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 (ƒÑ2aIFN; 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 &#8805; 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.