Tuesday Posters (11/15/2005)– HCV Treatment – 8:00AM – 6:30PM
Abstract ID: 66941
Category: JO7: HCV: Treatment
Relevance
of adherence in the treatment of acute hepatitis C: Final results of the German
HEP-HET Acute Hepatitis C II Trial.
J. Wiegand, Medical School Hannover, Hannover, Germany, P. Buggisch,
University Hospital Eppendorf, Hamburg, Germany, W. Boecher, Dept. Internal
Medicine I, Mainz, Germany, S. Zeuzem, Dept. Internal Medicine II, Homburg,
Germany, C. M. Gelbmann, Dept. Internal Medicine I, Regensburg, Germany, T.
Berg, Charite Campus Virchow, Berlin, Germany, W. Kauffmann, Vivantes Klinikum
Prenzlauer Berg, Berlin, Germany, B. Kallinowski, University of Heidelberg,
Heidelberg, Germany, M. Cornberg, Medical School Hannover, Hannover, Germany,
E. Jaeckel, Medical School Hannover, Hannover, Germany, H. Wedemeyer, Medical
School Hannover, Hannover, Germany, M. P. Manns, Medical School Hannover,
Hannover, Germany
Introduction:
Early treatment of acute
hepatitis C with interferon alfa-2b for 24 weeks effectively prevents chronic
infection. Conflicting data on the importance of adherence to therapy in acute
hepatitis C have been reported. Since the standard therapy of chronic hepatitis
C has changed from conventional to pegylated interferons the aim of this
multicenter nation-wide study was to analyze the efficacy an early treatment
with pegylated interferon alfa-2b in patients with acute hepatitis C.
Methods:
Between February 2001 and
February 2004 89 individuals with acute HCV infection were recruited at 53
different centers (18 university hospitals, 26 general hospitals, 9 private
gastroenterologists) in Germany. Patients recieved 1.5 μg/kg pegylated
interferon alfa-2b s.c. for 24 weeks. End of treatment response (ETR) and
sustained virological response (SVR) were defined as undetectable HCV-RNA (PCR)
at the end of therapy and after 24 weeks of follow-up, respectively.
Results:
In the total study population,
ETR and SVR were 82% and 71%, respectively. A subgroup analysis was performed,
because 13 patients were lost to follow-up. 70 individuals were adherent to therapy
and recieved 80% of the interferon dosage within 80% of the scheduled treatment
period. Follow-up was completed by 65 of 70 of the adherent cases. ETR and SVR
in this subgroup were 94% and 89%, respectively. ALT levels >500 U/l were
the only factor associated with successful treatment (p=0.039). ALT levels in
patients with HCV-genotype 2 and 3 were not significantly higher than in
individuals with HCV-genotype 1 and 4. Lost to follow-up rates did not differ
between the categories of recruiting centers (p=0.3). 8/13 individuals lost to
follow-up had a low social background with contact to the drug scene in 6
cases. However, drug abuse was not associated with lost to follow-up rates
(p=1.0). Adherence to therapy was not associated with gender or age of patients
(p=0.8).
Conclusion:
Adherence to therapy is the
most important factor for treatment response in acute hepatitis C. The high
number of drop out cases underlines the importance of thorough patient
selection and close monitoring during therapy.
Abstract ID: 67786
Category: JO7: HCV:
Treatment
Insulin Increases Hepatitis C Viral RNA Replication In Cell Culture.
H. Zhu, University of
Florida, Gainesville, FL, M. Butera, University of Florida, Gainesville, FL, M.
Addelmalek, University of Florida, Gainesville, FL, D. R. Nelson, University of
Florida, Gainesville, FL, C. Liu, University of Florida, Gainesville, FL
Background
It has been recently reported that insulin resistance and
higher insulin levels impair sustained response rate to peginterferon plus
ribavirin in chronic hepatitis C patients. However, the underlying mechanisms
of the clinical observations are not understood. It is plausible that insulin
may have an impact on HCV replication or interferon signaling pathways.
Aim
To determine the role of insulin in HCV RNA replication and
the role in the intracellular antiviral activity of interferon alpha (IFN)
alone or in combination with ribavirin.
Methods
Full-length (FL-Neo) and subgenomic (GSB1) HCV replicon cell
lines were treated with varying doses of insulin (10-100 uIU/ml) alone, or in
combination with varying doses of IFN (10-100 U/ml), or IFN plus ribavirin. At
48 hours and 72 hours, total RNA was extracted, followed by real-time RT-PCR
assay to determine the HCV RNA levels. For JAK-STAT signaling pathway analysis,
the incubation time was 30 minutes, followed by protein extraction and Western
blot analysis using tyrosinephosphorylation-specific anti-STAT1 and STAT3
antibodies.
Results
Replicon cells treated with higher than 40 uIU/ml insulin
exhibited 3-5-fold increase of viral RNA levels compared with the controls.
Insulin treatment for 48 or 72 hours has a minimal inhibitory impact (5-10%) on
interferon plus ribavirin antiviral efficacy compared with controls without
insulin treatment. Insulin treated cells did not show JAK-STAT pathway
activation. The addition of insulin did not have a significant impact on the
IFN-induced JAK-STAT activation in human liver cells.
Conclusions
Higher insulin levels promote HCV RNA replication in cell culture
system. Insulin does not have a significant direct impact on IFN or IFN plus
ribavirin antiviral activity. Our study suggests that hyperinsulinemia
negatively impacts IFN combination therapy through insulin’s pro-HCV
replication effect.
Abstract ID: 66844
Category: JO7: HCV:
Treatment
Glucose-6-Phosphate Dehydrogenase Deficiency Is Associated With Severe Anemia During Interferon and Ribavirin Therapy.
E. J. Bini, VA New York
Harbor Healthcare System & NYU School of Medicine, New York, NY, B. S.
Anand, Houston VAMC, Houston, TX, A. Aytaman, VA New York Harbor Healthcare
System, Brooklyn, NY, A. Samanta, East Orange VAMC, East Orange, NJ, I.
Cordoba-Rellosa, East Orange VAMC, East Orange, NJ, B. Nemchausky, Hines VAMC,
Hines, IL, H. H. Trevino, San Antonio VAMC, San Antonio, TX, M. A. Mah'moud,
VAMC, Columbia, SC, A. P. Weston, VAMC, Kansas City, MO, N. R. Pimstone, VAMC,
Mather, CA, S. Stancic, VAMC, Hudson Valley, NY, K. Chang, VAMC, Philadelphia,
PA
Background:
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the
most common enzymatic disorder of red blood cells. Although it is well known
that certain medications can trigger a severe hemolytic anemia in patients with
G6PD deficiency, it is unknown whether ribavirin (RBV) is associated with a
more severe anemia in patients with this disorder.
Aim
The aims of this multicenter study were to determine the
prevalence of G6PD deficiency in patients with chronic hepatitis C virus (HCV)
infection, and to evaluate the severity of anemia during interferon (IFN) and
RBV therapy in this population.
Methods
383 IFN naive patients from 11 medical centers in the U.S.
were enrolled. All patients were tested for G6PD deficiency and had hemoglobin
(Hgb) levels measured at baseline, week 2, week 4, and every 4 weeks during IFN
alfa and RBV treatment. RBV was administered at a dose of 1000 - 1200 mg/d and
dose reductions were performed if the Hgb was <10 g/dl. The nadir Hgb was
defined as the lowest Hgb recorded during therapy, and the decrease in Hgb was
calculated as the baseline minus the nadir Hgb.
Results
The mean age of the patients was 49.6 ± 6.1 years, 88.5% were
male, 46.0% were Caucasian, 32.9% were African American, 19.3% were Hispanic, and
1.8% were from other ethnic groups. G6PD deficiency was present in 30 of the
383 patients (7.8%) and did not differ between men and women (8.3% vs 4.5%, p =
0.56). The prevalence of G6PD deficiency differed significantly across ethnic
groups and was 15.9% in African Americans, 8.1% in Hispanics, 2.3% in
Caucasians, and 0% in other ethnic groups (p <0.001). Although the baseline
Hgb levels did not differ between patients with and those without G6PD
deficiency (15.5 ± 1.0 vs 15.2 ± 1.1 g/dl, p = 0.23), patients with G6PD
deficiency were significantly more likely to have lower nadir Hgb levels (10.8
± 1.3 vs 11.8 ± 1.4 g/dl, p <0.001), a greater decrease in Hgb (4.7 ± 1.5 vs
3.4 ± 1.6 g/dl, p <0.001), and lower Hgb levels at week 12 (11.6 ± 1.3 vs 12.6
± 1.5 g/dl, p = 0.001) and at week 24 (11.8 ± 1.2 vs 12.8 ± 1.5 g/dl, p =
0.002). In addition, RBV dose reductions for anemia were more frequent in
patients with G6PD deficiency (26.7% vs 14.7%, p = 0.11).
Conclusions
G6PD deficiency is associated with a more severe hemolytic
anemia during IFN and RBV therapy. HCV-infected patients, especially African
Americans, should be tested for G6PD deficiency prior to the initiation of
treatment and deficient individuals should be monitored closely during therapy.
This study was supported in part by a grant from Schering Plough Corp.
Abstract ID: 66976
Category: JO7: HCV:
Treatment
TREATMENT OF CHRONIC HEPATITIS C VIRUS IN ALLOGENEIC BONE MARROW TRANSPLANT RECIPIENTS
.
T. ASSELAH, Hôpital
Beaujon, Service d'Hépatologie, Clichy, France, R. PEFFAULT DE LATOUR, Service
d'hématologie, Paris, France, V. LEVY, Hôpital Saint Louis, Paris, France, C.
SCIEUX, Service d'Hématologie, Paris, France, A. DEVERGIE, Service
d'Hématologie, Paris, France, P. RIBAUD, Service d'Hématologie, Paris, France,
H. ESPEROU, Service d'Hématologie, Paris, France, R. TRAINEAU, Service
d'Hémobiologie, Paris, France, E. GLUCKMAN, Service d'Hématologie, Paris,
France, D. VALLA, Service d'Hépatologie, Clichy, France, G. SOCIE, Service
d'Hématologie, Paris, France, P. MARCELLIN, Service d'Hépatologie, Clichy,
France
Background and Aim
We recently reported an increased incidence of cirrhosis in
HCV-infected stem cell transplant (SCT) recipient in comparison with non
transplanted patients (1). Treatment of HCV-infected SCT recipients has been
poorly reported for 2 reasons: the incidence of cirrhosis has until recently
been underestimated and the concern that IFN might induce Graft-Versus -Host
Disease. Here, we describe our experience in the treatment of these patients.
Patients and Methods
Among 99 HCV-infected SCT recipients, 36 had HCV-related
liver lesions on biopsy requiring therapy. Because of HCV treatment
contraindication, only 61% of patients (22/36) could be treated. The mean age
of the patients at transplantation was 21.9 years (range, 11-41); 14 were male
(63%) and 8 (37%) were female. All patients had, prior to treatment, anti-HCV
antibodies, detectable serum HCV RNA by PCR and a fibrosis stage „d 1 with
presence of necro-inflammation (Knodell score). Patients were treated with IFN
alone or with a combination of IFN or PEG IFN with RBV (Ą2aIFN; 3 MU 3 times a
week; PEGƒÑ2b IFN 1.5 ƒÝg/kg/week; RBV 1000 mg (weigh < 75Kg) or 1200 mg
(weigh >75Kg)). 12 patients received more than 1 course of treatment.
Results
Combined therapy (PEG IFN: n=9, or standard IFN: n=9, in
combination with RBV) lead to sustained virological response (SVR) in 4/18
(20%) patients as compared to 2/20 (10%) in patients who received IFN alone. No
predictive factors of response were found. However among these 6 patients with
SVR, 4 had received combination therapy either as 1st line (PEG IFN plus RBV:
n=2) or as a 2nd line (IFN plus RBV: n=2) therapy. Then, 2 of 4 (50%) patients
who were initially treated with the gold-standard treatment obtained SVR.
Hematological toxicity was more frequent with combined therapy. While anemia
responded to erythropoietin and/or dose modification, thrombocytopenia when
appeared usually led to treatment interruption (n=3).
Conclusion
This study highlights the efficacy of combined therapy and
that undue safety concerns should not exist when treating this particular
population. Because we did not observe any difference in toxicity between both
association (PEG IFN or standard IFN, in combination with RBV), we advise
clinicians to begin with full dose association of PEG IFN/RBV. This treatment
clearly need close clinical and biological monitoring to prevent side effects.
Prospective clinical trials will be now crucial in assessing the efficacy and
safety of HCV treatment in this patient population, as well as the histological
benefit.
1 - Peffault de Latour R, Levy
V, Asselah T et al. Blood 2004;103: 1618-24.
Abstract ID: 64225
Category: JO7: HCV:
Treatment
PRETREATMENT LEVELS OF INTERFERON-GAMMA INDUCIBLE PROTEIN 10 kDa (IP-10) PREDICT VIRAL KINETIC RESPONSE AND OUTCOME IN DIFFICULT-TO-TREAT PATIENTS WITH CHRONIC HEPATITIS C VIRUS GENOTYPE 1 INFECTION RECEIVING PEGINTERFERON ALFA-2a AND RIBAVIRIN.
M. Lagging, Departments of
Infectious Diseases and Virology, Göteborg University, Göteborg, Sweden, A.
Romero, Dept of Virology, Göteborg University, Göteborg, Sweden, J. Westin,
Dept of Infectious Diseases, Göteborg University, Göteborg, Sweden, J.
Pawlotsky, Dept of Bacteriology and Virology, Universite Paris XII, CRETEIL,
France, S. Zeuzem, Saarland University Hospital, Homburg/Saar, Germany, F.
Negro, Divisions of Gastroenterology and Hepatology, Geneva University, Geneva,
Switzerland, S. W. Schalm, Dpt Gastroenterology & Hepatology, ErasmusMC
University, Rotterdam, Netherlands, B. L. Haagmans, Department of Virology,
Erasmus MC, Rotterdam, Netherlands, C. Ferrari, Laboratorio di Immunopatologia
Virale, Azienda Ospedaliera di Parma, Parma, A. U. Neumann, Faculty of Life
Science, Bar- Ilan University, Ramat-Gan, Israel, K. Hellstrand, Dept of
Virology, Göteborg University, Göteborg, Sweden
Background
The aim of this study was to investigate the predictive value
of baseline plasma IP-10 levels in difficult-to-treat patients with chronic HCV
genotype 1 infection with regards to initial viral kinetic response and final
treatment outcome.
Method
Plasma samples from 265 patients undergoing a multi-center
treatment trial were available for analysis with regards to IP-10 concentrations
prior to starting treatment with pegylated interferon a-2a and ribavirin. Of
these patients, 78 had a genotype 1 infection and a body mass index (BMI)
greater than 25 kg/m2, 83 had a genotype 1 infection and a baseline viral load
greater than 2 million IU/mL, and 41 patients had a genotype 1 infection, BMI
greater than 25 kg/m2, as well as a baseline viral load greater than 2 million
IU/mL.
Results
Significantly lower IP-10 levels were seen in patients who
achieved a rapid initial viral response as compared to those who did not in the
genotype 1 infected patients with a BMI greater than 25 kg/m2 (p=0.004) and
with a baseline viral load greater than 2 million IU/mL (p=0.001), Similarly,
statistically significant lower IP-10 levels were observed in patients
obtaining a sustained viral response as compared to those who did not in the
genotype 1 infected patients having a BMI greater than 25 kg/m2 (p=0.048),
having a baseline viral load greater than 2 million IU/mL (p=0.0005), and
having both a BMI greater than 25 kg/m2 and a baseline viral load greater than
2 million IU/mL (p=0.028). Using the cut-off levels of 150 and 600 pg/mL in the
genotype 1 infected patients having both a BMI greater than 25 kg/m2 and a
baseline viral load greater than 2 million IU/mL, we noted a positive and
negative predictive values of 71% and 100%, respectively.
Conclusion
Baseline IP-10 levels may predict the initial viral kinetic
response as well as the final therapeutic outcome in difficult-to-treat HCV
infected patients, and thus may prove helpful in targeting pharmaceutical
intervention to those most likely of having a favorable outcome, in reducing
the need for liver biopsies, and in avoiding unnecessary side-effects in
patients where current anti-viral therapy is futile.
Abstract ID: 65969
Category: JO7: HCV:
Treatment
Rapid Virological Response at Week 4 (RVR) of Peginterferon alfa-2a (40KD) (PEGASYS®) plus Ribavirin (RBV, COPEGUS®) Treatment Predicts Sustained Virological Response (SVR) after 24 Weeks in Genotype 1 Patients.
D. Jensen, Rush University
Medical Center, Chicago, IL, T. Morgan, VA Long Beach Healthcare System, Long
Beach, CA, P. Marcellin, Hopital Beaujon, Clichy, France, P. Pockros, The
Scripps Clinic, La Jolla, CA, R. Reddy, Hospital of the University of Pennsylvania,
Philadelphia, S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, P.
Ferenci, MedicalUniversity of Vienna, Internal Medicine IV, Vienna, Austria, B.
Willems, Universite de Montreal, Montreal, Canada
SVR rates were significantly higher in genotype (GT) 1
patients (pts) treated for 48 wks with peginterferon alfa-2a (40KD) (PEGASYS®)
+ RBV (COPEGUS®) 1000/1200mg/d than for 24 wks and/or with a lower RBV dose
(800 mg/d) [52% vs 29–42%; Hadziyannis. Ann Intern Med 2004]. However, 78 of
219 (36%) GT1 pts randomized to peginterferon alfa-2a (40KD)/RBV for 24 wks
achieved an SVR. Data was analyzed from this trial to identify factors that
might predict which GT1 pts are likely to achieve an SVR after 24 wks of treatment.
Methods
Pts with chronic hepatitis C were randomized to 24 or 48 wks
of peginterferon alfa-2a (40KD) + standard (1000/1200mg/d) or low dose RBV
(800mg/d). SVR = HCV RNA <50IU/mL after 24wks of untreated follow-up. RVR =
HCV RNA <50IU/mL after 4 wks. We used stepwise multiple regression analysis
(MLR) to identify baseline factors predictive of SVR in GT1 pts treated for 24
or 48 wks with standard dose RBV.
Results
Data from 729 GT1 pts with wk4 results were analyzed. 146/729
(20%) had an RVR. Pts with an RVR had both higher end-of-treatment (EOT) and
SVR rates than pts without an RVR (Figure). Pts with an RVR had lower relapse
rates between EOT and follow-up, regardless of treatment duration or RBV dose.
In contrast, relapse rates decreased with increasing duration of treatment and
RBV dose in pts without an RVR. RVR was more likely in pts with a baseline HCV
RNA level ≤ 0.5x106 than >1.5x106 copies/mL (odds ratio [OR] 9.7,
95%CI 4.2–22.5), and in pts with GT1b than 1a infection (OR 1.8, 95%CI 0.9–3.7).
Conclusion
Approximately 20% of GT1 pts achieved an RVR. Pts with an RVR
are more likely to achieve an SVR after 24 wks of peginterferon alfa-2a (40KD)
(PEGASYS®) + RBV (COPEGUS®) 1000/1200mg/d than those without an RVR because of
lower relapse rates. Use of RVR to guide treatment in GT1 pts should be
confirmed by further studies and tested in prospective trials.
Abstract ID: 66257
Category: JO7: HCV:
Treatment
Total clearance of ribavirin (CL/F) based ribavirin dosage improves the safety and effect of Interferon and ribavirin combination therapy for chronic hepatitis C.
Y. Karino, Sapporo Kosei
General Hospital, Sapporo, Japan, J. Toyota, Sapporo Kosei General Hospital,
Sapporo, Japan, N. Akutsu, Sapporo Kosei General Hospital, Sapporo, Japan, M.
Nakanowatari, Sapporo Kosei General Hospital, Sapporo, Japan, T. Arakawa,
Sappro Kosei General Hospital, Sapporo, Japan, M. Kuwata, Sapporo Kosei General
Hspital, Sapporo, Japan, J. Akaike, Sapporo Kosei General Hospital, Sapporo,
Japan, K. Yamazaki, Sapporo Kosei Genaral Hospital, Sapporo, Japan, T. Sato,
Sapporo Kosei General Hospital, Sapporo, Japan, T. Ohmura, Sapporo Kosei
General Hospital, Sapporo, Japan, S. Iino, Kiyokawa Hospital, Tokyo, Japan
Aim
We have advocated the close relationship of the total
clearance of ribavirin (CL/F) and hemolytic anemia during the combination
therapy of interferon and ribavirin (Rib). CL/F is an important factor for
improving combination therapy. Though the dosage of Rib is set based on patient
weight, in order to improve the safety and effect of combination therapy, we
analyzed the utility of dosage setting on the basis of CL/F.
Methods
Forty-three patients with chronic hepatitis C (male, 23
cases; female, 20 cases; mean age 52.2 years old, genotype: 1b/2a/2b£º33/4/6,
who took a combination therapy of PEGalpha 2b and Rib were used for analysis.
According to Karmar et al. (Amer. J of Kidney Disease 43:140-146, 2004), CL/F
was calculated as follows; CL/F(L/hr)=32.3 x BW x (1-0.0094 x Age) x (1-0.42 x
Sex)/Scr (BW=body weight, sex=0 for men and 1 for women, Scr=serum creatinin).
We set the dosage of Rib with the aim of 2250ng/ml of serum Rib level at the
4th week of therapy, i.e. 400mg for less than 8L/hr of CL/F, 600mg for 8 ¨C
18L/hr, 800mg for 18-28L/hr, and 1000mg for more than 28L/hr (CL/F group). As a
comparison of safety and effect, we used 146 cases of chronic hepatitis C who
took IFN and Rib combination therapy using BW based Rib dosage, i.e. 600mg for
<60kg, 800mg for 60-80kg and 800mg for >80kg 1000mg (BW group).
Results
The mean serum Rib levels at the 4th week of therapy were
2165ng/ml (CL/F group) and 2379ng/ml (BW group) (not significant). In the BW
group, the mean serum Rib level was high in cases with low CL/F
(<8L/hr)(p<0.01), but in CL/F group there was no difference of the mean
serum Rib level in each CL/F grade. As for the average decrease of hemoglobin
level until 8th week of therapy, few tendencies were recognized in the CL/F
group (not significant). The reduction of Rib dosage due to anemia within the
8th week of therapy was 33 out of 146 cases (23.9%) in BW group and 6 out of 32
cases (18.6%) in CL/F group. As for the withdrawal of Rib administration, there
were no cases in the CL/F group and 5 out of 146 cases (4%) in BW group. All of
the withdrawal cases were less than 12L/hr of CL/F. In the patients with high
viral load (>100KIU/ml) and HCV genotype 1b, disappearance of serum HCV RNA
by the 12th week of therapy (EVR) was achieved in 40 of 87 cases (46%) in the
BW group and 9 of 15 cases (60%) in the CL/F group.
Conclusion
CL/F based Rib dosage decreased the reduction or withdrawal
of Rib administration. Furthermore, CL/F based Rib dosage showed EVR rates
greater than the same class, in comparison with weight based Rib dosage. IFN
and Rib combination therapy should be done using CL/F based Rib dosage.
Abstract ID: 66501
Category: JO7: HCV:
Treatment
The TARGET Trial: Final results using 3.0μg/kg pegylated interferon alfa 2-b (Peg;Peg-Intron®) plus ribavirin (RBV;Rebetol®) for chronic hepatitis C patients who were nonresponders (NR) and relapsers (R) to previous therapy.
C. White, UT Southwestern
Medical Center at Dallas, Dallas, TX, C. Wentworth, UT Southwestern Medical
Center, Dallas, TX, P. Malet, UT Southwestern Medical Center at Dallas, Dallas,
TX, W. Lee, UT Southwestern Medical Center at Dallas, Dallas, TX, T. I. Group,
UT Southwestern Medical Center at Dallas, Dallas, TX, V. Cantu, UT Southwestern
Medical Center at Dallas, Dallas, TX, M. Orellana, None, Stockton, CA, R.
Strauss, Northwest Georgia Gastroenterology, Marietta, GA
BACKGROUND:
Retreatment using standard 1.5 μg/kg Peg + RBV of
patients with chronic hepatitis C who have failed previous therapy with
interferon (IFN) + RBV has generally yielded low sustained virologic response
(SVR) rates. Our aim was to study the response to retreatment with (double
dose) 3.0 μg/kg Peg + RBV on patients who failed previous treatment.
METHODS:
We enrolled, in a non-randomized fashion, 326 previously
treated patients (non-responders and relapsers to IFN + RBV) to treatment with
3.0 μg/kg Peg/week + RBV 13 + 2mg/kg/day for 72 weeks; 285 patients
reaching follow up week 24 were analyzed for
this abstract. Values for HCV RNA at week 12, 24, 48, and follow up 24
were compared to those obtained at baseline. RESULTS: HCV RNA response rates at
week 12, 24, 48, and follow up 24 are shown in Table 1. Overall sustained viral
response rate at follow up week 24 was 18%. Treatment was well tolerated in
most patients. Peg dose reductions were required in 15% and serious adverse
events (SAE’s) occurred in 8% of the patients.
SUMMARY:
A reasonable success rate can be reached in patients
undertaking a high dose regimen with minimal if any increase in side effects
over standard dosing. Response is determined by gender, previous treatment
response and the treatment used, with relapsers and those with previous
Rebetron having higher SVRs (29% and 25%) than previous non-responders, and
Peg/RBV patients (SVR=14% and 15% respectively).
CONCLUSIONS:
Motivated patients who have failed previous treatment should
be encouraged to consider repeat therapy with higher dosing, particularly women
who have been relapsers to Rebetron® therapy.
Abstract ID: 66947
Category: JO7: HCV:
Treatment
Interferon-Based Therapy in Chronic Hepatitis C Reduces Cirrhosis and Hepatocellular Carcinoma and Improves Survival: A Nation-Wide, Multicenter Study in Taiwan.
M. Yu, Kaohusiung Medical
University Hospital, Kaohsiung, Taiwan, Y. Liaw, Liver Research Unit, Chang Gung
University Memorial Hospital, Taipei, Taiwan, C. Lee, Kaohsiung Chang Gung
Memorial Hospital, Kaohsiung, S. Lin , Liver Research Unit, Chang Gung Memorial
Hospital, Taipei, Taiwan, C. Dai, Kaohusiung Municipal Hsiao-Kang Hospital,
Kaohsiung, W. Chang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan,
W. Chuang, Kaohusiung Medical University Hospital, Kaohsiung, Taiwan
Background/Aims
To evaluate the long-term effect of interferon-based therapy
on incidence of cirrhosis and HCC and on patients’ survival, adjusting risk
factors, including HCV genotype, a retrospective-prospective cohort study was
conducted in three medical centers and one regional core hospital in Taiwan.
Patients
1619 biopsy-proven chronic hepatitis C patients, including
1057 with interferon-based therapy and 562 untreated controls. Measurements:
The HCV genotype and sustained virologic response (SVR) to interferon-based
therapy were determined. The risk of cirrhosis and HCC during a follow-up
period of 1-15.3 (mean 5.18) and 1-16 (mean 5.15) years in treated and
untreated patients, respectively, was analyzed by using Cox proportional
hazards regression.
Results
Among patients without preexisting cirrhosis, cirrhosis developed
in 51 untreated patients and in 56 interferon-based-treated patients, including
27 nonresponders and 24 sustained responders. The cumulative incidence of
cirrhosis was 9.9% in treated patients and 44.1% in untreated patients (P =
0.0008). HCC developed in 54 untreated patients and in 51 treated patients,
including 39 nonresponders and 12 sustained responders. The cumulative
incidence of HCC was 12.2% in treated patients and 35.2% in untreated patients
(P = 0.0013). Sixteen patients (1.5%) from the untreated group and 28 (2.1%)
from the treated group, including 12 nonresponders (3.5%) and 4 (0.6%)
sustained responders, died. The cumulative survival rate did not differ between
treated patients (96.2%) and untreated patients (93.1%). Significantly lower
incidence of cirrhosis and HCC and death were observed in sustained responders,
but not in nonresponders when compared with untreated patients. HCV genotype 1
patients had significantly higher incidence of HCC but not cirrhosis than
genotype non-1 patients. In multivariate analysis, SVR and age were independent
factors associated with cirrhosis (risk ratio [95% CI]: 0.387 [0.246-0.608] and
1.035 [1.016-1.053], respectively). Preexisting cirrhosis, SVR, HCV genotype
and age were independent factors associated with HCC (risk ratio [95% CI]:
6.592 [4.413-9.849], 0.256 [0.142-0.461], 1.614 [1.091- 2.388] and 1.028
[1.008-1.048], respectively). Preexisting cirrhosis and SVR were independent
factors associated with patient death (risk ratio [95% CI]: 8.843 [4.104-19.05]
and 0.370 [0.138-0.986], respectively).
Conclusions
Successful interferon-based therapy significantly reduces the
risk for cirrhosis and hepatocellular carcinoma and improves survival. There is
HCV genotype-specific difference in hepatocarcinogenesis.
Abstract ID: 67660
Category: JO7: HCV:
Treatment
Cost-effectiveness of Peginterferon Alfa-2b Plus Ribavirin for Chronic Hepatitis C in HIV-HCV Co-infected Patients.
J. B. Wong, Tufts-New
England Medical Center, Boston, MA, M. Buti, Hospital Universitari Valle
Hebron, Barcelona, Spain, M. A. Casado, Pharmacoeconomics & Outcomes
Research Iberia, Madrid, Spain, L. Fosbrook, Schering Plough, Madrid, Spain, V.
Soriano, Hospital Carlos III, Madrid, Spain, R. Esteban, Hospital Universitari
Valle Hebron, Barcelona, Spain
Background:
Since the introduction of highly active anti-retroviral
therapy (HAART), hepatitis C (HCV) has emerged as the leading cause of non-AIDS
mortality. HCV treatment in HIV co-infection may be able to reduce future liver
deaths.
Aim:
To estimate the cost-effectiveness of peginterferon
a-2b+ribavirin for HIV-HCV co-infected patients with various CD4 levels.
Methods
Lifelong clinical and economic outcomes were based on Cox
proportional hazard models estimating the likelihood of developing Metavir
fibrosis stages F1, F2, F3 or F4 over time (using 2313 liver biopsies), a
metaanalysis of fibrosis progression in HIV-HCV infection, and recent UNOS,
SEER and NIH data (Wong AASLD 2003). AIDS-related mortality was based on a
Weibull proportional hazards survival model developed from 12,574 HIV-infected
patients starting HAART (Egger Lancet 2002). For 40-year olds with F2 fibrosis
and CD4 200-350 or >350, we compared no HCV therapy to peginterferon
a-2b+ribavirin. Viral response was based on 5 Spanish studies. Drug and disease
costs were based previously on published Spanish data updated to current costs
(Buti J Hep 2000) assuming a 12-week stopping rule. Cost-effectiveness results
are presented as incremental cost per discounted (3%) quality-adjusted life
year gained.
Results:
HCV therapy should increase life expectancy by 1.5 years and
1.2 quality-adjusted life years (a 16% increase) for CD4 200-350 and by 4.1
years and 3.2 quality-adjusted life years (a 31% increase) for CD4>350. For
sustained viral response=35.6% (n=267), cost-effectiveness ratios were €10,600
for CD4 200-350 and €9,100 for CD4>350. Varying the sustained viral response
over the 95% CI from 29.9% to 41.7% yielded cost-effectiveness ratios of
€12,000-€9,400 for CD4 200-350 and €9,800-€8,600 for CD4>350. If fibrosis
progression rates did not increase with co-infection, cost-effectiveness ratios
were €12,100 for CD4 200-350 and €8,900 for CD4>350. Among 30-year olds,
cost-effectiveness ratios were €12,100 for CD4 200-350 and €8,900 for
CD4>350 and, and among 50-year olds, they were €15,300 for CD4 200-350 and
€9,200 for CD4>350.
Conclusion:
Peginterferon a-2b+ribavirin should be cost-effective for
co-infected patients with F2 fibrosis and CD4>200, but especially for those
with CD4>350 because of their longer life expectancy and hence higher
likelihood of developing hepatic complications during their lifetime.
Abstract ID: 62516
Category: JO7: HCV:
Treatment
Effect of angiotensin II type1 receptor antagonist on insulin resistance and liver fibrosis of chronic hepatitis C patients.
J. Ito, Yamagata
University, Yamagata-city, Japan, T. Saito, Yamagata University, Yamagata-city,
Japan, R. Ishii, yamagata University, Yamagata-city, Japan, K. Sugahara,
yamagata University, Yamagata-city, Japan, K. Saito, yamagata University,
Yamagata-city, Japan, H. Togashi, yamagata University, Yamagata-city, Japan, S.
Kawata, yamagata University, Yamagata-city, Japan
Background:
Recent studies have demonstrated that insulin resistance is
more severely found in HCV patients than healthy controls and that insulin
resistance may contribute to fibrotic progression in the course of chronic
hepatitis C.
Aim:
To investigate the effect of angiotensin II type 1 receptor
antagonist on insulin resistance and liver fibrosis in chronic hepatitis C
patients.
Methods:
This study consisted of 30 consecutive patients with chronic
hepatitis C. The patients were randomized into 2 groups, one given oral
losartan, an angiotensin II type 1 receptor antagonist, at a daily dose of 50
mg in addition to ursodeoxycholic acid (600 mg/day) for 3 months (losartan
group) and the other given no treatment except ursodeoxycholic acid
administration (control group). Serum adiponectin, fasting insulin, collagen
type IV, plasma TGF-β1, and fasting glucose concentrations were compared
before and after treatment in each group. Insulin resistance (IR) was
determined by the homeostasis model assessment (HOMA) method. All patients
underwent liver biopsy before entry and again at completion of the study
period. The degree of fibrosis was expressed at the percentage of the total
area measured, by using a tablet measuring device for micromeasurement, and
termed as fibrosis area.
Results:
Body mass index was not significantly different before and
after the study in either group. In losartan group, serum adiponectin
significantly increased from 9.1±3.7 to 11.1±2.3 mg/ml (p<0.001) and HOMA-IR
significantly decreased from 1.9±1.0 to 1.5±0.6 (p<0.005). Serum type IV
collagen and plasma TGF-β1 concentration in losartan group significantly
decreased from 5.1±1.3 to 4.7±1.0 ng/ml (p<0.05), and from 23.8±7.8 to
15.7±3.2 ng/ml (p<0.001), respectively. Fibrosis area was also decreased
significantly in losartan group from 16.5±4.5 to 13.9±3.7 % (p<0.001).
However, no significant change was observed after the study periods in control
group.
Conclusions:
These results suggest that angiotensin II type1 receptor
antagonist have a beneficial role in improving insulin resistance and liver
fibrosis of patients with chronic hepatitis C.
Abstract ID: 64954
Category: JO7: HCV:
Treatment
EFFECT OF ETHNICITY ON THE PHARMACOKINETICS OF RIBAVIRIN (COPEGUS®) AND PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) IN PATIENTS WITH CHRONIC HEPATITIS C.
B. Brennan, Hoffmann-La Roche,
Nutley, NJ, R. Morrison, Northwest Kinetics, Tacoma, WA, C. Hagedorn,
University of Kansas Medical Center, Kansas City, KS, T. C. Marbury, Orlando
Clinical Research Center, Orlando, FL, M. Sulkowski, Johns Hopkins University,
Baltimore , MD, J. Grippo, Hoffmann-La Roche, Nutley, NJ, J. Gries, Hoffmann-La
Roche, Nutley, NJ
Background:
The study purpose was to evaluate the effect of ethnicity on
the pharmacokinetics (PK) of ribavirin and PEG-IFN alfa-2a (40KD) through a
comparison of Black and Hispanic Chronic Hepatitis C (CHC) patients with a
Caucasian control arm.
Methods:
Forty-seven CHC patients of three different ethnic groups (17
Blacks, 14 Hispanics and 16 Caucasians) received 8 weeks of ribavirin and
PEG-IFN alfa-2a (40KD) therapy according to the FDA approved dosing regimen
(ribavirin 1200 mg daily for patients ≥ 75 kg or 1000 mg daily for
patients < 75 kg; PEG-IFN alfa-2a (40KD) 180 μg qw). Serial blood
samples were collected predose and 0.5, 1, 3, 4, 5, 6, 8 and 12 hours after
dosing for ribavirin plasma concentrations and 0.5, 1, 3, 5, 8, 12, 24, 48, 72,
96, 120, 144 and 168 hours after dosing for PEG-IFN alfa-2a (40KD) serum
concentrations. PK samples were drawn following the first dose and at week 8
for single dose and steady state assessment, respectively. The PK parameters
(Cmax, Tmax, AUC(0-last), AUC(0-tau), CL/F) for ribavirin and PEG-IFN alfa-2a
(40KD) were estimated using noncompartmental methods. The primary value for
comparability testing for ribavirin and PEG-IFN alfa-2a was the ratio of
pharmacokinetic parameters (AUC and Cmax) in Black and Hispanic CHC patients
relative to Caucasian patients. An ANOVA was applied to natural log
dose-normalized Cmax and AUC of ribavirin and PEG-IFN alfa-2a (40KD). The
ratios of the geometric least squares means (LSM) and 90% confidence intervals
(CI) were determined.
Results:
The PK parameters of ribavirin were similar between Hispanic
and Caucasian CHC patients. The single dose Cmax was 33% lower (p<0.05) in Black
compared with Caucasian patients. While other ribavirin single dose and steady
state PK parameters were slightly decreased (approximately 20% lower) and
ribavirin clearance was slightly increased (approximately 28% higher) in Blacks
as compared to Caucasians, these differences did not reach statistical
significance. PEG-IFN alfa-2a (40KD) PK parameters were similar between Black
and Caucasian patients and between Hispanic and Caucasian patients.
Conclusion:
No ethnicity-based differences were observed in ribavirin PK
parameters between Hispanic patients and Caucasian patients or in PEG-IFN
alfa-2a (40KD) PK parameters between Black or Hispanic patients as compared
with Caucasian patients. A trend towards an increase in ribavirin clearance and
a decrease in exposure was observed in Black patients as compared with
Caucasian patients.
Abstract ID: 66985
Category: JO7: HCV:
Treatment
An Evaluation of the Cost-effectiveness of Peginterferon alfa-2a (40KD) (PEGASYS®) Plus Ribavirin (COPEGUS®) for the First Treatment of Mild Chronic Hepatitis C (CHC).
J. Hornberger, The SPHERE
Institute/Acumen, LLC, Burlingame, CA, G. Dusheiko, Royal Free and University
College School of Medicine, London, United Kingdom (Great Britain), G. Lewis,
Roche Products Ltd, Welwyn Garden City, United Kingdom (Great Britain), K.
Patel, Hoffmann-La Roche, Inc, Nutley, NJ
Background:
We previously demonstrated that peginterferon alfa-2a (40KD)
+ ribavirin (PEG alfa-2a/RBV) is a cost-effective treatment compared with
either no treatment or interferon combination therapy among patients with
moderate or severe CHC. However, the cost-effectiveness of PEG alfa-2a/RBV
compared with no treatment for adults with mild CHC has not been evaluated.
Methods:
Sustained virological response (SVR) rates for mild CHC
patients were obtained from a phase III multinational, randomized, controlled
trial (Zeuzem et al. Gastroenterology, 2004;127:1724). Mild CHC was defined as
a fibrosis score of 2/6 and necroinflamatory score of 3/18. With PEG
alfa-2a/RBV treatment, HCV genotype 1 (treated for 48 weeks) and genotype 2/3
(treated for 24 weeks) patients achieved SVR rates of 39% and 69%,
respectively. For those patients failing to achieve an SVR, age, gender and
ALT-specific rates of fibrosis progression were applied from published sources
and their disease progression was followed over their expected lifetime. The
impact of 12-week predictability testing on the cost of treatment was explored
in the model. Quality of life weights and NHS resource costs were based on
literature and estimated UK treatment patterns, respectively. Costs were
discounted at 6% and benefits at 1.5%.
Results:
Cost Effectiveness
·
The incremental cost effectiveness
of peginterferon alfa-2a (40KD) plus ribavirin vs. no treatment was £7025 (United Kingdom currency) per QULY gained in patients with mild CHC
and persistently ‘normal’ ALT. The
cost-effectiveness ratio varied substantially by HCV genotype.
Sensitivity analyses
· In our scenario analysis for patients with mild CHC and elevated ALT, we
found that the incremental cost per QALY gained in peginterferon alfa 2a (40KD)
plus ribavirin vs. no treatment was uniformly less than that in patients with
persistently ‘normal’ ALT. In mild CHC
patients with elevated baseline ALT , the incremental cost per QALY gained was £4898.
· The weighted analysis
combining mild CHC patients with elevated and persistently ‘normal’ ALT
suggested that the incremental cost effectiveness of peginterferon alfa-2a
(40KD) plus ribavirin compared with no treatment in all mild CHC patients was
£6174 per QALY gained.
· All incremental cost
per QALY gained estimates were below £30,000.
Ninety-five percent of the estimates for mild hepatitis patients with
persistently ‘normal’ ALT were below £11204, while 95% of the estimates for
patients was elevated ALT were below
£7767.
Conclusions
· The estimated ICERs for
peginterferon alfa-2a (40KD) plus ribavirin (Copegus) for newly diagnosed
patients with mild CHC were all less than £10,000 per QALY gained, regardless of
HCV genotype or ALT status. The findings
appear to be robust when subjected to probabilistic sensitivity analysis, with
100% of the simulated ICERs estimated to be below a threshold of £30000 per
QALY gained.
· The cost effectiveness
of peginterferon alfa 2a (40KD) plus ribavirin compared with no treatment in
patients with mild CHC is most likely a result of a reduction in the incidence
of future complications such as cirrhosis, hepatoceullular carcinoma and liver
transplantation, and an increase in life expectancy and QOL.
· The analysis suggests
that it is cost effective to treat mild CHC patients with peginterferon alfa 2a
(40KD) plus ribavirin, regardless of HCV genotype and baseline ALT.
· After 30 years, 16% of
patients treated with PEG alfa-2a/RBV had progressed to cirrhosis compared with
31% of untreated patients. In genotype 1 patients, PEG alfa-2a/RBV increases
quality-adjusted life expectancy (QALY) by 11 months compared with
no-treatment, yielding an incremental cost per QALY gained of £8,658. In genotype
2/3 patients, PEG alfa-2a/RBV increases QALYs by 1.6 years compared with no
treatment and has an incremental cost per QALY gained of £2,122.
Abstract ID: 62400
Category: JO7: HCV:
Treatment
HCV treatment patterns and utilization for HCV mono-infected and HCV/HIV coinfected patients in the Veterans Administration.
H. K. Tam, VA San Diego
Healthcare System, San Diego, CA, A. E. Phippard, VA San Diego Healthcare
System, San Diego, CA, R. W. Baran, Roche Laboratories, Nutley, NJ, L. L.
Lanza, RTI Health Solutions, Waltham, MA, S. A. Bozzette, VA San Diego
Healthcare System, San Diego, CA
Introduction
Hepatitis C virus (HCV) infection has been shown to correlate
highly with human immunodeficiency viral (HIV) infections.1,2 End-stage liver
disease has become a leading cause of morbidity and mortality in HIV-infected
patients since the introduction of highly active antiretroviral therapy
(HAART). Concerns regarding the proper
treatment of patients with HIV/HCV coinfection have been growing.
Current treatment for chronic HCV infection is based on the
use of various
preparations of interferon (IFN). Pegylated-IFN (PEG), as
well as combination therapy with ribavirin (Rib), is now replacing standard IFN
because of the once-weekly dosing and better efficacy of PEG.
Methods
Data were obtained from the Veterans Administration’s
National Patient Case Databases and contains medical, laboratory, and pharmacy
data on a random sample of patients receiving HCV care in the VA from January 2000
through January 30, 2003. The sample
consisted of 56,876 patients, including all 6744 patients with both HCV and HIV
infection and 50,132 patients with HCV alone.
Patients were observed from the HCV index date through
September 30, 2004 to assess HCV therapy initiation, and among those treated,
HCV therapy duration and resource use.
Results
Our sample included 26,987 patients with newly identified
HCV, and 16,824 patients with previously identified HCV receiving care in the
VA healthcare system during the study period.
Patients excluded from further analyses for having previously identified
HCV were similar to the analytic sample, although more likely to be white (57%
vs. 50%), and more likely to be coinfected (15% vs. 12%).
At baseline:
· Coinfected patients
were more likely to be younger (29% vs. 18%) and black (60% vs. 28%) compared
with HCV patients only.
· The majority (70%) of
coinfected patients were receiving HIV treatment in the 12 months prior to the
identification of HCV status.
During the follow-up period:
HCV treatment was initiated in 2,093 (7.8%) of all patients. HCV-only patients were twice as likely to
initiate treatment as coinfected patients (p<.001). HIV treatment status was not significantly
associated with HCV treatment among the coinfected.
· Rate of HCV treatment
initiation was higher for the HCV only patients compared with the coinfected
patients at 0.31 and 0.15 per 100 patient-months of observation, respectively,
p<.001.
· Treatment initiation
rates were highest for white HCV –only patients and lowest for black coinfected
patients, at 0.33 and 0.11 per patient-months of observation, respectively,
p<.001.
· Failure to receive HCV
therapy was associated with prevalence of psychiatric, cardiovascular,
endocrine, respiratory, circulatory, renal, and HIV-related conditions. Sixty-three percent of patients not receiving
HCV therapy during the study period had a psychiatric condition at baseline
compared with 49% of those receiving therapy during the same period,
p<.001. This association remained the
same after adjusting for HIV coinfection status and, among the coinfected
patients, after adjusting for HIV treatment status.
· Eighty percent (1675)
of treated patients received PEG+Rib as first treatment. Type of first therapy was not associated with
HIV status or HIV treatment status among the coinfected.
· Coinfected patients
initiated treatment later compared to HCV –only patients p<0001.
· Among the treated,
median time to first treatment was 16 months for HCV-only patients and 20
months for coinfected patients.
· Among the treated,
median time to first treatment was significantly long for blacks (19 months)
compared with whites (16 months).
· The median duration of
HCV therapy was 8 months among HCV-only patients compared with 7 months for
confected patients. More than 95% of
treated patients discontinued their first course of treatment of treatment by
15 months from initiation.
Conclusion
Consistent with other studies, a small proportion of HCV
patients were treated. Choice of HCV therapy
seemed appropriate, with PEG+Rib as the most common regimen. IV coinfection was more often present among
younger blacks. Among the coinfected and among blacks, treatment rates were
lower and initiation later. The
appropriateness of these seemingly low and differential treatment rates need to
be further evaluated in the context of HCV disease type and severity,
likelihood of response, and specific comorbidity (mental illness),l as well as
other factors (eg, social support, provider attitudes). Increases in resource use were apparent after
HCV treatment initiation; however,
utilization data are preliminary and seeming changes in patterns of service use
should not be considered conclusive or attributable to treatment.
Abstract ID: 63984
Category: JO7: HCV:
Treatment
Behaviour of sustained responders to anti-HCV treatment: may HCV infection be eradicated?.
A. Petrarca, Department of
Internal Medicine, University of Florence, Florence, Italy, U. Arena ,
Department of Internal Medicine, University of Florence, Florence, Italy, C.
Giannini, Department of Internal Medicine, University of Florence, Florence,
Italy, M. Monti, Department of Internal Medicine, University of Florence,
Florence, Italy, V. Solazzo, Department of Internal Medicine, University of
Florence, Florence , Italy, F. Giannelli, Department of Internal Medicine,
University of Florence, Florence, Italy, P. Caini, Department of Internal
Medicine, University of Florence, Florence , G. La Villa, Department of Internal Medicine, University
of Florence, Florence , Italy, G. Laffi, Department of Internal Medicine,
University of Florence, Florence , Italy, A. Zignego, University of Florence,
Florence, Italy
HCV infection may lead to both hepatic and extrahepatic
pathologies including mixed cryoglobulinemia (MC). The percentage of sustained
response (SR) to therapy significantly increased after introduction of
ribavirin (RBV) and pegylated IFN. SR was only rarely obtained in MCS.
Persistence of HCV infection, mainly in PBMC, has been recently shown, and the
possibility of clinical correlates suggested. The aim of this study was the
long-term follow-up of SR patients and to evaluate HCV persistence with very
sensitive methods.
Methods
63 SR pts after therapy for HCV infection (combined treatment
with IFN -pegylated in 33 pts- and RBV in all but 2 pts) were consecutively
recruited. Patients with risk conditions for reinfection (i.e., active drug
addiction) were excluded. 59 pts have been treated for HCV CLD and 4 for MC. 2
pts underwent OLT after SR. Mean f-u was 50.3 (18-101) m. Clinical evaluation
and blood drawing were obtained biannually; liver biopsy was taken at an
average of 29 m. after SR. Methods included HCV RNA detection by very sensitive
HCV PCR-hybridization assay (sensitivity 1-5 HCV IU/ml), TMA, rTth PCR (-
strand), direct sequencing, cultures of total PBMC, macrophages, and
lymphocytes with mitogens. In MCS pts t(14;18) and clonal BL expansion by
bcl2/JH and VDJ PCR were also tested.
Results
During f-u all serum and liver samples were negative both by
HCV PCR and TMA. Uncultured PBMC were positive in 2 MCS pts. These pts had
t(14;18)+ expanded BL clones before treatment, disappearance at the end, and
reappearance during f-u, with identity of preand post-treatment clones. HCV
genotypes in PBMC were also identical in pre- and posttreatment samples. Mild
residual arthralgia (2/2) and sicca syndrome (1/2), trace amounts of
cryoglobulins (CGs), altered RF and C4 values were detected during f-u. Culture
of PBMC with mitogens allowed detection of additional 2 cases with persistent
infection: in these pts trace amounts of CGs were detected before treatment and
disappeared after therapy.
Conclusions
This study suggests that combined therapy may lead to viral
eradication in the majority of HCV+ pts. Even if it is impossible to exclude
viral persistence at undetectable levels, it does not seem to have clinical
relevance even in the case of OLT. Persistence of viral infection in uncultured
PBMC was only observed in MC with clonal BL expansion. A tentative explanation
may be related to the expanded life of t(14;18)+ BL. Although a different
evolution of LPD may not be excluded, “occult” PBMC infection was accompanied
by mild clinical manifestations, thus indicating the interest for antiviral
treatment also in this condition.
Abstract ID: 64926
Category: JO7: HCV:
Treatment
Retreatment for Non-responders in Initial Interferon Therapy Suppresses Hepatocarcinogenesis and Improves Long-term Survival of Chronic Hepatitis C Patients.
K. IYODA, OSAKA NATIONAL
HOSPITAL, Osaka, Japan, M. KATO, OSAKA NATIONAL HOSPITAL, Osaka, Japan, Y.
IZUMI, OSAKA NATIONAL HOSPITAL, Osaka, Japan, T. UEDA, OSAKA NATIONAL HOSPITAL,
Osaka, Japan, T. NAKAMURA, OSAKA NATIONAL HOSPITAL, Osaka, N. HAYASHI, OSAKA
NATIONAL HOSPITAL, Osaka, Japan, T. OTA, OSAKA NATIONAL HOSPITAL, Osaka, Japan,
Y. NISHIMURA, OSAKA NATIONAL HOSPITAL, Osaka, Japan, A. TODAKA, OSAKA NATIONAL
HOSPITAL, Osaka, Japan, N. SHIRAHATA, OSAKA NATIONAL HOSPITAL, Osaka, Japan, E.
SATOMI, OSAKA NATIONAL HOSPITAL, Osaka, Japan, T. MICHIDA, OSAKA NATIONAL
HOSPITAL, Osaka, Japan, N. YUKI, OSAKA NATIONAL HOSPITAL, Osaka, Japan, K.
YAMAMOTO, OSAKA NATIONAL HOSPITAL, Osaka, Japan, M. IKEDA, OSAKA NATIONAL
HOSPITAL, Osaka, Japan
AIM:
Interferon (IFN) therapy for chronic hepatitis C patients
causes HCV RNA clearance or alanine aminotransferase (ALT) normalization.
Moreover, we had reported IFN retreatment reduced the risk for hepatocellular
carcinoma (HCC) and prolonged the long-term survival. However, the effect of
IFN retreatment for non-responders in initial IFN therapy is not known. We
investigated whether IFN retreatment for non-responders therapy prevents the
development of HCC and improves prognosis in this retrospective cohort study.
METHODS:
Five hundred and forty two patients with chronic hepatitis C
were received interferon monotherapy in Osaka National Hospital from 1987 to
2001. These patients were followed from 24 to 191 months after IFN therapy. The
HCC appearance rate and the survival rate were analyzed using Kaplan-Meier
technique and the log rank test. Independent factors associated with them were
studied using the stepwise Cox regression analysis.
RESULTS:
After 6 months from the end of initial IFN therapy, sustained
virological responders (SVR) with HCV RNA clearance were 187 patients,
transient responders (TR) with ALT normalization were 217 and non-responders
(NR) were 138. During observation period, forty two developed HCC, of whom 6
were SR, 10 were TR and 26 were NR. And twenty two died. The cumulative
incidence of HCC in TR was almost equal to that in SVR, but it was
significantly higher in NR than in SVR or TR (p=0.0006 or 0.0002). The
cumulative survival rate in TR was also equal to that in SVR, but it was significantly
lower in NR than in SVR or TR (p=0.0035 or 0.0006). Univariate analysis
associated the risk for HCC and the survival with the effect of IFN and age. In
NR, retreatment (NR-RT) with 2nd IFN therapy was found in 36 patients and
non-retreatment (NR-NRT) in 102. After 10 years of initial IFN therapy the
cumulative incidence of HCC was 11.3% in NR-RT and 27.5% in NR-NRT. It was
significantly higher in NR-NRT than in NR-RT (p=0.0053). The cumulative
survival rate was 95.2% in NR-RT and 76.0% in NR-NRT. It was significantly
lower in NR-NRT than in NR-RT (p=0.0052). No significant difference of
characteristics was observed between NR-RT and NR-NRT patients except platelet
count.
CONCLUSIONS:
The risk for HCC and the liver related death of
non-responders were significantly high compared to sustained and transient
responders in initial IFN therapy. However, IFN retreatment for non-responders
in initial IFN therapy decreased the incidence of HCC and ameliorated the
survival rate in them.
Abstract ID: 65281
Category: JO7: HCV:
Treatment
Hepatitis C Treatment Results in an Alaska Native / American Indian Population.
C. Christensen, Liver
Disease and Hepatitis Program, ANTHC, Anchorage, AK, D. Bruden, Arctic
Investigations Program, CDC, Anchorage, AK, S. Lvingston, Liver Disease and
Hepatitis Program, ANTHC, Anchorage, AK, J. Williams, Liver Disease and
Hepatitis Program, ANMC, Anchorage, AK, C. Homan, Liver Disease and Hepatitis
Program, ANTHC, Anchorage, AK, D. Sullivan, University of Washington, Seattle,
WA, D. Gretch, University of Washington, Seattle, WA, B. McMahon, Liver Disease
and Hepatitis Program, ANTHC, Anchorage, AK
Background:
Treatment response for chronic hepatitis C infection in
various ethnic populations has not been well studied. African American response
to interferon and ribavirin therapy has been shown to be significantly lower
than that of Caucasians. Less is known about other minority groups including
Alaska Natives/American Indians (AN/AI) as they have been underrepresented in
clinical trials. The purpose of this study was to characterize the treatment
response of an AN/AI cohort and to determine if their response is similar to
other ethnic groups reported. The Alaska Native Tribal Health Consortium
Hepatitis Program (Anchorage, AK) and the University of Washington (Seattle,
WA) has conducted a population-based longitudinal study of AN/AI patients
infected with hepatitis C to determine disease outcome since 1994.
Methods:
We retrospectively reviewed the medical records of AN/AI receiving
antiviral treatment at the Alaska Native Medical Center and regional Alaska
Native healthcare clinics between 1992 to 2004. Fisher’s exact test was used to
test HCV treatment response rate by genotype and confidence intervals were
exact.
Results:
Since 1992, 69 antiviral treatments were administered to 60
patients in the AN/AI healthcare system out of cohort of 800 chronic hepatitis
C patients. Fifteen patients received Interferon monotherapy and were excluded
from our analysis. Of the 48 patients receiving 54 Interferon/Ribavirin
combination treatments, 6 patients are pending outcome and for the 8 patients
who received 2 courses of therapy, only the first course of therapy was
included in the analysis. Of the 40 first treatment courses of combination
therapy in naïve patients, 11 (27.5%) treatments were discontinued primarily
due to intolerance to medication side effects or patient compliance. In an
intention–to-treat analysis, 35% (n=14) achieved a sustained virological
response (SVR). The SVR rate differed by HCV genotype (p-value = 0.005). Of
patients with genotype 1, 6.7% (1/15; 95% CI 0-32%) achieved a SVR versus 52%
(13/25; 95% CI 31%-72%) of patients with genotypes 2 and 3. Of patients who
completed their full course of treatment, 48.3% (14/29) had an SVR, 10% (1/10;
95% CI 0-44%) for patients with genotype 1 and 68% (13/19; 95% CI 43%-87%) of
patients with HCV genotypes 2 and 3 (p-value = 0.005).
Conclusions:
Although the number of patients treated is limited, results
to date suggest AN/AI infected with genotype 1 may respond less well than
Caucasians to combination therapy. Because treatment response of different
ethnic groups has not been adequately documented, efforts should be made to
encourage racial diversity in clinical trials.
Abstract ID: 66183
Category: JO7: HCV:
Treatment
Association between sustained virological response (SVR) and ALT levels in HIV-HCV co-infected patients who received peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT).
J. González-García, Hospital Universitario La Paz, Madrid, Spain, S.
Moreno, Hospital Ramón y Cajal, Madrid, Spain, M. von Wichmann, Hospital
Donostia, San Sebastian , Spain, E. Lissen, Virgen del Rocio University
Hospital, Seville, Spain, C. Tural, HIV clinical Unit. Hospital Universitari
Germans Trias Pujol, Barcelona , Spain, B. Clotet, Fundacio irsiCaixa,
Barcelona, Spain, F. Torriani, UCSD Epidemiology Unit, San Diego, CA, D.
Dieterich, The Mount Sinai Medical Center, New York, NY
In APRICOT, treatment with the combination of peginterferon
alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for 48 weeks produced
significantly higher SVR rates than peginterferon alfa-2a (40KD) monotherapy or
conventional interferon plus ribavirin (40% vs 20% and 12%, respectively, p
< 0.001) in patients with HIV-HCV co-infection. We investigate the
relationship between baseline ALT level and SVR in patients treated with
peginterferon alfa-2a (40KD) plus ribavirin.
Methods
HIV-HCV co-infected patients with detectable serum HCV RNA,
elevated ALT levels, and stable HIV disease were eligible for this randomized,
international trial. SVR, the primary outcome in the trial, was defined as
undetectable HCV RNA (<50 IU/mL) at the end of untreated follow-up (week
72). In this analysis, SVR rates were stratified by baseline ALT quotient
(qualifying ALT value divided by the upper limit of normal of the local
laboratory). We compared SVR rates between ALT strata with the Cochrane-
Mantel-Haenszel test stratified by region, genotype and CD4 cell count.
Results (table)
SVR rates increased significantly with ALT quotient. The SVR
rate among 106 patients with an ALT quotient >3 was 53%. A total of 49
patients had baseline ALT quotients >4, among whom 24 (49%) achieved an SVR.
Conclusion
· The most important
factor that influence the response to peginterferon alfa-2a (40KD) (PEGASY)
plus ribivirIn (COPEGUS) in patients with HIV/HCV coinfection are HCV genotype
and baseline HCV RNA level.
· The results of this
analysis demonstrated that the probability of achieving an SVR with
peginterferon alfa-2a (40KD) plus ribavirin increases with increasing ALT
quotient in patients with HIV/HCV coinfection.
· One-third of patients
with ALT quotient ≤ achieved an SVR.
Moreover, 52% of patients with HCV mono-infection and persistently
‘normal’ ALT levels treated with the same combination regimen as that in
APRICOT achieved an SVR. For this reason
a normal ALT level should not be a barrier to treatment in patients with
HIV/HCV coinfection.
· The majority of
patients who achieved an SVR also had a sustained biochemical response,
irrespective of baseline ALT quotient.
· The decision to treat
should not be based on the results of a laboratory test, but rather on a comprehensive
evaluation of patients and viral factors.
This is particularly important in patients with HIV/HCV coinfection, in
whom HCV-related liver disease progresses much more rapidly than in patients
with HCV mono-infection.
Abstract ID: 66478
Category: JO7: HCV:
Treatment
Tumor necrosis factor alpha promoter polymorphism at position ¡V308 predicts hepatitis C virus response to combination therapy with high dose interferon and ribavirin.
C. Dai, Kaohusiung
Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, M. Yu, Kaohsiung Medical
University Hospital, Kaohsiung, Taiwan, W. Chuang, Kaohsiung Medical University
Hospital, Kaohsiung, Taiwan, L. Lee, Kaohsiung Medical University Hospital,
Kaohsiung, Taiwan, M. Hsieh, Kaohsiung Medical University Hospital, Kaohsiung,
Taiwan, N. Hou, Kaohusiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, W.
Chang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
Background:
The G-to-A polymorphic sequence in the tumor necrosis factor
(TNF) alpha promoter gene at position -308 (TNF308.2) and -238 (TNF238.2) might
be associated with response to therapy in chronic hepatitis C (CHC). Methods:
Total 141 CHC patients undergoing combination therapy with high dose
interferon-alpha (IFN; 6 megaunits [MU] thrice weekly) and ribavirin for 24
weeks were enrolled. We performed polymerase chain reaction amplification,
followed by the Restriction Fragment Length Polymorphism (RFLP) method for -308
and -238 TNF-alpha promoter polymorphisms. Detection of serum HCV RNA was
performed using a standardized automated qualitative reverse transcription
polymerase chain reaction assay. HCV genotypes 1a, 1b, 2a, 2b and 3a were
determined by amplification of the core region using genotype-specific primers.
Pretreatment HCV RNA levels were determined using a branched DNA assay.
Results:
The genotype distributions were TNF308.1/TNF308.1:
TNF308.1/TNF308.2: TNF308.2/TNF308.2 = 108 (76.6%): 30 (21.3%): 3 (2.1%) with
the TNF308.2 allele frequency of 12.8% and TNF238.1/TNF238.1: TNF238.1/TNF238.2
= 139 (98.6%): 2 (1.4%). One hundred patients (70.9%) achieved sustained viral
response (SVR). In univariate analyses, SVR was significantly related to HCV
genotype non-1b (p<0.001) and lower pretreatment levels of HCV RNA
(P=0.005). Patients with high TNF-alpha production phenotype had a lower SVR
rate than patients with low TNF-alpha production phenotype (57.6% vs. 74.8%,
P=0.054). Based on multivariate regression analyses, the independent factors
predicting HCV SVR after combination therapy were HCV genotype non-1b, low
pretreatment HCV RNA levels, TNF 308.1 allele and higher scores for
necroinflammatory activity. After further stratification of the patients to
groups by HCV 1b or non-1b genotype infection or with high (>=200,000IU/ml)
or low (<200,000IU/ml) pretreatment HCV RNA levels, the SVR rate among 43
patients with genotype 1b infection and high HCV RNA levels was significantly
lower than among other 3 groups of patients (32.6% vs. 80%, 87.8% and 93.1%,
P<0.005, <0.0001 and <0.0001, respectively). Eight of the 43 patients
with genotype 1b infection and high pre-treatment HCV RNA levels had TNF308.2
and they all did not achieve SVR. The SVR rate was significantly lower than the
40% (14/35) among the other patients with TNF308.1 (P=0.029). The 2 patients
with TNF-alpha promoter TNF238.1/ TNF238.2 genotypes were females and both of
them achieved SVR.
Conclusions:
V308 TNF-alpha promoter polymorphisms predict HCV SVR to
combination therapy with high dose IFN and ribavirin, especially in patients
with genotype 1b infection and high viral load.
Abstract ID: 66605
Category: JO7: HCV:
Treatment
High selectivity and low cytotoxicity associated with R1479, a novel inhibitor of HCV replication.
W. Jiang, Roche Palo Alto, Palo Alto, CA, S. Le Pogam, Roche Palo Alto,
Palo Alto, CA, V. Leveque, Roche Palo Alto, Palo Alto, CA, H. Ma, Roche Palo
Alto, Palo Alto, CA, I. Najera, Roche Palo Alto, Palo Alto, CA, J. Hang, Roche
Palo Alto, Palo Alto, CA, M. Mulkins, Roche Palo Alto, Palo Alto, CA, G.
Heilek-Snyder, Roche Palo Alto, Palo Alto, CA, A. Jekle, Roche Palo Alto, Palo
Alto, CA, L. Garvin-Queen, Roche Palo Alto, Palo Alto, CA, J. Symons, Roche
Palo Alto, Palo Alto, CA, R. Devos, Argenta Discovery, Harlow, United Kingdom
(Great Britain), J. Martin, Consultant, Harpenden, United Kingdom (Great
Britain), N. Cammack, Roche Palo Alto, Palo Alto, CA, K. Klumpp, Roche Palo
Alto, Palo Alto, CA
The nucleoside analog R1479 was identified as a specific
inhibitor of HCV replication in subgenomic HCV replicon cells (IC50 = 1.2 microM).
Previous studies suggested HCV polymerase as the molecular target for the
corresponding triphosphate derivative (R1479- TP). In a transient replicon
system R1479 inhibited HCV RNA replication driven by genotype 1b polymerase
with similar potency as compared to that driven by genotype 1a polymerase (IC50
= 0.6 microM). R1479-TP inhibited native HCV replicase and recombinant NS5B
from genotype 1a and 1b with similar potency. In contrast, R1479- TP did not
inhibit the functionally related native influenza virus RNA dependent RNA
polymerase (RdRp) activity in vitro, suggesting high selectivity for the HCV
RdRp. R1479 did not inhibit influenza virus replication in MDCK cells. R1479
did not affect cell viability of Huh-7 derived replicon cells and did not
inhibit thymidine incorporation into cellular DNA at concentrations up to 1 mM.
R1479 associated cytotoxcity was low or undetectable in cell culture including
prolonged incubation times up to 8 days in a variety of cell types including
primary cells and cell lines under dividing and stationary conditions.
Cytotoxicity was lower with R1479 as compared to Ribavirin across all cell
types tested. Thus, R1479 was identified as a potent and highly selective
inhibitor of HCV polymerase mediated RNA synthesis and has been shown to
exhibit low overall cytotoxicity in cell culture.
Abstract
ID: 66606
Category: JO7: HCV:
Treatment
The novel nucleoside analog R1479 is a potent inhibitor of HCV polymerase and HCV replication in cell culture.
K. Klumpp, Roche Palo Alto, Palo Alto, CA, R. Devos, Argenta Discovery,
Harlow, United Kingdom (Great Britain), W. Jiang, Roche Palo Alto, Palo Alto,
CA, V. Leveque, Roche Palo Alto, Palo Alto, CA, H. Ma, Roche Palo Alto, Palo
Alto, CA, I. Najera, Roche Palo Alto, Palo Alto, CA, S. Le Pogam, Roche Palo
Alto, Palo Alto, CA, j. Hang, Roche Palo Alto, Palo Alto, CA, K. Sarma, Roche
Palo Alto, Palo Alto, CA, D. Smith, Roche Palo Alto, Palo Alto, CA, D. Heindl,
Roche Diagnostics GmbH, Penzberg, Germany, J. Symons, Roche Palo Alto, Palo Alto,
CA, N. Cammack, Roche Palo Alto, Palo Alto, CA, J. Martin, Consultant,
Harpenden
HCV polymerase activity is essential for HCV replication.
Targeted screening of nucleoside analogs identified R1479 as a specific inhibitor
of HCV replication in subgenomic HCV replicon cells (IC50 = 1.2 microM) with
similar potency as compared to 2’-C-methyl-cytidine (IC50 = 1.0 microM). R1479
showed no effect on cell viability or proliferation of HCV replicon cells or
Huh-7 cells at concentrations up to 1 mM. HCV RNA could be fully cleared from
replicon cells after prolonged incubation with R1479. The corresponding
5’-triphosphate derivative, R1479-TP, is a potent inhibitor of native HCV
replicase isolated from replicon cells and of recombinant HCV polymerase (NS5B)
mediated RNA synthesis activity. The potency of NS5B inhibition is dependent on
template RNA sequence, consistent with a nucleotide competitive inhibition
mechanism. R1479-TP inhibited RNA synthesis with a Ki value of 40 nM. On a HCV
RNA derived template substrate (cIRES) R1479-TP showed similar potency of NS5B
inhibition as compared to 2’-C-methyl-cytidine-TP. A point mutation in the
coding sequence of NS5B conferred HCV polymerase resistance to inhibition by
2’-C-methyl-cytidine-TP. The mutant NS5B enzyme was as sensitive to inhibition
by R1479-TP as wild-type NS5B. In contrast to 2’-C-methyl-cytidine, R1479
showed high apparent selectivity of HCV replication inhibition and did not
inhibit replication of BVDV in cell culture. R1479 is currently under
evaluation as a drug candidate for the treatment of HCV infection.
Abstract ID: 67412
Category: JO7: HCV:
Treatment
Repeated liver stiffness measurement using FibroScan® for the follow-up of untreated HCV patients and for the evaluation and monitoring of histological response in HCV responders: a prospective longitudinal study.
V. de Ledinghen, Hopital
Haut-Leveque, Pessac, France, L. Castera, Hopital Haut-Leveque, Pessac, France,
J. Foucher, Hopital haut-Leveque, Pessac, France, P. Bernard, Hopital
Saint-Andre, Bordeaux, France, R. Tournan, Hopital Haut Leveque, Pessac,
France, N. Le Provost, Hopital Haut Leveque, Pessac, France, P. Couzigou,
Hopital Haut Leveque, Pessac, France
Abstract ID: 67438
Category: JO7: HCV:
Treatment
Association of a single nucleotide polymorphism of the CTLA-4 gene with response to interferon-based treatment in patients with chronic hepatitis C virus infection.
E. Schott, Charite Universitaetsmedizin Berlin, Berlin, Germany, H. Witt,
Charite Universitaetsmedizin, Berlin, Germany, S. Tinjala, Charite
Universitaetsmedizin, Berlin, Germany, J. Halangk, Charite
Universitaetsmedizin, Berlin, Germany, V. Weich, Charite Universitaetsmedizin, Berlin,
Germany, A. Bergk, Charite Universitaetsmedizin, Berlin, Germany, G. Teuber,
Universitaet Frankfurt/M, Frankfurt, Germany, C. Sarrazin, Universitaet des
Saarlandes, Homburg, Germany, H. Klinker, Universitaet Wuerzburg, Wuerzburg,
Germany, P. Buggisch, Universitaetsklinikum Eppendorf, Hamburg, Germany, H.
Hinrichsen, Universitaet Kiel, Kiel, Germany, B. Wiedenmann, Charite
Universitaetsmedizin, Berlin, Germany, T. Berg, Charite Universitaetsmedizin,
Berlin, Germany
A T lymphocyte response is essential for the control of HCV
infection. Cytotoxic Tlymphocyte antigen 4 (CTLA-4) is an inhibitory receptor
expressed on activated T lymphocytes. Single nucleotide polymorphisms (SNPs) of
CTLA-4 are associated with favorable responses to combination therapy in HCV
genotype 1-infection. We investigated whether SNPs of CTLA4 influence early
viral and end of treatment response rates in patients treated with other
interferon-based regimens and in patients infected with different genotypes.
Cohort 1 comprised 336 treatment-naive HCV genotype 1-infected patients that
received therapy with pegIFN-a-2b and ribavirin and for whom week 12 virologic
response data was available (determined by quantitative bDNA assay, detection
limit 615 IU/ml). Cohort 2 comprised 608 patients (387 genotype 1, 38 genotype
2, 110 genotype 3, 18 genotype 4, 55 unknown) who had received different
interferon-based regimens (208 monotherapy, 391 combination therapy, 9
unknown). Patients were categorized as end of treatment responders (HCV-RNA
negative at the end of treatment, including sustained responders and relapsers)
and non-responders (HCV-RNA positive at the end of treatment). PCR was
performed using genomic DNA isolated from PBMC, SNPs were analyzed by
fluorescence resonance energy transfer using a LightCycler. In cohort 1, an
early virologic response was associated with the presence of the G allele of
SNP +49 (71.4% of carriers vs. 60.3% of non-carriers were HCV-RNA negative,
X2=4.3 p<0.05). In cohort 2, the end of treatment response was associated
with the presence of the G allele in patients that underwent monotherapy (54.5%
of carriers vs. 40.8% of non-carriers were HCV-RNA negative, X2=3.7, p=0.06).
Subgroup analysis showed that the association was only significant for men
(62.5% vs. 40.5%, X2=4.9, p<0.05) but not women (42.3% vs. 41%, p=ns) and
was present for genotypes 1/4 (48.4% vs. 22.4%, X2=9.0, p<0.01) but not
genotypes 2/3 (88.2% vs. 66.7%, p=ns). An association was also present for men
treated with any interferon-based regimen (65.9% vs. 54.5%, X2=4.1, p<0.05)
but not for women (61.2.0 vs. 65.3%, p=ns). An inverse association was found
for women treated with combination therapy (47.8% vs. 82.5 %, X2=4.2,
p<0.05) but not for men (47.5 vs. 60.7%, p=ns). This study establishes a relationship
between SNP +49 of CTLA4 and early virologic as well as end of treatment
response rates in patients with chronic HCV infection. It reveals a gender
difference of the association with response to interferon-based therapies and
shows a more pronounced effect for therapies of inferior efficacy (i.e.
monotherapy) or for hard-to-treat genotypes.
Abstract ID: 65108
Category: JO7: HCV:
Treatment
THE ROLE OF ANTIVIRAL THERAPY AFTER CHEMOTHERAPY ON THE CLINICAL OUTCOME OF HCV RELATED NON-HODGKIN LYMPHOMA (NHL).
V. La Mura, Second
University of Naples, Chair of Internal Medicine, Naples, Italy, M. Masarone,
Second university of naples, Chair of internal medicine, Naples, Italy, F.
Perna, Federico II University, Haematology Unit, Naples, Italy, A. De Renzo,
Federico II University, Haematology Unit, Naples, Italy, C. Marzocchella,
Second University of Naples, Chair of Internal Medicine, Naples, Italy, F.
Carrino, Second University of Naples, Chair of Internal Medicine, Naples,
Italy, M. Persico, second university of naples, Chair of Internal Medicine,
Naples, Italy
The prevalence of HCV infection in Non Hodgkin Lymphoma (NHL)
is high. No data exist reporting on HCV influence on the outcome of the
disease. Moreover, it is not known if antiviral therapy (interferon +
ribavirin) might be useful to modify the natural course of NHL disease in HCV
infected patients previously treated with chemotherapy. We retrospectively
observed 358 chemotherapy treated patients come to clinical observation during
the last 10 years. All the patients were tested for the HCV infection.
Epidemiological, clinical and histological characteristics together with the
calculation of disease free survival (DFS) and overall survival (OS) were
compared in HCV-positive (69/358) and HCV-negative patients. 25 HCV-positive
patients were treated with Interferon (INF) +Ribavirin at least one year later
chemotherapy discontinuation and the response to treatment was evaluated.
Disease free survival (DFS) and overall survival (OS) in HCV/NHL treated and
not-treated patients were tested.
RESULTS:
Prevalence of HCV infection was 19% and a significant
prevalence of indolent (based on histological evaluation) disease was found in
this group compared to HCV-negative patients. No clinical neither
epidemiological differences were rather found between the two groups as well as
no differences were found for OS and DFS. Sustained virological response (SVR)
to antiviral treatment in HCV-positive patients was 30%, lower than that
reported for patients affected with chronic active hepatitis (CAH).
Nevertheless, in chemotherapy treated NHL subjects, HCV antiviral therapy seems
to influence the outcome of the disease in terms of DFS (p<0.05) whereas the
difference at OS was not statistically significant though p value was 0.05. At
the multivariate analysis the independent factors related to a better clinical
outcome after chemotherapy in HCV infected NHL were the histology at the onset
of the lymphoma and the antiviral therapy.
CONCLUSIONS:
HCV does not influence, after chemotherapy, the clinical
outcome of NHL although the disease at the onset shows less aggressive in
HCV-positive patients. The efficacy of antiviral therapy in HCV positive NHL
patients is not as high as in CAH patients though it might show beneficial at
least in terms of DFS. A larger prospective study is warranted to confirm that.
Abstract ID: 67280
Category: JO7: HCV:
Treatment
Interim safety analysis of patients enrolled in the randomized, international REtreatment with PEgasys® in pATients not responding to prior peginterferon alfa-2b/ribavirin (RBV) combination therapy (REPEAT) study.
P. Marcellin, Hôpital
Beaujon, Clichy, France, B. Freilich, Baptist Medical Center, Kansas City, MO,
P. Andreone, University of Bologna, Bologna, Italy, C. E. Brandão-Mello,
University of Rio de Janeiro, Rio de Janeiro, Brazil, A. DiBisceglie, St. Louis
University, St. Louis, MO, R. Rai , Johns Hopkins University School of
Medicine, Baltimore , MD, D. Jensen , Rush University Medical Center, Chicago,
IL
Introduction
We initiated the REPEAT study, in which nonresponders to
peginterferon alfa-2b (12KD)/RBV were randomized to peginterferon alfa-2a
(40KD) (PEGASYS®) + RBV (COPEGUS®), to evaluate a high fixed dose induction
regimen plus extension of treatment beyond 48 wks. Here we report the planned
12wk interim safety analysis and evaluate the safety of the 12wk induction with
high-dose peginterferon alfa-2a (40KD).
Methods
Adults with quantifiable HCV RNA who were nonresponders to
previous Peginterferon alfa-2b (12KD)/RBV were eligible. Patients (pts) were
randomized to one of 4 groups (A,B,C,D):
· peginterferon alfa-2a
(40KD) + RBV 1000/1200 mg/d x 72 wks (A&C)
or x 48wks (B&D).
o
Groups A&B
received fixed induction doses (360μg/wk) of peginterferon alfa-2a (40KD)
in wks 1-12.
o
The peginterferon alfa-2a (40KD) dose was 180μg/wk for
the rest of treatment in groups A&B
and throughout treatment in groups B&D.
Patients and baseline
characteristics
· Patients were recruited
between September 2003 and March 2005.
· A total of 950 patients
were randomized to treatment (476 in the high-dose induction groups, Arms A and
B combined; 474 in the standard-dose group, Arms C and D combined). Overall,
942 patients received study medication following randomization.
· Demographic and
baseline characteristics were well matched between the two groups. The
population exhibited many ‘difficult to treat’ characteristics; most patients
were infected with HCV genotype 1, approximately one-quarter were cirrhotic,
and the mean HCV viral load was high (Table 1).
·
Results
Virological Response at Week 12
Conclusion
In a difficult-to-treat population, non-responders to prior
pegylated interferon alfa-2b (12KD) plus ribavirin, high rates of early
virological response were achieved at 12 weeks re-treatment with peginterferon
alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS)
· 45% with standard dose
- 360 μg/week
· 62% with induction dose
- 180 μg/week
Abstract ID: 61185
Category: JO7: HCV:
Treatment
ANTIVIRAL THERAPY IN PATIENTS WITH OCCULT HCV INFECTION.
M. Pardo, Fundación para el Estudio de las Hepatitis Virales, Madrid,
Spain, I. Castillo, Fundación para el Estudio de las Hepatitis Virales, Madrid,
Spain, E. Rodríguez-Iñigo, Fundación para el Estudio de las Hepatitis Virales,
Madrid, Spain, A. Pérez-Mota, Digestive Dept., Hospital Virgen de la Torre,
Madrid, Spain, V. Carreño, Fundación para el Estudio de las Hepatitis Virales,
Madrid, Spain
Occult HCV infection is defined by the presence of HCV-RNA in
liver cells but with undetectable anti-HCV and serum viral RNA. Patients with
occult HCV infection present abnormal liver function test and liver damage,
including liver cirrhosis (1).
Objective:
To assess the efficacy and safety of PEG-IFN plus ribavirin
therapy in occult HCV infection.
Methods:
Ten patients (7 males) with occult HCV infection (HCV-RNA in
liver by RTPCR and by in situ hybridization in the absence of anti-HCV and
serum HCV-RNA) were included. All of them had HCV genotype 1b in the liver,
abnormal ALT values (74.4 ± 22.2 IU/l) and HCV-RNA in peripheral blood
mononuclear cells (PBMC). In addition, all patients presented necroinflammatory
activity in the liver and 5 of them had liver fibrosis (4 cases F1 and the
other F2). Patients received standard doses of PEG-IFN plus ribavirin for 24
weeks and were followed monthly during therapy and every three months during
the postreatment follow up (24 weeks). All of them completed the treatment and
the antiviral therapy was well tolerated.
Results:
At the third month of treatment, 4/10 (40%) patients
normalized ALT levels, and in 6 cases (60%) HCV-RNA became undetectable in
PBMC. At the end of therapy, ALT values were normal in 8/10 (80%) patients. In
addition, 6/8 responder patients (75%) were HCV-RNA negative in PBMC while the
other 2 cases remained with viral RNA in their cells. The 2 patients who did
not achieve a biochemical response lost HCV-RNA in PBMC. At the end of the
follow-up 6/10 patients (60%) remained with normal ALT levels and HCV-RNA in
PBMC was negative in 7 cases (4 of them with normal ALT). A second liver biopsy
was performed in 5 patients. In all of them, HCV-RNA persisted in liver as
detected by real time RT-PCR and by in situ hybridization, although HCV-RNA
load in liver was significantly lower (p=0.043) in the postreatment biopsy (3.2
´ 104 ± 5.1 ´ 104 copies/mg total RNA) than in the basal one (2.4 ´ 105 ± 3.8 ´
105 copies/mg total RNA). Regarding liver histology, in 2 patients remained
unchanged while in the other 3 cases necroinflammatory activity and fibrosis
score decreased.
Conclusion
In conclusion, up to 60% of patients with occult HCV
infection treated with PEG-IFN plus ribavirin for 24 weeks presented a
sustained biochemical response. Loss of HCV-RNA in PBMC is observed in 70% of
patients. Finally, although viral RNA persists in the liver cells after
treatment, an improvement in the liver damage is achieved. All these data
demonstrate the pathological role of occult HCV infection in these patients.
(1) J Infect Dis 2004; 189:7-14
Abstract ID: 61867
Category: JO7: HCV:
Treatment
Peginterferon alfa-2a Pharmacokinetics in African American and Caucasian Americans infected with HCV genotype 1.
C. Howell, University of
Maryland School of Medicine, Baltimore, MD, T. Dowling, University of Maryland
Baltimore, Baltimore, MD, L. Jeffers, University of Miami, Miami, FL, T. Norah,
University of California San Francisco, San Francisco, CA, T. Wiley-Lucas, Rush
University Chicago, Chicago, IL, M. Haritos, University of Pittsburgh,
Pittsburg, PA
African Americans (AA) infected with hepatitis C virus (HCV)
genotype 1 have lower rates of HCV clearance than Caucasian Americans (CA)
following treatment with peginterferon alfa (PEGIFN) and ribavirin. This
difference is observed as early as day 2 of PEGIFN combination therapy.
Aim:
To determine whether there are racial differences in PEGIFN
pharmacokinetics (PK) during the first 4 wks of therapy in a subset of AA and
CA HCV genotype 1 patients (pts) enrolled in the Virahep-C study.
Methods:
401 treatment-naïve, HCV genotype 1 pts (196 AA and 205 CA)
were assigned to PEGIFNa-2a (180 mcg/wk) and ribavirin (1000-1200 mg/day) for
48 wks. Treatment was discontinued at wk 24 if the serum HCV RNA was detected.
Ninety-six pts who received PEGIFN without dose alteration during the first 4
wks of treatment and who had PEGIFN serum levels measured day (D) 0 (before
treatment) and on treatment days 1, 2, 3, 7, 14 and 28 were selected for PK
analyses. PEGIFN levels were measured by ELISA (Roche Diagnostics). The maximum
PEGIFN concentration (Cmax0-7), time to maximum concentration (Tmax0-7), and
area under the serum concentration-time curve (AUC0-7) values from day 0 to 7
were determined using non-compartment PK analysis (WinNonlin; Pharsight Corp.,
Mountain View, CA, USA).
Results:
At baseline, AA pts had a significantly lower mean serum ALT
levels (p = 0.003) than CA, but there were no racial differences in age, gender
distribution, body weight, BMI, alcohol or tobacco use, liver histology,
creatinine clearance, baseline HCV RNA levels, and HCV 1 subtype distribution.
Table. PEGIFN-2a PK results [mean (SD)]
|
|
Cmax0-7 (ng/mL) |
Tmax0-7 < D3 (%) |
AUC0-7 (ng*hr/mL) |
D28 PEGIFN (ng/mL) |
|
AA (n = 44) |
12.9 (7.9) |
90.9 |
1456.8(716.8) |
18.0 (7.8) |
|
CA (n = 52) |
10.7 (5.4) |
75 |
1276.7 (649) |
15.4 (7.2) |
|
p-value |
0.13* |
0.028** |
0.20* |
0.12* |
*t-test; **Fisher’s exact test
AA were more likely than CA to have Tmax < D3 than CA.
However, the unadjusted Cmax0-7, AUC0-7, and D28 PEGIFN-2a concentration were
similar in AA and CA. However, after adjusting for body weight, the D28 PEGIFN
level (but not Cmax and AUC) was higher in AA (p=0.04). There was a significant
correlation between AUC0-7 and the D28 PEGIFN-2a concentration (p < 0.001).
In multiple regression analyses, AA race (p = 0.04) and BMI category (p =
0.001) were associated independently with the D28 serum PEGIFN levels. There
were no associations with Cmax and AUC.
Conclusion:
AA and CA HCV genotype 1 pts exhibit differences in PEGIFN-2a
PK, with a shorter Tmax0-7 and a higher day 28 serum PEGIFN concentration
(adjusted for body weight) in AA. The relationship between PEGIFN PK and
treatment response in AA and CA pts remains to be determined.
Abstract ID: 62522
Category: JO7: HCV:
Treatment
The usefulness of elastometry using FibroScan502 for assessment of liver fibrosis stage in chronic hepatitis C.
T. Takeda, Department of
Hepatology, Osaka City University, Osaka, Japan, T. Yasuda, Department of
Hepatology, Osaka City University, Osaka, Japan, M. Nakaya, Department of
Hepatology, Osaka City University, Osaka, Japan, Y. Nakayama, Department of
Hepatology, Osaka City University, Osaka, Japan, S. Seki, Department of
Hepatology, Osaka, Japan, T. Tanaka, Department of Public Health, Osaka City
University, Osaka, Japan, S. Shiomi, Department of Nuclear Medicine, Osaka City
University, Osaka, Japan, H. Asai, Osaka Kyoiku University, Osaka, Japan
Background and Aims:
Staging of liver fibrosis is important for predicting the
clinical course of chronic hepatitis C, including the incidence of
hepatocellular carcinoma (HCC). Transient elastometry (FibroScan502; FS) is a
rapid and non-invasive method of assessing liver fibrosis. We examined liver
elastometry in patients with and without a sustained viral response (SVR) to
interferon (IFN) therapy.
Patients and methods:
One hundred and thirty four patients with chronic hepatitis C
admitted to Osaka City University Hospital were included in this study. Liver biopsy
was performed under ultrasonography on the patients less than six months before
FS measurement. Twenty patients who showed clear clinical and ultrasonographic
evidence of liver cirrhosis did not undergo liver biopsy. Pathological
assessment was made of sections from formalin-fixed and paraffin-embedded liver
biopsies stained with hematoxylin-eosin. We scored fibrotic stage according to
Desmet et al. Healthy volunteers and patients without liver disease were
enrolled as a control group (stage 0). Fourteen patients with a sustained
virological response to IFN therapy were enrolled. These patients underwent
liver biopsy before IFN therapy, and at least 6 months before measurement by
FS. We measured liver elastometry using FS. We examined the relationship
between elastometry and the stage of histological fibrosis.
Results:
Medians (50% levels) of FS measurement at each fibrosis stage
were as follows: 4.2 (3.7-4.8) in stage 0, 5.7 (4.4-7.8) in stage 1, 7.4
(5.1-12.0) in stage 2, 14.7 (11.7-21.0) in stage 3, and 24.0 (16.3-29.0) in
stage 4 (Kruskal-Wallis test p<0.0001). Patients with SVR were compared with
patients who were not treated with IFN. Median FS measurements were 4.0 and 7.4
(p=0.049) in stage 1, 4.5 and 10.5 (p=0.003) in stage 2, 7.7 and 16.2 (p=0.024)
in stage 3, and 6.3 and 25.3 (p=0.001) in stage 4, with and without SVR
respectively. In all stages, FS measurements for patients with a SVR were lower
than for patients who did not have IFN therapy.
Conclusion:
Elastometry measured using FibroScan502 correlated well with
the histological stage of fibrosis. Changes of liver fibrosis stage may be
estimated noninvasively using FibroScan502.