Saturday Poster Sessions,
HCV Treatment
Topic: Treatment - Pegasys
233. An Open
Label, Comparative, Multicenter Study Of
Peginterferon Alfa-2a Plus Ribavirin in The Treatment Of Patients With Chronic
Hepatitis C/Hepatitis B Co-Infection Versus Those With Chronic Hepatitis C
Monoinfection C. Liu; W. Chuang; C. M. Lee; S. S. Wu;
L. Y. Liao; H. T. Kuo; Y. C. Chao; C. L. Chen; P. J. Chen; D. S. Chen
Introduction:
Pilot studies using conventional interferon plus ribavirin (RBV)
for 6 months to treat patients with dual chronic hepatitis C and B infection
suggested that sustained hepatitis C virus (HCV) clearance rate comparable to
that observed in HCV monoinfected patients could be achieved. We have conducted
a multicenter clinical trial in mono and co-infected patients using
peginterferon-based combination therapy in
Methods:
Eligible patients with active HCV (serum ALT level >=1.5 X
ULN and HCV RNA ≥100,000 copies/mL), with (n=161) or without (n=160)
detectable HBsAg, were enrolled. Patients infected with HCV genotype 1 received
48 weeks of peginterferon alfa-2a 180 μg weekly plus 1000–1200 mg RBV
daily. HCV genotype non-1 patients received 24 weeks of peginterferon alfa-2a
180 μg weekly plus 800 mg RBV daily. The primary efficacy endpoint was
sustained HCV RNA clearance 24 weeks post-treatment (SVR) determined using an
in-house real-time PCR assay (lower limit of detection ~100–1,000 copies/mL).
Secondary efficacy parameters included HBV DNA response (<1,000 copies/mL)
and normalization of serum ALT at end of treatment and 24 weeks post-treatment.
Interim analyses are based on 275 patients (86%) who have completed treatment
and follow-up.
Results:
Patients were recruited from June 2004. The treatment and follow-up was completed in
August 2007 and reported in September 2007.
The majority of dually infected patients were male; The
group containing HCV genotype non-1 mono-infected patients had a higher
proportion of female
patients enrolled than the other patient
groups.
The ITT analysis included all patients that received at least
one dose of study treatment; withdrawn cases with missing data at 24 weeks
post-treatment were counted as treatment failure. A total of 26 (8.1%) patients were withdrawn
prematurely from the study
HCV response
HCV genotype non-1 infected patients had a slightly better
sustained response than genotype 1 patients in both HCV and HBV dually infected
and HCV mono-infected patients. HCV
clearance rates were comparable at the end of treatment (88% vs 94%) and 24
weeks posttreatment (86% vs 88%) for dually infected and HCV mono-infected
patients with non-1 genotype infection, respectively. The majority of HCV genotype 1 infected
patients with dual HCV/HBV infection achieved a sustained response (73%) after
24 weeks of treatment-free follow up and an even higher rate of HCV clearance
was achieved in HCV mono-infected patients (77%). A per protocol analysis, including data for all
patients completing 12 weeks of treatment, shows comparable end-of-treatment
and sustained responses.
HBV response
Virological
·
Of
the 145 dually infected patients with available data for analysis, 68 (46.9%)
had detectable serum HBV DNA pre-treatment
·
Of
the 68 patients with baseline detectable serum HBV DNA, HBV virologic response
(VR) was obtained in 47 (69.1%) at the end of treatment and in 38 (55.9%) at
the end of follow-up
·
Of
the 77 patients with baseline undetectable serum HBV DNA, rebound of HBV DNA
was found in 28 (36.4%), including 16 (20.8%) and 17 (22.1%) at the end of
treatment and follow-up, respectively
·
None
of the HBV rebounds was associated with an elevation of serum ALT >200 IU/L,
and almost all showed an HCV SVR
HBsAg clearance
·
10%
of the dually infected patients cleared HBsAg at the end of treatment-free
follow-up
Summary:
·
A
sustained HCV clearance rate of 73% was achieved at 24 weeks post-treatment in
the most difficult-to-treat patients dually infected with HCV genotype 1 and
HBV
·
In
HCV genotype non-1 dually infected patients, HCV clearance (86%) was achieved
to an extent comparable to that observed in HCV mono-infected patients (77% and
88% for genotype 1 and non-1 infected patients, respectively)
·
In
general there was little difference between HCV response rates between genotype
1 and non-1 infected patients at end of treatment and 24 weeks post-treatment
·
HBV
virologic response was obtained in 56% of the patients with dual HCV/HBV
infection
·
Importantly,
HBsAg clearance was observed in 10% of the dually infected patients
·
36%
of the dually infected patients whose serum HBV DNA were undetectable
pre-treatment experienced rebound of HBV DNA
Conclusion:
Combination therapy of PEGASYS and COPEGUS appears to be safe
and effective for treatment of patients dually infected with HCV and HBV.
Importantly, a substantial proportion of the dually infected patients
achieved HBsAg clearance – an important
indicator of long-term treatment success.
Topic: Treatment - Pegasys
A. Andriulli; C. Cursaro; R. Cozzolongo; A.
Iacobellis; M. R. Valvano; A. Mangia; N. Minerva; D. Bacca; M. Stanzione; A.
Scuteri; G. Montalto; P. Andreone
Background & Aims:
Half of patients with HCV-2 and HCV-3 infection attained
sustained virologic response (SVR) following Peg-interferon alfa-2a (Peg-IFN)
monotherapy. However, guidelines recommend Peg-IFN with ribavirin for 24 weeks
in all patients. Efforts to select patients who might benefit from Peg-IFN
monotherapy have not been pursued.
Methods.
In a multicenter trial, 144 HCV-2 and HCV-3 patients were
started on Peg-IFN alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day)
for 12 weeks: those with RVR at week 4 were randomized to either
discontinue ribavirin and remain on Peg-IFN alfa-2a, (n=59) or to
continue combination therapy (n=61). To delineate patients’ features that might
help identify individuals likely to benefit from ribavirin discontinuation, an
SVR prediction model was developed including gender, age, HCV genotype,
baseline HCV-RNA levels, BMI, ALT values, and advanced fibrosis. Stepwise
logistic regression analysis was used to compare P values and odds ratios for
the effect of prognostic factors on either SVR and RVR
rates.
Results:
In the 24 patients with no RVR, 15 (63%) were
end-of-treatment (EOT) responders, and 12 (50%) were SVR. Baseline features of
RVR patients randomized to ribavirin withdrawn or to standard treatment were
not different. All but one RVR patients had EOT response. As expected, SVR
rates were lower after discontinuation of ribavirin: 54% versus 82%
(p<0.001). Twenty-seven (46%) and 10 (17%) EOT patients, respectively,
relapsed during the follow up (difference, 29%, CI 27.5–30.6; p<0.001). In
the discontinuation group, low body weight (p=0.022), low BMI (p=0.034), low
viremia (p<0.01) genotype 3 (p=0.031) and mild liver disease (p<0.01)
were associated with SVR; in the multivariate analysis, low viremia and mild
liver disease remained significant predictors with respective odds ratios of
56.8 (C.I.4.3-745) and 27.3 (CI 1.4-521). In patients who did or did not
discontinue ribavirin, SVR rates were similar in those with < 300,000 IU/ml
viremia (86% vs. 81%) and in patients with intermediate viremia (70% vs. 71%),
but disappointingly low in those with >700,000 IU/ml viremia (37% vs. 88%,
p=0.004).
Conclusions:
·
In
HCV-2 and HCV-3 patients, withdrawn of ribavirin and continuation with Peg-IFN
alfa-2a monotherapy may be appropriate to attain SVR, providing viremia is
cleared early during therapy and associated with low baseline viral load.
·
Our
investigation warrants future prospective testing, since it can give rise to considerable
saving in cost and quality of life related to over-treatment
Topic: Treatment - Pegasys
M. von Wagner; W. Hofmann; G. Teuber; T. Berg; T.
Goeser; U. Spengler; H. Hinrichsen; H. Weidenbach; G. G. Gerken; M. P. Manns;
P. Buggisch; S. Zeuzem
Background:
The impact of amantadine on virologic response of
interferon-based treatment of chronic hepatitis C is controversial.
Dose-dependent increase in HCV RNA decline was observed for amantadine during
first weeks of interferon-based treatment.
Objectives:
Assessment of virologic response rates in patients with
chronic HCV 1-infection treated with 400mg amantadine or placebo in combination
with Peginterferon alfa-2a (40kD) and ribavirin for 48 weeks.
Patients and Methods:
Seven hundred and four previously untreated chronically HCV
genotype 1-infected patients (mean age 46 ± 12 yrs.) received
amantadine-sulphate (400 mg/day) (n=352) or placebo (n=352) in combination with
180 µg peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for
48 weeks. End of treatment and sustained virologic response after a 24-week
follow-up period were assessed by qualitative RT-PCR (Cobas Amplicor HCV,
sensitivity 50 IU/mL).
Results:
Demographic and baseline virologic parameters were similar in
both treatment groups. For 61 patients (9 %) liver cirrhosis or transition to liver cirrhosis were reported. No significant
differences were observed between patients receiving amantadine or placebo
regarding end of treatment and sustained virologic response, respectively.
Intent-to-treat virologic response rates are given in the Table. On-treatment
drop-out rate in the amantadine-group was significantly higher than in the
placebo-group (32% vs. 23%; p=.01). However, adverse events and laboratory
abnormalities were similar between both groups and per-protocol analysis
revealed similar virologic response rates in both treatment groups (52.8% vs.
54.5%).
Conclusion:
In this large placebo-controlled multicenter study,
amantadine even at a dose of 400mg/day did not improve virologic response of
antiviral treatment with peginterferon alfa-2a and ribavirin.
|
Virologic response |
All |
Peg-IFN + Ribavirin Amantadine |
Peg-IFN + Ribavirin Placebo |
|
end of treatment |
487/704 (69.2%) |
231/352 (65.6%) |
256/352 (72.7%) |
|
end of follow-up |
357/704 (50.7%) |
171/352 (48.6%) |
186/352 (52.8%) |
Topic: Treatment – Extrahepatic
Manifestations
D. Saadoun; M. Resche rigon; D. Sene; L. Perard; J. Piette;
P. Cacoub
Background:
Treatment of hepatitis C-related mixed cryoglobulinemia
(HCV-MC) remains difficult and one-third of patients continue to have active
disease while receiving anti-CD20 monoclonal antibody or antiviral therapy.
Objective:
To report the results of a prospective open study using
rituximab combined with Peg-Interferon (IFN)α2b-ribavirin
in HCV-MC vasculitis.
Patients:
Sixteen consecutive HCV-MC patients were treated with rituximab
(intravenously weekly for 4 weeks) combined with Peg-IFNα2b-ribavirin (for
12 months). All patients had severe active disease which was resistant to
previous combination antiviral therapy.
Results:
Fifteen patients (93.7%) showed rapid clinical improvement,
10 of whom (62.5%) were complete responders. Compared with clinical complete
responders, the partial or non responders had a 3.6 times longer duration of
vasculitis prior to therapy and a lower rate of early virologic response.
Complete response was associated with a significant reduction of cryoglobulin,
rheumatoid factor activity and HCV RNA and increased C4. Treatment was well
tolerated with no infectious complications. Flare-up of psoriasis and worsening
of peripheral neuropathy occurred in one patient each. Clinical relapse
occurred in two patients, which was associated with the simultaneous
reappearance of HCV RNA and cryoglobulin and an increase in the number of
peripheral blood B-cells.
Conclusion:
·
Rituximab
combined with Peg-IFNα2b-ribavirin may act synergistically and represents
a safe and effective therapeutic option in severe HCV-MC.
·
This
therapeutic schedule should be considered as induction therapy for HCV-MC
patients.
Topic: Treatment - Pegasys
237. Twice vs
Once Weekly Dosing
of Peginterferon Alfa 2a in Chronic HCV Genotype 1 Infection: Analysis of Early
Viral Kinetics
J. J. Feld; G. A. Lutchman; R. Loomba; A. A. Modi; Y.
Rotman; P. Nagabhyru; M. Ghany; T. Heller; V. Haynes-Williams; T. Liang; A. U.
Neumann; J. H. Hoofnagle
Background:
Treatment outcomes in chronic hepatitis C are highly
correlated with early viral kinetics. Pegylation of interferon greatly improved
treatment responses and allowed for once weekly dosing. However viral kinetic
data have shown that many patients receiving peginterferon weekly have a
rebound in HCV RNA between doses. This may result in suboptimal viral
inhibition and prolong time to clearance of viremia.
Aim:
To compare early viral kinetics
between once and twice weekly dosing of peginterferon in patients with chronic
HCV genotype 1.
Methods:
Consecutive patients with HCV genotype 1 were divided into 2
groups: Group A received peginterferon alfa 2a
180μg once weekly and weight-based ribavirin for 4 weeks and Group B
received an initial 180μg dose of peginterferon followed by 90μg
twice weekly plus ribavirin for 4 weeks. Both groups were then treated with
peginterferon 180μg once weekly and ribavirin for an additional 44 weeks.
HCV RNA was measured at 0, 12, 24, 48 and 72 hrs and at days 7, 9, 14, 21 and
28. Early viral kinetics and baseline characteristics were compared.
Results:
Patients in Group A (n=25) had similar baseline
characteristics to those in Group B (n=25): sex (56% vs 62% male), race (76% vs
80% Caucasian) and HCV RNA level (6.18 vs 6.29 log IU/ml). The groups had
similar first phase (day 0-3) kinetics (Group A -0.76 log vs Group B -0.10
log), but starting at day 3, HCV RNA levels diverged (Figure).
Note: 1 patient in Group B
became HCV negative and were not counted in the
results.
Treatment outcome
|
|
Group A |
Group B |
P value |
|
PCR( – )at Day 28 |
12 % |
17 % |
0.70 |
|
PCR (+) at week 12 |
61 % |
78 % |
0.37 |
|
EVR |
83 % |
83% |
1.0 |
|
SVR |
56 % |
47 % |
0.75 |
|
Relapse |
26 % |
24 % |
1.0 |
Conclusions:
·
Twice-weekly
dosing of peginterferon alfa 2a improves early viral kinetics in HCV genotype 1
infection.
·
There
was a trend towards improved second phase slope, which translated into a significant
difference in absolute decrease in HCV RNA at all time points from day 7 to 28.
·
The
change in HCV RNA did not differ before day 7 or after day 28, suggesting that
this difference was due to the twice weekly dosing regime during the first
month of therapy.
·
Although
there was no improvement in early or sustained viral clearance the study was
underpowered and not designed to evaluate these endp9oints. Furthermore, it may require longer than 1
month of twice weekly dosing to affects rates of EVR and SVR.
·
Base
on these data a larger study to assess the benefit of twice weekly dosing of
peginterferon alfa-2a is warranted.
Topic: Treatment - PEG-Intron
S. Maylin; M. Martinot-Peignoux; N. Boyer; M. Ripault;
A. C. Cardoso; N. Giuily; C. Castelnau; M. Nicolas-Chanoine; P. Marcellin
It is unclear whether hepatitis C virus (HCV) is eradicated
in patients with chronic hepatitis C who achieve a sustained virological
response [SVR). In this study, HCV-RNA was measured in serum, and peripheral
blood mononuclear cells (PBMCs) and a follow-up of anti-HCV antibodies were
performed in patients with chronic hepatitis C who achieved an SVR.
PATIENTS–METHODS:
215 patients with an SVR after a treatment with IFN alpha-2b
or PEG-IFN alpha-2b+ribavirin (PEG-IFN 1.5μg/kg/week, plus ribavirin
800-1200 mg /day according to weight), were included in this study. HCV-RNA was
tested: -(1) in serum for all the 215 patients every
year and at the time of PBMCs collection, -(2) in PBMCs collected in 71
patients 3.9±3.4 (0.5-10) years after treatment. HCV-RNA was detected with the
VERSANT HCV-RNA Qualitative assay (Qual TMA, Siemmens) (sensitivity 10 IU/ml).
In 70 patients HCV antibody titers were measured with the Axsym HCV 3.0
(Abbott), and with the third-generation HCV recombinant immunoblot assay (RIBA)
(CHIRON RIBA HCV 3.0 SIA).
RESULTS:
Patients were followed up for a mean of 2.7±1.4 years (range,
0.5 -10) years. Serum HCV-RNA remained undetectable in all the patients (1125
samples). HCV-RNA was detectable in the PBMCs sample for 1 patient (3 years
after treatment cessation). The kinetics of antibodies is shown on the figure.
The mean titers were 93±20 IU/ml and 41±20 IU/ml, before therapy and on the
last serum sample available, respectively (p<0001). A significant decrease was
observed for anti-NS5 and anti-NS3 with the RIBA assay (p=0.01).
CONCLUSION:
In our 215 patients with chronic hepatitis C and SVR,
evaluated up to 10 years after treatment cessation, none demonstrated late
relapse. HCV-RNA was detectable, by a very sensitive assay (TMA), in PBMCs in 1
patient. HCV antibody titers showed a marked decrease. These results
demonstrate a durable response to IFN alpha 2b or PEG-IFN alpha-2b+ribavirin
and indicate that SVR is associated with HCV eradication
Topic: Treatment – Liver Transplantation
239.
Preemptive Treatment of HCV After Liver Transplantation Is Unjustified Except
for Genotype 3a.
H. J. Merhav; L. Mieles; M. Ottman; S. Pappas; R. C.
Botero
Background:
Preemptive treatment (PT) of HCV after Liver Transplantation
(LT) is controversial due to the high morbidity, high cost and unclear
efficacy.
Methods and patients:
75 consecutive HCV LT recipients were followed prospectively
in a preemptive intent to treat protocol with pegylated interferon (PegI) and
ribavirin (Rib) for 48 weeks. Viral load and protocol biopsies were followed in
all treated patients Preemptive treatment was defined as starting less than 180
days after LT and before the onset of histologically proven recurrent HCV
(>Grade 1 Stage1). Viral genotype, pretreatment viral load, time to
initiation of treatment, immunosuppression, rejection episodes and completion
of treatment were analyzed for their effect on response.
Results:
Demographics: Pts. – n = 75. Age - 52±7.
Sex – 50 m, 25 f. HCC – 23. Follow up – 27 ± 13 m.
Actuarial Survival (patient and graft) – 1 year = 91 & 88%, 3 year = 84
& 81%
Of 75 LT patients (pts.) with HCV 29 (39%) qualified for PT.
14 pts. were treated after HCV recurrence was histologically documented. 32
pts. (43%) received no treatment against HCV. Reasons for exclusion were:
preoperative viral clearance – 9;. early
death – 3; psychosocial – 6; re-LT – 3; medical – 15; noncompliance – 5; early
HCV recurrence - 3. Of the 29 who started PT only 13 (17 & 45 %) completed
treatment. Of the 29 on PT 17 had complete response, 11 end of treatment
response and 6 sustained viral response (SVR). Of the
patients with SVR non were genotype 1a (3-3a, 1-2b,
1-1b, 1- indeterminate). Of 5 pts. with
genotype 3a in the PT group all cleared the virus with one recurrence. Of 15 pts. with advanced recurrence
(Grade >1 stage > 1) 12 had genotype 1a. No pts. With genotype 1a
achieved SVR. 2 pts. And 3 (4%) grafts were lost to
recurrent HCV. Of 15 pts. with
moderate to severe recurrent HCV (>Grade 1 Stage1) 12 were 1a, 2 2a and 1
4e. After censuring for early death and early recurrent hepatitis there was no
survival advantage in the non treated vs. the PT
group. There were no deaths, graft loss or rejection episodes associated with
treatment for HCV. 75% of PT patients required growth factor treatment. Intent
to treat SVR was 6% for the cohort, 20% for the PT group and 45% for the pts. that completed treatment.
Conclusions:
1.PT for HCV after LT is expensive, time
consuming and associated with considerable (though not lethal) morbidity. With
an SVR of 6% it appears to be unjustified to expose all HCV pts. to treatment. 2. Genotype 3a appears to respond favorably
and consistently to treatment and may be an indication for PT.
Topic: Treatment – Disease Progression
Ana-Carolina Cardoso, Rami Moucari, Nathalie Boyer,
Tarik Asselah, Asma Laatar, Marie-Pierre Ripault, Michèle Martinot-Peignoux,
Sarah Maylin, Pierre Bedossa and Patrick Marcellin. Service d’Hépatologie et
INSERM CRB3, Hôpital Beaujon, France Service d’Anatomie Pathologique et de
Microbiologie, Hôpital Beaujon, France A. C. Cardoso; R. Moucari; N. Boyer; T.
Asselah; A. Laatar; M. Ripault; M. Martinot-Peignoux; S. Maylin; P. Bedossa; P.
Marcellin
Background and Aim
The major consequence of chronic hepatitis C (CHC) is the
progression to cirrhosis and its potential complications: haemorrhage, ascites
and hepatocellular carcinoma (HCC). The influence of antiviral therapy on the
long-term outcome of CHC has not been determined. The aim of this study was to
evaluate the influence of antiviral therapy on the long-term outcome of CHC
patients with bridging fibrosis or cirrhosis.
Patients and Methods
278 consecutive patients with CHC and bridging fibrosis or
cirrhosis (METAVIR F3-F4) were retrospectively evaluated. They had all received
at least one treatment course with interferon (conventional or pegylated) with
or without ribavirin for at least 12 weeks. Sustained virological response
(SVR) was defined as undetectable HCV RNA in serum 24 weeks after treatment
discontinuation. Cumulative incidence of haemorrhage, ascites, and HCC were
compared between patients who developed or not SVR. The influence of treatment
response on histology was also assessed on paired-liver biopsies in 118
patients.
Results
The baseline characteristics of the study population were:
male gender (67%), mean age (55±10 years), mean BMI (25.8±4.8 kg/m2).
Mean serum HCV RNA ±
SD, log 10 IU/mL ± 0.6. Genotype distribution was: 1 (60%), 2(8%), 3
(16%), 4 (14%), and 5 (2%). Median follow-up period was 5 years (1-18) after
the first biopsy, and 2 years after the last treatment (1-15).
Sustained Virological
Response (SVR)
·
35%
of F3 and F4 patients achieved SVR, and SVR rates were similar (F3,39%; F4, 32%) regardless of METAVIR fibrosis score.
Predictors of Sustained
Virologic Response
·
Gentoype
(G1/4 vs. G2/3), baseline viral load ≥ 400,000 IU/mL vs. ≤ 400,000
IU/mL), and baseline count (<100,000 cells/mL vs. ≥ 100,000 cells/mL)
were significantly associated with SVR.
Liver Decompensation
·
Hemorrhage
and ascites occurred significantly less often in
patients who achieved SVR than in those who did not attain SVR.
Cumulative Incidence of
Hepatocellular Carcinoma (HCC)
·
HCC
occurred significantly less often in patients who
attained SVR than in those who did not attain SVR.
Liver Histology
Significantly more patients who attained SVR experienced
improvement in fibrosis score than did patients who did not attain SVR.
Conclusion
·
Antiviral
therapy is associated with SVR in more than 30% of chronic hepatitis C patients
with cirrhosis.
·
SVR
is associated with lower rates of complications of liver disease and HCC and
with significant regression of fibrosis and long-term improved outcome.
Topic: Treatment – Disease Progression
K. Ikeda; Y. Arase; Y. Kawamura; H. Yatsuji; H.
Sezaki; T. Hosaka; N. Akuta; M. Kobayashi; S. Saitoh; F. Suzuki; Y. Suzuki; H.
Kumada
Background:
Interferon therapy is effective in reducing
hepatocarcinogenesis and in improving survival rate of patients with
HCV-related chronic hepatitis, but the clinical influence of interferon is
considered less advantageous in elderly patients because of short longevity. In
order to elucidate the prognosis of elderly patients of 60 years or older, and
to evaluate the advantage of interferon treatment in the elderly, we analyzed a
large cohort of patients with chronic hepatitis type C from viewpoints of
hepatocellular carcinogenesis and survival period.
Patients and Method:
Among 7,235 patients with hepatitis C virus related chronic
liver disease in our hospital, prognosis of 2,379 elderly patients was
analyzed. A total of 459 elderly patients began interferon therapy before
development of liver cancer. The elderly cohort was observed for a median of
6.3 years (25% 2.6years, 75% 10.8years).
Results:
(1) Cumulative survival rates in untreated elderly patients
without overt cirrhosis were 94% at the end of 10th year and 79% at the 15th
year in high platelet (>=150,000/mm3) group, 87% and 73% in intermediate
(100,000-149,000/mm3) group, and 71% and 36% in low platelet group (<100,000/mm3),
respectively. (2) Fifth- and 10th-year hepatocarcinogenesis rates in the
intermediate and low platelet group (<150,000/mm3) were 12% and 22% in
interferon therapy group (N=85) and 19% and 43% in untreated group (N=474),
respectively (P=0.028). Multivariate analysis disclosed that interferon
independently decreased carcinogenesis risk with a hazard ratio of 0.53
(P=0.012) in the subgroups. In the high platelet group (>=150,000/mm3), on
the contrary, 5th and 10th-year carcinogenesis rates were 3% and 9% in interferon-treated
group (N=96), and 5% and 13% in untreated group (N=598), respectively (P=0.88).
(3) Interferon treatment significantly increased cumulative survival rates in
the subgroup of lower platelet group (P=0.0028), but did not affect in the
subgroups of higher platelet (P=0.20). Multivariate analysis also showed
interferon was significantly associated with a longer survival in the lower
platelet subgroup (hazard ratio 2.44, P=0.011).
Conclusions:
Initial platelet count was significantly associated the
survival time of the elderly patients with chronic hepatitis C. Interferon for
a subgroup of intermediate and low platelet count had significant advantages
from the viewpoints of hepatocarcinogenesis and survival.
Topic: Treatment - Pegasys
245. Efficacy
and Safety of Escitalopram for the Prevention of Depressive Episodes Induced by
Peg-Interferon Alpha2a and Ribavirin in Chronic Hepatitis C Patients. A
Double-Blind, Randomized, Placebo-Controlled Trial.
C. Diez-Quevedo; R. Planas; P. Castellvi; R. M.
Morillas; M. Gimenez; H. Masnou; R. Solà; P. Giner; R. Martín-Santos
Introduction:
Interferon is associated with a high prevalence of major
depression, which is one of the main reasons for treatment withdrawal and failure.
The aim of this study was to determine the efficacy and safety of an
antidepressant for preventing depression induced by pegylated interferon
(PegIFN) alpha2a in chronic hepatitis C (CHC).
Method:
Multicenter (15 Spanish hospitals) double-blind study of CHC
patients who were eligible for PegIFN-alpha2a and ribavirin (RBV) therapy.
Patients with mental disorders at baseline were excluded. They were randomly
assigned to receive the antidepressant escitalopram (15 mg/day) or placebo.
Treatment was begun 2 weeks before PegIFN therapy and continued for the
following 12 weeks. Main variables studied were the presence of a major
depressive episode, according to DSM-IV diagnostic criteria, and scores on the
Montgomery-Asberg Depression Rating Scale (MADRS) and the Hospital Anxiety and
Depression Scale (HADS). The study protocol conformed to the guidelines of the
Declaration of Helsinki and was approved by the Ethic’s Committees of all
centers involved and the Spanish Agency of Medicines. All patients signed a
written informed consent before entering the study.
Results:
A total of 133 patients were included (74% genotype 1), 67
treated with escitalopram and 66 with placebo. Eighty-three (62%) patients were
male, mean age 47 years. Seventeen patients (13%) had a past history of major
depression and 22 (17%) of substance abuse. Placebo and escitalopram groups did
not differ significantly in any measure at baseline.
During the first 12 weeks of treatment, only 1 patient (2%)
in the placebo group and 5 (8%) in the escitalopram group developed a major
depressive episode (Chi square = 2.67, p = 0.11). Total score of the MADRS
increased between baseline and week 12 in 2.2 points in the placebo group and
3.1 in the escitalopram group. Figures for the depression subscale of the HADS
were 0.7 and 1.0 respectively. Differences between both groups were not
statistically significant.
Conclusions:
·
Treatment
of chronic hepatitis C with pegylated interferon alpha 2a and ribavirin is
associated with a very low incidence of major depressive episodes (6 out of 133
pts, 4.5%)
·
In
CHC patients, pretreatment with an antidepressant is not an effective strategy
for reducing depression induced by PegIFN and RBV, at least in a population of
patients with low psychiatric risk.
·
On
the other hand, the use of escitalopram in CHC patients is safe regarding
biochemical and virological response to treatment at week 12.
This study has been supported by a
grant from Roche.
Topic: Treatment - PEG-Intron
246. Response
to Peginterferon alfa-2b + Ribavirin Combination Therapy in Genotype 2 and 3
Patients With Poor
Baseline Prognostic Factors: Results of the Canadian POWeR Program
R. J. Bailey; D. K. Wong; C. Cooper; N. Hilzenrat; K.
Peltekian; J. Daiter; N. Abadir; P. Marotta
Background:
This subanalysis of the POWeR study evaluated the effect of
fibrosis and baseline viral load on sustained virologic response (SVR) rates in
treatment-naive genotype 2 (G2) and G3 patients with chronic hepatitis C
treated with weight-based peginterferon (PEG-IFN) alfa-2b and weight-based
ribavirin (RBV).
Methods:
POWeR is an open-label observational trial conducted in
community and academic clinics across
Results:
276 G2 and 389 G3 patients enrolled in POWeR (38% of all
patients). Baseline viral load and fibrosis scores were available in 72% and 37%
of G2 and G3 patients, respectively. Numerically, more G3 than G2 patients had
high viral load (HVL; 49% vs 54%) and advanced fibrosis/cirrhosis (F3-F4) (40%
vs 33%). G3 patients had lower SVR rates than G2 patients (72% vs 79%, P=.04)
due to a lower end-of-treatment response (77% vs 86%, P=.01); relapse rates
were 7.6% (Geno 2), and 6.4% (Geno 3). G2 patients responded well regardless of
baseline viral load and fibrosis score (Table). G3 patients with low viral load
(LVL) attained SVR more often than those with HVL (76% vs 64%, P=.03). An
inverse relationship between SVR and fibrosis score was observed in G3
patients; 47% of G3 cirrhotic patients attained SVR.
Conclusions:
G2/G3 patients respond very differently to combination
PEG-IFN alfa-2b plus RBV therapy. G2 patients respond well regardless of
baseline characteristics. Conversely, lower response rates are observed in G3
patients who have poor prognostic factors. The lower response rate in the G3
population after 24 weeks’ treatment may not be detected in smaller studies
that combine G2/3 patients for analysis purposes. New treatment strategies such
as increased dose or duration of treatment are needed for G3 cirrhotic
patients. Future studies should avoid combining G2/3 patient populations when reporting
results.
SVR Rates Stratified by Baseline Viral Load and Fibrosis Score
|
|
SVR,*% |
|
|
|
G2 (n=276) |
G3 (n=389) |
|
HVL† |
83 |
64 |
|
LVL |
79 |
76 |
|
F0-F1 |
79 |
81 |
|
F2 |
81 |
68 |
|
F3 |
80 |
71 |
|
F4 |
76 |
47 |
*113/276 G2 and
136/389 G3 with fibrosis score, 201/276 G2 and 281/389 G3 with baseline viral
load data. †HVL=baseline HCV RNA levels >600,000 IU/mL or >2×106
copies/mL.
Topic: Treatment – Predictors of
Treatment Response
J. Huang; M. Yu; C. Dai; M. Hsieh; L. Lee; Z. Lin; S.
Chen; W. Chang; W. Chuang
Introduction:
Insulin resistance plays a key role in the entire suite of
glucose abnormalities. The impact of insulin resistance on the treatment
response of pegylated interferon-alpha plus ribavirin has not been fully
clarified. This study aimed to evaluate the role of insulin sensitivity and the
related viral factors in the treatment response in patients with HCV infection
in
Methods:
A total of 430 patients (243 males) were included (between
2/2003-3/2007). All patients were treated with 24-week course of peginterferon
alpha-2a (180 µg/week) and weight-based ribavirin
1000-1200 mg/day, with a 24-week follow-up period. We assessed insulin
sensitivity and beta-cell function of these patients in a fasting state
(homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis
model assessment of beta-cell function [HOMA-beta]) before treatment and 24
weeks after treatment.
Results:
Sustained virological response (SVR) were observed in 336/430
(78.1%) patients. The rates of SVR in genotype-1 and non-1 patients was 64.5% (118/183)
and 88.3% (218/247), respectively. The baseline HOMA-IR of those patients
achieving an SVR was significantly lower than that of those without (2.28 vs.
3.40, P=0.002). Multivariate logistic regression analysis demonstrated that
high baseline HOMA-IR (>=2.5) was a significant negative factor regarding to
SVR in all patients (OD=2.22, 95% CI= 1.26-3.91, P=0.006). For 172 non-diabetic
patients with genotype-1 HCV infection, the SVR rate (49.0%, 25/51) of those
with high baseline HOMA-IR was significantly lower than those without (72.3%,
87/121, P=0.004). Meanwhile, multivariate logistic regression analysis
demonstrated high baseline HOMA-IR was the most significant negative factor
associated with SVR in genotype-1 patients (OD=2.91, 95% CI= 1.38-6.58,
P=0.006), followed by viral load and age.
Conclusions:
Pretreatment insulin sensitivity contributes to treatment
response in chronic hepatitis C patients, especially for those with genotype-1
infection.
Correlation between pretreatment HOMA-IR and SVR in non-diabetic chronic hepatitis C patients receiving peginterferon plus ribavirin
|
|
Total, n=389 |
G-1, n=172 |
G-non-1, n=217 |
||||||
|
SVR+ |
SVR- |
P |
SVR+ |
SVR- |
P |
SVR+ |
SVR- |
P |
|
|
HOMA-IR |
|
|
|
||||||
|
>=2.5 |
85 (69.1%) |
38 (30.9) |
0.002 |
25 (49.0) |
26 (51.0) |
0.004 |
60 (83.3) |
12 (16.7) |
0.064 |
|
<2.5 |
220 (82.7) |
46 (17.3) |
|
87 (71.9) |
34 (28.1) |
|
133 (91.7) |
12 (8.3) |
|
Topic: Treatment – Pegasys
E. Hornfeldt; L. Stahle; R. Schvarcz; O. R. Weiland;
T. Carlsson; A. Hollander; K. Lindahl
BACKGROUND:
Patients with hepatitis C (HCV) genotype 1 and previous
non-responders to treatment with pegylated interferon (peg-INF) and ribavirin
(RBV) are a difficult-to-cure group. We have previously shown that high doses
of RBV (mean 2550 mg/d) offered high sustained virological response (SVR) in treatment-naïve
patients with hepatitis C genotype 1. The aim of this controlled study was to
evaluate the efficacy, safety and tolerability of high doses of RBV in
combination with standard dosed peg-INF in previous non-responders.
METHODS:
20 patients with HCV genotype 1 and previous non-responders
to peg-INF alfa-2a and RBV therapy received treatment with individualized high
dose of RBV in combination with peg-INF a-2a 180mg/week for 48 weeks.
Non-responders were defined as not achieving HCV-RNA <50 IU/mL at any time
during previous treatment. The initial RBV dose was individualized and
calculated from a pharmacokinetic formula based mainly on renal function aiming
at a high steady state concentration of RBV of >15 mmol/L. Plasma RBV
concentrations were measured during treatment by HPLC and if necessary the RBV
dose was adjusted to reach the target concentration. All patients received
erythropoietin (epo) at doses 10,000-60,000 IU, once weekly, starting 2 weeks
prior to initiation of antiviral treatment.
RESULTS:
We enrolled 10 patients (9 males), mean age 52 years (range
34-61) and 7 of
10 with fibrosis stage 3 on a 4-grade scale. The mean initial RBV dose was 2400
mg/d (range 1600-2800). To reach the target concentration within 6 weeks the
dose was raised to a mean RBV dose of 3000 mg/d (range 2400-4000). The mean
baseline haemoglobin level was 15.3 g/dL, at treatment week 6 mean haemoglobin
level was 13.4 g/dL and at week twelve 10.9 g/dL. Two patients have required
blood transfusions. Mean baseline viral load was 7.4 x 106 IU/mL, at treatment
week 12 median viral load dropped to 1400 IU/mL (mean drop 3.6 log). Ten
patients have reached treatment week 24 of whom 8 have HCV-RNA <15 IU/mL
(COBAS TaqMan).
CONCLUSION:
·
High-dosed
RBV in combination with peg-INF alfa-2a seems to offer a mean 3.6 log HCV-RNA
decline within 12 weeks in previous non-responders to standard-dosed
combination therapy with the same drugs.
·
High-dosed
RBV treatment is feasible and seems to be safe, but requires strict attention
regarding anemia.
·
Epo
probably contributes to tolerability, especially during the first 12 weeks. The
initial virological response is encouraging and the results from the completed
trial, including SVR will show if the response is sustained.
Topic: Treatment – Methadone
S. Mauss; D. Hüppe; E. Zehnter; M. Manns; G. Teuber;
T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern;
S. Kaiser; R. Prinzing; . The bng hepatitis study group
Objective:
The largest group of newly infected individuals with chronic
hepatitis C in the Western world are intravenous drug users. Emerging data support
treating individuals with peginterferon and ribavirin for chronic hepatitis C
after stabilisation on opioid maintenance therapy (methadone or buprenorphine).
However these data are based on small cohorts or substrata from trials with
small patient numbers. Here we report data from a cohort of 4130 patients
including 391 patients on opioid maintenance therapy.
Methods:
A total of 3547 patients treated with at least one dose of
peginterferon alfa-2b and weight based ribavirin are currently included in a
German multicentre cohort. Only patients included in this cohort beyond 72
weeks of baseline were included in this analysis (n=2016). Patients with
missing data at week 72 were counted as treatment failures. Univariate analysis
was performed for comparison of demographics in patients on opioid maintenance
vs. remaining patients (age, sex, ALT, BMI, HCV-RNA, genotype, ribavirin dose, peginterferon dose). For logistic regression analysis sex,
age, baseline HCV-RNA, HCV-genotype, BMI and opioid maintenance were used as
independent variables. The dependent variable was being HCV-RNA negative
(<600 IU/mL) or positive at week 72 (SVR).
Results:
Patients on opioid maintenance were younger 36 (range 18-63)
vs. 42 (range 18-78), p<0.0001), more had genotype 3 (51% vs. 35%,
p<0.0001), and median HCV-RNA levels were lower (66% vs. 50% <600.000
IU/mL, p<0.0001). SVR in all patients on opioid
maintenance 64% vs. 59% in the not receiving opioid maintenance therapy
(p<0.133). In logistic regression analysis, variables positively
associated with SVR were younger age, HCV-genotype 2/3 and baseline HCV-rna
<600.000 IU/mL (all p<0.0001). Female sex was not significantly
associated with SVR (P=.1).
Conclusion:
·
The
efficacy of PEG-IFN alfa-2b plus RBV was not different between chronic
hepatitis C patients receiving opioid maintenance therapy and patients not
receiving opioid maintenance therapy.
·
Because
of favorable factors for SVR such as HCV G3 infection, young age, and low
baseline HCV RNA, patients undergoing opioid maintenance therapy showed a trend
for better unadjusted SVR rates.
·
However,
after adjusting for variables associated with treatment outcome (age, genotype,
baseline HCV RNA), treatment outcome did not differ between patients receiving
and not receiving opioid maintenance therapy.
·
In
conclusion, treatment of chronic hepatitis C patients undergoing opioid
maintenance therapy in daily clinical practice is feasible, and success rates
are not inferior to results from prospective, controlled studies.
Topic: Treatment – PEG-Intron
P. Marotta; S. V. Feinman; C. Ghent; L. Scully; M.
Varenbut; J. Daiter; H. B. Witt-Sullivan; J. Robert; B. Romanowski; J. Farley;
N. Abadir; R. J. Bailey
Background:
To determine the impact of hepatitis C virus (HCV) genotype
(G), baseline viral load, weight, and fibrosis stage on SVR rates in
treatment-naive patients with chronic hepatitis C who were treated with
weight-based peginterferon (PEG-IFN) alfa-2b and weight-based ribavirin (RBV)
in a “real-life” observational setting. We report final SVR results from the
POWeR program.
Methods:
POWeR was an open-label observational trial conducted in
academic and community clinics ( total = 138) across
Results:
1977 patients initiated treatment. Patients were excluded if
they had undetectable HCV RNA at end of treatment but no 6-month follow up, had
no treatment data available, or had HIV/HCV coinfection. This analysis was
based on 1800 patients, including those who discontinued because of side
effects, lack of response, or personal reasons. Most patients were infected
with G1 (60%), followed by G3 (22%) and G2 (15%). Three percent of patients had
G4/G5/G6 or no specified genotype. Baseline viral load was available in 1477
patients; 52% had high viral load (HVL; >600,000 IU/mL or 2×106 copies/mL).
Liver biopsy specimens were available in 946 patients (53%), revealing F0-F2
fibrosis in 60% and F3-F4 fibrosis/cirrhosis in 40%. SVR rates were higher in
patients with minimal (F0-F2) fibrosis than in those with advanced (F3-F4)
fibrosis/cirrhosis (60% vs 35% P<.001) and in patients with low viral load
than in those with HVL (57% vs 50% P=.009). Baseline viral load and fibrosis
score were negative predictive factors for SVR in G1 and G3 patients but not G2
patients.
Conclusions:
·
Successful
treatment outcomes that match those from rigorous clinical trials can be
achieved in routine clinical practice
·
Despite
poor predictive factors (advanced fibrosis and high baseline viral load) in
this patient population, excellent SVR rates and low relapse rates with PEG-IFN
alfa-2b plus RBV were attained in a real-life observational setting
·
Observational
trials include a more heterogeneous patient population than populations
observed in controlled trials and provide useful information to practitioners
and regulators on postapproval drug use
·
Low
virologic relapse rates were observed with combination therapy with PEG-IFN
alfa-2b plus weight-based RBV
EOT, SVR, and Relapse Rates Stratified by Genotype
|
Genotype* |
EOT, % |
SVR, % |
Relapse, % |
|
All (n=1800) |
61.7 |
54.3 |
11.9 |
|
G1 (n=1078) |
50.2 |
41.6† |
17.2 |
|
G2 (n=276) |
85.5 |
79.0† |
7.6 |
|
G3 (n=389) |
76.9 |
72.0† |
6.4 |
|
G4/G5/G6 (n=41) |
70.7 |
65.9 |
6.8 |
*16
patients no genotype data. †P<.001.
EOT=end of treatment.
Topic: Treatment – Side Effects
J. Lang; P. Melin; D. Ouzan; M. Rotily; T. Fontanges;
P. Marcellin; M. Chousterman; P. Cacoub
Purpose :
The CHEOBS study is a French multicenter, prospective,
observational study designed to analyze the factors related to compliance with
the combination treatment with Peginterferon α-2b and Ribavirin in
patients (pts) with chronic hepatitis C virus (HCV) infection. This analysis
evaluates mental safety, quality of life, compliance to treatment and sustained
viral response (SVR) in pts presenting psychiatric disorders (ppd) before the
start of HCV treatment and compares them with those of pts not presenting
psychiatric disorders (nppd).
Methods :
From Jan 2003 to Dec 2004, 1,972 pts with chronic HCV infection
were included in CHEOBS and began antiviral therapy: 444 ppd pts and 1,528 nppd
pts. Among ppd pts, 232 (53%) had depressive disorders, 179 (40%) anxiety
disorders, 21 (5%) schizophrenia and 7 (2%) bipolar disorders. Baseline
characteristics and the impact of ppd on compliance, virological response and
quality of life (QoL, SF-36) were analysed.
Results :
At baseline (Day 0), ppd and nppd populations were different
as the ppd population was younger (45 years vs 47 years), with a lower
educational level (68% vs 53%), less well paid jobs (48% vs 61%), higher debts
(13% vs 5%), more chronic diseases (32% vs 26%), higher alcohol intake (31% vs
23%), higher tobacco (66% vs 42%) and drug consumption (9% vs 2%), and higher
rate of genotype 3 infection (30% vs 23%)(p<0.05). At the end of HCV
treatment, there was no significant difference between ppd and nppd populations
for compliance, duration of combination antiviral therapy (35 ± 17 vs 36 ± 17
weeks), premature antiviral therapy discontinuation due to adverse events or
the pts request (53% vs 52%). The results of SVR, mental adverse events and QoL
are shown in the Table.
Conclusion:
In a real life study, pts infected by HCV and starting HCV
treatment frequently present with psychiatric disorders. The ppd profile did
not have a negative impact on compliance, duration, premature treatment
discontinuation or SVR. The QoL was impaired by HCV treatment and its adverse
effects that was even more pronounced in nppd pts.
|
|
PPD |
NPPD |
P |
||||
|
schizophrenia |
bipolar disorders |
depressive disorders |
anxiety disorders |
Total |
|||
|
Mental Adverse events,% |
|
|
|
|
|
|
|
|
M3 |
63 |
75 |
62 |
59 |
60 |
35 |
<.001 |
|
M6 |
63 |
17 |
64 |
58 |
62 |
40 |
<.001 |
|
M9 |
50 |
86 |
64 |
49 |
56 |
37 |
<.001 |
|
M12 |
70 |
33 |
66 |
69 |
64 |
37 |
<.001 |
|
SVR,% |
44 |
50 |
52 |
48 |
50 |
48 |
.486 |
|
QoL* |
|
||||||
|
Physical score |
-3.3 ± 8 |
-20.9 ± 7 |
-6.5 ± 10 |
-3 ± 11 |
-5.2 ± 10 |
-5 ± 10 |
.710 |
|
Psychic score |
7.3 ± 19 |
-11.3 ± 5 |
-1.5 ± 12 |
-0.7 ± 13 |
-1.5 ± 13 |
-6.8 ± 12 |
<.001 |
*between
Day 0 and Month 12
Topic: Treatment – HIV/HCV Coinfection
F. Bani-Sadr; I. Goderel; C. Berendjem; C. Goujard; L.
Piroth; F. Lunel; P. Morand; E. Rosenthal; D. Salmon; G. Pialoux; P. Bedossa;
C. Perronne; P. Cacoub; F. Carrat; S. Pol
Background:
Long term benefit of HCV therapy in HIV/HCV co-infected
patients is unknown.
Methods:
We prospectively followed 383 patients who were enrolled in a
randomized controlled trial of interferon-ribavirin combination (RIBAVIC) and
who took at least one dose of study medication. The median follow-up in the
cohort was 60 months. We studied the risk of end-stage liver disease (ELD)
event defined as a liver decompensation, liver transplantation, hepatocellular
carcinoma, or death. A Cox’s regression analysis was performed with treatment
and HCV viral response entered as time-dependent covariate.
Results:
At entry, patients (40y, 73% male, 79% IVDU) belonged to the
CDC class A, B & C in 51, 34 & 14%, respectively, and were given HAART
in 83% with a mean CD4 cell count of 545/mm3, HIV RNA < 400 cp/ml
in 66%. The mean Metavir score was A 1.25, F 2.2; 33% had F3-F4. 97 patients
(25%) had a sustained viral response (negative PCR 6 months after therapy), 232
(61%) were HCV genotype 1 or 4 and 51 (39%) HCV genotype 2 or 3 infected non
responders. Twenty one patients (5.5%) experienced ELD events during the
follow-up (13 died). No patient had AIDS-related death. CD4 cell count <
350/mm3 (Hazard Ratio (HR) 2.7- IC95% 1.1-6.7; p=0.03), Metavir
fibrosis score (F3 or F4) (HR 3.2- IC95% 1.0-9.8; p=0.046), prothrombin time
<94% (HR 6.4- IC95% 1.4-28; p=0.01), platelets count < 190 000/mm3 (HR
4.6- IC95% 1.1-20; p=0.04) were independently associated with the risk of ELD.
HCV sustained viral response was associated with a decreased risk of ELD
although the effect did not reach statistical significance (HR 0.18- IC95%
0.02-1.33; p=0.09).
Conclusions:
·
Our
results suggest that HCV SVR achieved by interferon-ribavirin combination may
decrease the incidence of ELD in HIV/HCV Co-infected patients.
·
A
longer period of follow-up is necessary to reach a firm conclusion.
Topic: Treatment – Side Effect Management
G. Cabrera-Alvarez; L. Cañedo-Dorantes; J.
Reyes-Esparza; L. Rodríguez-Fragoso; N. Mendez-Sanchez; A. Burguete; V.
Madrid-Marina
Backgorund and Aim:
Chronic hepatitis C (HCV) infection has been associated with
the development of several extrahepatic alterations, including
thrombocytopenia. Currently it remains unresolved. Danazol, an attenuated
androgen has been succesfully used in patients with autoimmune
thrombocytopenia. The aim of the present study was to investigate the effects
of Danazol treatment for thrombocytopenia associated to peginterferon alfa-2a
and ribavirin therapy in naïve HCV patients.
Methods:
A prospective study carried out in patients with chronic
hepatitis C or liver cirrhosis patients who were under antiviral therapy. The
protocol was approved by the Review Board/Ethics committee of the Hospital. The
inclusion criteria including both gender, age (20 to 70 yr), without
co-infection with hepatitis B virus or human immunodeficiency virus (HIV-1/2),
thrombocytopenia during peginterferon alfa-2a and ribavirin therapy was defined
when the count was ≤ 90,000 platelets/mL in the last month. Danazol
300-600 mg/day was administered until the end of therapy. We considered as a control patients those on antiviral therapy who did not
receive adjuvant danazol due to only mild thrombocytopenia on antiviral
therapy, matched for baseline platelet count, presence of cirrhosis, age, sex
and HCV genotype. Efficacy was evaluated as the capacity to increase in
platelet counts until the end of the treatment period.
Results:
A total of 41 patients with HCV-associated thrombocytopenia
with PEG IFN/ribavirin treatment were studied: 26 patients (20 females, 6
males), mean age of 54.57± 8.40 yr who received danazol and 15 controls (9
females, 6 males), mean age of 55.8 ± 13 yr. Ninety percent of 41 patients had
cirrhosis and the HCV genotypes were similar between groups. The platelet count
increases in the Danazol group from baseline (75300 ± 11502) after treatment
(123,900 ± 30411 p=0.0063). Whereas in the control group the mean count range
from (238953.3 ± 141962.9 to 174200± 91643, p=0.9246) respectively. No association
between genotypes and thrombocytopenia was observed (P>0.05). Danazol safety
was assessed by the absence of collateral negative effects, except colestasis
reversible in two patients.
Conclusions:
·
Adjuvant
use of danazol is associated with increased platelets counts in patients on
antiviral therapy with interferon and rivabirin for HCV infection and
cirrhosis.
·
Although
the mechanisms of danazol’s action is unclear we
believe that maybe it involves impairment of macrophage-mediated clearance of
antibody-coated platelets via decreased Fc receptor expression like in
autoimmune thrombocytopenia.
·
This
is new therapeutic option to treat thrombocytopenia and maximize the sustained
virologic response.
Topic: Treatment – PEG-Intron
261. Relapse
rates among HCV Genotype 1 early
virological responders in a retrospective community-based cohort of patients treated with
PEGETRON® in
A. Yu; W. D. Hill; H. Mah; A. Mak; M. Krajden
PURPOSE:
Response profiles from a community-based cohort of HCV
genotype 1 infected patients undergoing a 48 wk course of Peginterferon alfa-2b
plus Ribavirin (PEGETRON®) in British Columbia were assessed for the impact of
residual viremia at wk 12 during Early Virological Response (EVR)
determination. End of Treatment (EOT) response, Sustained Virological Response
(SVR) and relapse rates were categorized with respect to whether a partial
virological response or early virological clearance was achieved at wk 12.
METHODS:
Databases maintained by BC PharmaCare and the British
Columbia Centre for Disease Control were used to calculate EOT, SVR and relapse
rates among genotype 1 patients whose wk 12 EVR result was reported between
RESULTS:
A total of 696 HCV genotype 1 patients underwent wk 12
testing during PEGETRON® treatment between
CONCLUSION:
·
Among
patients treated with PEGETRON® for 48 wks, EVR aviremic patients had an EOT
response rate of 90% and relapse rates of 10% to 32%.
·
In
contrast, EVR viremic patients had an EOT response rate of 32% and relapse
rates of 50% to 79%. The presence of residual viremia at wk 12 has an
unfavourable outcome with fixed duration therapy.
Topic: Treatment – PEG-Intron
G. Malizia; G. Giannuoli; E. Gallo; S. Madonia; E.
Aragona; O. Dino; G. Pietrosi; A. Rizzo; S. Patti; M. Vitale; P. Mondello; F.
Tinè
Background:
Treatment with pegylated interferon-a (PEG-IFN-a) and ribavirin
(RBV) induces sustained virologic response (SVR) in about 55% of patients with
chronic hepatitis C (HCV). Among several factors, HCV interference with IFN-a
signal transduction Jak-STAT pathway has been proposed as a possible
determinant of treatment failure. Viral kinetic studies have shown that early
viral response predicts SVR.
Aims:
To evaluate kinetics of STAT proteins in peripheral blood
mononuclear cells (PBMC) in comparison to viral kinetics and to assess whether
STAT kinetics may predict the outcome in HCV patients with low probability of
response.
Methods:
15 patients with HCV genotype 1 (n=12) or 4 (n=3) treated
with PEG-IFN-a 2b (1.5 mg/kg once weekly) plus RBV (1,000-1,200 mg daily) were
prospectively evaluated one hour before treatment (T0) and at days 1 (T1), 2
(T2), 7 (T7) and 14 (T14) for quantitative serum HCV-RNA and PBMC cytoplasmic
and nuclear STAT1 and STAT2. PBMC protein extracts were analyzed by Western
blot and EMSA.
Results:
Six patients (40%) achieved SVR, two (13.3%) were relapsers
and seven (46.7%) were virologic non responders (NR). HCV-RNA levels fell ≥1 log in many patients, mostly responders, at T1
and T2, with an intermediate increase at T7. At T14, only seven patients showed
a renewed ≥1 log HCV-RNA decline (5 SVR, 1 NR, 1 relapser). PBMC analysis
showed that STAT1-STAT2 nuclear translocation was restricted to the SVR
patients and one relapser with a proportion that progressively increased from
T1 to T14. Among the seven patients showing STAT1-STAT2 in the nucleus of PBMC
at T14, EMSA analysis showed both STAT2 and STAT1 DNA binding only in the six
SVR. Comparing early viral and STAT kinetics during the first two weeks, we
found that whereas the occurrence of a ≥1 log fall of HCV-RNA at T1 was
in most cases not associated to STAT1-STAT2 nuclear localization in PBMC, the
rate of this association increased through time, being highest at T14 (5 SVR,
one relapser). When we compared STAT kinetics at T14 and virologic response at
week 24, we found that among the eight HCV-RNA negative patients (six SVR and
both relapsers), only the six SVR showed also STAT1-STAT2 nuclear import and
DNA binding, whereas none of the seven HCV-RNA positive patients showed nuclear
STAT1-STAT2.
Conclusions:
Our data suggest that the variability of virological response
to treatment with PEG-IFN-a and RBV is associated with intrinsic differences in
the pattern of IFN signaling pathway and that STAT1-STAT2 nuclear translocation
and DNA binding in PBMC may predict SVR as early as two weeks after treatment
start.
Topic: Treatment – General
H. Hofer; J. Donnerer; K. Sator; K. Staufer; T.
Scherzer; C. Dejaco; M. Sator; J. Huber; H. Kessler; P. Ferenci
Background:
At present, combination therapy with pegylated
interferon-alpha and ribavirin is the treatment of choice for patients with
chronic hepatitis C (CHC). Due to the possible teratogenic effect of ribavirin
effective contraception is mandatory during antiviral therapy.
Aim:
Aim of the study was to evaluate seminal parameters,
ribavirin and HCV-RNA concentration in seminal fluid and serum prior to and
during antiviral treatment.
Patients and Methods:
So far, 10 male patients (mean age: 43±9 (years±SD) with CHC
who were treated with pegylated interferon-alpha-2a (Pegasys®,
Results:
HCV RNA was detectable in the seminal fluid of only one
patient prior to antiviral therapy (with a serum viral load of 4.04 MU/ml) and
was undetectable in all patients after 4 and 12 weeks of combination therapy.
Ribavirin concentration was substantially higher in the seminal fluid (week 4:
4.7±1.9 µg/ml, [mean±SD]; week 12: 4.3±0.4) than in serum (week 4: 2.2±0.3
[p=0.01]; week 12: 1.9±0.3 [p=0.02]). Morphological semen abnormalities were
common at baseline (asthenoteratozoospermia: n=4, asthenozoospermia: n=1,
teratozoospermia: n=3). Sperm density (BL: 70±31x106/ml, Week 4: 50±32, week 8:
59±43 [n.s.]), percentage of sperms with progressive motility (BL: 45±25%, Week
4: 30+28, week 8: 30+23 [n.s.]), and percentage of sperms with normal morphology
(BL: 21±14%, Week 4: 19±11, week 8: 11±6 [n.s.]) tended to further decrease
during antiviral therapy.
Conclusion:
·
HCV
RNA is detectable in seminal fluid only in a low proportion of CHC patients. In
contrast, pre-treatment semen abnormalities with reduced percentage of
spermatozoa with normal progressive motility and normal morphology are common
in patients with chronic HCV infection with further impairment during antiviral
therapy.
·
Ribavirin
concentration is twofold elevated in seminal fluid compared to serum levels,
which reinforces the need of contraception during antiviral combination
therapy.
Topic: Treatment – HIV/HCV Coinfection
A. Perrella; S. Grattacaso; M. Gnarini; C. Sbreglia;
L. Atripaldi; A. D'Antonio; O. Perrella
Objectives:
Pegylated recombinant Interferon plus ribavirin after HAART
induced immune system restoration is the treatment schedule in HIV/HCV patients
(pts). We aimed to evaluate the effect of Fosamprenavir on immune function in
naïve-drug coinfected patients before to start treatment with Interferon plus
ribavirin.
Methods:
We studied 10 naïve pts ( 4 F and 6 M) with HIV/HCV infection
with at least one year history of HCV persistent infection and treated with:
[(AZT 300mg + 3TC 300mg Twice) + (Fosamprenavir 700mg twice) + (RTV 100mg)],
assaying CD3+/CD4+, INF-γ and IL-4 ELISpot specific response (HCV-core peptides;
Pro-Immune,Oxford,UK), HIV and HCV Viral Load (Amplicor Roche system) and
Transaminasis before to start HAART treatment (T0) and every month. Sign Test
was used for statistic analysis.
Results:
At Time 0: CD4+ =186 ± 23 (mean ± s.d.); ALT= 121 ± 44; AST
=93 ±31; HCV-RNA = 569x103 ± 236x103 IU/mL; HIV-RNA =
90x103 ± 19x103 IU/mL, while Elispot was IFN-γ 62 ±
10 SFC and IL-4 93 ±12 Spot Forming Colonies (SFCs). At T1: CD4+ = 414± 63; HIV-RNA
= 209 ± 427 IU/mL but more surprisingly we had ALT = 22 ± 9; AST = 25 ±8;
HCV-RNA = 13x103 ± 30x103 IU/mL (two out of ten pts had
become negative at Viral load). Concerning ELISpot we had IFN-γ 112 ± 14
SFC and IL-4 = 52 ±16 SFCs. At T3: CD4+ 486 ± 48, with negative HIV and HCV
viral load and normal transaminasis serum levels. Differences were
statistically significant (p <.01).
Conclusion:
Fosamprenavir treatment in HAART schedule induces a decrease
of HIV-RNA with CD4+ increasing within the first month, but more interestingly
also a rapid HCV virological and biochemical response with a boost of Th1
immune network. Fosamprenavir treatment may be an important strategy in the
therapy of HIV/HCV naïve coinfected patients.
Topic: Treatment – General
B. Pearlman; C. Ehleben
Background:
For therapy-naïve, chronic hepatitis C- genotype 1-infected
patients, treatment with pegylated interferon and ribavirin for 48 weeks has
become the standard of care. For slow responders to treatment, there has been
interest in extending therapy duration in hopes of improving rates of sustained
virologic response (SVR). Two recent studies suggested that slow responders to
treatment enjoy improved SVR rates with 72 weeks of therapy compared to 48
weeks, because of a diminution in rates of relapse; however, both studies used
suboptimal doses of ribavirin (800 mg daily) (Gastroenterol 130:1086, 2006;
Gastroenterol 131:451, 2006). It is unclear if therapy prolongation in slow
responders would be beneficial, if weight-based ribavirin were utilized.
Methods:
We analyzed data from two studies in which slow responders
received either a customary treatment duration of 48
weeks or treatment extension to 72 weeks. One study was from the
Results:
Rates of SVR were significantly superior in slow responders
when treated for 72 weeks compared to 48 weeks, largely because of an
improvement in relapse rate (Table)
Conclusions:
·
Treatment
extension to 72 weeks relative to 48 improved SVR rates in slow-responders to
peginterferon and weight-based ribavirin, in two disparate patient populations.
·
SVR
was improved because of a decrement in relapse rate.
·
Results
should be confirmed in larger prospective trials.
|
|
Study Onea |
Study Twob,c |
|
Interferon type |
Peg alpha 2-b |
Peg alpha 2-a |
|
Ribavirin dose |
800-1,400 mg/day |
1,000-1,200 mg/day |
|
Study population |
100% genotype 1 |
>90% genotype 1 <10% genotype 4 |
|
Total sample size |
361 |
373 |
|
Slow responders analyzed (percentage total sample) |
101(28) |
41(11) |
|
SVR (48 weeks) |
18% (9/49) |
52% (13/25) |
|
SVR (72 weeks) |
38% (20/52) |
69% (11/16) |
|
Relapse rate (48 weeks) |
59% |
32% |
|
Relapse rate (72 weeks) |
20% |
18% |
*48% African American;
aHepatology, In-press,
2007; bAASLD 2006, abs #390; cEASL 2007, abs #641.
Topic: Treatment – General
G. J. Dore; M. E. Hellard; G. V. Matthews; P. S.
Haber; D. R. Shaw; B. Y. Yeung; K. Petoumenos; I. A. van Beek; G. W. McCaughan;
Y. Pan; R. A. Ffrench; W. D. Rawlinson; A. R. Lloyd; J. M. Kaldor
Introduction:
Short duration treatment for acute hepatitis C virus (HCV)
infection with pegylated interferon monotherapy has been shown to be highly
effective, but has been investigated to a very limited extent in injecting drug
users (IDUs), even though they are the population most at risk of infection in
many high-income countries. The Australian Trial in Acute Hepatitis C (ATAHC)
was funded by the US National Institutes of Health to examine the natural
history and treatment of recently acquired HCV in IDUs.
Methods:
A longitudinal cohort was defined by having a first positive
anti-HCV antibody test within 6 months of screening, plus either a negative
antibody test within the preceding 24 month period or acute clinical hepatitis
within the prior 12 months. Those in the cohort with detectable HCV RNA at
screening were assessed for treatment with PEG-IFN α-2a (180 mcg weekly
for 24 weeks), and follow up was undertaken in parallel protocols for both
treated and untreated participants. Treatment outcomes among the initial 50 HCV
monoinfected subjects commenced on treatment are presented on all subjects, and
separately on only those subjects with available HCV RNA assessment at week 24.
Results:
Since August 2004, 132 participants have been enrolled, with
85 (64%) commencing treatment, including 59 with HCV infection and 26 with
HIV/HCV co-infection. Of the initial 50 participants with HCV only who received
treatment (mean age 30 years, 66% male), 41 (82%) became infected via injecting
drug use. Fifty percent had HCV genotype
1, the median HCV RNA was 380,000 copies/ml, and 23 (46%) had symptomatic acute
infection. HCV treatment commenced a median 35 weeks (range, 18 – 81 weeks)
after the estimated date of infection.
In the initial 50 HCV monoinfected subjects undergoing
treatment, SVR rate was 56% by IIT. Poor
adherence (<80%) was seen in 34% of subjects. Factors associated with improved SVR were
treatment adherence (>80%) and absence of injection drug use during
treatment and post treatment follow-up.
Among 24 subjects with undetectable HCV RNA at week 24 and with week 48
assessment, one case of HCV RNArecurre3nce occurred and was consistent with
reinfection by HCV RNA sequencing.
Topic: Treatment – General
H. Ikeda; M. Suzuki; C. Okuse; M. Kobayashi; H.
Takahashi; N. Matsumoto; H. Yotsuyanagi; T. Yasuda; S. Iino; F. Itoh
Introduction:
It has been shown that 72 weeks (wks) of peginterferon plus
ribavirin combination therapy (PEG/R) for genotype 1 chronic hepatitis C (CHC)
patients, whose serum HCV RNA was positive at 4 wks of treatment increases
sustained viral response (SVR) rate. However, the prolongation of treatment
duration increases therapy discontinuation because of the decrease of
medication tolerability and the increase of medical expense. This result
suggests 72 wks of PEG/R is difficult for some patients to complete.
In this study, we focused on the patients with early viral
response. Since they represent about a half of patient population, an increase
of SVR rate of these patients should greatly affect the overall SVR rate. We
set short-term prolonged treatment durations of PEG/R for genotype 1b CHC
patients, depending on the time point when serum HCV RNA turned negative. And
its efficacy was evaluated.
Methods:
Total of 52 genotype 1b CHC patients (30 male, 22 female,
mean age 55±11years) were enrolled in this study from December 2004 to
September 2005. They were treated with peginterferon alpha 2b (1.0-1.5µg/kg/wk)
and ribavirin (600-1000mg/day) and serum HCV RNA levels were estimated every 4
wks. The viral response was defined and the treatment durations were determined
by the time point when serum HCV RNA turned negative. 1) 4 wks; rapid viral
response (RVR); 48wks duration, 2) 8 wks; early viral response (EVR); 52wks
duration, 3) 12 wks; EVR; 56 to 60 wks duration, 4) 16 to 24 wks; late viral
response (LVR); 72 wks duration. Patients with positive serum HCV RNA at 24 wks
finished treatment without prolongation of PEG/R. And we prospectively
investigated SVR rates of these groups.
Results:
Numbers of the patients achieved RVR, EVR and LVR were 4
(7.6%), 28 (53.2%) and 6 (11.5%), respectively. Only two patients (3.8%) could
not complete this treatment protocol. SVR rates of the RVR, EVR and LVR
patients were 100% (4/4), 78.6% (22/28) and 66.7% (4/6), respectively. The SVR
rate of these 3 groups was 78.9% (30/38). While 86.4% (19/22)
of male and 85.7% (6/7) of female under age of 55 achieved SVR, only 44.4%
(4/9) of female aged 55 or over achieved SVR.
Conclusion:
Our results suggest that the short-term prolonged treatment
duration of PEG/R determined by the time when serum HCV RNA turned negative is
a safe and effective treatment strategy for genotype 1b CHC patients. However,
this treatment is insufficient for female age 55 or over.
Topic: Treatment – Pegasys
V. I. Descalzi; S. E. Yantorno; S. M. Soria; F. M.
Cairo; N. Massenzio; J. E. Gonzalez; M. S. Munne; G. Picchio; F. G.
Villamil
O'Brien is a small rural town of
Goals:
to analyze results of combined
pegylated interferon α-2A (PEG) and ribavirin (RIB) therapy for 48 weeks
and to identify predictors of sustained virological response (SVR).
Methods:
the study included 32 patients (50%
males) aged 51±10 years. Viral load was investigated by Amplicor Monitor 2.0
and HCV RNA by RT-PCR. At baseline 21 patients (75%) had high VL (>800000
IU, mean 6.4±0.8 log IU) and only 9 (28%) elevated ALT. Liver biopsy showed
stage 0 in 2, I in 5, II in 12, III in 6 and IV (cirrhosis) in 5 patients by
METAVIR score. Patients received 180μg/week of PEG and 1000-1200 mg/day of
RIB according to body weight (> or <75 Kg).
Results:
Two patients discontinued therapy (weeks 2 and 8) due to
adverse effects and the remaining 30 completed 48 weeks. Dose reductions of PEG
were required in 5/30 (17%) patients and of RIB in 8/30 (27%). However, all
fulfilled the 80%/80%/80% rule at all time points of treatment. Thirteen
patients (43%) received G-CSF and 6 (20%) EPO. On an
intention-to-treat basis, virological responses were: 91% (29/32) at week 12
(EVR), 91% at week 24, 91% at week 48 (ETR) and 59%
(19/32) at week 72 (SVR). Predictors of SVR by univariate analysis were age
(48±2 vs. 56±2 years, p=0.039), significant alcohol (>80 grams in males and
>50 grams in females) consumption (10.5% vs. 45.5%, p=0.029), low fibrosis
stages (p=0.008) and cirrhosis (0% vs. 45.5%, p=0.001). Female gender (63% vs.
27%, p=0.058), lower BMI (25±1.5 vs. 29±1, p=0.08) and low VL (42% vs. 9%,
p=0.057) were more frequent among patients with SVR but the differences were
not significant. Fibrosis stage was the only independent predictor of SVR by
multivariate analysis (OR: 0.275, 95% CI: 0.101-0.752, p=0.012).
Conclusions:
1) Treatment with PEG-RIB of patients from O'Brien was
associated with a SVR of 59% despite that the majority had elevated VL (75%)and a significant proportion (34%) advanced disease with
fibrosis stages III or IV; 2) In this unique cohort of patients infected with
the same strain of HCV genotype 1b, histological severity was the only
independent predictor of SVR
This study was
supported in part by the Foundation for Research and Education in Liver
Diseases (FUNDIEH) and by Productos Roche SA
Topic: Treatment – PEG-Intron
272. Time to
HCV RNA Negativation in Hepatitis C Virus (HCV) Type 1-Infection During
PEG-Interferon-alpha-2B plus Ribavirin Therapy: Differences in Relation to the
Assay Sensitivity (Indiv-1 Study Group)
T. Berg; V. Weich; G. Teuber; H. Klinker; B. Möller;
J. Rasenack; H. Hinrichsen; T. Gerlach; U. Spengler; P. Buggisch; H. Balk; M.
Zankel; C. Sarrazin; S. Zeuzem
Introduction:
Exact determination of early virologic response has great
implication for designing a more refined treatment strategy in HCV infection.
To achieve this goal one needs accurate information regarding parameters which
govern the time to HCV RNA negativation. A disadvantage relies in the fact that
the available virologic tests differ in their sensitivity, i.e. they only give
an estimate whether viral replication is completely suppressed. In a
prospective study we therefore analysed the time to virologic response by
determining HCV RNA levels either by the quantitative bDNA or the highly
sensitive TMA test.
Methods:
433 patients received 1.5 ug/kg PEG-IFNa-2b
per week plus 800-1400mg RBV for at least 18-48 weeks. All patients were
examined by bDNA (detection limit 615 IU/mL) weekly until week 8 and at weeks
12, 24 and 48. bDNA-negative patietns were
additionally analysed by the TMA test (detection limit 5.3 IU/mL).
Results:
There is clear evidence that the frequency and time of
response observed during therapy was significantly lower when the HCV RNA
levels were calculated by the TMA assay. Thus a few clear answers can be given
from these data: 1. at week 12, 71% of the patients were negative by bDNA but
only 51% by TMA; 2. the average time necessary to induce HCV RNA negativity was
7.4 weeks for bDNA and 12.6 weeks for TMA (p< 0.05); 3. for
patients being already bDNA negative it still took 5.6 weeks (0-40) to also
become TMA negative. Forth: by bDNA testing, a steady increase of complete
virologic responses (<615 IU/mL) of around 10% per week (9-11%) was observed
within the first 4 weeks of therapy, but after the fourth week this phenomenon
became less pronounced. In contrast, as estimated by TMA, the HCV RNA
negativity rates remained constant within the first 12 weeks showing
frequencies of around 3.5-6.7% per week.
Conclusion:
The most important discrepancies between the two test systems
(bDNA vs TMA) with respect to frequency and rate of virologic response can be
observed within the first 12 weeks of therapy. At the end of treatment,
however, frequencies of undetectable HCV RNA levels did not differ greatly and
reached around 70% independently whether bDNA or TMA was used. From all these
data it emerges that there is a risk to overestimate virologic response rates
when HCV RNA levels are only assessed by the quantitative assay.
Topic: Treatment – Disease Progression
273. Impact
of antiviral therapy and response to treatment on long-term outcome of chronic
hepatitis C (CHC):a propensity
score analysis in a population-based cohort of 1159 patients
E. Monnet; J. Crouzet; A. Minello; T. Thévenot; A.
Gagnaire; V. Jooste; P. Hillon; V. Di Martino
Background:
The effect of antiviral therapy and sustained virological
response (SVR) on the long-term outcome of CHC has never been assessed through
population-based cohort study reflecting usual medical practice using clinical
endpoints. Concerns can be raised for clinical trials and observational studies
which suggested the clinical benefit of antiviral therapy regarding
representativeness of the studied population, follow-up duration, or selection
biases associated with treatment allocation.
Aim:
The aim of this study was to assess treatment and SVR effects
on the outcome of 1159 HCV monoinfected viremic patients recruited in a
well-defined population of 1,005,817 inhabitants, using the propensity score
technique to reduce bias in the comparison of non-randomized treatment groups.
Methods:
All HCV mono-infected viremic patients diagnosed in the study
area between 1994 and 2001 were included and followed for 4.9±2.6 years. 409
patients (35.2%) received antiviral therapy ((peg)-interferon-α ±
ribavirin), of whom 142 (34.7%) achieved SVR. The effects of antiviral therapy
and SVR on the risk of decompensated cirrhosis, hepatocellular carcinoma and
death (liver-related or not) were estimated separately by time-dependent Cox
regression analyses including a propensity score to adjust for observable
differences between treated and untreated patients and considering all the
demographic variables known to influence the natural history of CHC.
Results:
Treated and untreated patients were significantly different
for age, gender, place of residence, route of infection, self-reported
excessive alcohol consumption, and liver damage according to the Metavir score.
Using Kaplan-Meier estimates, the 5-year rates of decompensated cirrhosis and
of all-causes and liver-related deaths were 6.0%, 18.5% and 6.5% in untreated
patients, 2.6%, 4.9% and 2% in treated patients who did not achieve SVR, and
0.7%, 0% and 0% in treated patients who achieved SVR, respectively (p=0.019 and
p<0.0001 by log-rank tests). Propensity-adjusted multivariable Cox
regression failed to demonstrate a better outcome in patients who received
antiviral therapy, despite lower RR of cirrhosis decompensation (0.45) and
hepatocellular (0.29) and the 0% rate of death in patients who achieved SVR.
Interestingly, the risk of all-causes death was 0.48 for treated patients
without SVR (p=0.06).
Conclusion:
This population-based study suggests a benefit of antiviral
therapy on the long-term outcome of CHC. Using propensity-adjusted Cox
regression analysis, the complete demonstration should be given with a larger
studied population and/or a longer follow-up duration to increase the number of
events.
Topic: Treatment – General
G. Bortoletto; S. Realdon; F. Dal Pero; M. Gerotto; L.
Scribano; S. Boninsegna; D. Martines; A. Alberti
Background:
Insulin resistance (IR), a central feature of the metabolic
syndrome, has emerged as a key factor reducing the response to
Pegylated-Interferon (PEG-IFN) based therapy in chronic hepatitis C. The
pathogenic mechanisms underlying this association are still unclear.
Aim:
To examine the relationship of baseline serum insulin and of
homeostasis model of assessment insulin resistance (HOMA-IR) index with the
early virological response to PEG-IFN, taken as a measurement of the
intracellular response to Interferon (IFN) signaling.
Methods:
In 30 patients treated with weight-based doses of PEG-IFN
plus Ribavirin, baseline serum, insulin and HOMA-IR were measured the same day
of the first IFN injection. HCV-RNA levels were measured by RealTime PCR
(Abbott m2000, LoD 12 IU/mL) in all patients at baseline, as well as 24 hours
and at week 1, 4, 12 after treatment initiation to define the individual
kinetics of response.
Results:
Mean baseline insulin level was 13.38±7.21 mIU/L (range:
1.5-28) while, mean baseline HOMA-IR was 3.11±1.64 (range: 0.36-6.29). No
statistically significant association was found between baseline insulin levels
and baseline viremia or HCV-RNA decay at the different time-points during
therapy. On the other hand, when patients were stratified by baseline HOMA-IR,
those with high insulin resistance index showed a significant reduction in
virus decay already at 24 hours and thereafter compared to cases with lower
HOMA-IR (see Table).
By Kaplan-Meier analysis, patients with HOMA-IR>=4 had 0%
rate of HCV-RNA negativity during the first 12 weeks of treatment while, the
percentage of HCV-RNA negative cases among those with HOMA-IR<4 was 20% at
week 1, 40% at week 4 and 50% at week 12.
Baseline body weight and body mass index did not show a
significant association with virus decay.
|
|
HCV-RNA Log decay |
|||
|
HOMA-IR |
24 Hours |
Week 1 |
Week 4 |
Week 12 |
|
<3 |
1.11±0.52 p=0.04 |
0.44±0.61 p=0.12 |
1.68±1.84 p=0.12 |
3.29±2.46 p=0.05 |
|
|
|
|
|
|
|
>=3 |
0.55±0.71 |
0.14±0.43 |
0.71±0.70 |
2.34±2.36 |
|
<4 |
1.08±0.58 |
0.44±0.57 |
1.61±1.57 |
3.54±2.31 |
|
|
p=0.02 |
p=0.13 |
p=0.006 |
p=0.006 |
|
>=4 |
-0.05±0.35 |
-0.06±0.32 |
0.30±0.20 |
0.74±0.36 |
Conclusions:
We have demonstrated a direct effect of HOMA-IR on the early
response during PEG-IFN based therapy for chronic hepatitis C, independently of
insulin levels and BMI, suggesting that insulin resistance is the key factor in
reducing the cellular response to IFN in hepatitis C infected patients.
Topic: Treatment – Pegasys
E. Zehnter; S. Mauss; K. Boeker; T. Lutz; S. Racky; W.
Schmidt; R. Ullrich; I. Sbrijer; R. Heyne; A. Schober; C. John; K. Hey; B.
Möller; B. Bokemeyer; B. Kallinowski; S. Pape; U. Alshuth; D. Hüppe
Background:
HCV co-infection and related concomitant diseases, especially
of the liver, have become more important since antiretroviral therapy has
reduced morbidity and mortality associated with HIV. Clinical trials have
demonstrated that treatment with PEG and RBV can achieve high rates of SVR in
co-infected patients, but less is known about what happens in real life.
Methods:
The Association of German independent Gastroenterologists
(bng) in cooperation with Roche conducted an observational study. From March
2003 to May 2007 data from >20 000 patients were collected from >500
centers. Efficacy, safety and compliance data were recorded. An analysis for
naïve patients with HCV-mono (MONO) - or HCV/HIV coinfection (CO) who have been treated with PEG and RBV, was performed.
Due to the ongoing
character of the study, the status of data was frozen on
Results:
·
Between
March 2003 and May 2007 data from more than 20,000 patients have been
documented.
·
A
total of 13,596 treatment naïve patient screensings have been completed and
4,063 of these patients (29.9%) have been treated with peginterferon alfa-2a
(40KD).
·
679
patients (5.0%) of the cohort had a HCV/HIV coinfection.
·
Of
them 156 (23.0%) received a complete treatment with peginterferon alfa-2a
(40KD), in almost all cases plus ribavirin, whereas HCV patients without HIV
were treated in 30.2% of the patients (N=3907/12917).
·
Demographic
data of treated patients with HCV/HIV coinfection were: mean age 39.0
years. 76.9% of patients were male, the mean BMI was 23.3 kg/m2.
·
Genotypes
(HCV/HIV coinfection /HCV without HIV) for patients with HCV therapy: Genotype 1 (59.0% / 58.3%), genotype 2/3
(34.6%/38.6%) and genotype
Treatment
·
The
mean duration of HCV treatment for patients with genotype 1 was 34.3 weeks in
patients with HCV/HIV coinfection vs. 38.3 weeks for HCV patients without HIV
coinfection. For genotype 2/3-patients
the mean treatment durations were 31.9/24.0 weeks, respectively.
·
Discontinuations: A total of 66.156 patients with HCV/HIV
coinfection and 1062/3906 HCV patients without HIV coinfection (42.3%/27.2%)
have discontinued therapy: 37.9%/39.5%
due to virological non-response, 27.3/26.4% for poor tolerability, 13.6%/16.4%
were lost to follow-up, 15.2%/10.8% for personal reasons and 12.1%/9.4% for
lack of compliance.
Virological Response
·
Sustained
Virological Response (SVR): Complete
treatment data is available for 156 patients with HCV/HIV coinfection and 3906
HCV patients without HIV coinfection, who were treated according to consensus
recommendations. An SVR was achieved by
61/156 with HCV/HIV coinfection (39.1%) and 2104/3906 HCV patients without HIV
coinfection (53.9%).
Conclusion:
·
Although
HIV co-infection is a serious and hepatitis-accelerating disease only a third
of CO patients had been treated with PEG and RBV.
·
Although
patients with HCV/HIV coinfection urgently need HCV treatment, 40% of these
patients cannot be convinced of the indication.
The most frequent reasons for declining HCV treatment are fear of
therapy and missing understanding of the urgency of the therapy.
·
In this population, combination therapy was
found to be reasonable safe and sufficiently effective even under real-life
conditions.
·
A
challenge will be to convince co-infected patients of the need for therapy,
whilst minimizing the discontinuation rate and hence the extension of treatment
duration.
|
Characteristics of Treatment patients |
Co-infected (N=156) |
Mono-infected (N=3907) |
|
Age (mean yrs) Male (%) BMI (kg/m2) Duration of HCV (mean yrs) |
39.0 76.9 23.3 8.0 |
42.2 59.7 25.0 12.0 |
|
Genotype (%) G1 G2/3 Other |
59 38.6 3.1 |
58.3 34.6 6.4 |
|
SVR (%) |
39.1 |
53.8 |
Topic: Treatment – General
S. Mauss; D. Hüppe; E. Zehnter; M. Manns; G. Teuber;
T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern;
S. Kaiser; R. Prinzing; . The bng hepatitis study group
Objective:
The sustained viral response (SVR) in HCV-genotype 3 patients
differs substantially depending on baseline viral load and viral response to
therapy. Whereas patients with rapid viral response and low viral load show SVR
rates >80%, patients with high viral load and no rapid viral response may
reach SVR <50% after 24 weeks of therapy. These patients may be candidates
for longer treatment durations. Here we report SVR data from a cohort of 3547
patients including 1148 patients with HCV-genotype 3 treated for 24 vs. 48
weeks with peginterferon and ribavirin.
Methods:
All patients were treated with at least one dose of
peginterferon alfa-2b and weight based ribavirin as part of a German
multicentre cohort. Only patients who were beyond 24 weeks of follow up after
planned end of therapy (24 or 48 weeks) were included in this analysis (n=571).
Patients were stratified according to HCV-RNA below or above/equal to 600.000
IU/mL. Patients with missing data at end of follow up were counted as treatment
failures. Statistical analysis was performed using chi-square test.
Results:
157/207 (76%) of patients with genotype 3 and HCV-RNA
<600.000 IU/mL reached SVR after 24 weeks of therapy versus 82/115 (72%) after
48 weeks of therapy (p>0.05, n.s.). 123/160 (77%) of patients with genotype
3 and HCV-RNA >600.000 IU/mL reached SVR after 24 weeks of therapy versus
66/89 (74%) after 48 weeks of therapy (p>0.05, n.s.).
Conclusion:
Extending therapy from 24 weeks to 48 weeks for HCV-genotype
3 did not improve SVR rates regardless of baseline viral load. These results
confirm findings from the initial prospective, controlled study by Hadziyannis
et al. Ann Intern Med. 2004; 140(5):346-55. In addition SVR was comparable for
patients with low and high viral load. However it can not be excluded from this
study that a more targeted approach based on viral kinetics, i.e. slow viral
response, may be beneficial for a smaller subgroup of patients.
Topic: Treatment – PEG-Intron
279.
Treatment of Hemodialysis (HD) Patients With Chronic
Hepatitis C (CHC) Using an Escalating Dose Regimen of Pegylated Interferon
(PEG-IFN) alfa-2b
S. Tan; M. Abu Hassan; A. Abdullah; B. Ooi; S. Rampal;
T. Korompis; M. Merican
Background:
CHC is a prevalent condition among patients receiving HD, and
post-renal transplant CHC patients have poorer treatment-related outcomes.
Additionally, treatment with IFN therapy has been associated with graft
rejection. In this study, we evaluated the efficacy and safety of PEG-IFN
alfa-2b in CHC patients receiving HD.
Methods:
This study included treatment-naive CHC patients aged 18-70
years with compensated liver cirrhosis and adequate hematologic parameters.
Patients with coinfection, significant cardiovascular dysfunction, uncontrolled
diabetes, and any contraindications to IFN therapy were excluded. Of the 46 CHC
patients undergoing HD who were screened, 34 enrolled in the study. All
patients received PEG-IFN alfa-2b 0.5μg/kg/wk; doses were increased by
0.25μg/kg/wk every 4 wks if well tolerated. Maximum dose was defined as
1μg/kg/wk at 48 wks in patients with genotype (G) 1 and 24 wks in those
with G2/3. Patients unable to tolerate study medication were discontinued from
the trial.
Results:
Baseline patient characteristics included mean age of
41.4±11.9 years (61.8% ≥40 years); males, 44.1%; G1, 70.6%; G3, 29.4%;
mean body mass index, 22.6±4.4 kg/m2; median HD duration, 5.8 years
(range, 3.8-8.2 years); normal alanine aminotransferase (ALT) levels, 55.9%;
HCV RNA ≥700,000 IU/mL, 50%; and fibrosis ≥2 (modified Histology
Activity Index score), 26.5%. In total, 97% (33/34) of patients reached maximum
dose; however, 21% were unable to maintain that dose. Early virologic response
(EVR; undetectable HCV RNA [<50 IU/mL] at wk 12) was attained in 15 of 20 G1
patients; end-of-treatment (EOT) and sustained virologic responses (SVRs) were
attained in 10 of 15 and 9 of 18 G1 patients, respectively. Conversely, 8 of 10
G3 patients attained EVR, and EOT and SVRs were attained in 8/9 and 8/10 G3
patients, respectively. Almost 30% (11/34) of patients discontinued treatment
early because of adverse events (AE). The most commonly reported AE was anemia;
64.7% of patients required blood transfusions. Low-dose epoetin was administered
to 85.3% of patients during the trial. One patient died during the study of
acute coronary syndrome after the 41st dose.
Conclusions:
In total, SVRs were attained in 37.5% (9/24) of G1 patients
undergoing HD who were treated for 48 wks with an escalating dose regimen of
PEG-IFN alfa-2b monotherapy. In contrast, 80% (8/10) of G3 patients, who
received only 24 wks of this therapy, attained SVR. These results indicate that
G3 patients undergoing HD can be successfully treated with short-term PEG-IFN
alfa-2b monotherapy. Because PEG-IFN alfa-2b can be associated with AEs,
supportive therapy may be necessary.
Topic: Treatment – General
281.
Real-life Rates of Treatment Completion for HCV
A. A. Butt; M. Skanderson; K. A. McGinnis; C. K. Kwoh;
A. C. Justice
Background:
Rates and factors predicting treatment completion for HCV
infection in real-life settings are unknown.
Methods:
We assembled a national cohort of HCV-infected veterans from 1998-2003,
using the VA National Patient Care Database for demographic and clinical
information, Pharmacy Benefits Management database for pharmacy records and the
Decision Support Systems database for laboratory data. We studied the rates and
factors predicting treatment completion for HCV.
Results:
For the 134,934 veterans with at least 1 inpatient or 2
outpatient codes, 16,043(11.9%) were prescribed treatment. Among the 10,641
veterans with > 1 year of follow-up, 22.5% completed a 48 week course of treatment.
Non-completers were more likely to be black, have pre-treatment anemia,
coronary artery disease, depression and more aggregate comorbidities. In
multivariable analyses, non-completion was associated with baseline anemia (OR
0.66, 95%CI 0.56-0.78 for hemoglobin 10-14mg/dl) and depression (OR 0.78, 95%CI
0.69-0.89). Pegylated interferon was associated with higher rates of treatment
completion. HIV-coinfection did not affect completion rates.
Conclusions:
A minority of HCV-infected persons are prescribed treatment
and less than one-quarter complete a 48-week course. Anemia and depression are
potentially modifiable factors that must be addressed at a population level
before universal use of pharmacotherapy is advocated.
Baseline
characteristics of HCV infected persons who completed a 48 course of treatment
for HCV, and a flow sheet of analysis for the current study
Note: complete
lab data was available for 6,838 in ‘At least one year of follow-up.’ Complete lab data was available in 5,854 in
‘At least one year of follow-up’ data.
Topic: Treatment – Predictors of
Treatment Response
A. Iacobellis; B. Annicchiarico; M. Siciliano; G.
Niro; L. Accadia; N. Caruso; G. Bombardieri; A. Andriulli
Background:
Recent studies provided positive data on the impact of HCV
clearance by antiviral therapy in improving hepatic function in decompensated
cirrhosis. However, low tolerability of therapy and the risk for severe
infections render useful to single out those patients with a higher likelihood
of achieving a sustained virological response (SVR).
Aim:
to determine whether in decompensated
cirrhotics naïve to previous combined antiviral therapy RVR could predict SVR.
Methods: 104 cirrhotics underwent treatment with peginterferon alfa-2b (1.5 mcg/kg/wk) and ribavirin (800 or 1000 mg) for 24 weeks.
Patients:
mean age was 62 +/- 7 yrs; 63% of
patients were infected by geno 1/4; and 96% were staged in Child-Pough class B.
Results: SVR was achieved in 29 patients (28%), overall; 10 of them (15%) with
genotype 1 or 4, and 19 (48,7%) with genotype 2 and 3 (P < 0.01).
On-treatment viral clearances, according to HCV genotypes, are given in the
table. At treatment week 4, 36 patients cleared HCV (RVR), and 23 of them
achieved SVR (63,8%) at a significant difference
between genotypes: 9 of 18 genotype 1 and 4 patients (50%), and 14 of 18
genotypes 2 and 3 (78%; P < 0.01). All RVR patients who achieved SVR had a
pre-treatment viral load < 350.000 copies/mL.
Conclusion:
Decompensated patients with HCV-related liver cirrhosis
achieve on-treatment viral clearance at different time. Achieving the RVR
status may guide tailoring length of treatment. Two-thirds of patients infected
by genotypes 2 and 3 may achieve SVR with a treatment length as short as 24
weeks, provided they clear HCV at treatment week 4. In non-RVR patients with
the latter genotypes and in those infected by genotypes 1 and 4, the adopted duration of therapy appears insufficient to
attain optimal SVR rates. The present study further supports the feasibility of
antiviral treatment with Peg-interferon alfa-2b and ribavirin in Child-Pugh
class B cirrhotics.
Topic: Treatment – Predictors of
Treatment Response
284. Iron
Depletion and Response to Interferon in Chronic Hepatitis C (HCV)
: A Meta-Analysis
R. r. Mummadi; K. S. Kasturi; G. Sood
Background and Aim:
Hepatic iron content is known to influence the response to
interferon (IFN) in chronic Hepatitis C (HCV) patients. Several studies have
reported effect of Iron depletion on response to IFN in HCV. These studies are
heterogeneous in design and outcome measures. We performed a meta-analysis of
available studies (1995 through May 2007).
Methods:
Electronic database Medline, CINHAL and Science Citation
index were searched. RCTS comparing Interferon treatment (IFN) with Interferon
and Phlebotomy (IFN and Phlebotomy) were chosen for the meta-analysis.
Sustained Virologic Response (SVR) was the primary out come. Sustained
biochemical response (biochemical SR) and end of treatment Virologic response
(ETR) were also analyzed. Data was pooled using Fixed
effects (Peto odds Ratio) and Random effects (DerSimonian-Laird) method.
Results:
A total of 231 studies were identified among which 52 studies
were selected and reviewed.The studies with known causes of iron overload ( Hemochromatosis, alcohol abuse, Porphyria cutanea tarda or
transfusion related overload )were excluded. There were fifteen published
studies evaluating effect of IFN with phlebotomy as an adjuvant therapy. The
data was extracted from 5 studies (N=334) which met the inclusion criteria
(RCTS). IFN with phlebotomy compared with IFN alone increased the probability
of achieving SVR (Peto OR= 2.43 95 % CI 1.41-4.16)Virologic
ETR (Peto OR=2.34 95%CI 1.48-3.70), and biochemical SR (Peto OR = 2.02 95% CI =
1.22-3.33).There was no significant heterogeneity among the studies included in
meta-analysis. Sensitivity analysis excluding study with previous treatment
failures did not impact the resuts. None of these studies were done using
Pegylated IFN or ribavirin as treatment options.
Conclusions:
·
Phlebotomy
increased the probability of achieving SVR, Virologic ETR, biochemical SR in
patients with chronic hepatitis C.
·
A
RCT to assess the influence of phlebotomy on treatment with Pegylated IFN and
Ribavirin is needed.
Topic: Treatment – Pegasys
M. Bourliere; D. Ouzan; M. Rosenheim ; M. Doffoel; P. Marcellin;
J. Pawlotsky; L. Salomon; F. Fagnani; C. Hayem; I. Lonjon-Domanec; M. Vray
Objectives:
Previous studies conducted in
Methods:
Between November 2003 and December 2004, 324 physicians
recruited chronic hepatitis C patients treated with peginterferon alfa-2a
(40KD). Patient demography and liver histology assessment were recorded at
baseline and treatment and compliance were recorded every 3 months. Efficacy
outcome was evaluated with qualitative PCR more than 3 months after the end of
treatment.
Results:
Among the 2101 patients analyzed, 62% were male, the mean age
was 47±12 years, the mean body weight was 71±14 kg and 17% had cirrhosis.
Distribution of genotypes: GT1 53%, GT2 12%, GT3 25%, GT4 8%, GT5 2%. The
majority of the patients in the cohort were HCV treatment naïve (70%). Liver
biopsy and fibrosis markers were performed in 69% and 35% of the patients
respectively but the relative proportions changed during the conduct of the
study in favour of evaluating fibrosis markers. GT1 patients were biopsied more
often than GT2 and 3 patients (77% and 56% respectively). The overall SVR rate
was 57% (783/1377) in all patients and 63% (596/949) in naïve patients. Among
naïve patients, SVR rate was 52% in GT1 (227/438), 80% in GT2 (115/144), 74% in
GT3 (194/262), 55% in GT4 (42/76) and 59% in GT5 (10/17). Age below 40 years
(p<0.001; odds ratio (OR) [95% confidence interval (CI)] = 2.4 [1.7-3.2],
genotype 2 and 3 (p<0.001; OR [95% CI] = 2.7 [2.0-3.5], fibrosis less than
F2 (p<0.001; OR [95% CI] = 1.7 [1.3-2.2], and naïve status (p<0.001; OR
[95% CI] = 3.2 [2.2-4.6], were found to be independently associated with a
higher response rate in multivariate analysis.
Conclusions:
This large study confirmed the efficacy of peginterferon
alfa-2a plus ribavirin in the French clinical practice setting compared to
randomized controlled clinical trials*. The increasing role of fibrosis markers
rather than liver biopsy in the management of hepatitis C patient in
*Fried NEJM 2002;
Hadziyannis Annals 2004
Topic: Treatment – Predictors of
Treatment Response
C. E. Gordon; K. Uhlig; J. Lau; C. H. Schmid; A. S.
Levey; J. B. Wong
Background
Hepatitis C virus (HCV) infection has a prevalence of 13% in
hemodialysis (HD) patients and increases mortality. Interferon (IFN) and
pegylated-interferon (PEG-IFN) may eradicate HCV infection. We studied
predictors of sustained virological response rate (SVR) to IFN in HD patients
with HCV.
Methods
After performing a systematic review of IFN and PEG-IFN
treatment in HCV-infected HD patients published between 1966 and December 2006,
we extracted individual patient data (IPD) from included articles and acquired
additional data by contacting study authors. We used univariate and
multivariate logistic regression to identify predictors of SVR.
Results
Twenty studies of IFN monotherapy with 461 patients met
inclusion criteria and provided IPD for 428 patients. Three studies of PEG-IFN
involved 38 patients but did not supply IPD. The overall SVR was 41% (95% CI,
33-49%) with IFN and 37% (9-77%) with pegylated-IFN (PEG-IFN). Factors
associated with statistically significantly higher SVR with IFN using IPD
included: 3 MU or higher dose three times weekly (OR 3.3, 1.2-9.1), intended
treatment duration of at least six months (2.0, 1.1-3.9), treatment completion
(4.1, 2.4-6.8), lower HCV RNA at baseline (3.6, 1.9-6.7 per log10 lower RNA),
and female gender (2.1, 1.3-3.4). Early virological response (EVR), measured as
HCV RNA negativity 1-3 months into treatment, was also associated with
significantly higher SVR (5.1, 2.6-10.0). HCV genotype 1 and cirrhosis were not
associated with SVR. Despite limitations involving missing and clustered data,
multivariate analysis documented independent associations of SVR with dose,
duration, treatment completion, HCV RNA, and female gender.
Conclusions
HCV treatment in HD patients resulted in an overall SVR of
41% with IFN and 37% with PEG-IFN. SVR is higher in women, with low baseline
HCV RNA, or with early virological response, and with IFN antiviral therapy at
3 MU for at least 6 months and completion of intended treatment duration.
Topic: Treatment – General
V. Weich; B. Schlosser; J. Halangk; A. Bergk; F. van
Bömmel; T. Berg
Introduction:
Lipoproteins have been reported to be involved in the
infection cycle of hepatitis C virus. Former studies from
Aim:
The aim of the present observational study was to assess the
efficacy and safety of bezafibrate monotherapy in patients with advanced
chronic hepatitis C who failed previous combination therapy with
(peg)-interferon alpha and ribavirin.
Patients and Methods:
36 patients from our university hospital (mean age 61 years,
HCV type 1 [n=34], HCV type 3 [n=1],HCV type 4 [n=1],
stage 2 = 4 patients, stage 3 = 14 patients, advanced fibrosis [n=18]) received
daily oral bezafibrate treatment (400 mg per day) on the basis of a prospective
observational open-label study design. Clinical, biochemical and virological
data were evaluated during a mean treatment duration
of 12 months (range 2-49 months).
Results:
Three patients dropped out of the study complaining about
vertigo or palpitations within the first days of treatment. In the remaining 33
patients no significant adverse events were observed. During the treatment
course, a significant improvement in gamma-glutamyl transpeptidase levels
(p<0.0001) as well as alanine aminotransferase levels (p<0.001) could be
demonstrated in all patients. In 3 patients liver enzymes normalized
completely. No significant effect on viral load was observed. Only one patient showed viral decline of 1
log after 11 months of treatment.
Conclusion:
·
This
observational study provides evidence that bezafibrate is effective for patients
with chronic hepatitis C by reducing significantly ALT and GGT levels and could
be therefore a therapeutic option, especially for those, in whom peg-interferon
combination treatment was previously unsuccessful.
·
Further
larger and randomized clinical trials including also histological endpoints are
required to confirm these findings.
Topic: Treatment – General
293. Early
reduction of Ribavirin leads to retardation of viral clearance and affects SVR
Y. Karino; J. Toyota; T. Arakawa; Y. Kuwata; J.
Akaike; K. Yamazaki; T. Sato; T. Omura; S. Iino
Background:
It is said a reduction of ribavirin (RBV) will not impact the
SVR rate, but no examination has included the effect of the timing of the
reduction of RBV while it is known that the timing of HCV RNA loss strongly
relates to the SVR rate.
Aim:
To review the antiviral activity of
RBV from the effect of the timing of reduction of RBV on the timing of HCV RNA
loss.
Methods:
One hundred and twenty-four patients with genotype 1b and
high viral load (62 males, 62 females; mean age 55.9 years old) who received
PEG IFNα-2b plus RBV combination therapy for 48 weeks were included in
analysis. All patients received RBV by a total clearance of RBV (CL/F)-based
dose (we set 2250ng/ml as target blood concentration and calculated the dose of
RBV from CL/F, 2005AASLD). The dose of PEG IFNα-2b of 1.5μg/kg/week
was not reduced for the duration of administration. We determined the factors
affecting the timing of HCV RNA loss in patients for whom RBV was not reduced
(group A) by multiple regression analysis and prepared of a predictive formula.
Appling this predictive formula to patients in whom RBV was reduced, we
examined whether the timing of RBV reduction affects the timing of HCV RNA
loss.
Results:
Predictive formula based on multiple regression analysis was:
Estimated time of HCV RNA loss (week) = 1.8960 x Log HCV RNA (2W) + 8.5722,
where HCV RNA (2W) is HCV RNA level (KIU/ml) 2 weeks after the start of
treatment. This predictive formula allowed the good prediction of the actual
timing of HCV loss. When applied to patients with RBV reduced after 8 weeks of
treatment (group B) and in the first 8 weeks of treatment (group C), the fit
was 100% (group B) and 69% (group C) that of the actual timing of HCV RNA loss
with less than +/-4 weeks of predicted. With patients showing greater than +/-4
weeks difference between predicted and actual timing of HCV RNA loss (group C),
the actual timing was delayed from the predicted time. In other words, delay in
HCV RNA loss was statistically significant compared to without RBV reduction in
patients with early RBV reduction. SVR rate with group A, B, and C was 60%,
62.5%, and 38.5%, respectively, and reflected the difference in the timing of
HCV RNA loss.
Conclusions:
·
We
reviewed patients with genotype 1 and high viral load with and without RBV dose
reduction and correlation with the timing of HCV loss.
·
Because
HCV RNA loss was delayed in patients for whom RBV was reduced early in
treatment, it was thought that antiviral activity of RBV was expressed from a
relatively early stage in IFN + RBV combination therapy.
·
A
method of administration to avoid reducing RBV is important to improve the SVR
rate.
Topic: Treatment – IDU
295.
Treatment Uptake and Outcomes Among Current and
Former Injection Drug Users (IDUs) Receiving Directly Observed Therapy Within a
Multidisciplinary Group Model for the Treatment of Hepatitis C Virus (HCV)
Infection
K. Genoway; J. Grebely; F. Duncan; M. Viljoen; L. Gallagher;
D. Elliott; M. Khara; J. D. Raffa; S. deVlaming; B. Conway
Purpose:
We evaluated HCV treatment uptake and outcomes among current
and former IDUs attending a weekly peer-support group and receiving directly
observed HCV therapy (DOT).
Methods:
Beginning in March 2005, patients interested in receiving
treatment for HCV infection were referred to a weekly peer-support group and
evaluated for treatment. Utilizing the existing infrastructure for addiction
disease management, we have developed a model whereby the treatment of
addiction, HCV and other medical conditions are integrated under the DOT model
of care. Patients received directly observed therapy with pegylated interferon
alpha 2a or alpha 2b (PEG-IFN alpha 2a or alpha 2b), both in combination with
self-administered ribavirin (RBV).
Results:
Overall, 129 subjects were referred to the support group over
a period of 108 weeks, with the mean attendance being 15 subjects per week
(range 3-32). Overall, 10 (8%) did not medically qualify for treatment, 39
(30%) were lost to follow-up and 8 (6%) had completed or initiated treatment
for HCV infection prior to attending the group. We observed a high uptake of
HCV treatment among attendees, with 30% of subjects (39/129) currently under
evaluation and 26% (33/129) having initiated or completed treatment for HCV
infection. In a comparison of subjects that had initiated or completed
treatment for HCV infection (n=33) and those lost to follow up (n=39), those
having received treatment for HCV infection had a higher median attendance [34
meetings (Interquartile range, IQR = 11-33) vs. 2 meetings (IQR=1-3,
P<0.001)] and were more likely to attend >3 clinic visits (97% vs. 23%,
P<0.001) than those lost to follow up. To date, 31 patients (PEG-IFN alpha
2a/RBV = 15; PEG-IFN alpha 2b/RBV = 4) have initiated treatment for HCV
infection at our site and 18 have completed therapy, with 67% (12/18) of
subjects achieving an end of treatment response (Genotype 1 – 40%, Genotypes 2-
100%, Genotype 3 – 67%), despite ongoing drug use in 72% of patients during
treatment and early discontinuation in 56%.
Conclusion:
·
These
data demonstrate that with the appropriate programs in place, a high uptake of
HCV treatment can be achieved among IDUs referred to a peer-support group.
·
Depression
was a major cause of discontinuation, despite prophylactric antidepressant use
in 78%.
·
Moreover,
the treatment of HCV in current and former IDUs within a multidisciplinary DOT
program can be successfully undertaken, resulting in end of treatment responses
similar to those reported in randomized controlled trials.
Topic: Treatment – IDU
J. Grebely; J. D. Raffa; K. Genoway; G. Showler; F.
Duncan; M. Viljoen; M. Khara; S. deVlaming; C. Fraser; B. Conway
Purpose:
To evaluate HCV re-infection following SVR among IDUs having
received directly observed IFN alpha-2b or PEG-IFN alpha-2a/b in combination
with self-administered ribavirin in a directly observed therapy program.
Methods:
Viremic HCV-infected IDUs, with ALT >1.5x ULN, received 24
or 48 week therapy (based on HCV genotype) with ribavirin and interferon
alpha-2b, replaced by PEG-interferon alpha-2a/2b. Following treatment, subjects
were encouraged to return to the clinic at follow-up intervals of ~1 year and
were asked about their use of illicit drugs. HCV RNA testing by PCR was
performed and positive results were genotyped.
Results:
Overall, 28/51 subjects (55%) receiving IFN alfa-2b (n=12),
PEG-IFN alpha-2b (n=32) or PEG-IFN alpha-2a (n=7) achieved an SVR. Illicit
drugs were used by 21/51 (41%) in the 6 months preceding therapy and by 29/51
(57%) during treatment. In total, 28 subjects were followed for a mean of 1.1
years (range, 0-3.2 years) following SVR. In this period, 13/28 (46%) reported
using illicit drugs:
o
Illicit
drug use post-SVR (%) – 13 (46)
o
Injection
drug use post-SVR (%)
o
Injection
cocaine – 3 (11%)
o
Injection
heroin – 3 (11%)
o
Combined
injection drug – 5 (18%)
o
Eleven
subjects (39%) reported injection drug use.
o
Overall, 25/28 (89%) remained HCV RNA negative, 1 died of
hepatocellular carcinoma, 1 was lost to follow-up and 1 was positive for HCV
RNA. This subject received 17 weeks of PEG-IFN alpha-2b therapy and had viral
reoccurrence with the same genotype (G1), consistent with re-infection or viral
relapse. Therefore, viremia re-occurred in 1/28 (3.6%), providing an estimated
rate of re-occurrence of 4.0 cases per 100 person-years.
Conclusions:
o
Overall,
55% of current and former illicit drug users obtained an SVR.
o
Occurrence
of HCV viremia was 3.6% (2.6 cases/100 person-years).
o
This
is despite relapse to injection drug use in 46% of subjects.
o
Study
is limited given that no longitudinal data on equipment sharing available.
o
IDUs
with treatment-induced clearance may be protected from HCV re-infection either
through:
o
reduced
risk behaviors for acquisition; or
o
partial
protective immunity following successful treatment and enhanced clearance after
reexposure
o
These
data need to be confirmed in larger, prospective studies designed to evaluate
HCV reinfection in IDUs following treatment induced viremia.
Topic: Treatment – PEG-Intron
M. Korenaga; K. Korenaga; K. Uchida; T. Yamasaki; K.
Hino; I. Sakaida
Background:
Hepatitis C Virus (HCV) infection is linked to insulin
resistance which may contribute to fibrogenesis and carcinogenesis in chronic
hepatitis C. Glucose intolerance setting of chronic HCV infection could be
related etiologically to viral factors. However, IFN has been reported to
acutely induce insulin resistance and glucose intolerance. Although HCV is a
candidate for the development of insulin resistance, the effects of antiviral
treatment on impaired glucose metabolism remain unclear. The aim of this study
was to clarify whether insulin resistance was improved on Pegylated Interferon
alfa-2b Plus Ribavirin (PegIFN/RBV).
Methods:
Plasma glucose (PG) level and immunoreactive insulin (IRI)
level in the course of 75g oral glucose tolerance test (OGTT) were measured to
evaluate glucose intolerance in 0, 4 and 12 weeks after initial PegIFN/RBV. The
OGTT was performed after an overnight fast, and blood samples were taken at 0,
30, 60, 90 and 120 min following glucose ingestion. Then PG area under the
curve (AUC-G), IRI area under the curve (AUC-I) and HOMA-IR were calculated.
Simultaneously, oxidation rate of carbohydrate (%CHO), fat (%FAT) and nonprotein
respiratory quotient (npRQ) were calculated by using an indirect calorimeter.
Results:
We examined 25 biopsy-proven patients who received
PegIFN/RBV. Twelve patients (48%) were found to have diabetes while five (20%)
showed impaired glucose tolerance (IGT) at the pretreatment according to OGTT
as based on the revised diagnostic criteria of the American Diabetes
Association (1997). In the patients of diabetes and IGT (n=17), the AUC-G was
significantly decreasing (0w: 582±33 4w: 453±22: p<0.05) at week 4.Although
HOMA-IR did not change at week 12 (0w: 2.4±0.3, 12w: 2.3±0.5), the AUC-I was
decreased (0w: 212±25, 12w: 158±20: p<0.05). The %CHO increased (0w: 40±4,
12w: 50±6) and %FAT decreased (0w: 47±4 12w: 36±5), as a result, npRQ increased
(0w: 0.837±0.015, 12w 0.871±0.017: p<0.05) at week 12. No one shows severe
weight loss (5% down at pretreatment) and patients with normal glucose
tolerance did not change by week 12. Finally, patients with glucose intolerance
were divided into two groups by IFN response: Eleven were under detectable in
HCVRNA at week 12 as an EVR group and six were non EVR group. The AUC-G and
AUC-I were reduced by 35% (p<0.05) in EVR. However, the AUC-I did not change
in nonEVR, although the AUC-G was decreased by 17%.
Conclusions:
Insulin resistance and energy metabolism improved by the
administration of PegIFN/RBV, which had strongest effect against HCV. The
effects of rapid viral reduction might be important for restoring of glucose
tolerance in chronic hepatitis C.
Topic: Treatment – Predictors of
Treatment Response
T. Mizuta; Y. Eguchi; Y. Kawaguchi; K. Ario; H.
Takahashi; S. Iwane; N. Oza; I. Ozaki
Aim:
Recent studies have indicated that insulin resistance (IR)
might be an important factor associated with the virologic response to interferon
treatment for chronic hepatitis C, but little is known about its mechanism. IR
consists of hepatic IR (central IR) and muscle IR (peripheral IR). We analyzed
the effect of hepatic and whole-body (hepatic + muscle) IR on the efficacy of
peginterferon plus ribavirin treatment.
Methods:
Forty-three chronic hepatitis C patients with genotype 1b and
high viral load treated with peginterferon alpha-2b plus ribavirin for 48 weeks
were examined. Early virologic response (EVR) and sustained virologic response
(SVR) were obtained in 22 patients (51%) and 18 patients (42%), respectively.
We used two methods to evaluate IR; HOMA-IR, a marker of hepatic IR, and the
ISI composite, which indicates whole-body insulin sensitivity and is calculated as 10000/√FPG × FIRI × mean BS (0-120) ×
mean IRI (0-120) from a 75 g oral glucose tolerance test. Serum adiponectin
levels were measured and visceral fat areas at the umbilical level were
evaluated by computed tomography. We analyzed whether the HOMA-IR and ISI
composite values before treatment were associated with EVR or SVR
Results:
There were significant differences in HOMA-IR and ISI
composite values before treatment between EVR and non-EVR patients (HOMA-IR:
1.7 vs 3.0 , p=.0005; ISI composite: 5.7 vs 3.3,
p=.02). Similarly, there were significant differences in both between SVR and
non-SVR (HOMA-IR: 1.6 vs 2.8, p=.009; ISI composite: 6.0 vs 3.4, p=.003).
Analyzed according to HOMA-IR classes, EVR and SVR rates were 76% and 62% in
<2 (n=21), 32% and 26% in 2~4 (n=19), 0% and 0% in >4 (n=3),
respectively. According to ISI composite classes, EVR and SVR rates were 20%
and 13% in <3 (n=15), 60% and 45% in 3~6 (n=20), 100% and 80% in 6~9 (n=5),
67% and 100% in >9 (n=3), respectively. A positive predictive value for EVR
and SVR when ISI composite was >6 was 87.5% for both. Multivariate analysis
showed that >6 in ISI composite was the only factor associated with SVR. ISI
composite values were significantly positively correlated with serum
adiponectin levels and negatively with visceral fat areas.
Conclusions:
Whole-body, predominantly liver and skeletal muscle, insulin
sensitivity is strongly associated with the efficacy of peginterferon plus
ribavirin treatment. These data suggest that life-style interventions might
enhance the effect of anti-viral therapy in patients with chronic hepatitis C.
Topic: Treatment – General
299.
Evaluation of a multidisciplinary support program in hepatitis C treatment
M. Garcia-Retortillo; M. Giménez; C. Márquez; P.
Castellvi; R. Navinés; E. Clot; I. Cirera; E. Salas; R. Martín-Santos; R.
Solà
Introduction:
Adherence to antiviral treatment has been cited as a
potentially important factor in determining the outcome of therapy in hepatitis
C patients.
Aims:
To evaluate the multidisciplinary
support program (MSP) efficacy and its impact on the health-related quality of
life (HQL) during HCV treatment.
Method:
One hundred eighty-eight HCV naive patients were consecutively
treated in the Liver Section of the Hospital Mar: Group 1, 91 patients included
in the MSP (2005), and Group 2, 97 patients with conventional control
(2003-2004). All patients were treated with Peg-IFN alpha-2a and ribavirin
(RBV). The MSP team includes hepatologists, nurses, a pharmacist, a
psychologist and a psychiatrist. Uniform patient informing, open and flexible
visits scheduling, continued evaluation of psychiatric risk (PHQ and HADS),
active medication control, and standardized management of the secondary effects
were carried out during MSP. Patients receiving ≥ 80% of each assigned
drug for ≥ 80% of the expected duration therapy were
considered as adherent to the treatment. HQL was evaluated by SF-36 before and
at 1, 3, and 6 months during treatment.
Results:
No differences were observed between either group in terms of
age, gender, HCV-genotype, viral load and fibrosis degree.
Anti-depressives or anxiolytics were prescribed in 34 (37,4%) and 21 (21,6%) patients in each group, respectively (P
0.02). Patients in Group 1 showed better scores in all domain scales of health
status than the patients in Group 2. However, the differences only reached
statistical significance in terms of bodily pain, and in general and mental
health scores.
Conclusions:
The multidisciplinary support program (MSP) increases the
adherence to the antiviral therapy and improves the perception of the quality
of life during treatment.
|
|
Group 1 |
Group 2 |
P |
|
Adherence (%) |
95.6 |
80.4 |
0.0002 |
|
Withdrawal / drop-out (%) |
4.4 |
6.2 |
NS |
|
Drug dosages < 80% (%) |
0 |
13.4 |
0.0003 |
|
Mean hemoglobin decrease (mg/dL) |
3.1 |
2.9 |
NS |
|
Peg-IFN dosage 100% (%) |
100 |
89 |
0.02 |
|
RBV dosage 100% (%) |
98.8 |
80.2 |
0.0001 |
|
Erythropoietin (%) |
3.3 |
1 |
NS |
|
End of treatment response (%) |
86.8 |
78.3 |
0.1 |
Topic: Treatment – Predictors of
Treatment Response
301. The
Impact Of Steatosis And Steatohepatitis On The
Response To Treatment In Patients With Chronic Hepatitis C Infection.
T. J. Cross; A. Quaglia; J. Nolan; I. Fletcher; K.
Agarwal; P. M. Harrison
Background:
The impact of steatosis on sustained virological response
(SVR) in patients treated with pegylated interferon and ribavirin for chronic
hepatitis C (CHC) infection is controversial.
Aims:
We studied whether finding steatosis with or without
steatohepatitis on a pre-treatment liver biopsy (LB) influenced SVR in patients
with CHC subsequently treated with pegylated interferon and ribavirin.
Patients:
We assessed 204 consecutive patients treated for CHC between
January 2001 and January 2005. LB was performed in all patients before
treatment. The method described by Ishak was used to grade necro-inflammation
and stage fibrosis. Steatosis and steatohepatitis were graded using the
modified Brunt score. Patients were classified according to the presence or
absence of steatosis and steatohepatitis. Patients achieving SVR were labeled
as responders and those failing to achieve SVR as non-responders
Results:
179 patients were included in the final analysis after
exclusions, 72% male, median age 46 years (interquartile range 40 – 52). 127
patients had Ishak Fibrosis stage 3 or less (71%), and 31 patients (17.3%) were
cirrhotic (Ishak stage 5-6). 106 patients achieved an SVR (59%); the SVR rates
by genotype were: genotype 1 (35%), genotype 2 (82%), genotype 3 (79%), and
genotype 4 (57%). 98 patients had steatosis (51.9%). The Χ2 test for trend
demonstrated different rates of steatosis between the genotypes (P=0.14).
Steatosis was most prevalent in genotype 4, 6/7 (86%), although the numbers
were small. Genotype 3 had a high level of steatosis 34/54 (63%, p=0.053) and
genotype 2 had a low level, 12/37 (32%, p=0.008). Steatohepatitis was present
in 34 patients (19%), who were older (49 years vs. 44 years, p=0.03) and more
likely to have severe steatosis (grade 2-3 vs. 0-1, p<0.0001), and cirrhosis
(p<0.0001). Genotype had no effect on the likelihood of steatohepatitis
(p=0.69). Responders did not differ from non-responders in respect to gender,
age, the presence or severity of steatosis, necroinflammatory grade or
pre-treatment ALT. In a univariate analysis, reduced SVR was associated with
genotypes 1 and 4 (p<0.0001), cirrhosis (p<0.0001), steatohepatitis and
heavier patient weight (both p=0.009). But on multivariate analysis only
genotypes 1 and 4 (p<0.001), pretreatment weight (p=0.002) and cirrhosis
(p=0.06) were found to be associated with SVR.
Conclusion:
·
In
CHC, steatosis has no effect on SVR. Steatohepatitis is associated with severe
steatosis and liver disease progression but not SVR, which is mainly determined
by genotype, patient weight and the presence of cirrhosis
·
Therapeutic
strategies aimed at treating steatohepatis may improve SVR in at risk patients
·
Patients
at risk should have liver biopsy to assess for steatohepatitis
Topic: Treatment – PEG-Intron
302.
Consistency of Sustained Virologic Response (SVR) Across Weight Categories:
Results From the Canadian
POWeR (Peginterferon alfa-2b Prospective Optimal Weight-based Dosing Response)
Program
S. V. Feinman; C. Ghent; H. B. Witt-Sullivan; L.
Scully; M. Poliquin; W. Ghesquiere; R. Arlen; P. Marotta
Background:
This analysis examines the impact of body weight on SVR rates
in patients with chronic hepatitis C who received weight-based peginterferon
(PEG-IFN) alfa-2b plus weight-based RBV in the POWeR program.
Methods:
POWeR is an open-label,
observational trial conducted in academic and community clinics across
Results:
1977 patients initiated treatment. Patients were excluded if
they had undetectable HCV RNA at end of treatment but no 6-month follow-up, had
no treatment data, or had HIV/HCV coinfection. Patients (n=1800) in this
analysis included those who discontinued because of side effects, lack of
response, or personal reasons. Most patients were infected with G1 (60%),
followed by G3 (22%) and G2 (15%); 3% had other genotype. Liver biopsy specimens, available in 946
patients (53%), demonstrated varying degrees of fibrosis (F0-F2 [60%]; F3/F4
[40%]). There was no significant difference in fibrosis score or genotype distribution
across weight categories. There was a trend toward a higher incidence of F3-F4
fibrosis/cirrhosis in heavier patients. No statistically significant
differences in overall SVR, SVR by genotype, or SVR by fibrosis score were
observed among weight categories (Table). Overall SVR rates were higher in
persons with F0-F2 fibrosis than in those with F3-F4 fibrosis/cirrhosis (60% vs
35%, P<.001).
Summary:
• No statistically significant differences were observed in
overall SVR rates across patient body weight categories when a weight-based
PEG-IFN alfa-2b plus RBV regimen was used
Conclusions:
·
Weight-based
dosing of PEG-IFN alfa-2b (1.5 μg/kg/wk) plus RBV (800-1200 mg/d) is
appropriate for all body weights and produces consistent SVR rates across all patient
body weights
·
Community
and academic physicians can expect excellent SVR rates, regardless of patient
body weight
Consistency of SVR Rates Across Weight Categories
|
|
SVR,% |
|
||||
|
|
<50 kg |
50-<64 kg |
64-<75 kg |
75-<85 kg |
≥85 kg |
P |
|
Overall (n=1796)* |
64 |
57 |
53 |
51 |
56 |
NS |
*4
patients no weight data; 16 no genotype data.
Topic: Treatment – Predictors of
Treatment Response
M. Martinot-Peignoux; S. Maylin; R. Moucari; M.
Ripault; N. Boyer; N. Giuily; C. Castelnau; T. Asselah; P. Marcellin
Introduction:
It is well established that HCV genotype and baseline HCV-RNA
are good predictors of sustained virological response (SVR) in selected
patients included in clinical trials of pegylated interferon alpha (PEG-IFN)+ribavirin
(RBV). Limited knowledge is available on predictors of SVR in the general
population managed in routine clinical practice.
Methods:
408 patients consecutively treated with PEG-IFN
α-2b+RBV, were studied (221 naïves; 125 non-responders (NRs); 62 relapsers
(RRs). Patients with genotypes 1 or 4 and non-naive were treated 48 weeks and
patients with genotypes 2 or 3 for 24 weeks (PEG-IFN 1.5μg/kg/week; RIBA
800-1200 mg/day). Serum HCV-RNA was measured at baseline, week 4, week 12, end
of treatment and 6 months after the end of treatment with the quantitative
VERSANTR HCV 3.0 Assay (bDNA)(Siemens). Samples below
limit of quantification were tested with the VERSANTR HCV-RNA Qualitative Assay
(TMA)(Siemmens). SVR was defined as undetectable serum
HCV-RNA by TMA at the end of 6-month post-treatment follow-up. The
characteristics included in the logistic regression analysis were: baseline
viral load (≤vs>400x103IU/ml), HCV genotype (1, 2, 3, 4, 5), gender,
age (≤vs>45y), histology grade (A0-1≤vs>A2-3), fibrosis stage
(F0-2≤vs>F3-4) assessed with Metavir score, serum ALT, pretreatment
status, rapid virological response at week 4 (RVR4)(TMA undetectable) and rapid
virological response at week 12 (RVR12) (>2 log viral drop) of therapy.
Early viral kinetic was analyzed at weeks 1 to 4 in a subgroup of 78 patients.
Results.
Overall SVR rate was 46%; SVR rates were 53%, 25% and 65% in
naives, NRs and RRs, respectively.
Univariate Analysis:
o
All
parameters, except sex, were significant predictors in treatment-naive patients
o
RVR
and EVR were significant predictors in all patient groups
o
Sex
was not a significant predictor for any patients
o
Age
was a significant predictor for treatment-naive patients and RRs but not NRs
o
Fibrosis
(activity grade and fibrosis score) was a significant predictor for
treatment-naive patients but not for RRs or NRs
Conclusions.
o
For
treatment-naive patients, RVR (undetectable HCV RNA at week 4 of therapy) is
the strongest independent factor for prediction of SVR
o
For
patients who were NRs to previous therapy, high initial viral load (>5 log10
IU/mL) and absence of EVR (<2 log10 decrease in HCV RNA from baseline at
week 12 of therapy) are the strongest predictors of non-SVR
o
Therefore,
the following should be assessed during anti-HCV therapy:
|
Timing |
Assessment |
|
Treatment initiation |
Quantification of serum HCV RNA |
|
Week 4 of therapy |
Qualitative detection of serum
HCV RNA to predict SVR |
|
Week 12 of
therapy |
Quantification of
serum HCV RNA to predict non-SVR |
Topic: Treatment – Predictors of
Treatment Response
M. Martinot-Peignoux; S. Maylin; M. Ripault; R.
Moucari; N. Boyer; N. Giuily; C. Castelnau; P. Marcellin
Introduction:
Pretreatment viral load is an important predictor for
treatment outcome in patients with chronic hepatitis C. Recently, Zeuzem et al.
(AASLD 2006) proposed 400 000 IU/ml (assessed with the COBAS TaQMan HCV assay)
as the optimal cut-off to best discriminate low and high VL, based on the
probability to achieve SVR in patients treated with peginterferon (PEG-IFN)
alpha 2a+ribavirin (RBV).
Aim:
Our study aimed to analyze the positive predictive value
(PPV) of this cut-off value at baseline, the PPV of rapid virological response
at week 4 (RVR4) and the negative predictive value (NPV) of non early
virological response at week 12 (non-EVR12), in patients treated with PEG-IFN
alpha 2b+RBV.
Patients-Methods:
408 patients (221 naive; 187 non-naive)
consecutively treated with PEG-IFN alpha-2b+RBV (PEG IFN 1.5μg/kg/week,
plus RIBA 800-1200 mg /day according to weight), were included in this study.
Patients with genotypes 1, 4 or 5 or non-responders were treated 48 weeks;
naive patients infected with genotypes 2 or 3 were treated 24 weeks. Serum HCV
RNA was measured at baseline, week 4, week 12, end of treatment and 6 months
after the end of treatment with the quantitative VERSANTR HCV 3.0 Assay (bDNA)
(Siemens Medical Solution Diagnostics). Samples below the limit of
quantification were tested with VERSANTR HCV RNA Qualitative Assay (TMA)
(Siemens Medical Solution Diagnostic). SVR was defined as undetectable serum
HCV RNA by TMA at end of 6 months post-treatment follow-up. At treatment
initiation PPV was defined with a cut-off set up at ≤ 400 103IU/ml; at
week 4 the PPV was defined as TMA undetectable or ≥ 2 log drop baseline
viral load; at week 12 the NPV was defined as TMA detectable or < 2 log drop
baseline viral load.
Results.
The overall SVR rate was 46% (53% in naïve patients and 38%
in non-naïve patients).
Conclusions.
·
Undetectable
HCV RNA at week 4 (RVR) when assessed with a sensitive assay (TMA) is more
accurate (96%-100%) than baseline cut-off (≤400 103IU/ml) to predict SVR
both in naive and in experienced patients.
·
The
absence of EVR at week 12 (less than 2 log reduction of HCV RNA) is a strong
predictor (96%-100%) of non response to therapy independently of the patients pretreatment status.
·
Monitoring
of patients during therapy with PEG-IFN plus RBV should include
o
Qualitative
detection of serum HCV RNA at week 4 to predict SVR
o
Quantification
of serum HCV RNA at treatment initiation and week 12 to predict non-SVR (no EVR
and no SVR)
|
|
PPV |
PPV |
PPV |
NPV |
NPV |
|
|
Baseline |
Week 4 |
Week 4 |
Week 12 |
Week 12 |
|
Viral Load |
<400000 IU/ml |
TMA negatif |
≥ 2 log drop |
TMA positif |
< 2 log drop |
|
All the patients |
62% |
97% |
70% |
87% |
98% |
|
Naives |
63% |
96% |
78% |
83% |
100% |
|
Non-Responders |
27% |
100% |
50% |
90% |
96% |
|
Relapsers |
76% |
100% |
70% |
76% |
100% |
Topic: Treatment – Predictors of Treatment
Response
F. Poordad; C. Kambili
Background:
Assessing viral kinetics in response to peginterferon
(PEG-IFN) alfa and ribavirin (RBV) can help predict treatment response among
patients with chronic hepatitis C. Hepatitis C virus (HCV) RNA levels decrease
rapidly after initiation of treatment with PEG-IFN alfa-2b/RBV. To determine
the value of assessing early viral kinetics during PEG-IFN alfa-2b/RBV therapy,
positive and negative predictive values (PPVs; NPVs) of rapid and early
virologic response (RVR; EVR) for sustained virologic response (SVR) were culled
from PEG-IFN alfa-2b articles or abstracts.
Methods:
Published PEG-IFN alfa-2b data were evaluated for PPVs and
NPVs for RVR and/or EVR. PPVs and NPVs were calculated if not reported but RVR and/or
EVR rates and SVR rates were available. RVR was defined as undetectable HCV RNA
at wk 4 of treatment (lower limit of detection <50 IU/mL in most studies).
EVR was defined as undetectable HCV RNA or a ≥2 log10 decrease
from baseline at wk 12 of treatment.
Results:
Patients from applicable trials (N>2000) were monoinfected
with HCV or coinfected with HCV/HIV and were treated with PEG-IFN alfa-2b (1.0
or 1.5μg/kg/wk or 50-150μg/wk) and various doses of RBV
(800-1400mg/d). Treatment duration was 48 or 24 weeks, generally depending on
genotype (G). Attaining RVR was highly predictive of attaining SVR in patients
with any genotype who were treated for 48 wks (PPV 89%), in G1/4 patients
treated for 48 wks (PPV 81%), and in G2/3 patients treated for 24 wks (PPV
85-90%). Not attaining RVR was a less reliable predictor of not attaining SVR
for all genotypes (NPV 59%); NPVs were 84% among G1/4 and 44-63% among G2/3
patients. G2/G3 patients were analyzed separately in 1 study; the PPV and NPV
for RVR were 89% and 50%, respectively, for G2 patients and 100% and 57%,
respectively, for G3 patients. Failure to attain EVR was a consistent indicator
of failure to attain SVR (NPV 95-100%), whereas attaining EVR was a less
reliable predictor of attaining SVR (PPV 67-72%) for all genotypes. Among
African Americans, NPVs and PPVs for EVR were 100% and 48-83%, respectively.
Studies in G4 patients revealed NPVs for EVR of 86-100% and PPVs for EVR of
76-100%.
Conclusions:
Predictability of response to PEG-IFN alfa-2b/RBV applied to
mono- and coinfected patients. EVR was a better negative than positive
predictor of SVR and can be used to guide treatment cessation in G1/4 patients
who do not respond by week 12 of treatment. RVR was an excellent positive but
poor negative predictor of SVR for all genotypes. RVR can be used as a patient
motivator and can reliably be used as part of the treatment algorithm for
future studies and in clinical practice.
Topic: Treatment – Predictors of
Treatment Response
T. Oze; N. Hiramatsu; Y. Inoue; N. Kurashige; M.
Kurokawa; T. Yakushijin; T. Igura; K. Imanaka; M. Oshita; H. Hagiwara; E. Mita;
T. Ito; T. Hijioka; H. Yoshihara; Y. Imai; E. Hayashi; M. Kato; Y. Minami; K.
Ohkawa; S. Kiso; T. Kanto; T. Takehara; A. Kasahara; S. Tamura; N. Hayashi
Background & Aim:
The early viral response, defined as undetectable or at least
a 2-log decrease in HCV RNA level after 12 weeks of treatment, is very
important for predicting which hepatitis C patients are not likely to display a
sustained viral response (SVR) to peginterferon (Peg-IFN) plus ribavirin (RBV)
combination therapy. In this study, we investigated the relationship between
the viral kinetics during the first 8 weeks and the antiviral outcome to
identify factors with a high positive predictive value (PPV) or negative
predictive value (NPV) for SVR. Patients & Methods: This study was conducted
at
Results:
At week 2, 33 out of 39 patients who had undetectable (<5
KIU/ml) or at least a 2-log decrease in HCV RNA achieved SVR (PPV = 85%).
Ninety-one of 93 patients with less than a 1-log decrease in HCV RNA did not
achieve SVR (91/93, NPV = 98%). At week 4, 21 patients had undetectable serum
HCV RNA (<50 IU/ml), and achieved SVR (21/21, PPV = 100%). Seventy-five
patients had less than a 1-log decrease in HCV RNA, and none achieved SVR
(75/75, NPV = 100%). Similarly, at week 8, 73 patients had less than a 2-log
decrease in HCV RNA, and none achieved SVR (NPV = 100%).
Conclusion:
Early viral kinetics in the first 8 weeks can predict PPV and
NPV for SVR; especially useful are the 1-log decrease in HCV RNA at week 4 and
2-log decrease at week 8, which are excellent markers for NPV in Peg-IFN and
RBV combination therapy.
PPV and NPV for SVR
|
change in HCV RNA |
week of therapy |
PPV for SVR |
NPV for SVR |
|
2-log decrease or <5 KIU/ml |
2 |
85% (33/39) |
87% (101/116) |
|
1-log decrease or <5 KIU/ml |
2 |
74% (46/62) |
98% (91/93) |
|
PCR negative (<50 IU/ml) |
4 |
100% (21/21) |
64% (240/376) |
|
2-log decrease or <5 KIU/ml |
4 |
67% (102/152) |
94% (99/105) |
|
1-log decrease or <5 KIU/ml |
4 |
59% (108/182) |
100% (75/75) |
|
PCR negative (<50 IU/ml) |
8 |
82% (111/135) |
79% (220/278) |
|
2-log decrease or <5 KIU/ml |
8 |
64% (156/242) |
100% (73/73) |
|
1-log decrease or <5 KIU/ml |
8 |
59% (156/265) |
100% (50/50) |
Topic: Treatment – PEG-Intron
T. Oze; N. Hiramatsu; Y. Inoue; N. Kurashige; M.
Kurokawa; T. Yakushijin; T. Igura; K. Imanaka; M. Oshita; H. Hagiwara; E. Mita;
K. Katayama; H. Yoshihara; A. Inoue; Y. Imai; E. Hayashi; M. Kato; M. Nishikawa;
Y. Minami; T. Tatsumi; T. Kanto; T. Takehara; A. Kasahara; S. Tamura; N.
Hayashi
Background & Aim:
Patients with early viral response (EVR), defined as
undetectable or at least a 2-log decrease in HCV RNA level after 12 weeks of
treatment, show a high probability of SVR in pegylated interferon (Peg-IFN) and
Ribavirin (RBV) therapy for chronic hepatitis C patients with genotype 1. We
evaluated the effect of Peg-IFN alfa-2b and RBV dose reduction on EVR in
patients with genotype 1 and high viral load.
Patients & Methods:
This study was conducted at
Results:
Of the 839 patients, 45 discontinued therapy due to side
effects before week 12. Of those who completed 12 weeks of treatment, 48%
(326/675) achieved c-EVR. Of the c-EVR patients, 75% achieved SVR, while 29%
with late viral response, defined as undetectable serum HCV RNA from 13 to 24
weeks, achieved SVR. In patients who received 12 - 14 mg/kg of RBV, the c-EVR
rate was 36% (5/14) for those given 0.75 µg/kg (50%) - 1.2 µg/kg (80%) of
Peg-IFN, 54% (15/28) for those given 1.2 - 1.5 µg/kg of Peg-IFN, and 61% (42/69)
for those given 1.5 - 1.8 µg/kg of Peg-IFN. Similarly, the c-EVR rate was 30%
(13/43), 56% (104/186), 53% (34/64) in patients who received 10 - 12 mg/kg of
RBV, 42% (11/26), 49% (35/71), 56% (22/39) in those who received 8 - 10 mg/kg
of RBV, and 36% (5/14), 50% (9/18), 60% (6/10) in those who received 6 - 8
mg/kg of RBV. No decline in c-EVR rate was observed among patients with more than 1.2 µg/kg of Peg-IFN, but the c-EVR rate declined
among those with less than 1.2 µg/kg of Peg-IFN (p < 0.001, Fisher exact
test).
Conclusion:
Peg-IFN reduction up to 80% (≥1.2 µg/kg/week) can
maintain approximately 50% of EVR regardless of the RBV dosage.
Topic: Treatment – Pegasys
310. Effects
of systematic nurse-provided therapeutic education on adherence and efficiency
of PEG-Interferon-a2a(Pegasys®)-ribavirin
treatment in chronic hepatitis C (Pegobs Protocol).
D. Larrey; A. Salsé; G. Pageaux; N. Funakoshi; D.
Ribard; O. Boutet; V. Hyrailles; B. Niang; E. Vaucher; J. Arpurt; A. Rémy; S.
Dahmouni; N. Kharlova; J. Daurès
Introduction:
Failures of PEGIFN-a2a/b-ribavirin combination in chronic
hepatitis C are mainly due to a poor adherence and side effects. TT
optimization is currently recommended. However no prospective study has still
been performed for assessing the effect of systematised therapeutic education.
Aim:
To assess the effect of systematic nurse-provided therapeutic
education on adherence and efficiency of PEGIFN-a2a (Pegasys®)-ribavirin in pts
with chronic hepatitis C.
Patients and methods:
Multicentric, prospective study, randomized in 2 groups: GrA:
systematic nurse consultation after medical consultation at D0, W4, 8, 12, 24,
36; performed with a standardised questionnaire for the assessment and
education on the disease and its TT; GrB: pragmatic follow-up. Comparison was
made between an experimented center (center 1) and newly formed nurses.
Results:
239 randomized pts: GrA 123 ; GrB
116 ; center 1 : 128 pts. Baseline : no difference between groups for age, sex
ratio, BMI, alcohol intake, contamination type, previous PEGIFN TT 42,6 vs 36%,
genotypes prevalence, mean viremia and ALT, fibrosis score.
Adherence to TT better (p<0,05) (GrA vs GrB) at W24 : 75,6
vs 64,5%, end of treatment (EOT) 73,7 vs 61,9% ; it was even better for center
1 : W12 : 90,8 vs 74,6% ; W24 : 86,2 vs 65,1% ; EOT 83 vs 60,3%. Accordance of
TT duration with protocol for 24W : 83,6 vs 76,7% ; 48W : 69,7 vs 53,2% ;
center 1 : 24W : 94,1 vs 90% ; 48W : 79,1 vs 48,8%.
HCV RNA disapparence was more frequent (p<0,01) in GrA vs
GrB at W12 : 72,8 vs 57,1% ; W24 : 75,2 vs 59,8% ; EOT : 70,6 vs 52%. For
center 1 : W12 : 76,9 vs 55,7% ; W24 : 86,1 vs 62,9% ; EOT : 80 vs 55%.
Sustained virological response (SVR) was significantly higher
: 37,7 vs 25% for all pts ; naïve : 46,4 vs 31% ; re-TT : 25 vs16% ; center 1 :
overall 48,4 vs 24% ; naïve : 66,7 vs 37% ; re-TT : 32,3 vs 7%. SVR according
to genotypes: HCV1, 4,
Conclusion:
The systematic nurse-provided therapeutic education is
significantly associated with a better adherence to the TT and a better
virological response. The beneficial effect was more significant in pts treated
48 W and in center with nurse particulary experimented for therapeutic
education (center 1).
Comments:
These results show : 1) the
importance of therapeutic education in the TT of hepatitis C particularly in the
most difficult groups with relatively resistant genotypes and previous
therapeutic failures ; 2) the importance of nurse experience in therapeutic
education.
We
thank Roche Laboratory for its support.
Topic: Treatment – PEG-Intron
P. Deltenre; V. Canva; A. Louvet; S. Dharancy; L.
Bocket; A. Hollebecque; J. Boitard; C. François; S. Castelain; G. Duverlie; J.
Henrion; P. Mathurin
Introduction:
Treatment is recommended in HCV patients (pts) with normal
ALT only for viral eradication. HCV viral kinetics during antiviral therapy
comports a two phase decline. The second slow δ phase is related to
infected cell loss. δ phase is predictive of
sustained virological response (SVR) and may be estimated by reduction of viral
load (VL). In pts with normal ALT, a good estimate of the δ phase is
required to determine as soon as possible the need to continue treatment.
Aim:
to determine the earliest and optimal
time when decline of logVL becomes the best estimate of δ phase in HCV
patients with normal ALT prospectively treated with peginterferon α2b and
ribavirin for 6 or 12 months.
Methods:
The prediction of viral kinetics was expressed by the AUROC
curves. Viral load were assessed at 1, 4, 8 hours, days 1 to 4, 7, 14, 21, 28
and 2 and 3 months during treatment.
Results:
24 pts (17 with genotype 1) were included. On overall
patients, the median ALT level was 26±6 IU/L. There was no significant
fibrosis. Median baseline VL was 284500 IU/ml (95% CI: 119000-413000). SVR was
achieved in 62% (53% for genotype 1 pts). On overall patients, reduction of VL
at day 21 was the earliest time estimating SVR (AUROC curve of logVL:
0.848±0.086, p<0.0001) but day 28 has the highest AUROC curve of logVL for
estimating SVR (0.981±0.02, p<0.0001). Months 2 and 3 didn’t have better
AUROC curves of logVL than day 28. In a sensitivity analysis restricted to pts
with genotype 1, reduction of VL at day 28 had a better predictive value of SVR
than reduction of VL at day 21 (AUROC curves of logVL: 0.962±0.04 vs
0.759±0.13, p=0.02). No SVR was observed in genotype 1 pts with a decline of VL
<1 log from baseline to day 28. In terms of optimal cut-off in genotype 1
pts, a decline of VL ≥2 log at day 28 was the best predictor of SVR
(sensibility 95%, specificity 76%, PPV 85%, NPV 91%). 40% of the pts were below
this cut-off and had <10% of probability of SVR and 60% were above and had
>80% of probability of SVR.
Conclusions:
In HCV genotype 1 pts with normal ALT, reduction of VL at day
28 is the best estimate of the δ phase. As viral eradication is the only aim,
the use of this endpoint may avoid waiting until 3 months to decide treatment
discontinuation in genotype 1 pts with low probability of SVR.
Topic: Treatment – General
315.
Hepatitis C treatment outcomes in the Rhode Island Department of Corrections
K. Chew; S. A. Allen; L. E. Taylor; J. D. Rich; E.
Feller
Introduction:
As many as 83% of the
Methods:
We reviewed charts of all male inmates identified as having
initiated HCV treatment between October 2000 and April 2004. HCV-infected
individuals were identified by HCV antibody screening at intake for known risk
factors, elevated aminotransferase levels, or per individual request. Treatment
followed standard guidelines with weight-based dosing of both PEG-INT alfa-2b
and ribavirin. End of treatment response (ETR) was defined as undetectable
serum HCV RNA at end of treatment, and sustained virologic response (SVR) as
undetectable serum HCV RNA 6 months post-treatment. Endpoints were completion
of therapy plus 6 months for SVR, therapy discontinuation, and loss to
follow-up.
Results:
At data collection, 71 patients had reached an endpoint as
defined above. The majority was white (80%). The cohort included genotype 1
(65%), genotype 2 (17%), genotype 3 (13%), genotype 4 (5%). Ninety-nine percent
had a history of substance use (drug injection, non-injection drug use, or
alcohol use). All 13 African-Americans (AA) had genotype 1. Of 59 patients having
liver biopsy, 41 (70%) had early stage disease, defined as stage 0-1, 1-2, or
2. Overall ETR was 39% (28 of 71) and SVR, 28% (20 of 71). Response rate was
lower for genotype 1 (ETR 33%, SVR 18%) compared to genotype 2 (ETR 64%, SVR
60%) and genotype 3 (ETR 56%, SVR 50%). Of inmates with genotype 1, no
statistical difference existed in ETR or SVR by race (33% ETR in AA vs. 34% in
whites; 22% SVR in AA vs. 18% in whites). Thirty-three patients completed
treatment and 31 stopped for reasons including side effects (26) or initial
non-response (5); 7 did not return for follow-up.
Conclusion:
Our results support the limited data available that
acceptable HCV treatment outcomes can be achieved in prisons. Our small study
indicates a difference in treatment response by genotype, but no difference by
African-American vs. white race for genotype 1. Incarceration may be the only
time that this difficult-to-access population intersects with the health care
system long enough for evaluation and treatment. The correctional system has
unique potential for HCV management and reducing the reservoir of infection,
targeting those at high risk of transmission.
Topic: Treatment – Side Effects
V. M. Byrnes; A. Miller; E. Hill; C. Weinstein; D.
Alsop; R. E. Lenkinski; N. H. Afdhal
Background:
Altered cerebral metabolites and cognitive dysfunction are
common findings in chronic HCV infection. The neurologic benefit of HCV
clearance has not been well described.
Aim:
To assess the effect of PIFN and HCV
clearance on cerebral metabolites, cognition and mood.
Methods:
Fifteen patients with non-cirrhotic HCV were evaluated by MRI/MR
spectroscopy, neuropsychometric testing and Beck’s depression inventory before,
during and after treatment with PIFN. Three cerebral metabolites, including
choline (Cho), myoinositol (MI) and N-acetyl aspartate (NAA), were measured
from 3 different brain regions (basal ganglia, left frontal cortex and left
dorso-lateral prefrontal cortex) and expressed as a ratio to the control
metabolite creatine (Cr). Seven HCV positive controls (not taking PIFN) were
also assessed at 2 time points, 3 months apart to determine (i) the variability
of cerebral metabolites over time and (ii) the ‘practice effect’ of repeat
cognitive testing.
Results:
At 12 weeks, 13/15 patients had undetectable HCV RNA
(<600IU/ml). Of these, 8 were persistently negative for HCV RNA, 5 relapsed,
and 1 was lost to follow up. PIFN therapy had no effect on cerebral
metabolites. Cerebral Cho/Cr and MI/Cr were significantly reduced in the basal
ganglia at the time of follow up when compared to baseline in sustained
virological responders (SVR) but not in non-responders/relapsers (NR/R), p=0.03
and p=0.03, respectively. There were no significant differences observed in
cerebral metabolites over time in controls.
Memory and executive functioning significantly improved on
PIFN when compared to baseline in treated patients (p=0.006, p= 0.002) and in
controls (p=0.03 and 0.02). This improvement was preserved in SVRs (p=0.02 and
p=0.04) but not in NR/R. Attention significantly improved on PIFN in treated
subjects (p=0.03). Language and motor skills were unaffected by PIFN or viral
clearance. There was a significant increase in depression scores on PIFN
(p=0.02) but no change when compared to baseline in SVRs and NR/R.
Conclusion:
PIFN does not alter cerebral metabolites but improves
cognition in HCV patients. HCV clearance decreases metabolic markers of
cerebral inflammation and activation and improves cognition in SVRs, likely due
to the clearance of HCV from brain tissue. This study demonstrates the cerebral
benefit to HCV clearance.
Topic: Treatment – PEG-Intron
S. Shakado; D. Morihara; S. Nishizawa; A. Anan; T.
Tanaka; S. Inomata; S. Ueda; T. Matsumoto; Y. Takeyama; M. Irie; K. Iwata; T.
Sohda; S. Sakisaka
Aim:
The aim of this study was to clarify the most useful
predictors for the therapeutic effects of a combination therapy with
peginterferon alpha-2b (PEG) and ribavirin (Rib) in patients with chronic
hepatitis C.
Patients and methods:
In patients infected with the hepatitis C virus (HCV)
genotype 1b with a high viral load, we investigated 54 patients (26 males and
28 females) who completed treatment with PEG+Rib for 48 weeks and followed up
for more than 6 months. We compared a group of serum HCV RNA-negative patients
at 6 months after the end of treatment (SVR) with a group of serum HCV
RNA-positive patients at 6 months after the end of treatment (NR), regarding age,
gender, body mass index, alanine aminotransferase levels, HCV RNA levels
(RT-PCR method), HCV core antigen levels (Lumispot EIKEN HCV antigen kit, EIKEN
CHEMICAL, Tokyo, Japan), the time when HCV RNA became negative and the
administration rate of PEG and Rib.
Results:
SVR was obtained in 21 patients (38.9%), NR in 24 (44.4%),
and withdrawal in 9 (16.7%). Although the pretreatment HCV RNA levels were not
statistically different between the SVR and NR groups, the pretreatment levels of
the HCV core antigen were significantly lower in the SVR group than those in
the NR group (4099.7 vs 7868.8 fmol/L, p<0.05). The rate of HCV core antigen
loss after one month of treatment was significantly higher in the SVR group in
comparison to that of the NR group (100 vs 50.0%, p <0.05). In the SVR
group, there were significantly more cases with a level of pretreatment HCV
core antigen less than 7000 fmol/L (83.3 vs 41.2%, p <0.05). The dose
reduction rate of PEG and/or Rib was significantly lower in the SVR group than
those in the NR group (p<0.05). An administration rate of PEG and/or Rib of
more than 80% of a dose adjusted for body weight was significantly higher in
the SVR group (p <0.01).
Conclusion:
A pretreatment HCV core antigen level of less than 7000
fmol/L and a loss of the HCV core antigen after one month of treatment are both
valuable predictive markers of SVR of PEG+Rib in Japanese patients with chronic
hepatitis C. An extended treatment duration to obtain an administration rate of
PEG and Rib of more than 80% of a dose adjusted for body weight may increase
the SVR rates in patients with chronic hepatitis C by reducing the rate of
relapse.
Topic: Treatment – Disease Progression
T. Scherzer; K. Reddy; K. Staufer; H. Hofer; P.
Steindl-Munda; P. Ferenci
BACKGROUND:
Antiviral treatment results in a sustained virologic response
(SVR) in 50 to 75% of patients with chronic hepatitis C. Long term follow up
studies have observed ongoing SVR in the overwhelming majority. Thus chronic
hepatitis C is considered “cured” if a SVR is achieved. Consequently, it is
expected that in SVRs long term complications of HCV related chronic liver
disease including HCC are eliminated or have a decreased incidence.
RESULTS:
We report on 5 patients (#1-3 from
#1: After a relapse following a six months interferon (IFN)
monotherapy he achieved a SVR after one year treatment with IFNα-2b TIW
and ribavirin (RBV) in 1999. Ultrasonography in 12/05 showed a normal liver,
but a tumour in the right adrenal. The biopsy revealed a metastasis from HCC.
At resection the macroscopic appearance of the liver was normal. 8 months later
a tumour in the right adrenal was resected and was a metastatic HCC.
#2: After two 48 week courses (relapse after 1. treatment) of
pegIFNα2a/RBV she achieved a SVR in 2001.4 years later an elevated AFP
level (47ng/ml) was noted; liver sonography was normal, but revealed a 5 cm HCC
in segment 5/6 a year later. At segmental resection the liver was firm but
macroscopically did not have cirrhosis. HCV-RNA was undetectable in the tumour
tissue.
#3: Following two courses (relapse after 1. treatment) of
pegIFNα2a/RBV she achieved a SVR in 2004. In 2007 she complained of upper
abdominal discomfort and sonography showed a multifocal HCC.
#4: After 2 years treatment with 60 μg/week PEG-IFN-2b
and 800mg/d RBV he achieved an SVR in 2001. A large HCC was detected in 2006.
It was unresectable and he was placed on chemotherapy.
#5: Pretreatment liver biopsy showed stage 0
fibrosis. He achieved SVR following 1 year PEGIFN alfa-2b/RBV in 2003.
HCC was diagnosed in 2006. A staging laparoscopy revealed a non-cirrhotic
liver, but tiny peritoneal implants in the peritoneum. He was placed on
chemotherapy.
CONCLUSION:
·
Successful
antiviral treatment in HCV patients does not prevent development of HCC even in
non-cirrhotic livers.
·
Long-term
follow up of patients with SVR is mandatory and should include screening for
HCC.
Table 1
|
Pat. |
Fibrosis Grade* |
Genotype |
Mode of infection |
SVR |
HCC detected year (age) |
|
#1/m |
2 |
3a |
i.v. drugs |
1999 |
2006 (54) |
|
#2/f |
3 |
1b |
BloodTx |
2002 |
2007 (67) |
|
#3/f |
4 |
1b |
Unknown |
2004 |
2007 (51) |
|
#4/m |
4 |
1a |
BloodTx |
2001 |
2006 (53) |
|
#5/m |
0 |
1b |
i.v.drugs |
2003 |
2006 (52) |
*pretreatment
Topic: Treatment – Predictors of
Treatment Response
K. L. Lindsay; C. Morishima; E. C. Wright; J. L.
Dienstag; M. L. Shiffman; G. T. Everson; A. S. Lok; H. L. Bonkovsky; W. M. Lee;
T. R. Morgan; M. Ghany; H.
BACKGROUND:
Peginterferon with ribavirin therapy leads to a sustained
loss of serum hepatitis C virus (HCV) RNA in at least half of patients with
chronic hepatitis C. Viral kinetic studies, which describe profiles of patients
who respond to treatment, suggest hypotheses to explain the mechanism of action
of interferon alpha and ribavirin. Very little information is available to
explain why virologic suppression does not occur in some patients.
METHODS:
We evaluated potential factors associated with the lack of a
week-20 virologic response in a cohort of previous nonresponder patients with
advanced fibrosis undergoing retreatment with peginterferon alfa-2a and
ribavirin. Among 1,145 patients enrolled in the HALT-C Trial, 588 who received
more than 80% of prescribed therapy for 20 weeks were analyzed. Medication
compliance was assessed at each visit by patient self-report, interviews, and
returned peginterferon vial counts. Factors related to null response in
univariate analyses were entered into a multivariate logistic regression with
backward stepwise selection to assess their relative importance. Analyses were
performed with the SAS version 9.1.
RESULTS:
By week 20, 245 patients (41.7%) had undetectable HCV RNA
(full), 186 (31.6%) had >1 log decrease (partial), and 157 (26.7%) had <1
log decrease (null) virologic response. Virologic null response was associated
independently with African American race, genotype-1 infection, and less
reduction in body weight, platelets, and WBC – markers of systemic responses to
interferon – during treatment (all p < 0.005).
CONCLUSIONS:
On-treatment variables associated with virologic null
response to peginterferon with ribavirin suggest the lack of a systemic
response to interferon, perhaps related to host genetic or environmental
factors. These data have important implications for the design and analysis of
retreatment trials and trials to evaluate new specifically targeted antiviral
therapy for hepatitis C. Further studies are needed to discern whether
interferon resistance, viral resistance, or both are playing a role in
treatment-adherent patients who have no virologic response to interferon
treatment.
Topic: Treatment – Pegasys
R. Reddy; D. Messinger; M. Popescu; S. J.
Hadziyannis
Background:
The prognosis of pts with chronic HCV is influenced by viral
factors such as HCV genotype (G) and HCV RNA level as well as pt factors such
as age, gender, race, cirrhosis and drug adherence.
The demographics of HCV infection are shifting with an increasing number of pts
now in their 50’s. To assess the impact of age on SVR rates we analyzed the
data from two large phase III studies of PEG-IFN alfa-2a (40KD) plus ribavirin
(RBV) (Fried et al. NEJM 2002 and Hadziyannis et al. Ann Intern Med 2004).
Methods:
We included pts who had HCV G1 and were randomised to 48 wks
of treatment with PEG-IFN alfa-2a (40KD) 180µg/wk plus RBV 1000/1200mg/d. SVR
was defined as undetectable HCV RNA by qualitative PCR after 24 wks of
untreated follow-up.
Results:
Overall, the SVR rate in pts ≤50 years was 52.3%
(n=438) and 38.9% in the 131 pts who were >50 (p=0.007). SVR rates in pts
aged >50 years were heterogeneous and varied according to previously
well-established prognostic factors (Table). In particular, SVR rates were
higher in pts without advanced fibrosis, those with low baseline serum HCV RNA
levels, those pts who received ≥80% of the planned dose of PEG-IFN and
those patients who received ≥60% of the planned dose of RBV. Overall, age
did not influence whether pts completed therapy (75.6% of pts ≤50 vs
73.3% of pts >50 years [p=0.5954]). However, there was a trend towards lower
cumulative PEG-IFN exposure in older pts (7235µg in pts ≤50 vs 6868µg in
pts >50 [p=0.0986]) and a significantly lower cumulative RBV exposure in
older pts (304g in pts ≤50 vs 252g in pts >50 [p<0.0001]). Decreasing
RBV exposure to <60% of target has been associated with a dramatic reduction
in SVR rates (Reddy et al. Clin Gastro Hepatol 2007). In our study more pts
>50 years had dose reductions resulting in <60% of target RBV exposure
than pts ≤50 years (38% vs 22%). Discontinuation rates due to any AE was
similar in those ≤50 (11.4%) compared to those >50 years old (11.5%).
Conclusions:
·
Subgroups
of HCV genotype 1 patients >50 years can achieve high SVR rates (particularly
those with a low baseline viral load or without cirrhosis).
·
Older
patients (>50 years) had more ribavirin dose reductions due to laboratory
abnormalities.
·
Maintaining
exposure to peginterferon alfa-2a (40KD) and/or ribavirin during treatment is
essential to achieving high SVR rates, particularly in older patients.
·
More
attention is required when modifying dose of ribavirin in older patients; small
decrements are advisable in order to maintain the highest tolerable ribavirin
exposure.
·
The
assessment of virologic response at weeks 4 and 12 can be used to predict which
patients are most likely to achieve an SVR, regardless of age as high SVR rates
are achieved by all patients with an RVR or cEVR.
·
In
summary, older HCV patients are an important population and a full treatment
course with pegylated interferon plus ribavirin should be considered based on
their on-treatment week 4 and week 12 response.
Characteristics and treatment outcomes in 131 pts aged >50yrs
|
Characteristic |
Prevalence
(%) |
SVR
(%) |
|
Male : Female White : Black : Other race BMI <30 : ≥30 |
60 : 40 81 : 5 : 15 84 : 16 |
36.7 : 42.3* 38.7 : 16.7 : 47.4* 40.0 : 33.3* |
|
Cirrhosis/bridging : Minimal fibrosis |
34 : 66 |
28.9 : 44.2† |
|
HCV RNA <400 000 : ≥400 000 IU/mL |
23 : 77 |
56.7 : 33.7** |
|
ALT Quotient ≤3 : >3 |
63 : 37 |
38.6 : 39.6* |
|
<60 : 60–<80 : ≥80% planned exposure to: PEG-IFN RBV |
25 : 14 : 61 38 : 20 : 42 |
18.2 : 16.7 : 52.5** 16 : 42.3 : 58.2** |
*p=NS;
†p<0.01; **p<0.05
Topic: Treatment – Pegasys
Y. Rotman; B. B. Borg; A. Soza; R. Loomba; A. A. Modi;
J. J. Feld; E. Rivera; E. Doo; T. Heller; M. Ghany; A. U. Neumann; T. Liang; J.
H. Hoofnagle
Introduction:
Chronic infection with hepatitis C virus (HCV) genotypes 2
& 3 is highly responsive to the combination therapy with peginterferon and
ribavirin. Use of lower doses of peginterferon and ribavirin may reduce side
effects without loss of efficacy.
Aim:
To determine whether a lower dose of
peginterferon is better-tolerated and just as effective as the standard dose
and to compare the viral kinetics of the two regimens.
Methods:
Patients were treated with peginterferon alfa-2a (kindly
provided by Roche Laboratories,
Results:
30 patients were treated with the LD and, to date, 18 of a
planned 30 patients with the SD regimen. Among those receiving LD, 19 (63%)
achieved an SVR compared to 10 of 12 patients (83%) receiving SD who have
completed treatment and follow up. The 3 non-responders and 4 of 8 relapsers
after LD therapy were retreated with ET, and all but one (86%) achieved an SVR.
Viral kinetic analyses showed that the mean reduction in HCV RNA levels at 48
hours (first phase) was -1.1 log with LD vs. -2.5 log with SD (p<0.001).
This difference persisted up to day 14 (-2.6 vs. -3.6, p=0.04) and the
mean second phase slope was less with LD (-1.2 log/week) than SD (-2.3
log/week) (p=0.08). Patients receiving SD became HCV RNA negative
earlier than those in the low-dose group (log rank, p<0.01), such
that by week 12, all patients treated with SD (100%) but only 86% treated with
LD were HCV RNA negative. Viral kinetics could not predict relapse, the most
common cause for treatment failure. In the 7 LD patients who were retreated
with ET, viral kinetic measurements were superior with the standard dose of the
ET regimen than the initial low dose. Side effects were measured using a visual
analogue scale. Patients on LD peginterferon had significantly less fatigue and
felt better overall during therapy than patients receiving SD. Depression
scores, however, did not differ. Serious adverse events occurred in 2 patients
in both groups (sarcoidosis and acute coronary event with LD; fatal drug
overdose, and severe mastoiditis and anemia in SD group).
Conclusion:
Although better tolerated, a reduced dose of 90 μg/week
of peginterferon is significantly less potent and, in combination with 800 mg
of ribavirin, provided an unacceptably lower SVR rate in patients with chronic
hepatitis C, genotypes 2 and 3.
Topic: Treatment – General
J. S. Olson ; A. Zaman; K. D.
Ingram; J. R. Phelps
Purpose:
Interferon therapy is associated with worsening of underlying
depression, and clinicians frequently screen for depression before starting
interferon. Bipolar affective disorder (BAD) patients often present with
symptoms of depression rather than mania, and as a result these patients can be
misdiagnosed with unipolar depression if a positive depression screen is not
followed up with an appropriate screen for subtle or inactive manic traits. Our
aim was to assess the prevalence of BAD in hepatitis C patients with a positive
depression screen, and to determine if BAD is associated with an increased rate
of psychiatric complications during interferon therapy.
Methods:
Retrospective study performed at the OHSU Hepatology Clinic
from 12/04 to 9/06. All adult patients initiating interferon therapy (n=112)
were given the Physicians Health Questionnaire (PHQ-9); a validated,
self-administered survey of depressive symptoms used as a sensitive screening
tool for unipolar depression. Patients with a positive PHQ screen were asked to
complete the Mood Disorders Questionnaire; a validated, sensitive and specific
screening tool for BAD. Chart review was performed on all 112 patients for the
six month period following initiation of interferon. Psychiatric complications
(change in psychiatric medications, referral to psychiatry, visits to the ER,
hospital admissions, and discontinuation of interferon therapy) were recorded.
Results:
Three groups were formed:
·
Group
A: 89 patients had a negative PHQ depression screen; and adverse psychiatric
events occurred in 28 patients (31.5%).
·
Group
B: 16 patients had a + PHQ depression screen, but a negative MDQ screen for
manic traits; and adverse events occurred in 5 patients (31.3%).
·
Group
C: 7 patients had a + PHQ depression screen, and a + MDQ screen for manic
traits; and adverse events occurred in 5 patients (71.4%).Chi Square comparison
of groups showed a statistically significant increase in adverse events in
group C compared with group A (p=.045). The increased rate of complications in
group C compared with group B approached statistical significance (p=.169).
Conclusions:
This is the first study of its kind to evaluate the rate of
BAD in interferon patients with a positive depression screen. BAD as defined by
a + MDQ screen was common (7/23 patients), and was also associated with a
markedly higher rate of psychiatric complications during interferon treatment
when compared to both patients without depression, and to patients with
depression without manic traits. This preliminary study highlights the
importance of follow up screening for BAD in patients with a positive
depression screen.
Topic: Treatment – PEG-Intron
P. Cacoub; D. Ouzan; T. Fontanges; J. Lang; P. Melin;
M. Rotily; M. Varastet; P. Marcellin; M. Chousterman
Objective:
The CHEOBS study is a French multicenter, prospective,
observational study designed to analyse the factors related to compliance with the
combination treatment with peginterferon α-2b (peg-IFN) and ribavirin
(RBV) in patients with chronic hepatitis C virus (HCV) infection. Main results
in patients with a genotype 2 or 3 infection are presented.
Patients and Methods:
From January 2003 to December 2004, 705 out of 2001 patients
included were infected with a genotype 2 or 3 virus among which 674 patients
had sufficient data to be analyzed: 370 patients (group 1) received an
educational program to optimize the tolerance and the efficacy of HCV treatment
whereas 304 pts (group 2) had no specific formation. Baseline characteristics,
impact of the educational program on compliance and sustained virological
response (SVR = 6 months after stopping therapy) were assessed.
Results:
The mean age was 45 ± 11 years, 59% were male, 17% were
unemployed and 6% had poor socio-economic conditions. Patients were excessive
alcohol consumers (170, 25%), smokers (354, 53%), drug abusers (current [28,
4%], past [332, 50%]), had past depression (180, 27%) and/or current
psychiatric disorders (158, 24%). HCV viral load was >800,000 IU for 173
patients (38%) and genotype was 2 (202, 30%) or 3 (472, 70%). A high stage of
fibrosis was frequent: Metavir F2–F3 (211, 42%), cirrhosis (69, 14%).
Co-morbidities included HIV co-infection (26, 4%), HBV co-infection (9, 1%), or
other chronic diseases (153, 23%).
At baseline, there were no significant differences between
groups in sociodemographic characteristics, except indebtedness (P = .02).
Depression, psychiatric disorders, current drug abuse, and METAVIR F2 or F3
fibrosis stage were significantly greater in the education group than in the
no-education group
Patient-Reported
Adherence to PEG-IFN alfa-2b and RBV Combination Therapy
·
The
overall rate of adherence to combination therapy was 65% (301/466) at 3 months
and 55% (209/383) at 6 months
·
Therapeutic
education given during the first 3 months of treatment significantly helped
stabilize the proportion of patients adherent to combination therapy until the
end of treatment (Figure 2)
o
At
3 months of treatment, the proportion of adherent patients was similar in the 2
groups (66% in the education groups vs 63% in the no-education group)
o
At
6 months, the proportion of adherent patients decreased in the no-education
group (to 47%) but not in the education group (61%; P = .01)
Virologic Response ≥21
Weeks After the End of Treatment
·
The
overall SVR rate was 72% (367/511)
o
15%
of patients were nonresponders
o
14%
of patients were relapsers
·
Virologic
response (Figure 2) was more favorable in the education group than in the
no-education group; however, the difference was not statistically significant
o
SVR
rates were higher (75% vs 68%) and relapse rates were lower (11% vs 16%) in the
education group than in the no-education group
·
Therapeutic
education benefited patients infected with G2 or G3, especially those infected
with HCV G2 and low baseline viral load (data not shown)
o
Patients
with baseline viral load ≤800,000 UI/mL attained higher SVR rates (80% vs
59%; P = .07) than those with baseline viral load >800,000 UI/mL; relapse
rates were also lower (4% vs 21%; P = .05)
Conclusion:
·
This
is the first prospective study to evaluate adherence in patients infected with
HCV G2 or G3 and the first study to assess adherence in real life
·
Therapeutic
education improved the proportion of patients adherent to combination therapy
at 6 months
·
There
was a beneficial impact of education on virologic response—increased SVR rate
and lower relapse rate—however, the differences were not statistically
significant
·
In
clinical practice, the proportion of patients with psychiatric disorders or
drug addiction was substantial, and therapeutic education may provide a benefit
to these difficult-to-treat patients
Topic: Treatment – PEG-Intron
W. Vogel; H. Brunner; A. Maieron; I. Graziadei; M.
Rosenbeiger; K. Jilek; R. E. Stauber; D. Wolkersdorfer
Introduction:
Prognosis of chronic hepatitis C (CHC) seems to be similar in
patients with persistently normal transaminases (PNALT) and in those with
elevated (EALT). In addition, the response to therapy with interferon and
ribavirin is similar in both groups of patients. However, further studies are
needed. In this prospective, multi-center, open-labeled clinical trial 231
treatment-naive patients with biopsy-proven CHC with normal or elevated ALT
levels received PegIntron 1,5 µg/kg/wk & Rebetol 0,8-1,2g/d for 48 weeks
(genotype 1/4) or 24 weeks (genotype 2/3).
Study design:
Patients were stratified according to elevated or normal
(median of 3 measurements over >3 months) ALT, high or low viral titer
(cut-off 800.000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and
genotypes (GT) 1/4 or 2/3. From these 231 patients 47,6%
had PNALT and 52,4% had EALT. 76,6% with GT 1 or 4
(77,3% of the PNALT and 76% in the EALT group) and 23,4% patients with GT 2 or
3 (22,7% of the PNALT and 23,9% in the EALT group) were enrolled. The median
ALT in the PNALT group was 28 U/ml (GT 1 or 4) and 24 U/ml (GT 2 or 3) and 78
U/ml (GT 1 or 4) and 131 U/ml (GT2 or 3) in the EALT group.
Results:
The pretreatment characteristics were comparable between the
two groups. 65.5% of patients with PNALT had a viral load lower or equal
800,000 IU/ml vs. 63,6% of patients with EALT.
Results of liver biopsies at baseline were available from 147
patients. 46,4% in the PNALT group had Metavir score
F0-F1, compared to 31.4% for EALT group.
Virologic Response
o
Virologic
response (undetectable HCV RNA) was similar in patients with PNALT and EALT
levels throughout treatment and at the end of follow-up
o
Week
4 response
o
119
of 231 patients were evaluated (64 PNALT; 55 EALT)
o
In
45.4% of patients, HCV RNA was undetectable (response rate: 46.9% PNALT and
43.6% EALT)
o
Week
12 response
o
177
of 231 patients were evaluated (83 PNALT; 94 EALT)
o
In
74.6 % of patients, HCV RNA was undetectable (response rate: 80.7% PNALT and
69% EALT)
o
End-of-treatment
response (110 PNALT patients; 121 EALT patients)
o
In
70.6% of patients, HCV RNA was undetectable at end of treatment
§
Response
rate: 73.6% PNALT and 67.8% EALT
§
Response
rate: 65.5% G1/4 and 87% G2/3
o
SVR
§
In
49.4% of patients, HCV RNA was undetectable 24 weeks after treatment cessation
o
Response
rate: 50.9% PNALT and 47.9% EALT
o
Response
rate: 44.6% G1/4 and 64.8% G2/3
§
End-of-treatment
and SVR rates were higher for G2/3 patients than G1/4 patients, regardless of
baseline ALT levels
• SVR rates were significantly higher for patients in the
PNALT group with baseline viral load <800,000 IU/mL than for patients with
baseline viral load ≥800,000 IU/mL (58.3% vs 36.8%, P = .03)
Conclusions:
o
Fibrosis scores (F0-F1) were
significantly lower in patients with chronic hepatitis C and PNALT levels than
in those with EALT levels
o
SVR rates were similar in patients
with PNALT and EALT levels
o
SVR rates were higher for G2/3
patients than G1/4 patients, regardless of baseline ALT levels
o
When treated with PEG-IFN alfa-2b
plus ribavirin, attainment of SVR is independent of baseline ALT level in
patients with chronic hepatitis C.
Topic: Treatment – Pegasys
H. Berak; A. Kolakowska-Rzadzka; M. Wasilewski; J.
Stanczak; K. Szamotulska; K. Bardadin; A. Horban
PATIENTS:
212 patients chronically infected with non 2/3 HCV genotypes
were treated 48 weeks with peginterferon alfa-2a (Pegasys, group A) and peginterferon
alfa-2b (Pegintron, group B), both plus standard doses of ribavirin. A and B
pts were divided into groups with low ( ≤600,000
IU/mL) and high (>600,000 IU/mL) pretreatment viral load (VL) to compare the
efficacy of treatment. 17 pts were lost to observation (9 in group A and 8 in
group B). The analysis concerned 195 (92%) pts: 92 (91,1%)
treated with Pegasys and 103 (92,8%) treated with Pegintron.
METHODS:
Liver biopsies were analyzed according to the Knodell’s and
Scheuer’s scores. The main study outcome was undetectable HCV RNA on week 72
(SVR), 24 weeks after end of treatment. HCV RNA was performed, determined with
HCV RNA ASSAY and viral load (VL) with CA HCV MONITOR TEST (both of ROCHE DIAGN
SYS.). Statistical analysis was performed with Chi-squared.
RESULTS:
No statistically significant difference was found on the
positive SVR in group A vs B and low pretreatment VL: 20 (66,7%)
pts in group A and 17 (58,6%) in group B (p=0,523). Ten (33,3%)
pts in group A and 12 (41,4%) in group B had detectable HCV RNA. Thirty (48,4%) pts with high pretreatment VL in group A and 32 (43,2%)
in group B had positive SVR (p=0,549), and 32 (51,6%) in group A and 42 (56,8%)
in group B had detectable HCV RNA.
Conclusion:
There were higher proportions of patients with SVR treated
with peginterferon alfa-2a (Pegasys). The low pretreatment VL is a good
predictor of SVR.
|
|
PEGASYS (group A) |
PEGINTRON (group B) |
||||||
|
OVERALL |
92 |
103 |
||||||
|
HCV RNA baseline viremia |
≤ 600 000 IU/mL |
> 600 000 IU/mL |
≤ 600 000 IU/mL |
> 600 000 IU/mL |
||||
|
30 |
62 |
29 |
74 |
|||||
|
SVR |
HCV RNA |
HCV RNA |
||||||
|
(-) |
(+) |
(-) |
(+) |
(-) |
(+) |
(-) |
(+) |
|
|
20 (66,7%) |
10 (33,3%) |
30 (48,4%) |
32 (51,6%) |
17 (58,6%) |
12 (41,4%) |
32 (43,2%) |
42 (56,8%) |
|
|
gender: male female |
15* 15* |
32** 30** |
15* 14* |
48** 26** |
||||
|
fibrosis score: 1-2 3-4 unknown |
28* 1* 1 |
49** 10** 3 |
23* 6* 0 |
51** 18** 5 |
||||
gender: *p=0,895, **p=0,118 fibrosis score: *p=0,044, **p=0,213
Topic: Treatment – Pegasys
328. PEG
Interferon ALFA-2A Monotherapy in Dialysis Patients Infected with Hepatitis C
Virus
R. Zachoval; P. Buggisch; P. Reinke; R. Woitas; A.
Michelsen; M. Fuchs; W. Böcher; E. Schulte-Frohlinde; J. Encke; B.
Kallinowski
AIM:
Hepatitis C is an important cause of liver related morbidity
and mortality under hemodialysis. Data about the efficacy of antiviral
treatment with pegylated interferons (Peg-IFNs) are limited in this difficult
to treat patient group. Theoretically Peg-IFN alfa-2a should be preferable to
Peg-IFN alfa-2b due to the fact that <10% is eliminated by the kidneys. We
conducted a multicenter controlled trial to assess the efficacy and tolerability
of Peg-IFN alfa-2a monotherapy 135µg
PATIENTS & METHODS:
Thirty-eight patients were included: 23 males(61%),
mean age 48 years(25-68), mean HCV-RNA 872.749 IU/ml(1523-5.560.000), 29
patients(83%) genotype 1, 3 patients(8%) fibrosis stage 3/4.
Patients received 135µg Peg-IFN alfa-2a
RESULTS:
36.8% (14/38) of the patients had a sustained viral response,
17/38(44.8%) were nonresponders and 7/38(18%) had a viral relapse. Dose reduction
of Peg-IFN alfa-2a was necessary in 4 patients due to hematologic
abnormalities; in 10 patients treatment was discontinued (SAEs N=8, patients’
decision N=2). Twelve SAEs were noted during the study including fatal
myocardial infarction, coronary bypass operation, retinal infarction, seizures,
pneumonia, decompensation of cirrhosis (1 patient
each).In the pharmacokinetic substudy tolerability was comparable in both
dosage groups. The observed side effects in this patient cohort were comparable
to those observed in patients with normal renal function. Stable concentrations
of Peg-IFN alfa-2a were reached within 4-7 weeks in both groups (13 ng/ml with 135µg and 24 ng/ml with 180µg respectively).
CONCLUSION:
·
Peg-IFN
alfa-2a monotherapy (135µg qw) has a good efficacy in hemodialysis patients
(SVR 36.8%).
·
The
180µg weekly dose which might be even more efficient should be evaluated in a
larger trial; repeated injections of Peg-IFN alfa-2a lead to safe and constant
drug concentrations in the serum of patients with end stage renal disease.
·
The
high rate of SAEs even with Peg-IFN-monotherapy in this group of patients with
considerable comorbidity warrants meticulous patient selection and calculation
of the potential risk versus the benefit.
Topic: Treatment – Side Effects
T. Tajuddin; E. Ryan; J. Hegarty; C. O'Farrelly
Introduction:
Haematological growth factors, particularly GM-CSF and G-CSF,
are frequently used to treat anaemia in HCV-infected patients receiving
therapeutic interferon alpha. However, targeted use of these factors may also
have important immunoregulatory roles in patients who fail to respond to
conventional therapy. Previous studies have shown that these non-responsive
patients can be identified, prior to treatment, by high levels of the
chemokine, CXCL10. It has also been shown that GM-CSF can inhibit CXCL10
expression. In preliminary studies, we found that PBMCs from non-responsive HCV
patients secreted low levels of the haematological growth factor GM-CSF
compared with patients who responded to interferon alpha.
Aim:
The aim of this study was to determine the relationship
between GM-CSF, CXCL10 and HCV infection in chronically infected patients with
a view to developing a rationale for targeted therapeutic use of GM-CSF.
Methods:
Circulating GM-CSF was measured in twenty-seven women who had
been exposed to HCV-contaminated anti-D immunoglobulin and thirteen healthy
controls by ELISA. HCV infected patients had detectable levels of circulating
GM-CSF (controls: 0 pg/ml ± 3.4, PCR- 5pg/ml ± 20.7, PCR+ 25 pg/ml ± 18.7); the
PCR+ group had significantly more circulating GM-CSF than the healthy controls
(p= 0.04), although there was significant inter-individual variation in levels.
Peripheral blood mononuclear cells (PBMCs) stimulated with toll-like receptor
(TLR-3 and TLR-7) agonists secreted significant quantities of GM-CSF indicating
that the raised levels of circulating growth factor in HCV-infected patients
were virally induced. GM-CSF suppressed interferon alpha-mediated induction of
the chemokine CXCL10 by PBMCs.
Conclusions:
These data suggest that targeted use of therapeutic GM-CSF
may overcome CXCL10-mediated inhibition of interferon alpha responsiveness in
chronic HCV infection.
Topic: Treatment – Extrahepatic
Manifestations
331.
Hepatitis C Associated Systemic Cryoglobulinemia: Successful Treatment With
Plasma Exchange.
J. C. Hofmann; R. G. Gish
Introduction:
Acute treatment of mixed cryoglobulinemia associated with
hepatitis C is indicated for systemic disease characterized by renal
dysfunction, cutaneous vasculitis, or peripheral neuropathy.
Methods:
We reviewed the medical records of 21 patients (pts) who were
diagnosed with moderate to severe hepatitis C associated cryoglobulinemia from
January, 2005 to May, 2007 and referred for plasmapheresis treatment. The mean
age of pts was 54 years (46-64 years old); 11 pts (52%) were male. 18 pts (86%)
had HCV genotype 1A or 1B. The median HCV RNA was 733,900 IU/ml
(73,620-9,370,000 IU/ml). All pts had positive cryoglobulin studies; median
cryocrit was 1.7% (0.3-5.0%). 18 pts (86%) had significant elevation of
rheumatoid factor (RF). 79-90% of pts had low complement levels.
Clinical Presentation:
17 pts (81%) presented with renal disease. 11 pts (52%) had
chronic renal insufficiency and 6 pts (29%) presented with acute renal failure
requiring hemodialysis (HD). Of 17 pts with renal disease, thirteen (76%) had a
renal biopsy; 12 pts (92%) had MPGN. 17 pts (81%) had elevated 24-hour urine
protein; 13 of these pts (76%) had nephrotic range proteinuria. 13 pts (62%)
presented with active vasculitic skin lesions. 7 pts (33%) had peripheral
neuropathy.
Treatment:
19 pts (90%) received a course of inpatient plasma exchange
(PE) every other day; mean number of PE treatments (txs) was 8.4 (5-12 txs). 2
pts (9.5%) received outpatient PE. After completion of inpatient PE txs, 8 pts
(38%) received low dose cyclophosphamide to prevent rebound of immune complex
production. 5 pts (24%) underwent weekly rituximab (4-6 doses). 15 pts (71%)
started weekly pegylated alpha interferon after completion of PE txs; 12 pts
(57%) started daily ribavirin.
Results:
20 pts (95%) experienced clinical improvement. Of 13 pts with
nephrotic range proteinuria, 9 pts (69%) had significant decline in urinary
protein. 3 of 6 pts (50%) on HD were able to stop dialysis. 17 pts (94%) had a
marked decrease in RF with twelve pts (67%) normalizing their RF levels. 12 pts
(92%) demonstrated significant improvement in vasculitic skin lesions. 6 pts
(86%) experienced slight improvement in symptoms of peripheral neuropathy. 3
pts (14%) with refractory disease required several inpatient courses of PE. 6
pts (29%) received weekly maintenance PE txs.
Conclusion:
Plasma exchange is an effective therapy for hepatitis C
associated cryoglobulinemia, especially in acute treatment of progressive renal
disease and cutaneous vasculitis. Some patients may require maintenance
plasmapheresis treatment. Successful long-term response to antiviral therapy is
essential in controlling this disease.
Topic: Treatment – Pegasys
T. Kagawa; H. Shiozawa; S. Kojima; S. Takashimizu; N.
Nagata; M. Numata; F. Morino; Y. Nishizaki; N. Watanabe; S. Matsuzaki; T.
Mine
Background & Aim:
Reduction or discontinuation of interferon (IFN) dosage by
adverse effects leads to unfavorable results in the treatment of chronic
hepatitis C. To prevent dose reduction by alleviating adverse effects is
important to increase sustained virological response (SVR). Granulocyte
colony-stimulating factor (G-CSF) is often used to increase neutrophils, but is
costly. We conducted a trial to evaluate whether 8-week oral administration of
meloxicam, a COX-II specific non-steroidal anti-inflammatory drug, would
decrease the rate of patients requiring dose reduction of pegylated (PEG) IFN
in the treatment of chronic hepatitis C.
Patients & Methods:
The enrollment criteria was (1) presence of serum HCV-RNA,
(2) neutrophil count ≥ 1,500 /μl, (3) platelet count ≥ 90,000
/μl, and (4) serum hemoglobin ≥ 10 g/dl. Sixty patients given weekly
subcutaneous administration of PEG-IFN alfa-2a (180 μg) for 48 weeks were
allocated into the meloxicam group (n = 22) and the control group (n = 38)
before treatment. Meloxicam was given orally at a dose of 10 mg once a day for
8 weeks since IFN treatment started. Patients were not allowed to receive
G-CSF. Dose of PEG-IFN was reduced to 90 μg when neutrophil and platelet
counts fell down below 750 /μl and 50,000 /μl, respectively.
Results:
Age, pretreatment neutrophil and platelet counts, and body
weight were not significantly different between groups. Any adverse effects of
meloxicam were not observed. Cumulative rate of patients who required dose
reduction was significantly lower in the meloxicam group (Kaplan-Meier plot, P
< 0.05). In the meloxicam group, 9.1% and 40% of patients required dose
reduction until week 8 and throughout the treatment, respectively. On the other
hand, 44.7% and 71.9% of the control group required dose reduction until week 8
and throughout the treatment, respectively. Major cause of dose modification
was neutropenia. Meloxicam relieved a decline of neutrophils within first 8
weeks from 54.2% to 44.2% (P < 0.05). The COX proportional hazards
regression model revealed that lower pretreatment neutrophil count (adjusted
HR: 3.0 per 1,000 /μl-decrease, 95% C.I.: 1.5-6.1, P = 0.002) and not
receiving meloxicam (adjusted HR: 3.6, 95% C.I.: 1.4-8.9, P = 0.007) were
significantly associated with dose reduction. SVR was obtained in 42.9% of the
control group and 68.2% of the meloxicam group,
however, multivariate logistic analysis revealed that viral serotype and viral
load were only independent factors associated with SVR.
Conclusions:
Eight-week administration of meloxicam prevented dose
reduction of PEG-IFN by relieving a decline of neutrophil count in the
treatment of chronic hepatitis C.
Topic: Treatment – PEG-Intron
D. Hüppe; E. Zehnter; M. Manns; S. Mauss; G. Teuber;
T. Dahhan; U. Meyer; B. Möller; N. Dikopoulos; T. Witthöft; J. Brack; M. Stern;
S. Kaiser; R. Prinzing; . The bng hepatitis study group
BACKGROUND:
Pegylated interferon (PEG-IFN alfa) and Ribavirin (RBV) are
standard of care for hepatitis C (HCV) treatment. Since there are no large
controlled studies for genotype (GT) 4 patients (pts), available cohort data
are of interest in order to better define response rates and suitable treatment
strategies.
METHODS:
A total of 285 sites (75 with GT 4 pts) have treated a total
of 4130 HCV pts, of whom 126 were GT 4. The results of GT 4 pts who had reached
an observational period beyond 72 weeks after baseline are described. Pts
without available HCV-RNA data 24 weeks post therapy were counted as treatment
failures. Data are analyzed using standard summary statistics.
RESULTS:
GT 4 pts had a mean age of 41 years, 61% (n=75) were male.
48% (n=59) were German, 6% (n=8) Italian, 12% (n=15) Egyptian, 4% (n=5)
Ethiopian, and 6% (n=5) Turkish. Three
percent (n=4) of the pts showed cirrhosis and 5% were coinfected with HIV and
2% were coinfected with HBV.
88% (111/126) of the pts received PEG-IFN and RBV as primary
therapy, 12% (15/126) were retreated after unsuccessful IFN mono-therapy. 38%
(48/126) received standard PEG-IFN dose (1.5 mg/kg body weight), 35% (44/126)
received lower and 25% (31/126) higher doses. 72% (91/126) received standard
weight-dosed RBV (1000/1200 mg/day).
As of yet, 58 pts have reached the 24 weeks follow-up after
end of therapy. Normalization of ALT was seen in 55% (32/58) of the pts at
follow-up. 47% (27/47) of the pts analyzed thus far showed sustained virologic
response (SVR), 16% (9 pts) relapsed, 22% (13 pts) were non-responders, and 16%
(9 pts) were lost to follow-up or missing.
In patients with baseline HCV-RNA <600.000 IU/ml (LVL) SVR
rate was 67% (16/24) and 48% (10/21) in the HVL group (<600.000 IU/mL). More nonresponders
were seen in the HVL group (38%; 8/21) than in the LVL group (13%; 3/24).
CONCLUSION:
·
Efficacy
of PEG-IFN alfa-2b plus RBV in patients with HCV G4 infection is comparable,
but not superior, to results in patients with HCV G1 infection within this
German cohort of patients
Topic: Treatment – Pegasys
337. PEG-IFN
alfa-2A plus Ribavirin is
T. Witthoeft
Introduction:
Pegylated IFN alfa plus ribavirin is the standard treatment in
patients with chronic hepatitis C. However, so far not all patients can be
cured due to different genotypes, disease history, stage of fibrosis and
resistance to interferon.
Methods:
We conducted a single center study comparing pegylated IFN
alfa-2a (180ug) plus ribavirin (800-1200mg) and high dose induction therapy
with Consensus interferon (CIFN) plus ribavirin (800mg) in a therapy-naive
cohort. CIFN was given at 18ug daily for 8 weeks followed by 9ug per day
subcutaneously. RBV was added from the beginning at 800mg daily. Pegylated IFN
was given at the recommended dosage and RBV was added in a weight based manner
in patients with GT 1 and 4 and 800mg in GT 2 and 3. 52 patients received
pegylated IFN and ribavirin and 50 patients received CIFN and ribavirin. PCR
was performed by using the Cobas Amplicor assay. Treatment was stopped if
HCV-RNA PCR was positive at week 24. Both groups were well matched in regard to
age, sex and genotype.
Results:
The treatment was well tolerated on both treatment groups.
However, patients in the CIFN treatment group experienced significantly more
side effects (e.g. fever, muscle pain, weight loss, depression, lower WBC)
compared to patients treated with pegylated IFN plus RBV due to the higher
amount of daily interferon. Patients with low viral load (< 800 000 IU/ml)
and women did respond better in both treatment groups in regard to SVR.
Conclusions:
Treatment regimen with pegylated interferon and ribavirin is
superior in regard to SVR and tolerablitiy. Side effects are more common and
severe in patients taking CIFN daily resulting in a higher drop out rate and
lower SVR. CIFN might be favourable for difficult to treat patients with high
viral load or non response to conventional standard therapy.
Demographics and results
|
|
PEG-IFN a-2a plus RBV |
CIFN plus RBV (800mg) |
|
Male (n) |
29 |
26 |
|
Female (n) |
23 |
24 |
|
GT 2 / 3 (n) |
26 |
30 |
|
GT 1 / 4 (n) |
26 |
20 |
|
SVR 2 / 3 (%) |
85 |
73 |
|
SVR 1 / 4 (%) |
58 |
48 |
|
Cirrhosis (n) |
4 |
3 |
|
Drop offs (n) |
0 |
4 |
Topic: Treatment – Disease Progression
W. P. Hofmann; B. Kronenberger; J. Bojunga; B. Stamm;
U. Mihm; M. von Wagner; E. Herrmann; S. Zeuzem; C. Sarrazin
Introduction:
The importance of osteoporosis as a complication of end-stage
chronic liver disease is well known. However, significant osteopenia may
already be present in non-cirrhotic patients with chronic hepatitis C (CHC).
Furthermore, the administration of antiviral therapy may have an influence on
bone metabolism. While interferon alfa has been shown to decrease bone
resorption in vitro and may be beneficial for bone mineral density in vivo,
less consistent data are available for ribavirin.
Patients and Methods:
Thirty non-cirrhotic patients with CHC genotype 1 infection
were treated with peginterferon alfa and ribavirin for 48 weeks. Dual-energy
x-ray absorptiometry was performed at baseline, after 48 weeks of therapy, and
at the end of a 24-week follow up period. Bone mineral density (BMD), and
T-scores / Z-scores were assessed. Additionally, levels of serum C-terminal
propeptide of type I collagen, bone-specific alkaline phosphatase, and
osteocalcin were measured.
Results:
Thirteen of the 30 non-cirrhotic patients had osteopenia
(43%) and manifest osteoporosis was present in 4 patients (13%). Antiviral
therapy led to a significant increase of femur neck and hip BMD (baseline vs
end of treatment, p<0.05) as well as T-scores (p<0.05) and Z-scores
(p<0.01). While in patients with sustained virologic response (n=19) most
parameters remained highly above baseline values by the end of the 24-week
follow up period, patients with virologic relapse (n=11) had a decrease of BMD,
T-scores and Z-scores thereafter that did not differ from baseline values.
Levels of osteocalcin decreased significantly during antiviral therapy,
remained below the baseline levels in sustained responder, but showed an
increase in relapser patients by the end of the 24-week follow up period
(p=0.05).
Conclusion:
·
Osteopenia
is detectable in a substantial proportion of non-cirrhotic patients with CHC.
·
Antiviral
therapy with peginterferon alfa and ribavirin leads to a lasting increase of
bone mineral density in those patients who achieve a sustained virologic
response.
Topic: Treatment – Predictors of
Treatment Response
340. Factors
Impacting SVR in HCV Genotype 1 Patients with EVR and Week 24 Negativity
R. H. Ghalib; C. Levine; A. Steephen; A. Mubarak; J.
Weinstein
Background:
Current guidelines for treatment of chronic HCV utilize the
EVR with ≥2 log decrease in virus as an indicator of patients who are
likely to respond to therapy. Reports indicate a 72% SVR rate in patients with
an EVR. The purpose of this study was to evaluate factors impacting the SVR
rate in chronic HCV genotype 1 patients who have achieved an EVR at treatment
week 12 with viral negativity at week 24.
Methods:
This was a retrospective cohort analysis of HCV genotype 1
patients treated with PEG IFN plus ribavirin. All patients who achieved an EVR
and were HCV RNA undetected at week 24 of treatment were included. “Slow viral
responders” had a ≥2 log decrease with detectable virus at week 12
achieving undetectable virus at week 24.
Results:
Total number of patients was 143 (92 men, 51 women). Age
range was 22-70 (mean 47.1 ± 8.4). Race was White 112 (78%), Black 17 (12%),
and Hispanic 14 (10%). Fibrosis was stage 0-1 in 21, stage 2 in 47, stage 3 in
31, and stage 4 in 34 patients. At treatment week 12, 107 (75%) patients
achieved an undetectable HCV RNA with the remaining 26 (25%) patients being
slow viral responders (Table 1). SVR rate in the group with undetectable virus
at week 12 was 78% (p=0.0001). In patients with slow viral response, the most
important factor impacting SVR was the week 12 HCV RNA <100 IU/ml vs. ≥100
IU/mL with 10/20 (50%) and 0/16 (0%), respectively (p=0.006). Additional
factors demonstrating a trend in different SVR rates were race, baseline viral
count, and PEG IFN used. Racial differences comparing White with non-White
demonstrated a trend with 9/18 (33%) and 1/9 (11%), respectively (p=0.2). Patients
with high baseline viral load (>400,000 IU/mL) had lower SVR than those with
low viral load (0/4 and 10/32, respectively, p=0.25). In slow viral responders,
SVR rate with PEG IFN alfa-2a vs. alfa-2b were 9% and 36%, respectively
(p=0.10).
Conclusions:
·
Slow
viral responders, with a ≥2 log decrease but delayed viral clearance
until week 24, have a significantly reduced chance of SVR with standard 48 week
treatment than those with undetectable virus, 27% vs. 78% respectively.
·
Significantly
higher SVR rates were found in patients who were virus positive with HCV RNA
level <100 IU/mL vs. ≥100 IU/mL at week 12.
·
Trends
toward lower SVR rates were also seen in difficult to treat patients: non-White
race and high baseline viral count.
·
Further
investigation is needed to improve SVR rates in patients who are slow viral
responders.
Number of Patients With Undetectable HCV RNA
|
Week 12 Viral Response |
n |
Week 48 |
SVR |
p Value |
|
≥2 log decrease and viral clearance at week 24 |
36 |
26 (72.2%) |
10 (27.7%) |
0.001 |
|
HCV RNA negative |
107 |
95 (88.8%) |
83 (77.6%) |
Topic: Treatment – HIV/HCV Coinfection
342. Negative
Impact of Abacavir on Response to pegIFN plus RBV in HIV/HCV Coinfected
Patients
P. Barreiro; E. Vispo; I. Maida;
J. Pineda; J. Mira; I. Santos; J. Girón; D. Merino; A. Rivero; V. Soriano
Background:
The choice of antiretrovirals may influence outcome of
pegylated-interferon (pegIFN) plus ribavirin (RBV) therapy. While didanosine
and zidovudine have to be avoided due to greater risk of side effects, little
is known on the influence of abacavir, which is a guanosine analog as RBV.
Methods:
All HIV/HCV patients receiving first-line pegIFN plus RBV therapy
between 2002 and 2005 in three Spanish hospitals were retrospectively analyzed.
Main demographics, HCV features and antiretrovirals were recorded. Baseline
liver fibrosis and RBV plasma levels at week 4 were also available for a large
subset of patients.
Results:
A total of 426 HIV/HCV patients (80% males, mean age 41
years, 80% on HAART, mean CD4 count 567 cells/µl)
received at least one dose of pegIFN plus RBV. At baseline, mean HCV-RNA 5.8
log IU/ml, 65% genotypes 1 or 4, and 40% Metavir ≥F3. The SVR was 38%
(G1/4, 26%; G2/3, 61%). Factors associated with non-SVR in the multivariate
analysis (OR [95% CI] p) were: higher baseline HCV-RNA (10.31 [3.70-28.57]
<0.001), HCV genotype 1/4 (7.75 [2.56-23.25] <0.001), Metavir ≥F3
(4.03 [1.32-12.50] 0.01), and lower RBV plasma trough levels (1.64 [1.03-2.56]
0.04). The use of abacavir predicted non-SVR (2.04 [1.08-3.85] 0.03) when RBV
levels were not included in the model. The negative impact of abacavir on HCV
suppression was recognized at weeks 4, 12, 48 and 72. However, it was not
appreciable in the subset of patients with RBV plasma trough levels >2.2
µg/ml.
Conclusions:
·
Treatment
with peg-ifn plus weight adjusted doses of RBV provided SVR in 38% of HIV
infected patients.
·
Baseline
HCV RNA, HCV-genotype and plasma levels of RBV have a strong influence the rate
of SVR.
·
The
use of ABC as part of HAART is associated with reduced chances for SVR.
·
The
negative effect of ABC was:
o
Particularly
evident in patients with lower exposure to RBV
o
In
part influenced by greater degrees of liver fibrosis at baseline
·
As
RBV and ABC share phosphorylation pathways, a possible intracellular
interaction between both drugs may explain these findings.
Topic: Treatment – HIV/HCV Coinfection
343.
Sustained Virologic Response (SVR) To Peg-Interferon Plus Ribavirin In Genotype-4
HCV-HIV Coinfected Patients
L. Martín-Carbonero; M.
Puoti; J. García-Samaniego; M. Romero; E. Losada; A. Mariñó; K. Abiguerrengoa;
M. Núñez; P. Barreiro; V. Soriano
Background:
HCV Genotype 1 and 4 respond worse to pegylated interferon
(pegIFN) + ribavirin (RBV). For this reason most of the studies joint patients
with these genotypes for SVR rates and factors associated with response.
However, in most trials genotype 4 sample is small,
and real factors associated with response can be biased.
Methods:
All genotype 4 HIV-HCV infected patients who received
treatment with pegIFN+RBV in two different multicentric studies (PRESCO and
ROMANCE) were retrospective analyzed. Baseline viral load (BVL), undetectable
HCV-RNA at week 4 (RVR), decrease of 2 log at week 12 (EVR) were assessed as
predictive factors of response. Results are given as median (IQR) and
percentage. Univariate and multivariate logistic regression analysis was
performed.
Results:
Overall, 75 patients (60 men) were evaluated. Median age and
CD4 cell count were 40 and 598, respectively. 49% of patients had HIV-RNA <
50 copies/ml, 71% had elevated aminotransferase levels and 31% had F3-4
fibrosis. Median HCV BVL was 5.7 log/ml. RVR was obtained in
10 (20%) patients and EVR in 26(42%). In an intention to treat (ITT) and
on-treatment analysis (OTT), sustained virological response (SVR) was achieved
in 21/75 (28%) and 21/62 (34%) of patients, respectively. In the multivariate
analysis (OTT) BVL (OR for every log increment 0.08 95%IC:0.008-0.8)
and EVR (OR 6.5 95%CI:1.3-30.8) were independently associated with SVR. HCV
baseline cut-off to predict response could not be established, as sensitivity
was low: the best cut-off was 5.7 log HCV-RNA with a sensitivity
of 0.3.
Conclusion:
In this large series of patients with HCV-4/HIV coinfection
treated with pegIFN+RBV we confirm than genotype 4 is a difficult to treat
genotype. BVL and RVR are the best predictors of response. However, we could
not establish a good baseline HCV-RNA cut-off to predict response.
Topic: Treatment – HIV/HCV Coinfection
P. Labarga; E. Vispo; P.
Barreiro; J. García-Samaniego; S. Rodriguez-Novoa; C. Castellares; A. Amor; V.
Soriano
Background:
The efficacy of IFN-based therapy is lower in patients with
chronic hepatitis C and HIV coinfection. The number of HCV/HIV patients who
failed to clear HCV with suboptimal therapy in the past has increased rapidly.
They might be good candidates for re-treatment with pegIFN plus weight-adjusted
RBV.
Methods:
Prospective study of therapy with
pegIFN-α2a (180 μg weekly) plus RBV (<75 kg: 1000/d; >75 kg:
1200 mg/d) for 12 months in HIV/HCV patients non-responders or relapsers to a
suboptimal IFN-based therapy. Main endpoint was the achievement of SVR. Advanced liver
fibrosis (ALF) was defined as >9.5 kPa using FibroScan. RBV plasma trough
levels were measured by UV-HPLC.
Results:
A total of 51 patients were included (80% males; mean age 42
years; mean CD4 count 696 cells/μl; 90% on HAART; 89% with undetectable
HIV-RNA; mean HCV-RNA 6.1 log IU/ml; 72% G1-4; 59% with ALF). Prior suboptimal
regimens were IFN monotherapy (23%), IFN+RBV (27%) and peg-IFN+RBV 800 mg/d
(50%). Mean length of these treatments was 6.6 months. Overall, 64% were
non-responders and 36% relapsers.
Re-treatment with pegIFN+RBV provided SVR in 39% of patients
(27% for G1-4 vs 70% G2-3; p=0.02 ). SVR was lower in
non-responders than relapsers (30 vs 58%; p=ns), as in patients with ALF vs
non-ALF (18 vs 60%; p=0.02). RBV plasma trough levels at week 4 were comparable
between SVR and non-SVR (2.53 vs 2.13 ug/ml). In the multivariate analysis,
factors independently associated with the attainment of SVR (OR [95% CI] p)
were: non-ALF (50 [2.12-100] p=0.02), lower baseline HCV-RNA log IU/ml (16
[1.5-166] p<0.05) and G2-3 (33.3 [1.03-166] p<0.05).
Conclusions:
Re-treatment with pegIFN-α2a plus weight-adjusted RBV
for 12 months allows HCV clearance in a significant proportion of HIV/HCV
patients. The better chances of HCV eradication were seen in patients with mild
liver fibrosis, low HCV-RNA, and G2-3.
Topic: Treatment – IDU
346. Feasibility
of combination therapy for chronic hepatitis C in IVDU in the framework of an heroin
detoxification protocol.
A. Ciaccio; D. Ferraro; G.
Alaimo; A. Maggio; A. Craxì; P. L. Almasio
Background and aims.
HCV infection is highly prevalent among intravenous drug
users (IVDU), but only few receive standard-of-care antiviral treatment albeit
small-scale studies suggest feasibility of treatment in this cohort, but also
high rates of withdrawal from therapy affecting its efficacy. We aimed to
assess adherence and sustained viral response (SVR) to therapy in a cohort of
HCV-infected drug addicts within the framework of an
heroin detoxification protocol.
Patients and protocols.
Sixty-seven consecutive anti-HCV positive IVDU patients
currently on methadone or buprenorphine were referred to a Liver Unit by 4
Addiction Centres, to considered for antiviral
therapy. PEG-interferon alfa-2b 1.5 μg/wk and Ribavirin 800-1,400 mg/day
according to body weight were given for 24 (genotype 2 or 3) or 48 weeks
(genotype 1 or 4), and observed for 24 weeks thereafter. Patients were followed
for the entire period directly by the Addiction Centre.
Results.
Seven patients were excluded (3 being HCV RNA negative, 3
because of alcohol abuse, one for morbid obesity) and 60 were treated. This
analysis is conducted on 41 subjects who have completed treatment and follow-up
at the current time. Thirty-nine were males (mean age 32.4 yrs, mean duration
of IVDU 9.1 yrs). Sixteen patients had HCV genotype 1, 2 genotype 2, 17
genotype 3 and 1 genotype 4. The overall withdrawal rate under therapy was 44%.
Seventeen out of 22 (77%) patients who prematurely discontinued therapy were
classified as early drop-outs (discontinuation within the fourth week): in all
cases but one, the cause of discontinuation was primary non-compliance.
Sustained viral response was 34% (18% in G1-4 and 41% in G2-3) on intention to
treat analysis and 73% (40% in G1-4 and 100% in G2-3) by per protocol analysis.
None of the patients enrolled was lost to the heroin detoxification program.
Both the mean time of abstinence from IVDU and the mean duration of former IVDU
were comparable between the patients with adequate and those with suboptimal
adherence. Remarkably, adherence to the antiviral regimen was higher in the
group treated with buprenorphine than in methadone maintenance (8 out of 14,
57.1% vs. 4 out 17, 23.5%, p 0.06).
Conclusions.
Patients with chronic hepatitis C on an
heroin detoxification regimen may be effectively treated with PEG-Interferon
and ribavirin, without any unexpected side effect or loss of efficacy of the
opioid maintenance regimen. The high rate of voluntary discontinuation (mostly
within he first 4 weeks of therapy) cannot be predicted by sociodemographic
factors, but buprenorphine may be more effective than methadone in helping the
patients to adhere to the schedule.
Topic: Treatment – General
347.
Description of Patients with Viral Breakthrough During PEG IFN and
Ribavirin Treatment for Chronic HCV Genotype 1
R. H. Ghalib; C. Levine; A.
Steephen; A. Mubarak; J. Weinstein
Purpose:
The purpose of this study was to evaluate factors impacting
viral breakthrough in patients undergoing PEG/RBV treatment for hepatitis C
genotype 1.
Methods:
This was a retrospective cohort analysis of HCV genotype 1
patients treated with pegylated interferon plus weight-based ribavirin from
2003 to present. All genotype 1 patients who were HCV RNA undetected prior to
week 24 of treatment were included in the sample.
Results:
The total number of genotype 1 patients who underwent
treatment was 431 with 209 achieving an undetectable HCV RNA prior to week 24
of treatment. The number of patients with documented viral breakthrough was 22
(17 males and 5 females). Age range was 24-58 (mean 45.8.1 ± 6.6). Race
distribution was White 13 (59%), Black 7 (32%), Hispanic 1 (5%) and Asian 1
(5%). Fibrosis was stage 0-1 in 3, stage 2 in 11, stage 3 in 4, and stage 4 in
4 patients. BMI was normal in 6 (27%), overweight in 6 (27%), and obese in 10
patients (45%). Baseline viral load was <400,000 IU/mL in 6 (27%) and
>800,000 IU/mL in the remaining 16 (73%). At treatment week 4, 1 patient was
HCV RNA undetectable with a viral breakthrough prior to week 12. At week 12, 9
patients had HCV RNA undetectable with viral breakthrough in 4 prior to week
24, 2 prior to week 40, and 3 at week 48. The other 12 patients had
undetectable virus on or before week 24 with viral breakthrough in 1 prior to
week 24, 8 prior to week 40 and 3 at week 48.
During treatment, 7 patients (32%) were noncompliant with
dosing (2 with ribavirin, 1 with IFN and 4 with both), 9 patients (41%) had
dose reductions (5 with ribavirin, 1 with IFN and 4 with both), and the
remaining 5 (23%) patients were all viral undetectable by week 12 and had no
known noncompliance or dose reductions of medications.
Conclusions:
·
The
majority of patients who suffered a viral breakthrough during treatment with Peg/RBV
for chronic hepatitis C had experienced either dose modifications or were
noncompliant with dosing of one or both medications.
·
However,
viral breakthrough happened in some genotype 1 patients
with favorable predictors of SVR, including low viral load and week 4 and 12
negativity, when neither dose modification nor noncompliance to medications
occurred.
·
This
data emphasizes the importance of maintaining compliance during HCV treatment
even when undetectable levels of virus have been attained.
Topic: Treatment – General
A. Riili; A. Gramenzi; C.
Cursaro; M. Salerno; F. Felline; A. Scuteri; R. Vukotic; G. Vitale; L. Pirillo;
M. Bernardi; P. Andreone
Background:
difficult-to-treat patients with chronic hepatitis C
constitute a large number of heterogeneous patients characterized to resistance
to standard antiviral treatment mainly due to a slow HCV-RNA clearance.
Recently, it has been suggested that extension of treatment to 72 weeks
improves the response in this subset of pts.
Methods:
we enrolled 65 difficult-to-treat
genotype 1 HCV pts (38 males, mean age: 54±11 yrs) defined by at least one of the
following criteria: HCV-RNA serum levels ≥6x105 UI/ml (36
pts), presence of cirrhosis (10 pts), non-response to previous antiviral
treatment (31 pts). Patients were treated with PEG-IFNα2b 1.5 mg/kg plus Ribavirin
800-1,200 mg/day. HCV-RNA was assayed monthly during the first 6 months and pts
resulting HCV-RNA negative (<50 UI/ml) continued the treatment for further
12 months starting since the moment of HCV-RNA negativization. After 6 months
pts who did not achieved a HCV-RNA negativization, withdrew from the study and
were considered non-responders. Study end-point was undetectable HCV-RNA 6
months after treatment cessation (SVR).
Results:
HCV-RNA was negative in 5 pts (8%) after one month of
treatment, in 8 (12%) after two, in 25 (39%) after three, in 6 (9%) after four,
in 4 (6%) after five and in 9 (14%) after six months. Eight pts (12%) did not achieved HCV-RNA negativization within the first six months
and stopped treatment. Up to now 61 patients completed the treatment period and
58 the 6 month of follow-up. A SVR was obtained in 40/58 pts (69%). The absence
of cirrhosis and the naive status were the only predictive factors of SVR
(p=0.009 and p=0.005, respectively).
Conclusions:
·
Extending
antiviral treatment for 12 months after HCV-RNA negativization is a rational
approach to treat HCV difficult-to-treat patients.
·
Although
the study population was heterogeneous, this type of patients are not selected
and very commonly encountered in the medical practice and it is crucial to
define a treatment strategy in this setting.
Topic: Treatment – Predictors of
Treatment Response
S. Pianko; W. Sievert; E. Gane; H. Harley; S. D.
Bowden; R. McCaw; P. Palmer; M. Perlman; K. McLelland; C. Law; G.
Investigators
Aim:
To assess the impact of viral clearance at week 2 of therapy on
the sustained virologic response (SVR) rate of HCV genotype 3 infected patients
with a high viral load.
Methods:
The GET-C study is an ongoing study designed to evaluate
extended therapy in genotype 3 patients with a baseline viral load
>400,000IU/ml. Patients were randomized to receive Peg IFN alpha 2b 1.5ug
/kg per week plus weight based ribavirin for 24 or 48 weeks. We assessed the
predictive value of a week 2 and week 4 virologic response
on the sustained virologic response rate. Viral load was determined using the
Versant HCV RNA 3.0 bDNA assay (Bayer Diagnostics) (limit of detection 615
IU/ml) at baseline, week 2, 4, 12, 24, 36, 48 and 72 where applicable. All data
was collected in an electronic case record form. Statistical analysis was
performed using the Fisher's
Results:
Baseline demographics were similar in responders and non
responders. To date, of the first 43 patients who have completed therapy and
follow up, 42 patients had week 2 virologic data available. Of 42 patients, 30
(71%) achieved viral suppression to below 615 IU/ml at week 2. Of those who
achieved this, 28 had an SVR with a positive predictive value (PPV) of 93%. 12
patients did not clear virus by week 2, of these, 5 did not have an SVR with a negative
predictive value (NPV) of 42%. The impact on SVR of achieving a viral load
reduction to <615IU/ml at week 2 was statistically significant (p=0.011). Of
42 patients, 39 (93%) were below 615 IU/ml at week 4. Seven patients who were
positive at week 2 were negative at week 4 and 4/7 achieved a SVR (57%).
Conclusion:
An ultrarapid virological response at week 2 was highly
predictive of SVR (PPV 93%). These data in 42 genotype 3 patients with high
viral load suggest that week 2 may be a useful time for predicting SVR.
Patients who fail to attain an undetectable viral load by week 2 have a
significantly reduced chance of achieving a SVR and may benefit from extended
therapy, which is being evaluated in the GET-C study.
Topic: Treatment – Side Effects
D. Evon; A. Verma; K. Simpson; K. Dougherty; M. W.
Fried
Background:
The incidence of psychiatric symptoms among patients treated
with peginterferon and ribavirin (pegIFN/RBV) in registration trials ranges
from 20%-30%. However, rigid entry criteria in these studies often excluded
participation by patients with histories of mental health and substance use
disturbance (MH/SUD). This may underestimate the burden of psychiatric side
effects in the general HCV population who undergo HCV treatment. The purpose of
this study was to investigate the incidence and outcomes of psychiatric
symptoms in patients treated for HCV who were not enrolled in sponsored
research studies.
Methods:
Electronic medical records were reviewed from 215 patients
who underwent treatment with PegIFN/RBV from 2002-2006 at a university-based
hepatology center. Logistic regressions, adjusted for gender, age, and race,
explored the relationship between history of MH/SUD and the development of
psychiatric symptoms on treatment.
Results:
Patients were mostly male(59%),
Caucasian 79%), with a mean age of 45.
1) The cumulative history of any MH/SUD
was 67%. History of SUD was present in 48%, history of
depression in 47%, and 14% had a history of anxiety.
2) Prior use of psychotropic medication:
39% had taken psychotropics previously, and 80% continued on meds during
therapy. A total of 39% were taking meds at the start of treatment.
3) Development of psychiatric symptoms
on therapy: 46% endorsed depressive symptoms, 19% endorsed anxiety symptoms,
and 46% endorsed irritability. Cumulatively, 64% of patients indicated mood
disturbance on therapy. The majority of psychiatric symptoms developed between
weeks 2-18 (median=7), and rarely after week 20. Logistic regressions, adjusted
for demographics, showed that a history of depression predicted the development
of depression on therapy. The association was similar for developing anxiety
and irritability.
4) Management of psychiatric symptoms:
Of those who developed mood symptoms, 60% required an intervention such as
prescribing an antidepressant, dose reductions (14%), or treatment discontinuation
(12%). 40% of patients who developed symptoms did not require interventions
beyond close observation.
Conclusions:
This large observational study provides important insights
into the incidence and management of psychiatric symptoms in an unselected
sample of patients treated for HCV. Those treated outside of study protocols
have higher rates of MH/SUD comorbidity, psychotropic med use, and exhibit
higher rates of mood disturbance on therapy compared to previous reports in the
literature. Despite this, most patients are able to complete therapy with
specific interventions to manage psychiatric symptoms.
Topic: Treatment – Pegasys
J. Bronowicki; P. Melin; N. Talbodec; D. Capron; J.
Raabe; I. Beurthon; V. Canva; A. Weiss; D. Lucidarme; S. Fratte; C.
Chandelier
The occurrence of depression was reported in 20-30 % of cases
in the studies which assessed peginterferon alfa and ribavirin in chronic
hepatitis C. However, in these studies the diagnosis of depression was based
only on the clinical impression of the investigators.
Aims:
The aims of our study were to evaluate the incidence of
depression during the treatment with peginterferon alfa-2a plus ribavirin in
chronic hepatitis C in the real life with the help of the Mini-International
Neuropsychiatric Interview (MINI), a short structured diagnostic interview for
DSM-IV and ICD-10 psychiatric disorders and to make the correlation between the
MINI results and the diagnosis made by the clinician and with the Beck
Depression Inventory score (BDI).
Patients and methods:
150 HCV mono-infected patients treated with peginterferon
alfa-2a plus ribavirin are expected to be enrolled in this multicentric study.
The incidence of depression will be assessed at baseline, at weeks 4, 12, 24,
at the end of the treatment and at the end of follow up with the MINI, the
clinician feeling and the BDI score.
Results:
The results from baseline to week 12 of the 123 first
enrolled patients are presented in this intermediate analysis. The baseline
patients characteristics were as follows: mean age: 48 years, male: 73 (59 %),
history of IVDU: 53 (43 %), history of alcohol abuse: 29 (24 %), history of
psychiatric events 30 (24 %), genotype 1: 67 (54 %), F3-F4 fibrosis: 45 (37 %),
naïve patients: 73 (59 %). At baseline, the MINI revealed a current major
depression in 9 patients (7 %), 7 received anti-depressant therapy before (n=5)
or after (n=2) the beginning of peginterferon. Between the baseline and week
12, 21 (18 %) major depressions were diagnosed by the MINI. In 16 cases (76 %),
the clinicians considered that there was no depression. Finally, an
anti-depressant therapy was started in 17 cases (81 %). On the other hand, in 7
cases (6 %) the diagnosis of major depression was made by the clinician but not
confirmed by the MINI. The correlation between the MINI and the BDI was poor.
Conclusion:
·
The
incidence of depression between the baseline and week 12 was of 18 %. Major
depression seems to be under-diagnosed by the clinicians.
·
The
systematic use of Mini-International Neuropsychiatric Interview (MINI), a short
structured diagnostic interview for DSM-IV psychiatric disorders may be of
interest during peginterferon therapy.
This
study was supported by Roche
Topic: Treatment – PEG-Intron
Y. Katano; M. Ishigami;
Background/Aim:
Combination therapy with pegylated interferon (PEGIFN) and
ribavirin is standard therapy for patients with chronic hepatitis C (CHC).
There is evidence that patients with CHC and persistently normal alanine
aminotransferase (PNALT) levels respond similarly to those with elevated
alanine aminotransferase (ALT) levels to treatment with interferon and ribavirin,
however, such data with PEGIFN alfa-2b and ribavirin are currently few. The aim
of this study was to evaluate whether patients with PNALT levels and patients
with elevated ALT levels respond similarly to the combination therapy with
PEGIFN alfa-2b and ribavirin.
Methods:
299 chronic hepatitis patients infected with hepatitis C
virus (HCV) genotype 1 were treated with PEGIFN alfa-2b 1.5
µg/kg/wk plus ribavirin 600-1000 mg/d for 48 weeks. Among this group 54
patients, had at least 3 normal ALT levels over the 3 months prior to
treatment, were defined as patients with PNALT levels. The evaluation of
efficacy was sustained virologic response (SVR), defined as undetectable serum
HCV RNA at 24 weeks after completion of treatment.
Results:
Liver histology in patients with PNALT levels were
significantly milder compared with that in patients with elevated ALT levels.
Overall, 50.0% of patients with PNALT levels and 43.7% of those with elevated
ALT levels were SVR (p=0.395). In male, SVR rates of 46.4% and 51.8% were
obtained in the PNALT group and elevated ALT group, respectively (p=0.605). In
female, SVR rates of 53.9% and 31.7% were obtained in the PNALT group and
elevated ALT group, respectively (p=0.036).
Conclusions:
·
The
efficacy of PEGIFN alfa-2b and ribavirin combination therapy in CHC patients
with PNALT levels is similar to that in patients with elevated ALT levels.
·
In
particular, female patients with PNALT levels should be considered for curative
therapy.
Topic: Treatment – Predictors of Treatment
Response
E. A. Mena; O. E. Ventura; L. M. Blatt; M. J.
Tong
Background:
The role of nonalcoholic steatohepatitis (NASH) must be
considered as a predictor of response to interferon based therapies in the
Latino population. The aim of this study is to determine if steatosis and
diabetes influence sustained virologic response (SVR) rates. Understanding the
pathophysiology of NASH could help clarify pharmacological options and defining
the role of treatment of NASH in overall treatment of HCV.
Methods:
Retrospective chart review of 205 Latino Americans referred
to the
Results:
Of the 205 patients, 67% were born in the
Summary:
There were no statistical differences in SVR with respect to
weight, BMI, diabetes. This may be due the low samples size of the population.
However, there were trends that need to be further analyzed. 67% of our
population had steatosis on liver biopsy. Patients with steatosis on biopsy
tended to have a lower SVR (33%) compared to those with no steatosis (46%). The
diabetic patients had a lower SVR of (26%) compared to our nondiabetic patients
with an SVR of (40%).
|
|
SVR (%) |
NR (%) |
RR (%) |
|
Steatosis |
33 |
53 |
14 |
|
W/o Steatosis |
46 |
42 |
13 |
|
Diabetes |
26 |
47 |
26 |
|
W/o Diabetes |
40 |
49 |
11 |
Topic: Treatment – Consensus Interferon
H. S. Yee; K. Tortorice; S. Chapman; F. Cunningham; S.
Currie
Background:
Approximately 50% of chronic hepatitis C patients who receive
current standard of therapy (peginterferon alfa plus ribavirin) are
nonresponders to treatment. Currently, there is no FDA-approved treatment for
HCV nonresponders or relapsers to peginterferon alfa plus ribavirin. Despite
limited published data and limited criteria for use, some providers may
consider using consensus interferon (CIFN, Infergen®) in combination with
ribavirin as a treatment option in these patients. To date, there have not been
any large studies evaluating provider practice patterns and treatment outcomes
of CIFN in HCV nonresponders or relapsers to peginterferon alfa plus ribavirin.
Objective:
To evaluate treatment outcomes and utilization patterns of
CIFN with or without ribavirin in chronic HCV nonresponders and relapsers to
peginterferon alfa plus ribavirin.
Methods:
A retrospective review was conducted in veterans who were
prescribed CIFN with or without ribavirin in the national VA Healthcare system
from
Results:
776 patients were prescribed CIFN, mostly in combination with
ribavirin. The majority who received CIFN were prior nonresponders/relapsers to
peginterferon plus ribavirin. Patients were predominantly male (95.4%), with a
mean age of 55.4 ± 5.57 years; 40.3% were Caucasian, 25.5% were African
American, 3.9% were Hispanic, and 30.3% were Other/Unknown. In 134 VA medical
facilities, 73 (54.5%) did not prescribe CIFN. In the remaining 61 prescribing
facilities, there was a 15-fold difference in patients receiving CIFN between
the lowest and highest quartiles of prescribers (14.96 OR, 9.83-22.77 95%CI).
766 patients received consensus interferon plus ribavirin with a mean treatment duration of 3.1 months. Virological data were available and 23.5% of
patients treated with consensus interferon/ribavirin were HCV RNA negative
≥ 3 months post treatment.
Conclusion:
o
Consensus
interferon is used frequently, primarily in combination with ribavirin in prior
nonresponders/relapers to peginterferon and ribavirin.
o
Over
57% of patients discontinued consensus interferon use in less than 3 months of
starting treatment.
o
12%
(28/237) remained HCV RNA undetectable at least 3 months post-treatment with
consensus following treatment with peginterferon and ribavirin.
o
Further
analysis is needed to compare consensus interferon response in prior
peginterferon and ribavirin nonresponders versus relapsers.
o
24%
(12/51) of treatment-naïve patients remained HCV RNA undetectable at least 3
months post-treatment with consensus interferon.
o
Factors
associated with outcomes and consensus interferon +/- ribavirin and other
practice variations need to be further assessed.