistic analysis showed that host-induced
flares was the only independent predictor for response to therapy (p = 0.003,
RR 3.5 CI 95% 0.9 to 13.9)
Conclusions
Flares are
not more common in responders than in non-responders to Peg-interferon alpha-2b
therapy. Virus-induced flares, which occur after an increase in HBV DNA level,
and most probably indicative for increased expression of viral antigens, did
not lead to treatment response. In contrast, host-induced flares which were
followed by an HBV DNA decrease were highly associated with treatment response.
B.E. Annicchiarico, M. Siciliano, A. Milani, A.
Franceschelli, G. Bombardieri
Istituto di Patologia Speciale
Medica e Semeiotica Medica - Universitŕ Cattolica Del Sacro Cuore, Rome,
Italy
Introduction
The poor prognosis of decompensated HCV cirrhosis strongly recommends effective antiviral therapy. A sustained virological response could slow further clinical deterioration and could reduce the risk of hepatocellular carcinoma. Moreover, sustained response could avoid HCV reinfection in patients submitted to liver transplantation. However, some concern exists about the safety of pegylated interferon and ribavirin combination therapy in decompensated cirrhotics, expecially in front of a reduced virological response. As a result, randomized controlled trials evaluating this treatment in chronic HCV infection have excluded, until now, patients with decompensated cirrhosis.
Aim/Methods
Aim of our study was to evaluate safety and efficacy of combination therapy in decompensated cirrhosis. Thirty-one cirrhotics (aged from 37 to 73, 16 males, 19 with genotype 1a/1b) who have experienced ascites, encephalopathy (HE), varices, spontaneous bacterial peritonitis (SBP), jaundice or coagulopathy, were studied. Main laboratory and clinical features at the beginning of the treatment are reported in the table.
Results
All patients started pegylated interferon 12KD 1.5 mcg/Kg of body weight/week and ribavirin ≥10.6 mg/Kg of body weight/day. Twenty-four or 48 weeks of treatment were planned, according to genotype and early virological response. Eleven patients reduced pegylated interferon dose for neutrophils < 0.75X109/L and 4 for platelets < 45X109/L. Two patients reduced ribavirin dose for hemoglobin < 10.0 g/dL. No patient discontinuated pegylated interferon for neutrophils < 0.5X109/L or platelets < 25X109/L. One patient discontinued ribavirin for hemoglobin < 8.0 g/dL. Two patients discontinued therapy respectively at the fourth and at the12th week for neurological deterioration. Fifteen patients (48.4%) obtained early virological response, 12 (38.7%) end-of-treatment response, and 10 (32.3%) sustained virological response. The means of end-of-therapy MELD and Child-Pugh scores in the 15 patients who obtained at least early virological response were respectively 8.5 (range 6 to14) and 7.2 (range 7 to 8).
Conclusion
Even in decompensated HCV cirrhosis, combination therapy with pegylated interferon and ribavirin is safe and efficacious.
A.L. Ballesteros, O. Miró, S. López, D. Fuster, S.
Videla1, E. Martínez, G. Garrabou, A. Salas, H. Côté, J. Tor, C. Rey-Joly, R.
Planas, B. Clotet, C. Tural
Background
It has been suggested that the addition of RBV as a part of treatment for chronic hepatitis C virus (HCV) in human immunodeficiency virus (HIV) co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function.
Design
Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HIV/HCV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their same antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus Peg-IFN alfa-2b therapy (HCV-treated group).
Methods
We assessed peripheral blood mononuclear cells (PBMCs) mitochondrial DNA (mtDNA) content (quantitative real-time polymerase chain reaction), and mitochondrial respiratory chain (MRC) function of complexes II, III and IV (spectrophotometry), at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy
Results
Times on ddI or d4T exposure were 194±54.9 and 131±66.5 weeks in the HCV-treated and control groups, respectively. There were no differences between both groups at baseline, either in mtDNA content (0.9±0.1 and 1.2±0.6; p=0’02), the enzyme activity of MRC complex II (22±2 y 24±9; p=0.86), III (82±41 y 55±24; p=0.08) and IV (41±13 y 41±10; p=1) or clinical parameters. Throughout the study, mitochondrial measurements remained stable in the HCV-treated group (figure) and without differences when we compared HCV-treated and control groups at 24 weeks: [mtDNA (1.1±0.6 and 1.2±0.6; p=0.68), the enzyme activity of MRC complex II (31±14 y 25±11; p=0.23), III (63±14 y 69±34; p=0.54) y IV (54±20 y 44±19; p=0.21)].
Conclusions
In our study, the addition of RBV and Peg-IFN during a 24-week period in HIV/HCV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop
M.
Basso, F. Torre,A.
Grasso, G.F. Percario, E. Azzola, S.
Artioli, N. Pelli, A. Picciotto
Aim
Our aims
were to evaluate the rate of SVR in patients relapser to a previous course of
standard IFN combination therapy when retreated with PegIntron alfa 2b (1
mcg/kg/week) and ribavirin (800-1200 mg daily) for 24 (genotypes 2-3) or 48
weeks (genotypes 1-4) and to assess if very early HCV-RNA detection could have
a role in predicting sustained virological response.
Patients and methods
Seventy-eight
patients were enrolled. HCV-RNA was assessed at 2, 12, 24 or 48 weeks and at
the end of follow-up (24 weeks). 50 patients were genotypes 1 or 4; 28
genotypes 2 or 3. We had 29 females and 49 males. Patients’ age was (value
expressed as median & range) 48 yrs (22-65).
Results
We had 32
sustained responders (41%; 22 genotype not 1), 11 relapsers (14%; 9 genotype 1)
and 25 non responders (32%; 23 genotype 1). 10 patients dropped out of therapy
(13%; 7 genotype 1). In an intention to treat evaluation, the total rate of non
responders was 45%. HCV-RNA at week 2 was available in 59 patients. It was
negative in 10 patients (17%, all with favourable genotypes) and remained
negative at week 12, at the end of treatment and patients became sustained
virological responders. Of the 49 positive patients at week 2, 20 turned out
HCV-RNA negative at 12 weeks (40%) and another 8 at the end of treatment (for a
total of 28 out of 49; 57%). Of these 28 patients only 17 became sustained
virological responders (35%). Conclusions: Therapy with PEG-IFN alfa 2b plus
ribavirin is effective in responder-relapsers (41% SVR overall rate). A 24
weeks course is sufficient in favourable genotypes, while genotype 1and 4
patients probably require PEG-IFN higher dose.
Conclusion
Early
HCV-RNA clearance can’t identify sustained responder patients, but its positive
predictive value could have a role in addressing expensive pharmacological
support, such as erythropoietin and granulocyte growth factors, to patients who
have a high likelihood of achieving a SVR.
C.
Bonny, C. Roche,
H. Fontaine, T. Poynard, C. Hézode, D. Larrey, P.
Marcellin, M. Bourličre, J.P. Bronowicki, P. Merle, J.P. Zarski, C. Nicolas, K.
Randl, G. Bommelaer, A. Aberge
Introuction
Prevalence
of HCV genotype 5 in France is 2%. Little is known about virological response
in this population. HCV genotype 5 are considered as bad responders and usually
treated 48 weeks as genotype 1 or 4.
Aim
The aim of
our study was to assess the antiviral response in naďve patients treated by
Interferon (or Peg-Interferon) with Ribavirin for 48 weeks.
Patients and methods
We performed
a retrospective study in order to estimate the virological response after a
treatment of 48 weeks in naďve HCV genotype 5 patients. A total of 82 patients
were included. Twenty eight patients received standard Interferon (3 MU*3/week)
(G1) and 54 were treated by Peg-Interferon
(1.5 mcg/kg/week or 180 mcg/week) (G2), associated with Ribavirin (800-1200
mg/day). Sustained virological response (SVR) was defined as an undetectable
HCV RNA at week 72. Patients were considered as adherent if they received ≥
80% of both their total Interferon and Ribavirin doses for ≥ 80% of the
expected duration of therapy (AASLD 2004).
Results
Baseline
characteristics were: mean age 58 years, sex ratio 1.4 (M/W), fibrosis score
(Metavir): 63% ≥ F2, 22% F4 and pre-therapeutic viral load > 800000
UI/mL: 52%. Transmission routes were: transfusions (54%), intravenous drug use
(2%), others (18%) and unknown (39%). SVR rate in intend-to-treat analysis was
achieved in 61% (64% in G1 and 60% in G2, p: NS). In univariate analysis, the
rate of SVR did not depend on age (<vs.≥ 45 years), sex, fibrosis
score (<vs.≥ F2) and viral load (<vs.≥ 800000 UI/mL). SVR was
84% (16/19) in adherent and 54% (32/59) in non adherent patients (p<0.05).
In our study, 35 patients received a Ribavirin dose ≤ 800 mg/day. SVR
rate depended only on Ribavirin adherence. SVR rate was statistically superior
(p<0.01) in Ribavirin adherent patients 86% (18/21) versus non adherent
patients 53% (30/57).
Conclusion
Combination
therapy (standard or Peg-Interferon plus Ribavirin) is efficient in 61% of
HCV-type 5 infected patients. Ribavirin adherence strongly improves SVR (86%).
This is the first study realized in a large cohort of HCV genotype 5 patients
showing that these patients are good responders to combination therapy.
K. Cesario, F. Khandwala, K. Edwards, W.
Carey, D. Barnes, N. Zein
Background/Aims
It has
been suggested that obese hepatitis C virus (HCV) patients have a more rapid
progression of liver disease and lower rates of response to antiviral therapy.
Aims were to assess the association between obesity and histological stage of
liver disease, and to determine if weight-based dosing with pegylated
interferon alfa-2b (PEG2b) is more likely to result in a sustained virological
response (SVR) than standard dosing with pegylated interferon alfa-2a (PEG2a)
in obese HCV patients.
Methods
All treatment-naďve,
Caucasian patients with chronic HCV genotype 1 at Cleveland Clinic Foundation
between 2001 and 2004 were identified. Those who received at least one dose of
PEG with ribavirin at the recommended doses were included. Patients were
classified by body mass index (BMI): obese (>30kg/m2) or nonobese
(<30kg/m2). Demographic features and presence of steatosis, fibrosis or
inflammation on pretreatment liver biopsy were compared. SVR, defined as
negative HCV-RNA 6 months after discontinuation of therapy, was determined both
overall and based on the type of therapy received.
Results
Mean BMI
of obese group (n=42) was 35kg/m2, and 25kg/m2 in the nonobese group (n=91)
(p<0.001). Obese patients had higher baseline HCV-RNA levels (850 vs 350
x103IU/mL, p<0.0001) and higher likelihood of steatosis on pretreatment
liver biopsy (40% vs 16%, p=0.02). Frequency of advanced fibrosis (60% obese vs
44% nonobese) or marked inflammation (11% in both groups) was not significantly
different. SVR data were available in 35 obese and 61 nonobese patients.
Multivariate logistical analysis showed that mild hepatic fibrosis (OR 2.70,
p=0.063), lower pretreatment HCV-RNA (OR 0.93, p=0.052) and weight-based dosing
(OR 4.76, p=0.003) were independently associated with overall SVR. SVR in
patients who received weight-based doses of PEG2b (n=46) was similar in obese
(9/17, 52%) and nonobese (14/29, 48%) patients. However, SVR in those treated
with standard-dosed PEG2a was lower in obese (2/11, 11%) than nonobese (8/29,
28%) patients.
Conclusions
Obese and
nonobese HCV patients have different virological and histological profiles.
Obese and nonobese patients have equal SVR when treated with weight-based doses
of PEG2b. However, when treated with standard-dosed PEG2a, obese patients are
less likely to attain SVR. Prospective studies are required.
P. Colombatto, P. Ciccorossi, F. Oliveri, A.M. Maina, L.
Civitano, B. Coco, D. Flichman, R.
Sacco, F. Bonino, M.R. Brunetto
Introuction
The lack of
2 Log10 viral load decline after 3 months of therapy has a high NPV (97%) but a
low PPV (65%) in identifying sustained responders (SR). We developed a
bio-mathematical model where the dynamics of viral load and infected cells are
simulated by fitting 1st month HCV-RNA and ALT decline in order to evaluate
whether SR can be predicted by computing the residual number of infected
hepatocyte at the end of therapy (Ieot).
Methods
Sixty six
consecutive patients (49 males and 17 females, mean age 50.2 years, range:
26-70) treated with IFNa2b (18) or PegIFNa2b (48) plus Ribavirin in 2 clinical
trials with different duration of therapy (180 or 360 days according to HCV
genotype for IFNa2b and 270 days regardless to HCV genotype for PegIFNa2b
treated patients). ALT and HCV-RNA (Cobas Amplicor HCV Monitor®, Roche) were
measured at 0, 2, 4, 7, 14, 21, 28 days, at 3 and 6 months during therapy.
Results
The model
fit 60 patients and failed in 3 SR with ALT increase after IFN and in 3
patients with viremia breakthrough during therapy. In the 54 patients who
completed the original treatment schedule, Ieot
correlated with treatment outcome showing a mean value of 1.15∙10^2cells/ml
(range: 2.0-7.26∙10^2) in 30 (12 gt 1a/b and 18 gt 2-3) SR; 2.26∙10^4
cells/ml (range: 4.08∙10^4 -8.32∙10^4) in 8 (5 gt 1a/b and 3 gt
2-3) relapsers and 1.65∙10^6 cells/ml (range: 3.07∙10^3 -1.017∙10^7)
in 16 (15 gt 1-4 and 1 gt 3a) non responders (HCV-RNA >50 IU at the end of
therapy), (ANOVA, P = 0.002). A value of Ieot < 1000 cells/ml identified all
SR pts with 100% sensitivity, 95.8% specificity, 96.8% PPV, 100% NPV and 98.1%
diagnostic accuracy. A stopping rule based on Ieot > 1000 cells/ml (assessed
at 1 month) would have reduced by 91 months the duration of non effective
treatments overcoming by far the cost of the additional HCV-RNA determinations.
Conclusion
Ieot
computed by our bio-mathematical model is an accurate and cost effective tool
to avoid ineffective therapy in patients with chronic hepatitis C and may be
used to tailor individual treatment duration.
M. Kugelmas, W.J. Semon, G.
Spiegelman, R. Reindollar
Background
Hematologic
toxicity is one of the most common reasons for dose reduction or
discontinuation when treating chronic hepatitis C. In turn, these dose
reductions negatively affect chance of achieving early virologic response (EVR)
during therapy of patients with genotype 1 chronic hepatitis C (HCV-1) (Davis,
Hepatology 2003). Aims and
Methods
We are
comparing standard of therapy (ST) with pegylated interferon alfa 2b (IFN) plus
weight-based ribavirin (RBV) in patients with HCV-1 to an adjuvant therapy (AT)
regimen where anemia is supported with darbepoetin alfa (starting with
hemoglobin <12 or <75% of baseline), neutropenia is supported with
filgrastim (ANC <900 mm3), and more lenient cut-off levels for
thrombocytopenia are allowed in order to try to prevent dose reductions due to
hematologic toxicity. The study is powered to show a 22% difference in SVR in
favor of the adjuvant therapy arm.
Results
To date 58
patients with HCV-1 have received at least 12 weeks of therapy. Thirty-eight
are men, 59% have high viral load (HVL >800,000 IU), age is 45±7 years old,
fibrosis score (Sheuer scale) is 1.7±1.0, average weight is 79±13 kg, 7% are
African American and 9% are Hispanic. Of 26 patients receiving ST 73% have
achieved an EVR, and of 32 receiving AT regimen 78% have EVR. Eleven patients
in the AT arm received growth factors (9 darbepoetin and 2 filgrastim) for
management of hematologic side effects, but only one required dose reduction
(RBV for hemoglobin <10 gm/dL). One other patient in the AT arm had a RBV
dose reduction for nausea. Nine patients in the ST arm had dose reductions
(34.6% in the ST arm vs. 6% in the AT arm, p= 0.03). Baseline hemoglobin fell
from 15.2±1.2 gm/dL to 11.7±1.2 gm/dL in the ST arm and from 15.9±1.4 gm/dL to
12.3±1.2 gm/dL in the AT arm.
Conclusions
Use of
growth factors prevent dose reductions of
pegylated IFN and RBV in patients receiving anti HCV-1 therapy and maintain more physiologic hemoglobin levels.
Continuation of the study will show whether use of growth factors may allow for
higher antiviral efficacy.
E.M. Martínez-Bauer, F.J. Crespo,
M. Romero-Gómez, R. Moreno-Otero, R. Sola, N. Tesey, X.
Forns, J.M. Sanchez-Tapias
Aim
The aim of this study
was to develop simple scoring indexes to predict virological response prior to
or early during pegylated interferon plus ribavirin combination therapy in
naďve, HCV genotype 1 infected patients with chronic hepatitis C.
Methods
Two indexes, a
baseline predictive index (BPI) and a week 4 of therapy predictive index (W4PI)
were constructed using data from a cohort of 104 patients consecutively treated
with pegylated interferon alfa-2b and ribavirin at a single hospital. The
validity of BPI and W4PI was assessed in an external cohort of 141 comparable
patients recruited and identically treated at four independent hospitals.
Virological response was defined by negative HCV-RNA at the end of therapy and
24 weeks after treatment withdrawal. No response was defined by persistence of
HCV-RNA after 24 weeks of therapy or by relapse.
Results
Serum HCV-RNA
concentration, AST:ALT ratio, serum cholesterol, and a calculated non-invasive
score aimed to estimate liver fibrosis were independently associated to response
by uni and multivariate analysis of baseline data in the estimation cohort. At
week four of therapy, BPI and clearance of HCV-RNA were independently
associated to response. BPI and W4PI were formulated using these variables and
the power of these indexes to predict response was explored by receiving
operator (ROC) curves. The area under the ROC curve in the estimation group and
in the validation group were, respectively, 0.856 and 0.847 for BPI, and 0.908
and 0.907 for W4PI. In the estimation cohort, a BPI score lower than 6.60 had
97% sensitivity and 92% negative predictive value and a score higher than 9.70
had 96% specifity and 91% positive predictive value. A W4PI score lower than
1.35 had 97% sensitivity and 93% negative predictive value and a score higher
than 6.02 had 98% specifity and 96% positive predictive value. The predictive
values of BPI and W4PI in the validation group were closely similar.
Conclusion
In conclusion, BPI and W4PI may be valuable for therapeutic decision and to design studies for evaluation of alternative therapeutic strategies in genotype 1-infected patients with chronic hepatitis
S. Mauss1, F. Berger1,
G. Felten2, D. Hueppe2, G. Schmutz1
1Center For HIV and Hepatogastroenterology, Duesseldorf,
Germany
2Practice for Gastroenterology,
Herne, Germany
Background
Recent
studies in HCV-monoinfected patients may suggest differences in the efficacy or
tolerance of the two currently approved pegylated interferons. Prospective,
controlled studies are ongoing, but data will not be available before 2006.
Methods
To gain
controlled, comparative data we conducted a matched pair analysis for patients
treated with peginterferon alfa-2a or peginterferon alfa-2b from our data base
(n=427). Eligible were all patients with first interferon-based therapy and
follow-up since initiation of therapy for at least 18 months for hcv-genotype 1
(n=90) or 4 (n=4) and 12 months for genotype 2 (n=18) or 3 (n=54). Patients
were matched within each center for hcv-genotype and hcv-rna (< vs.
>800.000 IU/mL). Therapy consisted of peginterferon alfa-2a (180 µg qw) or
peginterferon alfa-2b (1.5 µg/kg qw) plus ribavirin 800-1200 mg bid based on
weight. Primary endpoint is hcv-rna <100 IU/ml 24 weeks post treatment
(SVR). For statistical analysis Mann Whitney and Fisher test was used. At
baseline patients treated with peginterferon alfa-2a had a median age of 39
years, and median hcv-rna of 453000 IU/mL, not statistically different from
peginterferon alfa-2b 40 years and hcv-rna 489000 IU/mL. Body mass index tended
to be lower in the peginterferon alfa-2a group, 23.5 kg/m2 vs. 24.9
kg/m2 (p=0.06).
Results
Sustained virologic
response (SVR) and relapse after end of treatment response (EOTR) are shown in
the table. Premature discontinuation due to adverse events or patient request
was identical with 27/83 patients (32%) each.
Conclusion
In this
matched pair analysis no statistical significant differences in efficacy and
tolerance were observed between peginterferon alfa-2a and peginterferon
alfa-2b.
G. Taliani1, A. Aceti2, M. Capanni3, F. Esperti4, C. Ferrari5, P. Forte6, L. Framarin7, V. Guadagnino8, F. Leoncini1, S. Luchi9, N. Marino10, F. Mazzotta10, S. Milani2, C. Pasquazzi2, F. Rosina7, D. Tacconi11, T. Stroffolini12, A.L. Zignego13