Tuesday Posters (11/15/2005)– HCV Treatment – 8:00AM – 6:30PM

 

 

Abstract ID: 64900

Category: JO7: HCV: Treatment

Are there differences in sustained virological response (SVR)rates in patients with HCV genotype 2 or 3 infection and persistently ‘normal’ ALT activity undergoing treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®)?

a. alberti, University of Padova, Padova, Italy, R. Reindollar, Carolina Center for Liver Disease, Charlotte, NC, M. Romero-Gomez, Hospital Universitario de Valme, Seville, Spain, D. Prati, Ospedale “A. Manzoni”, Lecco, Lecco, Italy, P. Couzigoue, Hepato Gastroenterology Department Hautleveque, Pessac, France, S. Zeuzem, Saarland University Hospaital, Homberg, Germany

 

In patients with chronic hepatitis C and persistently ‘normal’ ALT levels, Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS) produced SVR rates of 72% and 78% after 24 and 48 weeks of treatment, respectively, in patients infected with HCV genotype 2/3 (Zeuzem et al, Gastroenterology 2004; 127:1724). However, as some studies have shown different outcomes in genotype 2 and 3 patients, we examined, separately, SVR rates in patients infected with HCV genotypes 2 and 3 patients who were enrolled in this large, randomized international study.

 

Methods

Patients infected with chronic HCV genotype 2 or 3 and with ALT levels ≤30IU/L on ≥3 occasions over 18 months were randomized to receive 24 or 48 weeks treatment with peginterferon alfa-2a (40KD) 180μg/week plus low-dose ribavirin (800mg/day). All patients were monitored for 72 weeks. The primary endpoint was SVR, determined by qualitative PCR (HCV RNA <50 IU/mL COBAS AMPLICOR® HCV Test, v2.0), after 24 weeks untreated follow-up. In this ITT analysis, differences in efficacy between HCV genotype (2 vs 3) and duration of treatment (24 vs 48 weeks) were assessed by Cochran–Mantel–Haenszel test, stratified by geographical region. SVR rates were also analysed after stratification by HCV RNA (> and ≤800,000 IU/mL; HVL vs LVL).

 

Results

In the 117 patients who were randomized to 24 or 48 weeks treatment, SVR rates were similar in genotype 2 and 3 patients (77% vs 71% respectively, p=0.135; odds ratio [OR, stratified by treatment] = 0.49 [95% CI = 0.18–1.29]). SVR rates between the two treatment groups were similar in patients infected with genotype 2 and 3 (Table). The number of patients with genotype 3 infection and HVL was too low to allow evaluation.

 

 

Conclusion

Overall, in patients with persistently ‘normal’ ALT levels, similar outcomes were seen in patients with HCV genotypes 2 and 3 following treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®). Thus, the conclusions based on the combined genotype 2/3 data are valid when outcome data from patients infected with the two genotypes are considered separately.
Abstract ID: 65103

Category: JO7: HCV: Treatment

PEGYLATED INTERFERON PLUS RIBAVIRIN VERSUS NON-PEGYLATED INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C – A COCHRANE SYSTEMATIC REVIEW.

M. Simin, The CHBGroup, Dept. 7102, H:S Rigshospitalet, DK-2100 Copenhagen, Copenhagen, Denmark, J. Brok, The CHBGroup, Dept. 7102, H:S Rigshospitalet, DK- 2100 Copenhagen, Copenhagen, Denmark, D. Stimac, Departement of Gastroenterology, Clinical Hospital Center of Rijeka, Rijeka, Croatia, C. Gluud, The CHBGroup, Dept. 7102, H:S Rigshospitalet, DK-2100 Copenhagen, Copenhagen, Denmark, L. Gluud, The CHBGroup, Dept. 7102, H:S Rigshospitalet, DK-2100, Copenhagen, Copenhagen, Denmark

 

Aim:

We aimed to assess the beneficial and harmful effects of pegylated interferon plus ribavirin versus non-pegylated interferon plus ribavirin in patients with chronic hepatitis C.

 

Material and methods:

We identified randomised clinical trials through The Cochrane Library, MEDLINE, EMBASE, LILACS, and SCI EXPANDED until May 2005. Outcomes were reported as relative risks (RR) or weighted mean differences (WMD) both with 95% confidence interval (CI) based on random effects meta-analyses. Rare events were estimated by Peto odds ratio (OR).

 

Results:

We included 17 randomised clinical trials with 5184 participants. Pegylated interferon plus ribavirin had significantly beneficial effect on sustained virological response (RR 0.80, 95% CI 0.73 to 0.88) compared with non-pegylated interferon plus ribavirin. There were no significant differences between the two interventions regarding liver-related morbidity plus all-cause mortality (OR 1.22, 95% CI 0.33 to 4.51), histological inflammation (RR 0.54, 95% CI 0.24 to 1.23), histological fibrosis (RR 1.05, 95% CI 0.87 to 1.27), or post-treatment quality of life (WMD 0.20, 95% CI -1.96 to 2.36). Pegylated interferon plus ribavirin was associated with significantly lower quality of life during treatment (WMD 1.50, 95% CI 0.32 to 2.68) and increase of adverse events: neutropenia (RR 1.96, 95% CI 1.32 to 2.90), thrombocytopenia (RR 2.05, 95% CI 1.15 to 3.68), arthralgia (RR 1.19, 95% CI 1.05 to 1.35), and injection-site reaction (RR 1.85, 95% CI 1.36 to 2.53).

 

Conclusion:

Pegylated interferon plus ribavirin significantly increase the proportion of patients with sustained virological response, but also the risk of adverse events. We recorded no convincing evidence that pegylated interferon plus ribavirin reduces mortality or liver-related morbidity.


Abstract ID: 65347

Category: JO7: HCV: Treatment

Early Viral Kinetics in Patients with Chronic Hepatitis C and End Stage Renal Disease During Therapy with Peginterferon alfa-2a.

G. A. Lutchman, National Institutes of Health, Bethesda, MD, A. Neumann, National Institutes of Health, Bethesda, MD, M. Ghany, National Institutes of Health, Bethesda, MD, T. Heller, National Institutes of Health, Bethesda, MD, B. Borg, National Institutes of Health, Bethesda, MD, J. J. Feld, National Institutes of Health, Bethesda, MD, R. Loomba, National Institutes of Health, Bethesda, MD, Y. Park, National Institutes of Health, Bethesda, MD, T. Liang, National Institutes of Health, Bethesda, MD, J. Hoofnagle, National Institutes of Health, Bethesda, MD

 

Background:

Chronic hepatitis C (HCV) infection is common in patients with end stage renal disease (ESRD), particularly those on hemodialysis. Initial reports suggest a lower sustained virological response (SVR) to pegylated interferon (PEG) and ribavirin therapy and a greater incidence of side effects. It is unclear if the poor response to therapy is due to lack of efficacy of interferon or to inadequate dosing due to intolerance.

 

Aim:

To compare the early viral kinetics to PEG alfa-2a mono-therapy in patients with HCV genotype 1 infection with and without ESRD.

 

Methods:

Patients with HCV infection with normal renal function were randomized to PEG alfa-2a and ribavirin (1000-1200 mg/day) (Group A) or monotherapy with PEG alfa-2a (Group B) for 4 weeks after which both groups received combination therapy for another 44 weeks. Patients with ESRD (CrCl <10 ml/min) and HCV infection (Group C) were treated with PEG alfa-2a for 4 weeks after which ribavirin was added in low escalating doses. The current analysis is focused on the analysis of viral kinetics in the first 4 weeks of therapy in the two groups (B and C) receiving PEG á-2a monotherapy. Blood samples were taken at baseline, 12, 24, 48, 72 hrs and at weeks 1, 2, 3 and 4. HCV RNA was measured using Cobas Amplicor (LD < 50 IU/ml).

 

Results:

Viral kinetic analyses were available on 24 patients in Group B (9 men, 2 African Americans) and 7 in Group C (7 men, 4 African American). Patients with ESRD had significantly lower ALT (35±16 vs. 95±81 IU/L, p<0.01) but had similar baseline viral levels (6.1 vs. 6.3 log) and similar histological findings of necroinflammation and fibrosis on liver biopsy. Patients with renal disease had a lower maximal 1st phase decline (0.52 vs. 0.87 log IU/ml), greater viral rebound (0.37 vs. 0.27 log IU/ml) and lower overall viral decline during the first week (0.16 vs. 0.60 log IU/ml), but none of these differences reached statistical significance. However patients with ESRD had a significantly slower 2nd phase decline (-0.11 vs. -0.25 log/ wk, p=0.05) compared to patients without ESRD. In addition, 7/7 patients with ESRD had a 2nd phase decline less than 0.3 log/wk, which was predictive of non-SVR in previous studies, while this was true for 13/24 (54%) of patients without ESRD (p<0.05, Fishers Exact).

 

Conclusions:

Patients with chronic HCV infection and ESRD appear to have a significantly slower 2nd phase viral decline during PEG alfa-2a mono-therapy than those with normal renal function. Although this may partially account for poorer treatment responses, these findings need to be confirmed in a larger cohort.


Abstract ID: 66167

Category: JO7: HCV: Treatment

Persistence with Hepatitis C Therapy in the Department of Veterans Affairs (VA).

S. Usman Iqbal, Boston University School of Public Health, Boston, MA, F. Cunningham, Hines VA Hospital, Hines, IL, A. Lee, Boston University School of Public Health, Boston, MA, D. R. Miller, Boston University School of Public Health, Boston, MA, A. W. Law, Roche Laboratories, Nutley, NJ, L. Kazis, Boston University School of Public Health, Boston, MA

 

Background:

Two forms of combination therapies, peginterferon alfa-2a with ribavirin (PEG-IFN a-2A/RIB) and peginterferon alfa-2b with ribavirin (PEG-IFN a-2B/RIB), are currently used for the treatment of hepatitis C infection (HCV). However, limited data are available on patient persistence with prescribed therapies.

 

Objectives:

To evaluate and compare treatment persistence with PEG-IFN a-2A/RIB and PEGIFN a-2B/RIB.

 

Methods:

We conducted a retrospective analysis of 5,611 VA patients > 18 years of age who were newly-diagnosed with HCV mono-infection. Patients who received their first prescription of either combination therapy between October 2003 and September 2004 were included in the study. Using pharmacy data, persistence was defined as the period from the date of the first peginterferon prescription filled to the date of discontinuation. Persistence was estimated using the Kaplan-Meier method. Likelihood ratio test of equality over strata was performed to detect any differences in persistence between the treatment groups.

 

Results:

During the study period, 57.8% patients received PEG-IFN a-2A/RIB and 42.2% on PEG-IFN a-2B/RIB. The treatment groups were similar in regards to age, gender, and race distribution. The median duration of therapy was 5.4 months (95% CI: 5.2 to 5.5) for PEG-IFN a-2A/RIB and 4.6 months (4.4 to 4.8) for PEG-IFN a-2B/RIB. Treatment-specific persistence and 95% CI at 12, 24, 36, and 48 weeks since treatment initiation are shown in the table. Likelihood ratio test of equality in persistence between treatment groups yielded Chi-square=26.4, with p<0.0001.

 

Conclusion:

Persistence with PEG-IFN a-2A/RIB therapy was significantly greater than with PEG-IFN a-2B/RIB in VA patients diagnosed with HCV. These results may have implications for the clinical management of HCV patients and treatment outcomes.


Abstract ID: 66294

Category: JO7: HCV: Treatment

Hepatic steatosis in patients with HIV-HCV co-infection enrolled in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT): Clinical characteristics and response to treatment.

m. Rodriguez-Torres, Fundación de Investigación de Diego, Santurce, PR, R. SOLA, LIVER SECTION. HOSPITAL DEL MAR, BARCELONA, Spain, N. Clumeck, CHU Saint-Pierre, Brussels, Belgium, E. Lissen, Virgen del Rocio University Hospital, Seville, Spain, H. Sette Jr., Instituto de Infectologia Emilio Ribas, São Paulo , Brazil, P. Buggisch, Universitaetsklinikum Hamburg-Eppendorf, Hamburg, Germany, J. DePamphilis, -, Nutley, NJ, D. Dieterich, The Mount Sinai Medical Center, New York , NY

 

Peginterferon alfa-2a (40KD) (PEGASYS®) + RBV (COPEGUS®) produced higher SVR rates (40 vs 20 and 12%, respectively, p<0.001) and histological response rates (57 vs 39 and 41%, respectively, p ≤ 0.04) than peginterferon alfa-2a (40KD) monotherapy or IFN/RBV in APRICOT. Hepatic steatosis in co-infection is not well studied. We analyzed data from pts with paired biopsies in APRICOT to identify factors associated with steatosis at baseline, the impact of baseline steatosis on the probability of an SVR, and the impact of viral eradication on steatosis.

 

Methods

Co-infected pts were randomized to peginterferon alfa-2a (40KD) 180 μg/wk + RBV 800 mg/d or placebo, or IFN 3MIU 3x/wk + RBV x48 wks. Biopsies were obtained 15 months before enrollment (BL) in all pts and at end of follow-up in pts at some centers. A central study pathologist evaluated pre and post-treatment biopsies in blinded fashion. Steatosis was defined as >5% of hepatocytes with fatty changes per low power field. SVR was defined as undetectable serum HCV RNA (<50 IU/mL) at wk 24 of untreated follow-up (wk72).

 

Results

Paired biopsies were submitted for 283/860 pts overall, 65 of whom had steatosis at baseline. At BL, pts with steatosis were more likely to have genotype (GT) 3 infection (p<0.0001), a histological diagnosis of bridging fibrosis/cirrhosis (p=0.0311), higher HCV RNA (p=0.0132), elevated serum triglycerides (p=0.0132), abnormally high random blood glucose levels (p=0.0097), and higher ALT quotients (p=0.0067) than pts without steatosis. Overall 26/65 (40%) of pts with and 73/218 (33%) of pts without steatosis at BL had SVRs. In those treated with peginterferon alfa-2a (40KD) + RBV 12/21 (57%) of pts with and 38/69 (55%) of pts without steatosis at BL had SVRs. Achievement of an SVR in the overall population of pts with paired biopsies and in those treated with peginterferon alfa-2a (40KD) + RBV (21/90 had steatosis at BL) was associated with a significantly lower incidence of steatosis at wk 72 (vs BL; Table).

 

Conclusion

Hepatic steatosis is associated with GT3 infection in co-infected pts. The presence of steatosis does not appear to reduce the overall probability of achieving an SVR. Viral eradication with peginterferon alfa-2a (40KD) + RBV is associated with a reduced incidence of hepatic steatosis in co-infected pts.

 


Abstract ID: 67086

Category: JO7: HCV: Treatment

Early ribavirin improves sustained virological responses in acute HCV infection in HIV positive individuals.

M. Danta, Centre for Hepatology, London, United Kingdom (Great Britain), J. Turner, Centre for Sexual Health and HIV Research, London, United Kingdom (Great Britain), R. Johnson, Centre for Sexual Health and HIV Research, London, R. Lascar, Centre for Sexual Health and HIV Research, London, United Kingdom (Great Britain), M. Johnson, Department of HIV medicine, London, United Kingdom (Great Britain), G. Dusheiko, Centre for Hepatology, London, United Kingdom (Great Britain), I. Williams, Centre for Sexual Health and HIV Research, London, United Kingdom (Great Britain), R. Gilson, Centre for Sexual Health and HIV Research, London, United Kingdom (Great Britain), S. Bhagani, Department of HIV medicine, London, United Kingdom (Great Britain)

 

Aims:

To describe the virological outcomes of two different treatment strategies for acute HCV infection in HIV infected individuals.

 

Method:

Acute HCV was defined by seroconversion to anti-HCV within six months of a negative result and/or a positive HCV RNA. HIV-positive individuals presenting with acute HCV infection at two centres were offered treatment, but with different standard regimens. At centre 1 (early ribavirin) all individuals persistently positive for HCV RNA by RT-PCR 12 weeks after presentation were offered pegylated interferon alpha-2b (1.5 μg/kg) and ribavirin (>10.6 mg/kg) for 48 weeks. At centre 2 (delayed ribavirin) individuals were offered immediate treatment with pegylated interferon alpha-2a or -2b for 24 weeks. Ribavirin (800mg/d) was then added if individuals were still positive for HCV RNA at week 12.

 

Results:

Baseline characteristics were similar in individuals at centre 1 (n=24) and centre 2 (n=15); mean age (35.7 vs 36.3 years), mean CD4 count (583 vs 515 cells/mcl), on HAART (58% vs 47%), HCV genotype 1/4 (83% vs 87%), mean HCV viral load (6.4x106 IU/ml at both) and baseline mean ALT (177 vs 362 IU/ml). The mean time to treatment from diagnosis was 15.2 weeks (centre 1) and 6.4 weeks (centre 2). Sustained virological responses (SVR) were available in 26 patients. SVR were significantly better using initial combination pegylated interferon plus ribavirin compared to delayed ribavirin (61% (centre 1) vs. 23% (centre 2), p<0.001). The median duration of treatment was 34 weeks (centre 1) and 25 weeks (centre 2). Side effects were similar between the two centres. The mean fall in haemoglobin was not different between the regimes (2.7 g/dl (centre 1) vs. 2.6 g/dl (centre 2), p=ns). HIV parameters were not significantly impacted with treatment.

 

Conclusions:

The optimal treatment schedule for acute HCV in HIV co-infection is not known but our experience suggests that pegylated interferon alone has poor efficacy. In contrast to acute HCV mono-infection, ribavirin in the first 12 weeks significantly improves the long-term virological outcomes in HIV-infected patients with acute HCV. Despite the majority of patients having HCV genotypes 1/4, SVRs of 61% were achieved with combination pegylated interferon and ribavirin.


Abstract ID: 67172

Category: JO7: HCV: Treatment

CYTOKINE RESPONSE IN CHRONIC HEPATITIS C (CHC) PATIENTS TREATED WITH PEGYLATED INTERFERON PLUS RIBAVIRIN.

M. Trapero Marugán, Liver Unit. Hospital Universitario de La Princesa, Madrid, Spain, Madrid, Spain, R. Moreno-Otero, Liver Unit. Hospital Universitario de La Princesa, Madrid, Spain, L. Garcia-Buey, Liver Unit. Hospital Universitario de La Princesa, Madrid, Spain, J. Moreno-Monteagudo, Liver Unit. Hospital Universitario de La Princesa, Madrid, M. Vitón, Immunology Service. Hospitla Universitario de La Princesa, Madrid, Spain, C. Muñoz, Immunology Service. Hospital Universitario de La Princesa, Madrid, Spain, M. Borque, Molecular Biology Unit. Hospital Universitario de La Princesa, Madrid, Spain, X. Salcedo-Mora, Liver Unit. Hospital Universitario de La Princesa, Madrid, Spain

 

AIMS:

1) To compare the cytokine profiles in peripheral blood mononuclear cells (PBMCs) from patients with CHC and healthy controls. 2) To analyse the cytokine profiles in CHC patients during combination therapy. 3) To correlate the cytokine production with sustained virological response (SVR).

 

METHODS:

A total of 44 caucasian genotype 1 naive patients with CHC received PEG-IFNa2a (weekly) plus RBV (1-1.2 g/day) for 48 weeks. Besides, 16 healthy controls were studied. The intracitoplasmic expression of IL-4, IFNg and TNFa, and surface CD4 and CD8 markers from PBMCs, both resting and stimulated, were measured using flow cytometry. SVR was defined as HCV-RNA negativity after 6 months follow-up. Statistics: Student´s t test, c2 test and ANOVA test, logistic regression.

 

RESULTS:

All 44 patients (mean age 45.2±8.1 years) finished follow-up. Healthy controls presented a higher percentage of CD8 T cell than CHC patients (22.1±7 vs 16.9 ±10; p<0.004), higher expression of IFNg by CD4 resting T cells (0.03±0.02 vs 0.87 ±1.3; p<0.02), higher expression of TNFa by CD8 (29.8±17.3 vs 19.5±17.3; p<0.05) and CD4 stimulated T cells (36.3±9.9 vs 26.7±22.3; p<0.02) and lower intracitplasmic expression of IL-4 by CD4 T cells (1.3±0.7 vs 2.7±2.9;p<0.01). During treatment, IL-4, IFNg and TNFa levels fell progressively in all patients. After follow-up, 26 patients had SVR (59.1%), 13 relapsed (29.5%) and 5 were non-responders (11.4%). At the first month during treatment, expression of TNFa by CD4 T cells was higher in patients with a SVR than in NR (36.46±24.9 vs 17.2±20.7; p<0.01). At the third month, the percentage of CD4 T cells was lower in patients with a SVR (34±16 vs 44±15.3; p<0.04), stimulated-IL-4 expression by CD4 T cells was lower in patients with SVR (1.9±4.2 vs 3.9±4.2; p<0.05) and TNFa expression by CD4 T cells was higher in patients with a SVR (48.8 ±20.9 vs 31.2 ±23; p<0.01). At the end of treatment, expression of IFNg by CD8 stimulated T cells was higher in SVR (17.3±14 vs 10±8.5; p<0.04) as well as the expression of IFNg by CD4 stimulated T cells (10.7±8.2 vs 5.9 ±5.5; p<0.03). After a multivariate analysis, predictive factors of a SVR were: percentage of CD4 T cells and expression of TNFa by CD4 stimulated T cells at first month of treatment, expression of IFNg by CD4 T cells at third month of treatment, and expression of TNFa and IFNg by CD8 stimulated T cells, AST and ALT levels and hemoglobin.

 

CONCLUSIONS:

IFNg and TNFa expression by CD4 and CD8 T cells (cytokine response type 1) during antiviral treatment is associated with SVR suggesting the replication control and later clearance of HCV.


Abstract ID: 67356

Category: JO7: HCV: Treatment

PEG-IFN alpha 2b (1.5 mcg/kg/wk) + rib (800-1400 mg daily) is significantly more effective than PEG-IFN alpha 2b (1.0 mcg/kg/wk) + rib (800-1400 mg daily) in men with GT 1 and women with GT 2/3: Final results of a prospective, randomized, controlled trial.

S. L. Flamm, Northwestern University Medical School, Chicago, IL, J. Goldman, Gastroenterology Assoc., Hazel Crest, IL, J. Cahan, Consultants in Gastroenterology, Munster, IN, G. Nelligan, Rockford Clinic, Rockford, IL, D. Chua, Summit Digestive and Liver Disease, Oakbrook Terrace, IL, B. Shapiro, Northwest Healthcare, Hoffman Estates, IL, M. Bawani, Gastroenterologists, Ltd., Libertyville, IL, R. Yapp, Digestive Health Services, SC, Downers Grove, IL, E. Jurkovic, Digestive Disease Consultants, Kankakee, IL, R. Brown, Columbia University Medical Center, New York, NY, S. Skahen, Northwestern University Medical School, Chicago, IL, T. Jackson, Northwestern University Medical School, Chicago, IL

 

Background:

PEG-IFNa2b (1.5 mcg/kg/wk) + ribavirin (800mg/d) is effective for pts with chronic hepatitis C virus (HCV). The medications have many side effects and frequently require dose reduction or discontinuation. PEG-IFNa2b (1.0 mcg/kg/wk) monotherapy data yield equivalent SVR in comparison to PEG-IFNa 2b (1.5 mcg/kg/wk) monotherapy. SVR and tolerability of PEG-IFNa2b (1.0 mcg/kg/wk) + ribavirin are unknown.

 

Aim:

We sought to determine the efficacy and tolerability of PEG-IFNa2b [1.0 mcg/kg/wk vs 1.5 mcg/kg/wk] in combination with ribavirin to determine if lower dose PEG-IFN a 2b is equally effective as the standard dose. Methods: Pts with HCV (+ HCV RNA) were evaluated within the context of a prospective, randomized, controlled, multi-center trial comparing PEG-IFNa2b (1.0 mcg/kg/wk) [LD] + riba(800-1400mg/d) vs. PEG-IFNa2b (1.5 mcg/kg/wk) [SD] + riba(800-1400mg/d). Demographic, serological (ALT), virologic (HCV RNA level and genotype) and histological data were obtained. Meds. were given for 24 wks (HCV GT 2/3) or 48 wks (HCV GT 1). Tolerability (side effect profile and d/c rate) was determined. SVR data are reported.

 

Results:

312 pts were randomized; 281 received meds. (133 in SD and 148 in LD) and are included in the analysis. There were significantly more men (p=0.01) and GT 2/3 (p=0.01) in the LD grp. Mild and advanced fibrosis were evenly distributed between the grps. There was a strong trend for better overall SVR in the SD 70/133 (53%) vs LD 65/147 (44%). There was also a strong trend for better SVR in GT 1 SD 47/104 (45%) vs. LD 34/99 (34%). In men, SVR in GT1 was significantly better in SD 30/62 (48%) vs LD 14/50 (28%),p=0.05. In women, SVR in GT1 was similar SD 17/42 (40%) vs LD 20/49(40%). There was also a strong trend for better overall SVR in GT2/3 SD 23/29 (79%) vs. LD 31/48 (65%). In men, SVR in GT2/3 was equivalent SD 15/20 (75%) vs LD 19/24 (79%). In women, SVR in GT 2/3 was significantly better in SD 8/9 (89%) vs LD 12/24 (50%),p=0.05). There was a strong trend to benefit with SD with 10-15% > SVR in mild and advanced fibrosis grps. There were no significant differences in tolerability (9% d/c rate in both SD and LD and 20% PEG dose reduction in SD vs 10% in LD), p=NS.

 

Conclusions:

1)Standard dose PEG-IFNa2b + riba was significantly more efficacious in men with GT 1 and women with GT 2/3 compared to LD. 2)There was a strong consistent trend to SVR benefit in ALL treatment sub-grps including GT 1l, GT 2/3, men, women, mild and advanced fibrosis. 3)There were low d/c and dose reduction rates in both groups. 4)The results of the large prospective trial comparing SD and LD PEG-IFNa2b regimens are awaited to confirm these findings.


Abstract ID: 67749

Category: JO7: HCV: Treatment

Treatment outcomes to combination therapy in patients with HCV genotype 6.

M. Nguyen, Stanford University Medical Center, Pacific Health Foundation, Palo Alto, CA, H. Trinh, Pacific Health Foundation, San Jose, CA, R. T. Garcia, Pacific Health Foundation, San Jose, CA, K. Hoda, Pacific Health Foundation, San Jose, CA, E. Keeffe, Stanford University Medical Center, Palo Alto, CA

 

PURPOSE:

The prevalence of HCV infection in Southeast Asia is approximately 6%. HCV genotype 6 and its subtypes (also known as genotype 7, 8, and 9) are found in 30- 35% of this population. However, little is known regarding the natural history as well as response to antiviral therapy in this large patient population with HCV genotype 6.

 

METHODS:

To examine treatment response to antiviral therapy in patients with HCV genotype 6, we performed a retrospective review of all patients who were evaluated and started on treatment with either interferon 3MU tiw + ribavirin 800 mg/d (IFN+RBV) or pegylated IFN (1.5mcg/kg for PEG IFN-á2b and 180 mcg for PEG IFN- á2a weekly) and RBV 1000-1200 mg/d (PEG IFN+RBV) between 1/2001 and 12/2003 at a single U.S. center. Primary end point was overall SVR in all treated patients, and analysis was intention-to-treat. Student t-test and chi-square statistics were used to compare various clinical variables between the 2 treatment groups. Multivariate analysis was used to identify potential predictors of SVR.

 

RESULTS:

A total of 81 patients were identified (39 with genotype 6, 6a, 6b; 37 with genotype 7, 7a, 7b; and 5 with genotype 8, 8a, 8b). Mean age was 57±10, 73% were male, 17% had known cirrhosis, 12% had previous treatment with IFN monotherapy Forty patients (49%) received IFN+RBV and 41 (51%) received PEG IFN+RBV. Treatment completion rate was 77% for the IFN+RBV group and 78% for PEG IFN+RBV. Sixty-three (78%) patients were treated with a 24-week course and 18 (22%) with a 48-week course. There were no statistically significant differences in age, sex, SVR or treatment duration between the 2 treatment groups. Overall SVR was 51%. SVR was 48% for patients treated with 24-week course and 65% in the 48-week group (p=0.21). On multivariate analysis, only treatment completion is an independent predictor of a SVR (OR=9.1, p=0.02).

 

CONCLUSIONS:

In this Southeast Asian population with HCV genotype 6 and a treatment completion rate of 78%, overall SVR to combination therapy was 51%. There is a trend for higher SVR (65%) in those treated for 48 weeks as compared to the 24-week group (48%) but this difference did not reach statistical significance. Therefore, until further data from large, prospective studies are available, patients with genotype 6 who are candidates for therapy should be offered a 48-week course of therapy.


Abstract ID: 67872

Category: JO7: HCV: Treatment

Modeling Ribavirin Pharmacokinetics in HIV-1/HCV-Coinfected Patients Predicts Higher Intracellular Ribavirin Concentration in Sustained Viral Responders.

H. Dahari, Los Alamos National Laboratory, Los Alamos, NM, R. M. Ribeiro, Los Alamos National Laboratory, Los Alamos, NM, M. Zeremski, Weill Medical college of Cornell University, New York, NY, T. Licholai, Weill Medical college of Cornell University, New York, NY, I. Haller, Weill Medical college of Cornell University, New York, NY, A. S. Perelson, Los Alamos national Laboratory, Los Alamos, NM, A. H. Talal, Weill Medical college of Cornell University, New York, NY

 

Background:

In hepatitis C virus infection, ribavirin (RBV) has recently been proposed to act as a viral mutagen that increases second phase HCV RNA decay in patients who exhibit low interferon effectiveness. The pharmacokinetics of pegylated interferon (PEGIFN) and RBV have not been evaluated simultaneously. We sought to evaluate any association between RBV and pegylated IFN &#61537;-2b pharmacokinetics, and its influence on the outcome of treatment.

 

Methods:

Twenty-four IFN na&iuml;ve, HIV/HCV-co-infected patients received PEGIFN (1.5 &#61549;g/kg) once weekly plus daily ribavirin (1.0 g or 1.2 g) for up to 48 weeks. Blood samples were frequently obtained during the first 16 days of treatment and monthly thereafter. Plasma samples were assayed for RBV using high performance liquid chromatography and for PEG-IFN using a validated electrochemiluminescence-based assay. A one-compartment pharmacokinetics model (OPK) was used to fit each patient’s longitudinal PEG-IFN plasma concentration, whereas a two-compartment model (TPK), which accounts for RBV in plasma and in cells, was needed to fit the RBV plasma concentration. Statistical significance was determined using nonparametric methods and Spearman rank correlations.

 

Results:

Six patients (25%) had a sustained virological response (SVR). Baseline HCV RNA titers (5.3 vs. 6.4 log cp/ml, p<0.006) and RBV area-under-the-curve (AUC) in plasma during the first three days of therapy were significantly lower in SVR than non-SVR (AUC [0, 72 hr] 1.56 vs. 2.8 mg/ml hr, p<0.03). A significant inverse correlation was found between RBV AUC [0, 72 hr] and PEG-IFN AUC [0, 72 hr] (r=-0.6, p<0.007). Although PEG-IFN pharmacokinetic parameters were similar in SVR and non-SVR patients, preliminary fits indicate that the mean RBV transport rate constant from the cellular compartment into plasma was significantly lower in SVR (3.6 x 10-3 vs. 2.8 x 10-2 hr-1, p<0.008). Thus, the predicted mean steady-state concentration in the cellular compartment was significantly higher in SVR than in non-SVR (1.35 vs. 0.522 g/ml, p<0.01).

 

Conclusions:

Our model suggests that cellular RBV transport is enhanced early in treatment in SVR patients as predicted by the increased mean steady-state cellular concentration in SVR patients, by the lower plasma RBV concentration during the first three days, and by a lower RBV transport rate from the cellular compartment into plasma.  Consequently, differential RBV transport early in treatment, eventually leading to higher RBV accumulation in the cellular compartment, may differentiate SVR from non-SVR patients.


Abstract ID: 61871

Category: JO7: HCV: Treatment

Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to prior therapy with either interferon alfa and ribavirin or pegylated interferon and ribavirin.

K. Chen, Chicago Medical School, North Chicago, IL, P. Seraphin, Loyola University medical Center, Maywood, IL, L. Murphy, Loyola University Medical Center, maywood, IL, N. Shah, Loyola Univ. Medical Center, Maywood, IL

 

Background:

Current standard therapy for HCV based on pegylated interferon (Peg IFN) and weight-based ribavirin (RBV) results in approximately 50% of patients achieving a sustained viral response (SVR). There are no approved treatment alternatives for patients who fail to respond to Peg IFN + RBV. We reviewed our experience with the use of consensus interferon (IFN alfacon-1) and RBV in these nonresponder (NR) patients.

 

Methods:

All patients were treated initially with IFN alfa-2a or Peg IFN + RBV. Those who failed to clear HCV RNA and were classified as NR were then retreated with IFN alfacon-1 + weight-based RBV (800 mg-1200 mg/day) for at least 48 weeks. Pretreatment liver biopsy, HCV genotype, viral load and usual demographics were collected for all subjects. Patients on IFN alfacon-1 + RBV retreatment were allowed to use growth factors to continue with their treatment as needed. IFN alfacon-1 was given to all patients at a starting dose of 15 mcg/daily with weight based RBV. Doses were adjusted as necessary for hematological side effects.

 

Results (table):

79 patients were screened and 76 patients were treated with IFN alfacon-1 and RBV (65% Caucasian, 16% African American, 4% Hispanic, 15% other); 49 male and 27 female; age ranged from 20-76 years (Mean. 61 (80%) had HCV genotype 1; 36 (47%) had Metavir fibrosis F3/F4. At the end of treatment (week 48), 55 (72%) patients were HCV RNA negative. At week 72, 38 (50%) achieved an SVR. One patient on treatment underwent liver transplantation and stopped treatment. At that time, his viral load had dropped to 1,830 copies/mL.

 

RESULTS

 

Week 48 (end of treatment)

Week 72 (SVR)

HCV RNA negative

55 (72%)

38 (50%)

 

Conclusions:

These data suggest that IFN alfacon-1 and weight-based RBV are a potential alternative in Peg IFN plus RBV NR HCV patients. In addition, NR patients with advanced disease (F3/F4) tolerated this therapy well and should be candidates for retreatment with IFN alfacon-1 and RBV. Further study is warranted to confirm these findings.


Abstract ID: 62587

Category: JO7: HCV: Treatment

Peginterferon-a 2b and Ribavirin Treatment in Patients with Hepatitis C Virus-Related Systemic Vasculitis.

d. saadoun, Department of internal medicine, Pitie-salpetriere Hospital, Paris, Fr, paris, France, n. limal, service de médecine interne, paris, France, d. sene, service de medicine interne, paris, France, O. lidove, service de médecine interne, paris, France, J. Piette, service de médecine interne, paris, France, P. Cacoub, service de médecine interne, paris, France

 

Objective:

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV) which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen-driven B-cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears as the key trigger. The present trial was established to investigate the efficacy of Pegylated-interferon-a (PegIFN-a) with ribavirin in patients with HCV-MC vasculitis.

 

Methods:

Nine consecutive HCV-MC patients received PegIFN a-2b (1.5 μg/kg/week) plus oral ribavirin (800 to 1200 mg/day) for at least 6 months. The response to treatment was analysed by comparing clinical, immunologic, and virologic parameters at the initial evaluation and during followup.

 

Results:

The mean duration of Peg-IFN a and ribavirin was 13.5 ± 2.8 months. After a mean follow-up of 18.7 months after stopping treatment, all nine patients are alive. Seven patients (77%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5/9 (55%) and complement levels normalized in 77% of patients. One patient had a partial virological response with a complete clinical response. A clinical relapse of MC vasculitis occured in another patient associated with reappearance of HCV RNA. Treatment was well tolerated and no side side effects required discontinuation of therapy.

 

Conclusion:

Treatment with PegIFN a-2b and ribavirin can achieve a complete clinical response in most patients with HCV-MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter period than that previously reported with IFNa and ribavirin.


Abstract ID: 62599

Category: JO7: HCV: Treatment

Efficacy of PEG-IFN alfa-2b vs. PEG-IFN alfa-2a + ribavirin regimens in treatment naïve chronic HCV patients: A cumulative meta-analysis of retrospective data from 6 clinic sites.

HCV Meta-Analysis Working Group, MetaWorks Inc., Medford, MA, P. L. Almasio, University of Palermo, Palermo, Italy, L. Cavalletto, University of Padova, Padova, Italy, L. Chemello, University of Padova, Padova, Italy, A. Craxi, University of Palermo, Palermo, Italy, K. Fahrbach, MetaWorks Inc., Medford, MA, D. Frame, MetaWorks Inc., Medford, MA, C. Y. Ling, MetaWorks Inc., Medford, MA, S. Mauss, Center for HIV and Hepatogastroenterology, Duesseldorf, Germany, F. F. Poordad, Center for Liver Disease and Transplantation, Cedars-Sinai, Los Angeles, CA, S. D. Ross, MetaWorks Inc., Medford, MA, N. N. Zein, The Cleveland Clinic Foundation, Cleveland, OH, S. Herrine, Thomas Jefferson University, Philadelphia, PA, C. Trepo, Hôpital Hotel Dieu, LYON Cedex 02, France

 

Objective:

To elucidate differences in effectiveness of weight-based (alfa-2b) and fixed dose (alfa-2a) pegylated interferons + ribavirin (PEG-IFN+RIB) treatment regimens in treatment-naïve chronic HCV patients in settings outside of clinical trials.

 

Methods:

European and US clinical investigators identified primarily through independent congress abstracts and collecting data under relevant institutional ethical guidelines were recruited to contribute de-identified data for meta-analysis. Eligible patients were treatment-naïve adults with chronic HCV (G1, G2, or G3), receiving PEGIFN + RIB, consecutively treated since 1/2001. Patients in clinical trials, with HIV or HBV co-infection, or decompensated liver disease were excluded. The primary efficacy measure was sustained viral response (SVR), i.e., absence of detectable HCV RNA 6 months after end of treatment response (EOTR). Data were meta-analyzed using a hierarchical generalized linear model (HGLM) to control for patient- and site-level variation, and an adjusted odds ratio (OR) was calculated for the difference between PEG-IFNs. Patient selection criteria and analytic methods were determined prospectively by an expert panel. Prognostic impact of treatment regimen, weight, site, baseline ALT quotient, age, gender, and race were assessed.

 

Results:

Six sites (2 US, 2 Germany, 2 Italy) contributed data, totaling 824 patients (61% male, 94% Caucasian, mean age 46, mean weight 76 kg). The two groups were comparable in terms of baseline characteristics and RIB dosing (mean 957 mg for PEGIFN alfa-2b, 987 mg PEG-IFN alfa-2a). SVR in G1 patients was significantly (p=0.017) higher for PEG-IFN alfa-2b vs. PEG-IFN alfa-2a.

 

Table 1. SVR by drug and genotype

 

Higher SVR rates were also achieved with PEG-IFN alfa-2b for G2 and G3 patients, though this difference was not significant. Between-site heterogeneity was apparent in G2 and G3, but not G1, analyses.

 

Conclusion:

Treatment with PEG-IFN alfa-2b has an advantage relative to PEG-IFN alfa-2a in the achievement of SVR in treatment-naïve adults with chronic HCV, G1. Additional clinic sites are being identified through the literature to validate observations from this initial analysis. Further analyses will evaluate secondary endpoints of early response, EOTR, and relapse, as well as incorporating additional patient covariates into the HGLM model.


Abstract ID: 63531

Category: JO7: HCV: Treatment

Erythropoietin Increases Platelets Count During Antiviral Therapy With Interferon and Ribavirin for Chronic Hepatitis C Virus Infection.

U. Borate, Albert Einstein Medical Center, Philadelphia, PA, K. Rothstein, Albert Einstein Medical Center, Pghiladelphia, PA, V. Araya, Albert Einstein Medical Center, Philadelphia, PA, S. J. Munoz, Albert Einstein Medical Center, Philadelphia, PA

 

Erythropoietin (EPO) is now often used to treat ribavirin-induced anemia in patients with chronic hepatitis C (HCV) virus infection, hoping to neutralize a reduced probability of SVR caused by anemia-related dose reductions. As a growth factor, EPO may also stimulate platelet production. Indeed recombinant human EPO stimulates platelet production in mice and rats, and EPO administration has been reported to increase platelets counts in patients on dialysis and on chemotherapy.

 

AIM:

To determine whether HCV patients on anti-viral therapy and receiving EPO exhibit a change in platelet counts.

 

METHODS:

A careful retrospective analysis of platelet counts of HCV patients on antiviral therapy at a liver center. Platelet counts were evaluated just prior to start of EPO (baseline), and then at week 2, and months 1, 2, 3, 4,5 and 6 into therapy with pegylated interferon and ribavirin. Patients received adjuvant EPO (40,000 U/ wk) for severe anemia associated with ribavirin therapy. Controls: patients on antiviral therapy who did not receive adjuvant EPO due to only mild anemia on antiviral therapy, matched for baseline platelet count, presence of cirrhosis, age, race, sex and HCV genotype. We excluded patients who received EPO for less than a month, had irregular follow up, or had concomitant disease or medications known to influence platelet counts.

 

RESULTS:

40 patients were studied: 20 received adjuvant EPO and 20 served as controls. 5 % had established cirrhosis. Age, gender, genotype and ethnicity were similar between groups. Predictably, patients on EPO exhibited an increase in haemoglobin (2.1±0.3gm/dl), but also showed an increase in platelet count as early as 2 weeks into EPO therapy. In contrast, platelet count did not change appreciably in controls. The increase in platelet count associated with adjuvant EPO became more pronounced and significant at 1, 2 and 3 months into therapy (PC: + 42,500, + 40,000 and + 47,500 per cc respectively; p=0.03,0.04, 0.04).

 

CONCLUSIONS:

Adjuvant use of erythropoietin is associated not only with increased hemoglobin but also with increased platelets counts in patients on antiviral therapy with interferon and ribavarin for chronic HCV infection. The extent of EPO effect on platelet counts was a rise between 30,000 to 47,500/cc. It would appear that adjuvant EPO may contribute to maintaining optimal doses of antiviral therapy by supporting both, hemoglobin and platelet levels. The effect of EPO on the latter may be particularly beneficial in cirrhotic patients who are often thrombocytopenic prior to the start of antiviral therapy. These observations warrant further characterization by prospective studies.


Abstract ID: 65190

Category: JO7: HCV: Treatment

Impact of baseline hepatitis C virus (HCV) RNA and genotype on the efficacy of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in patients with compensated cirrhosis/bridging fibrosis.

P. Marcellin, Hopital Beaujon, Clichy, France, S. Roberts, The Alfred Hospital, Melbourne, Australia, A. Alberti, DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, PADOVA, Italy, c. trepo, Hopital Hotel Dieu, Lyon, France, S. Zeuzem, Saarland University Hospital, Homburg, Germany, H. Sette Jr., Instituto de Infectologia Emilio Ribas, São Paulo , Brazil, J. T. Brouwer, Reiner de Graaf Hospital Group, Delft, Netherlands, A. Horta-Vale, Clinica DMI, Portugal, Portugal, E. Gane, Middlemore Hospital, Auckland, New Zealand

 

Introduction

We have shown that peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) is superior to conventional interferon plus ribavirin in patients with cirrhosis/bridging fibrosis, with SVR rates of up to 37% (vs 25%; A531, AASLD 2004). We have now determined if this superiority is consistent when baseline HCV RNA level and genotype are considered.

 

Methods

Interferon-naïve adults with quantifiable HCV RNA, elevated serum ALT, and compensated liver disease who had been enrolled in two phase III trials were analysed. Patients received peginterferon alfa-2a (40KD) 180 mg/wk plus either low-dose (800 mg/day) or standard-dose (1000/1200 mg/day) ribavirin for 24 or 48 wks. SVR (HCV RNA <50 IU/mL COBAS AMPLICOR® HCV Test, v2.0 during wks 12–24 of followup) rates of each of the four peginterferon alfa-2a (40KD) plus ribavirin regimens were compared with conventional interferon alfa-2b 3 MIU tiw plus ribavirin 1000/1200 mg/day for 48 wks (one of the arms in one study). Combined data (all four Peginterferon alfa-2a (40KD) plus ribavirin regimens) were also analysed. Differences in efficacy were assessed by Cochran–Mantel–Haenszel test stratified by genotype (1 vs non-1) and HCV RNA (> vs ≤800,000 IU/mL; HVL vs LVL).

 

Results

·       A total of 2181 patients were randomized to combination treatment and received at least one dose of study medication in the two trials.  Of these, 431 (19.8%) had compensated cirrhosis/bridging and were included in this analysis.

·       Compared with all patients enrolled in the two trials, patients with compensated cirrhosis/bridging fibrosis tended to be older (47 vs. 43 years) and were more likely to be male (73% vs. 67%).

·       The overall SVR rate in all patients with compensated cirrhosis/bridging fibrosis who received 48 weeks’ treatment with peginterferon alpha-2a (40KD) plus ribavirin 1000/1200 mg/day was 48%, compared with 33% in patients treated with conventional interferon alfa-2b plus ribavirin 1000/1200 mg/day (p=0.00106).  The higher SVR rate in patients with compensated cirrhosis/bridging fibrosis receiving peginterferon alfa-2a (40KD) plus ribavirin when the analysis was restricted to genotype 1 patients (37% vs. 25%, p=0.1500), or patients with HCV genotype 2/3 69% vs. 48%, p=0.1026), or when patients were stratified according to baseline HCV RNA level.

·       SVR rates in genotype 1 patients with compensated cirrhosis/bridging fibrosis receiving peginterferon alfa-2a (40KD) plus ribavirin 1000/1200 mg/day for 48 weeks (the recommended treatment regime) and conventional interferon alfa-2b plus ribavirin 1000/1200 mg/day for 48 weeks.

o      Genotype 1 patients with a baseline HCV RNA level ≤ 800,000 IU/mL had a higher SVR rate than those with a baseline HCV RNA level >800,000 IU/mL in both treatment groups.

o      SVR rates were consistently better in genotype 1 patients receiving peginterferon alfa-2a (40KD) plus ribavirin vs. conventional interferon alfa-2b plus ribavirin, irrespective of HCV RNA level.

o      SVR rates in HCV genotype 2/3 patients with a baseline HCV RNA level ≤ 800,000 IU/mL receiving the various peginerferon alfa-2a (40KD) plus ribavirin treatment regimens ranged from 57-100%.

o      SVR rates in HCV genotype 2/3 patients with a baseline HCV RNA level >800,000 IU/mL receiving the various peginterferon alfa-2a (40KD) plus ribavirin treatment regimens ranged from 58-71%.  However, the number of genotype 2/3 patients receiving low-dose ribavirin for 48 weeks was small.

o      Overall, 5/7 (71%) HCV genotype 2 patients with compensated cirrhosis/bridging fibrosis achieved an SVR following treatment with peginterferon alfa-2a (40KD) plus the recommended dose of ribavirin (800 mg/day) for the recommended duration (24 weeks).  This included 3/5 (60%) patients with a baseline HCV RNA level > 800,000 IU/mL.

o      Similarly, 10/13 (77%) HCV genotype 3 patients with compensated cirrhosis/bridging fibrosis receiving peginterferon alfa-2a (40KD) plus ribavirin 800 mg/day for 24 weeks achieved an SVR, including 9/12 (75%nt) patients with baseline HCV RNA level >800,000 IU/mL.

o      Only three patients with compensated cirrhosis/bridging fibrosis infected with HCV genotype 2/3 receiving peginterferon alfa-2a (40KD) plus ribavirin 800 mg/day for 4 weeks had a baseline HCV RNA level ≤ 800,000 IU/mL; all of these patients achieved an SVR.

o      Genotype (genotype 1 vs. non-genotype), baseline HCV RNA (≤ 8000,000 IU/mL) and enrolment at a US center were the only significant baseline predictors of an SVR in the overall patient population with compensated cirrhosis/bridging fibrosis.

o      In genotype 1 patients, treatment duration, HCV RNA level, ALT quotient, bodyweight, and age were significant predictors of an SVR. 

 

Conclusion

o      In HCV genotype 1 patients with compensated cirrhosis/bridging fibrosis, the recommended treatment regimen of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) 1000/1200 mg/day for 48 weeks produced an overall SVR rate of 37%, while HCV genotype 2 and 3 with compensated cirrhosis/bridging fibrosis, the recommended regimen of peginterferon alfa-2a (40KD) plus ribavirin 800 mg/day for 24 weeks produced SVR rates of 71% and 77% respectively.

o      In genotype 1 and 2/3 patients with compensated cirrhosis/bridging fibrosis treated with peginterferon alfa-2a (40KD) plus ribavirin, SVR rates were higher in patients with low compared to high HCV RNA levels, although very few patients with genotype 2/3 infection had low baseline HCV RNA levels.

o      These data confirm that current treatment recommendations for patients with chronic hepatitis C can be applied in patients with compensated cirrhosis/bridging fibrosis.

o      HCV genotype and baseline HCV RNA level were significant and independent predictors of an SVR in patients with compensated cirrhosis/bridging fibrosis.


Abstract ID: 65965

Category: JO7: HCV: Treatment

The increase of von Willebrand factor as a new predictor of response to combination antiviral therapy in patients with chronic hepatitis C.

M. Homoncik, Dep. of Internal medicine IV, Div. of Gastroenterol. and Hepatol.,

Vienna, Austria, E. Formann, Int. Med IV, Vienna, Austria, W. Sieghart, Dep. of

Internal medicine IV, Div. of Gastroenterol. and Hepatol., Vienna, Austria, P. Ferenci,

Dep. of Internal Medicine IV, Div. of Gastroenterol. and Hepatol., Vienna, Austria, A.

Gangl, Dep. of Internal medicine IV, Div. of Gastroenterol. and Hepatol., Vienna,

Austria, M. Peck-Radosavljevic, Dep. of Internal medicine IV, Div. of Gastroenterol.

and Hepatol., Vienna, Austria

 

Background:

Von Willebrand factor (vWF) is an acute phase protein which increases during combination antiviral therapy. There is no method up to date to differentiate between sustained virological responders and relapsers during the therapy of hepatitis C. The aim of this study was to investigate if the vWF can predict sustained virological response during antiviral combination therapy.

 

Methods:

Eighty two consecutive patients with chronic hepatitis C were included. Patients with genotype 1 or 4 (n=51) received 180 μg PEG-IFN-á2a 1/week and 1000-1200 mg ribavirin daily over a period of 48 weeks. Patients with genotype 2 or 3 (n=31) received 180 μg PEG-IFN-á2a 1/week and 800 mg ribavirin daily over a period of 24 weeks. vWF-Ag levels were measured before, during, and 6 months after the combination therapy. Data are presented as mean ± 95% confidence intervals (CI).

 

Results:

50 patients were sustained virological responders (SVR), 23 were relapsers and 9 non-responders. Baseline vWF was mean 194% (164-222%) and was not different between the 3 groups. vWF increased to a maximum of 267 % already after 4 weeks of the therapy (p<0,05). The vWF was higher in relapsers than in SVR starting with week 4 of therapy and the greatest difference was noted on week 24 of therapy: mean 301% (95% CI: 257-346 vs. 237% (95% CI: 215-259%), p<0,01). Accordingly, 6 months after the end of therapy vWF was higher in relapsers than in SVR (186 %; CI: 147-224 vs. 142%; CI: 125-157 p=0,05).

 

Conclusion:

The increase in vWF during combination antiviral therapy is significantly higher in patients who will relapse as in patients who will be SVR. This can be explained by systemic inflammation induced by hepatitis C virus. Further studies in larger patients groups are needed to investigate a predictive value of vWF on SVR.


Abstract ID: 66081

Category: JO7: HCV: Treatment

ALTERATIONS OF LEPTIN LEVELS DURING IFN-á TREATMENT IN PATIENTS WITH CHRONIC VIRAL HEPATITIS B AND C: Evidence of an IFN-á-mediated suppression of leptin production.

C. Liaskos, Research Lab of Internal Medicine, Medical School, Larissa, Greece, T. A. Zografos, Research Lab of Internal Medicine, Medical School,, Larissa, Greece, E. Togousidis, Research Lab of Internal Medicine, Medical School, Larissa, Greece, K. Zachou, Research Laboratory of Internal Medicine, Medical School, Larissa, Greece, N. Gatselis, Research Lab of Internal Medicine, Medical School, Larissa, Greece, E. Rigopoulou, Academic Liver Unit, Medical School, University of Thessaly, Larissa, Greece, A. Germenis, Laboratory of Immunology and Histocompatibility, Larissa, Greece, G. N. Dalekos, Academic Liver Unit & Research Lab of Internal Medicine, Medical, Larissa, Greece

 

Background/Aims:

Serum leptin levels in chronic hepatitis C (CHC) patients have been reported to be different than normal and in many cases associated with characteristics of liver histology. The aim of this study was to determine leptin levels in serial samples from patients with chronic hepatitis B (CHB) and CHC treated with interferon-alpha (IFN-á) and to evaluate whether there is (are) any association(s) between leptin levels and patients’ characteristics.

 

METHODS:

Sera from 63 CHB and 42 CHC patients were investigated at four timepoints (before, during treatment with IFN-á, end of treatment and end of follow-up) for the presence of leptin using an enzyme-linked-immunosorbent-assay. The control groups consisted of 36 patients with autoimmune liver diseases and 44 healthy, all matched for body mass index with CHB and CHC patients.

 

RESULTS:

Leptin levels before IFN-á administration were significantly higher in both CHB and CHC groups compared to healthy (p<0.004) and disease controls (p=0.0001). During the course of IFN-á a significant reduction of serum leptin levels was found in both CHB and CHC groups (p=0.0001) while at the end of follow-up leptin levels did not differ compared to both control groups. Biochemical or virological response to treatment was not associated with the leptin reduction in both viral groups.

 

CONCLUSIONS:

This study provides for the first time convinced evidence of a standard kinetic profile of serum leptin levels in CHB and CHC patients treated with IFN-á. Actually, leptin levels reduced significantly at the end of IFN-á treatment and remain sustained at low levels up to the end of follow-up. As the clearance of the viruses was not associated with the alterations of leptin levels, we suggest IFN-á as a potential direct inhibitor of leptin production.


Abstract ID: 66690

Category: JO7: HCV: Treatment

Randomized Trial of Pegylated Interferon for the Treatment of Acute HCV in Seattle Injection Drug Users.

C. Wang, University of Washington, Seattle, WA, L. Cook, Fred Hutchinson Cancer Research Center, Seattle, WA, M. Krows, University of Washington, Seattle, WA, K. Ng, Fred Hutchinson Cancer Research Center, Seattle, WA, E. Hough, Public Health Seattle & King County, Seattle, WA, H. Thiede, Public Health Seattle And King County, Seattle, WA, E. Krantz, University of Washington, Seattle, WA, K. Jerome, University of Washington, Seattle, WA, A. Bagabag, Fred Hutchinson Cancer Research Center, Seattle, WA, H. Hagan, Center for Drug Use and HIV Research, New York, NY, L. Corey, University of Washington, Seattle, WA, A. Wald, University of Washington, Seattle, WA

 

OBJECTIVE:

To determine the efficacy of pegylated interferon for the treatment of acute hepatitis C infection in injection drug users (IDU)

 

METHODS:

Subjects were recruited from longitudinal studies of IDU in Seattle. Acute hepatitis C was defined by seroconversion to anti-HCV positive within 6 months of screening in a previously seronegative IDU. Subjects with acute hepatitis C with detectable serum HCV and no contraindications to pegylated interferon (PEG) therapy were randomized to receive 6 months of PEG or to 6 months of observation. Study endpoints were lack of detection of hepatitis C virus (HCV) measured 6 months after treatment discontinuation or after 6 months of observation. Reinfection was assessed by comparing the HCV genotype present in baseline and subsequent serum samples. HCV genotype was determined using the Abbott HCV Genotype ASR assay.

 

RESULTS:

9 subjects have been randomized to treatment and 12 to control. In the treatment and control arms, 5 of 9 subjects (55%) and 8 of 12 subjects (67%) had genotype 1 infection, respectively. Age, gender, and baseline viral load did not differ between the two groups. For the 4 treatment subjects reaching the study endpoint, 3 achieved an SVR and 1 subject was a nonresponder. For the 7 control subjects reaching the study endpoint, 1 subject naturally cleared virus and 6 have developed chronic HCV. Two treatment subjects and 1 control subject who are still in follow-up became reinfected by a different HCV genotype after initially achieving undetectable serum HCV levels. Thus, a total of 3 reinfections have occurred in this study (Figure 1).

 

CONCLUSIONS:

In a randomized trial of PEG for acute HCV in IDU, PEG resulted in SVR in 3 of 4 subjects (75%) completing treatment and follow-up. In untreated controls, 6 of 7 subjects have developed chronic infection (86%). The reinfection rate in this trial is higher than reported in published studies, with 3 of 21 (14%) of subjects becoming reinfected within 6 months of viral clearance.

 


Abstract ID: 66739

Category: JO7: HCV: Treatment

Pharmacodynamic effects of pegylated interferon-alpha2b differentiate sustained virologic responders from nonresponders in hepatitis C virus/human immunodeficiency virus coinfected patients.

R. M. Ribeiro, Los Alamos National Laboratory, Los Alamos, NM, A. . Talal, Weill Medical College of Cornell University, New York, NY, K. . Powers, Los Alamos National Laboratory, Los Alamos, NM, M. Grace, Schering-Plough Research Institute, Union, NJ, C. Cullen, Schering-Plough Research Institute, Union, NJ, M. Hussain, Schering-Plough Research Institute, Union, NJ, A. S. Perelson, Los Alamos National Laboratory, Los Alamos, NM

 

Background & Aims:

Pegylated interferon alpha (PEG-IFN) has become standard therapy for hepatitis C virus (HCV) infection. However, the weekly dosage of this product leads to waxing and waning concentrations of PEG-IFN during the dosing interval. We sought to evaluate whether PEG-IFN alpha pharmacokinetics and pharmacodynamics may partially account for differences in treatment outcome.

 

Methods:

Twenty-four IFN naïve, HCV and human immunodeficiency virus-1 (HIV-1) co-infected patients received PEG-IFN alpha-2b (1.5 &#956;g/kg) once weekly plus daily ribavirin (13 mg/kg) for up to 48 weeks. Blood samples were obtained frequently after the first three PEG-IFN doses. HCV RNA levels were determined using a real-time reverse transcriptase polymerase chain reaction assay, and PEG-IFN alpha concentrations were measured using a validated, electrochemiluminescence-based assay. HCV kinetic models incorporating pharmacokinetic and pharmacodynamic parameters, to account for changing drug effectiveness between doses, were developed to model changes in HCV RNA under treatment.

 

Results:

Six patients (25%) were sustained viral responders (SVR) and the rest were nonresponders (NR) – in this group we include two patients that showed an end of treatment response. We found significant pharmacodynamic differences between SVR and NR patients. The PEG-IFN alpha-2b concentration that decreases HCV production by 50% (EC50) was lower in SVR (0.17 vs. 0.33 &#956;g/L, p=0.05). In addition, both the average effectiveness and the ratio between average PEG-IFN concentration and EC50 were significantly increased in SVR, after the first (0.84 vs. 0.55, p=0.005; 13 vs. 2.0, p=0.01, respectively) and second doses (0.85 vs. 0.58, p=0.032; 17 vs. 2.5, p=0.02, respectively). Baseline log10 HCV RNA levels were significantly lower (5.2 vs. 6.4 log10, p=0.003) and second phase viral decay (delta) was significantly faster (0.52 vs. 0.18 /day, p=0.015) in SVR than in NR.

 

Conclusions:

Pharmacodynamic measurements, namely the EC50 and the ratio between average PEG-IFN concentration and EC50, are different in SVR and NR co-infected patients. In contrast, pharmacokinetic measurements do not differ between SVR and NR patients. Thus, a successful treatment response does not appear to be due to different serum PEG-IFN alpha2b concentrations, rather it appears to depend on patient or virus response to similar concentrations of PEG-IFN. Because of waning PEG-IFN alpha effectiveness between doses, models that incorporate pharmacokinetics maybe more accurate then models that assume constant efficacy when evaluating HCV kinetics in patients treated with PEG-IFN alpha-2b.
Abstract ID: 67281

Category: JO7: HCV: Treatment

Safety and efficacy of 24-week course of pegylated interferon-Ą2a and ribavirin for the treatment of acute HCV infection in HIV positive patients.

S. Dominguez, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, France, J. Ghosn, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, France, M. Valantin, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, France, A. Schruniger, Hopital Pitie Salpetriere, Service de Virologie, Paris, France, P. Bonnard, Service des Maladies Infectieuses, Hopital Tenon, Paris, France, V. Thibault, Hopital Pitie Salpetriere, Service de Virologie, Paris, T. Poynard, Hopital Pitie Salpetriere, Service d'Hépatologie, Paris, France, C. Katlama, Hopital Pitie Salpetriere, Service des Maladie Infectieuses, Paris, Y. Benhamou, Hopital Pitie Salpetriere, Service d'Hépatologie, Paris, France

 

Background:

Treatment of acute hepatitis C (HCV) in HIV-infected patients have been poorly addressed.

 

Objective:

To evaluate the efficacy and tolerability of a 24-week course of of Pegylated interferon a2a (PEG-IFNa2a) and ribavirin (RBV) for the treatment of acute HCV infection in HIV positive patients (pts).

 

Methods:

HIV-positive pts with acute HCV infection defined by simultaneous ALT elevation, documented HCV seroconversion to anti-HCV positive antibody (Ab) and positive qualitative HCV RNA (Cobas Amplicor HCV 2.0, lower limit of detection of 50 UI/ml) were included in a prospective open study. In order to document more precisely time of HCV infection, HCV Ab and HCV RNA were retrospectively performed on stored serum samples available in the 12 months before diagnosis.Pts with detectable HCV RNA (> 50 UI/L) at least 12 weeks after diagnosis were treated with PEG IFN a2a (180 μg/week) and RBV (800 mg/day) for 24 weeks. Patients were followed every 4 weeks during the pretherapeutic and treatment periods. Sustain virological response (SVR) was defined by a negative qualitative HCV RNA 24 weeks after the end of treatment (EOT).

 

Results:

A total of 25 consecutive homosexual men were included. Unprotected sex intercourse was the only identified risk factor of HCV contamination in all pts with a concomittent active syphilis in 7 pts. At baseline 24 patients were on HAART, 21 pts had HIV RNA <200 copies/mL and a median CD4 count of 451/mm3. HCV genotypes(GT) distribution was: GT1 =7 , GT3 =7 and GT4 =11 . Only one pt with GT3 had a spontaneous negativation of serum HCV RNA at week 3 and remained HCV RNA negative untill 48 weeks. Of the remaining 24 pts, 5 refused anti-HCV therapy and 19 pts started anti-HCV therapy. Median HCV RNA at treatment initiation was 1096 KUI/ml (range 101-4373), median ALT was 311(range 82-1271), median time from diagnosis to treatment initiation was 13 weeks. Of the 14 patients who achieved the 24 weeks post-therapeutic period, 10 had a SVR (71%). All of the patients with SVR became HCV RNA negative by week 12 of therapy. One pt (GT 1)achieved HCV RNA negativation and relapsed 12 weeks after EOT. Treatment is still ongoing in 5 pts. There was no safety issue in all treated pts. There was no substantial changes in HIV RNA and in CD4 count 24 weeks after EOT.

 

Conclusion:

Treatment of acute hepatitis C with pegylated interferon (180μg/w) and RBV (800 mg/d) for 24 weeks lead to a high SVR rates in HIV infected patients. Early recognition and treatment of acute HCV infection is mandatory in HIV population to prevent chronic evolution because of the poor efficacy of anti HCV therapy in chronic HCV infection.


Abstract ID: 67720

Category: JO7: HCV: Treatment

Soluble Interleukin 2 Receptors Plasma Levels among Responder and Non-responder Patients with Chronic Hepatitis C.

A. Montano-Loza , Instituto Nacional de Ciencias Medicas y Nutricion, Mexico , Mexico, M. Ramirez-Iglesias, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico, Mexico, G. Gabriela Gutierrez-Reyes, Universidad Nacional Autonoma de Mexico, Mexico , Mexico, R. Nuñez, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico, Mexico, S. Cruz, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico, Mexico, F. Gallegos, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico, G. Robles-Diaz, Universidad Nacional Autonoma de Mexico, Mexico , Mexico, D. Kershenobich, Universidad Nacional Autonoma de Mexico, Mexico , Mexico

 

Background / Aim:

It has been suggested that soluble interleukin-2 receptor (sIL-2R) may be a more specific parameter than the disappearance of HCV RNA for assessing total and hence more sustained elimination of HCV infection (J Hepatol 1999; 31:612). In the present study, we analyzed the levels of sIL-2R before therapy and at various time points throughout the therapy period with pegylated IFN (PEG-IFN)-α 2a or -α2b plus ribavirin, to determine the prognostic value for treatment response of this soluble serum receptor.

 

Patients & Methods:

A series of 28 consecutive patients with chronic hepatitis C (CHC) were enrolled and treated for 6-12 months according to their genotype. Nineteen patients, genotype 1 (18) and genotype 2 (1) recibed PEG-IFN-α 2b plus ribavirin and 9 patients, genotype 1 (6), genotype 2 (2) and genotype 3 (1) were treated with PEG-IFN-α2a. Blood samples were drawn at baseline, 48 hours, 1, 3, 6, 9 and 12 months during treatment period and 6 months after it was stopped. The differences in the receptor levels among both groups were analyzed with Mann-Whitney U non-parametric test. P values ≤0.05 were considered statistically significant.

 

Results:

A total of 16 (57%) patients achieved sustain virological response (SVR) independently of the type of PEG-IFN used (PEG-IFN-α2a 56% vs. PEG-IFN-α2b 58%). Basal serum sIL-2R levels were significantly lower in patients with CHC that achieved SVR with PEG-IFN-α2a or -α2b plus ribavirin, compared with nonresponders (2001 ± 1275 pg/ml vs. 737 ± 543 pg/ml; P = 0.006). Througth the study period and independently of the type of PEG-IFN administrated, the pattern of lower sIL-2R was sustained among patients that achieved a SVR (Figure). Levels of sIL-2R among nonresponders remain persistently elevated, even after 6 months after the treatment was stopped (1631 ± 1086 pg/ml vs. 448 ± 174 pg/ml; P < 0.001

 

Conclusions:

Our results show that determination of sIL-2R before treatment with PEGIFN-α2a or -α2b plus ribavirin may be a prognostic factor of SVR. The persistent low serum sIL-2R during treatment may be associated with HCV-specific Th1 inflammatory response.


Abstract ID: 62076

Category: JO7: HCV: Treatment

IDENTIFYING A SUBSET OF PATIENTS WHO DO NOT WARRANT PRETREATMENT LIVER BIOPSY FOR HEPATITIS C (HCV).

K. Watson, St Vincent's Hospital,, Fitzroy, Australia, P. Desmond, St Vincent's Hospital, Fitzroy, Australia, S. Bell, St Vincent's Hospital, Fitzroy, Australia

 

Most patients with HCV are required to have a liver biopsy before they can access subsidised treatment. The major clinical reason for the biopsy is to determine whether patients have cirrhosis, as this would be an indication for a longer duration of treatment. Clinical predictors of cirrhosis suffer from lack of sensitivity and specificity. The aim of this study was to use our large database of people with HCV to determine negative predictors of cirrhosis i.e. which patients should not be biopsied. A prospective database of patients with HCV has been maintained since 1990 and now contains 6000 records. Of these 1322 have had liver biopsies. We performed multivariate analysis and discriminant analysis, to determine factors with the highest negative predictive value for cirrhosis (i.e. most strongly predictive of non-cirrhosis). These were duration of infection, ALT level, recent and past alcohol and current age. Current age is a clinically accessible surrogate for duration of infection In many patients, ALT level may be a surrogate for co-factors alcohol or non-alcoholic fatty liver disease. A clinical predictive model was constructed using the combination of these factors. Receiver operating characteristic (ROC) curves were constructed to determine the best threshold for the ALT level (80) to maximise the negative prediction of severe fibrosis. The most powerful variable was age, in the case of people with injecting drug use as a risk factor, or duration of infection where blood transfusion or tattoo were the most distant risk factors. The positive predictive value (PPV) of age <40 for prediction of mild disease (Metavir score 0-2) was .88 overall (.91 in females, .88 in males). In contrast, the positive prediction of severe fibrosis was quite inaccurate (as previous work has shown). The combination of age< 40 and ALT<80 gave an almost 100% PPV for mild disease. Using this clinical model very few patients under the age of 40 have cirrhosis. In this situation biopsy is not justified, most especially if the ALT is <80. Adoption of his recommendation would have avoided 180 out of 1322 biopsies in our clinic. We are investigating further evidence-based algorithms which could refine the indicators for biopsies in other subsets of patients. A rationalisation of the requirement for liver biopsy would eliminate a barrier to treatment, increase access to treatment and decrease both risk and costs.


Abstract ID: 62110

Category: JO7: HCV: Treatment

Primary Care Based Hepatitis C Treatment: Collaborating to Improve Access, Adherence and Outcomes.

D. Gardenier, Mount Sinai School of Medicine, New York, NY, D. Alfandre, Mount Sinai School of Medicine, New York, NY, T. Schiano, Mount Sinai School of Medicine, New York, NY, N. O'Connor-Moore, Mount Sinai School of Medicine, New York, NY, T. G. McGinn, Mount Sinai School of Medicine, New York, NY

 

BACKGROUND:

Hepatitis C (HCV) has an estimated seroprevalence of 1.8% in the US. Among underserved inner-city populations, however, rates may be as high as 8%. Access to health care, as well as the ability to navigate complex subspecialty care, is deficient among populations where incidence of HCV is highest. In addition, comorbidities such as depression, cardiac disease, substance use and diabetes are prevalent in this population and often exclude patients from treatment. Traditionally, HCV Ab+ patients have been referred to hepatology for evaluation, decreasing hepatologist availability where it is often already scarce.

 

METHODS:

In 2003 we implemented a collaborative program to assess the feasibility of evaluating patients and offering them treatment in primary care. All HCV Ab+ patients diagnosed in our inner-city primary care practice were evaluated, educated and counselled without referral. To be included, patients had to be treatment naïve, monoinfected, age 18 to 65, and noncirrhotic. For genotypes 1 and 4, an ultrasound and liver biopsy were obtained. Patients with advanced liver disease or renal insufficiency, as well as nonresponders, relapsers and the coinfected were not eligible and referred. Patients meeting the entry criteria were offered standard-of-care peginterferon and ribavirin combination therapy.

 

RESULTS:

To date, 217 HCV Ab+ patients have been evaluated. The predominant risk factor was IVDU (79%). 86% of patients were Hispanic or African American. The mean number of comorbidites was four. 35 (16%) had no detectable RNA. Of the remaining 182 (84%) with viremia, 92 (51%) were ineligible for treatment and 24 (13%) were or are still undergoing evaluation. 66 (36%) of the viremic patients were eligible for treatment. Of those, 32 (48%) were lost to follow up, refused or deferred treatment. 17 (26%) patients have completed treatment in primary care. Of those, 5 (29%) had a sustained viral response, 10 (59%) were non-responders and 2 (12%) relapsed. Five patients were withdrawn from treatment for side effects. 177 (82%) of the 217 patients evaluated were not referred to hepatology. 18 patients were referred: 8 (44%) had advanced liver disease and 10 (56%) for retreatment after non-response.

 

CONCLUSIONS:

Our experience indicates that collaborative evaluation and treatment of patients in the primary care practice may increase access to treatment in higher risk, more difficult to treat populations. Evidence and experience suggests that access is improved, treatment results are similar, and inappropriate referrals to the hepatology practice are reduced, by collaboratively evaluating and treating patients in the primary care setting.


Abstract ID: 62918

Category: JO7: HCV: Treatment

The association of fatigue with poor virologic response in patients receiving interferon alpha plus ribavirin for the treatment of hepatitis C.

C. L. Raison, Emory University, Atlanta, GA, C. M. Pariante, Institute of Psychiatry - King's College London, London, L. Capuron, Emory University, Atlanta, GA, B. Chen, Emory University, Atlanta, GA, B. J. Woolwine, Emory University, Atlanta, GA, C. Bruno, Kaiser Permanente, Atlanta, GA, I. Jacobson, Weill Medical College of Cornell University, New York, NY, A. H. Miller, Emory University Department of Psychiatry and Behavioral Sciences, Atlanta, GA

 

IFN-alpha plus ribavirin for hepatitis C virus (HCV) is notorious for inducing fatigue, which in turn may influence treatment response. Accordingly, fatigue and other factors  relevant to treatment outcome were examined in 98 HCV-infected patients undergoing therapy with pegylated IFN-alpha-2b (PEG IFN) plus ribavirin. PEG IFN plus ribavirin resulted in profound and persistent fatigue as assessed by the Chalder Fatigue Questionnaire (CFQ). Sixty-five percent of patients exhibited a moderate to severe increase in fatigue as defined by a ¡Ý5 point increase in the CFQ during treatment. Patients who exhibited a ¡Ý3 g/dl decrease in hemoglobin (Hb) concentration were significantly more likely to experience a moderate or severe increase in fatigue and were significantly more likely to undergo ribavirin dosage reduction. At study conclusion, 59% of the patients were HCV RNA negative. Increasing fatigue was associated with reduced rates of being HCV RNA negative after 24 weeks of treatment. Indeed, mild, moderate and severe increases in CFQ scores were respectively associated with a 79%, 56% and 40% rate of being HCV RNA negative at 24 weeks (Chi-square=10.48, df=2. p<0.01; Cochrane-Armitage trend test, z=3.22, p<0.005). A moderate or severe increase in fatigue (¡Ý5 point increase in the CFQ) was associated with a greater likelihood of being HCV RNA positive after 24 weeks of treatment, even after controlling for other factors that predicted 24 week HCV RNA status, including viral genotype, PEG IFN and/or ribavirin dosage reduction, and race (adjusted OR, 3.2; 95% CI, 1.2-8.8, p<0.05). Moreover, patients who were HCV RNA positive after 24 weeks of treatment had significantly greater increases in fatigue during therapy than patients who were HCV RNA negative (delta CFQ for HCV RNA positive=6.8¡À2.8 vs. 4.9¡À3.1 for HCV RNA negative, t=3.11, p<0.005). This represents a 40% greater delta CFQ score in HCV RNA positive patients than in patients who were HCV RNA negative at 24 weeks. HCV RNA positive patients also had a higher mean maximum CFQ score during treatment than patients who cleared virus (8.0¡À2.0 vs. 6.8¡À2.9, t=2.32, p<0.05). No relationship was observed between baseline (pre-treatment) fatigue and HCV RNA status at 24 weeks. In conclusion, the development of fatigue is common during IFN-alpha therapy and is related in part to decreases in Hb concentration. In addition, fatigue appears to have an independent relationship with HCV RNA status at 24 weeks, suggesting a shared pathophysiologic pathway between the development of fatigue and treatment on response.


Abstract ID: 62951

Category: JO7: HCV: Treatment

Different Clinical Presentation and Treatment Response of Chronic Hepatitis C in Asian Americans Verses Non-Asian Americans.

H. Hoang, Univeristy of California Irvine, Orange, CA, N. L. Kyulo, University of California, Irvine, Orange, CA, V. Xia, University of California, Los Angeles, Loa Angeles, CA, J. Hoefs, University of California, Irvine, Orange, CA, L. L. Bui, University of California, Irvine, Orange, FL, M. Wu, University of California, Irvine, Orange, CA, K. Hu, University of California, Irvine, Orange, CA

 

BACKGROUND:

The clinical presentation and treatment response of chronic hepatitis C (CHC) could vary among ethnic groups, but little is known whether these differences are also present in Asian Americans (AA).

 

AIMS:

The present study was aimed to compare the clinical presentation and treatment response of CHC in AA verses Non-Asian Americans (non-AA).

 

METHODS:

The medical records were retrospectively reviewed in 317 consecutive CHC patients presented to the Liver Clinic at Univ. of California, Irvine Med. Ctr. from January 1998 to January 2005. The inclusion criteria were positive HCV RNA PCR, liver biopsy-proven chronic hepatitis, negative HBsAg and anti-HIV, and naïve to HCV treatment at the entry. After excluding 179 cases who did not meet the inclusion criteria, 138 CHC patients [AA=70; non-AA=68 (White=62; Hispanic=6)] were included in this study. Seventy-seven (AA=31; non-AA=46) received PEG-interferon alfa-2a plus ribavirin treatment, including 60 (AA=27; non-AA=33) accomplished a full course (i.e. 24 weeks for HCV genotype 2 and 3, 48 weeks for other HCV genotypes) of the treatment and 24 weeks of post-treatment follow-up.

 

RESULTS:

AA patients presented with significantly older age (54.8+8.8 vs. 46.3+11.6, p=0.0002), but lower mean body mass index (BMI, 22.5+2.8 vs. 31.5+7.8, p< 0.0001), and lower frequencies of obesity (i.e. BMI > 30, 0.0% vs. 48.8%, p<0.0001), history of excessive alcohol use (19.2% vs. 58.1%, p<0.0001) and injection drug user (IDU, 0.0% vs. 53.7%, p<0.0001) than non-AA patients. The mean HCV RNA level (4.0 +8.6 x 106 vs. 3.5+4.3 x 106, p=0.63) and the frequency of HCV genotype-1 (64.1% vs. 62.5%) were not significantly different in both groups, but HCV genotype-6 was more frequently seen in AA patients than non-AA patients (20.5% vs. 0.0%, p=0.002). Early discontinuation of the HCV treatment was less common in AA patients than non-AA patients (12.5% vs. 28.8%, p=0.09). The intent-to-treat (i.e. all patients who received HCV treatment) sustained virologic response (SVR, 74.2% vs. 51.1%, p=0.04) was significantly higher in AA patients than non-AA patients. After adjusting for gender, BMI and HCV genotype, AA-ethnicity was independently associated with the intent-to-treat SVR.

 

CONCLUSIONS:

Compare to non-AA patients, AA patients with CHC presented with significantly older age, but lower frequencies in history of obesity, excessive alcohol use and IDU. AA ethnicity was independently associated with a significantly higher intent to-treat SVR.


Abstract ID: 64072

Category: JO7: HCV: Treatment

Combination Therapy Using Pegylated Interferon and Ribavirin in Patients with Psychiatric Illnesses.

F. Barakat, University of California San Diego, San Diego, CA, M. Carlson, University of California, San Diego, San Diego, CA, D. Oliver, University of California, San Diego, San Diego, CA, E. Barber, University of California, San Diego, San Diego, CA, J. Travasso, University of California, San Diego, San Diego, CA, M. Verbeck, University of California, San Diego, San Diego, CA, L. Richards, University of California, San Diego, San Diego, CA, E. Alpert, University of California, San Diego, San Diego, CA, W. Perry, University of California, San Diego, San Diego, CA, T. Hassanein, University of California, San Diego, San Diego, CA

 

Chronic Hepatitis C (CHC) infected patients have a high prevelance of psychiatric disorders. Interferon and Ribavirin combination therapy exacerbates psychiatric disorders and/or leads to premature discontinuation of treatment.

 

Aims

Our aims were: 1) describe the treatment course of pts with psychiatric disease, and 2) explore whether pts with psychiatric illnesses can be safely treated with IFN based therapy.

 

Methods:

Between 1997 and 2005, 1300 consecutive pts with CHC (+/- other liver diseases) and psychiatric illness were considered for IFN based therapy. Of these, 271 pts had CHC alone + psychiatric illness. 108 were deemed psychiatrically stable for treatment. We report on 80 pts who completed a course of Pegylated Interferon and Ribavirin therapy.

 

Results:

The mean age was 48.8 ± 6.5 years; 46% were male, 71% Caucasian, 15% African American, 5% Hispanic, and 9% Other. 64% had Depression, 17% had Bipolar Disorder, 9% had Schizophrenia (Sz), and 10% had Anxiety. All pts were on psychotropic medications and were clinically stable. Baseline median lab values showed: ALT of 65 (17-476) IU/L, AST of 50 (19-323) IU/L, Platelet count of 225 (54-390) 1000/mm3 and HCV viral load of 500,000 (7,810-3,590,000) IU/mL. 53% had none to moderate fibrosis on liver biopsy. 66% were Genotype 1. 73% successfully reached end of treatment (24 or 48 weeks based on genotype). 16% discontinued early due to exacerbation of psychiatric disorder (5/51 Depression, 6/14 Bipolar and 2/7 Sz), 7% due to drug related adverse events and 4% due to non-adherence. See table for virologic response. There were no significant differences between psychiatric diseases in terms of early discontinuation or treatment response (p=0.10 and 0.68, respectively).

 

Conclusions:

1) Pts with preexisting psychiatric illness tolerated treatment with Pegylated Interferon and Ribavirin well, and 2) The type of psychiatric illness did not affect the patient’s compliance, ability to complete treatment duration or response to treatment.

 


Abstract ID: 64161

Category: JO7: HCV: Treatment

LOW RATES OF SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON AND RIBAVIRIN THERAPY IN GENOTYPE 3 INFECTED PATIENTS WITH COMPENSATED CIRRHOSIS.

A. Aghemo, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, M. Rumi, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, R. D'Ambrosio, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, R. Soffredini, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, G. Ronchi, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, E. Del Ninno, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy, S. Gallus, Istituto di Ricerche Farmacologiche, Milan, Italy, M. Colombo, IRCCS Maggiore Hospital, University of Milan, Milan Italy, Milan, Italy

 

Background

HCV 3a infected patients enrolled into megatrials showed high rates (>80%) of sustained virological responses (SVR) to 6 month-interferon (IFN) and ribavirin (RBV) therapy. Thus, these patients were defined as “easy to treat” and pretreatment assessment of liver histology unnecessary.

 

Aim

To assess SVR rates and response predictors in HCV 3a patients enrolled in field trials, i.e. outside of randomized controlled trials.

 

Methods

All naive to IFN patients who were consecutively seen at our center in Milan between January 2000 and September 2003 without major contraindications to IFN/RBV therapy, were studied. Results 91 HCV 3a infected patients were enrolled. 71 (46 males, 11 with cirrhosis) received 1.5 mcg/Kg PegIFNalfa2b at weekly intervals and 800-1200 mg ribavirin/day for 24 weeks, 20 (11 males, 6 with cirrhosis) received IFN 3MU t.i.w. plus 800-1200 mg ribavirin/day for 24 weeks. Overall 68 (75%) had had a SVR. The 17 patients with cirrhosis, defined as Ishak staging score ≥5, had significantly lower SVR rates than the 74 non cirrhotic patients (35% vs 84%; age and sex adjusted odds ratio 10.1; 95% C.I. 2.4 - 41.7), due to high rates of relapse after a response (57% vs 9%: age and sex adjusted odds ratio for a relapse in cirrhosis 8.36; 95% C.I. 1.69 - 41.23). Pretreatment virus load, degree of steatosis or type of IFN were not associated with SVR rates.

 

Conclusions

Low rates of SVR were obtained in HCV 3a infected patients with histological evidence of cirrhosis due to frequent post treatment relapse. Thus, liver biopsy remains an important decision making step in the management of HCV 3a patients, whereas extended treatment with IFN/RBV should be considered.


Abstract ID: 64168

Category: JO7: HCV: Treatment

DIFFERING IMMUNE EFFECTS OF PEG-IFN-ALPHA 2B AND IFN-ALPHA 2B COMBINED WITH RIBAVIRIN FOR CHRONIC HEPATITIS C.

K. Ishii, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Y. Sumino, Division of Gastroenterology and Hepatology, Tokyo, Japan, K. Higami, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, Y. Fujita, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Shinohara, Division of Gastroenterologu and Hepatology, Toho University, Tokyo, Japan, T. Ikehara, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Shinohara, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, K. Matsumaru, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, H. Nagai, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, M. Watanabe, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan, K. Miki, Division of Gastroenterology and Hepatology, Toho University, Tokyo, Japan

 

BACKGROUND/AIM:

The response rate to pegylated interferon (PEG-IFN)-alpha plus ribavirin is higher than that for conventional IFN-alpha plus ribavirin in patients with chronic hepatitis C virus (HCV) infection, although the mechanism remains unclear. The goal of this study was to investigate differences in the effect on the immune system of patients with chronic hepatitis C (CHC) between PEG-IFN-alpha 2b and conventional IFN-alpha 2b combined with ribavirin.

 

PATIENTS AND METHODS:

Twenty-three adults with biopsy-proven CHC (15 men and 8 women) were studied, all of whom had infected with HCV serotype1. The enrollment criteria included an age between 33 and 67 years (median age: 54 years) and a baseline serum HCV-RNA level (quantified by RTPCR: Amplicor Ver.2.0 high range; Roche) between 220 and 5000 KIU/ml (median: 1540 KIU/ml). A regimen of IFN-alpha 2b (6 MU daily for 2 weeks followed by 6 MU thrice weekly) and ribavirin (600 mg/day for a body weight < 60 kg or 800 mg/day for a body weight > 61 kg) was given to 14 patients, comprising 8 men and 6 women with a median age of 54 years and a median serum HCV-RNA of 1330 KIU/ml before starting therapy. The other 9 patients (7 men and 2 women with a median age of 54 years and a median serum HCV-RNA of 1870 KIU/ml before starting therapy) were treated with PEG-IFN-alpha 2b (1.5 micro g/Kg) once weekly plus same doses of ribavirin (600 – 800 mg/day for a body). Blood samples were collected on days 0, 3, 7, 14, and 28 during therapy. Flow cytometry was used to assess cytoplasmic expression of IFN-gamma and IL-4 by peripheral CD4 + T cells, and the percentage of IFN-gamma + and IL-4 - (Th1) cells or IFN-gamma - and IL-4 + (Th2) cells was calculated. In addition, NK cells in the peripheral blood were measured using a 51Cr-release assay.

 

Results:

Baseline percentages of peripheral blood Th1 cells, Th2 cells, and NK cells did not different significantly between the groups. After the start of therapy, the percentage of Th1 and Th2 cells peaked on day 3, and thereafter decreased gradually until day 28 in both groups. However, the percentage of Th1 cells was always higher than in patients treated with PEG-IFN-alpha 2b than in patients treated with conventional IFN-alpha 2b, and the percentage of Th2 cells always lower in patients treated with PEG-IFN-alpha 2b than in patients treated with conventional IFN-alpha 2b. In contrast, the percentage of peripheral blood NK cells did not change during the study period in either group.

 

CONCLUSIONS:

Our results suggest that pegylation may have an immunomodulatory effect as well as IFN itself, and may alter the host immune response to favor the eradication of HCV.
Abstract ID: 64306

Category: JO7: HCV: Treatment

Fasting triglyceride levels before, during and after treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (RBV, COPEGUS®) in patients infected with HCV genotype 2 or 3: The ACCELERATE serum triglyceride substudy.

M. Shiffman, Medical College of Virginia Commonwealth University, Richmond, VA, A. Gibas, Lancaster General Hospital, Lancaster, PA, J. Rasenack, University Universitatsklinik Freiburg, Freiburg, Germany, A. Soman, Roche Products Ltd, Welwyn Garden City, United Kingdom (Great Britain), S. Zeuzem, Saarland University Hospital, Homburg, Germany

 

Introduction

Retrospective data indicate that serum triglyceride levels in patients with chronic hepatitis C tend to increase during conventional interferon therapy. This phenomenon, however, has not been rigorously evaluated in large trials. Moreover, it has not been assessed in patients receiving pegylated interferon plus ribavirin, which constitutes the treatment of choice for chronic hepatitis C.

 

ACCELERATE is a large (n=1400), multinational, randomized, phase IV trial conducted to investigate whether the duration of therapy in patients infected with hepatitis C virus (HCV) genotype 2 or 3 can be further reduced without affecting efficacy, but with potential safety/tolerability benefits and reductions in treatment costs. In ACCELERATE, patients were randomized to 16 or 24 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®). A substudy of ACCELERATE prospectively examined the effects of therapy on fasting serum triglyceride levels.

 

Objective

The aim of this study was to evaluate fasting serum triglyceride levels before, during and after treatment with peginterferon alfa-2a (40KD) plus ribavirin in genotype 2 or 3 patients enrolled in ACCELERATE, a large, randomized, multinational study.

 

Patients

Patients eligible for inclusion in ACCELERATE were treatment naïve adults aged ≥ 18 years with quantifiable serum HCV RNA (>600 IU/mL), elevated alanine aminotransferase activity and compensated liver disease. All patients were required to be infected with HCV genotype 2 or 3. Exclusion criteria included previous treatment with anti-HCV therapies.

 

Study design

·       The study design of ACCELERATE is illustrated in Figure 1. Patients were randomized according to country and HCV genotype to receive peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 800 mg/day for 16 or 24 weeks.

·       The first 100 patients enrolled in each treatment group participated in the triglyceride substudy.

·       Patients included in the triglyceride substudy had a fasting triglyceride level measured at baseline, and at the end of treatment and follow-up. Patients were required to fast for 12 hours before each blood collection. Patients who did not have a fasting triglyceride collection recorded at all three time points were excluded from the analysis.

 

·       Each patient’s highest fasting triglyceride concentration was categorized according to National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria.

Statistical analysis

·       Fasting triglyceride concentrations were summarized using descriptive statistics.

Results

·       A total of 111 of the 200 patients who participated in the triglyceride substudy had fasting triglyceride measurements collected at all three time points. Of these, 60 and 51 patients received treatment for 16 and 24 weeks, respectively.

·       Baseline demographic and disease characteristics of all patients included in the triglyceride substudy are reported below.

·        

Baseline characteristics:

 

·       In both treatment groups, median serum triglyceride levels increased from baseline to the end of treatment, but decreased towards baseline levels during follow-up.

·       A similar pattern was seen when median serum triglyceride levels were analyzed separately in genotype 2 and genotype 3 patients. Triglyceride levels increased slightly from baseline to treatment end, but decreased towards baseline levels during the untreated follow-up period in both HCV genotype 2 and 3 patients treated for 16 and 24 weeks.

·       At all three time points, median serum triglyceride levels remained within the normal range (0.45–1.69 mmol/L); this occurred when triglyceride levels were analyzed according to treatment duration and HCV genotype.

·       Overall, 3 of 60 patients treated for 16 weeks received a fibrate (gemfibrozil) either for prophylaxis (n=1) or for the treatment of adverse events (n=2). No patients treated for 24 weeks received a fibrate.

·       Two patients in each treatment group had a very high triglyceride level (≥5.64 mmol/L) at treatment end. However, all these patients had high levels (2.25 to <5.64 mmol/L) at baseline, and levels had declined by the end of follow-up.

·       No patient with a triglyceride level ≥ 5.64 mmol/L at treatment end experienced clinically significant adverse events.

·       The proportion of patients with a fasting triglyceride level ≥ 2.25 mmol/L increased from baseline to the end of treatment in both groups, but decreased during follow-up.

·       At the end of the follow-up period, seven patients in each treatment group had a triglyceride level ≥ 2.25 mmol/L.

·       In one patient, the level was  ≥ 5.64 mmol/L.

 

Conclusion

·       Median serum triglyceride levels increased during 16 or 24 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in patients infected with HCV genotype 2 or 3. However, median levels remained within the normal range during treatment and declined during follow-up, which suggests that the increases in fasting triglyceride levels were transient and not clinically significant.

·       Final efficacy and safety data from ACCELERATE will be available in early 2006.


Abstract ID: 64377

Category: JO7: HCV: Treatment

SUSTAINED VIROLOGICAL RESPONSE TO TREATMENT IN 100% OF PATIENTS RECENTLY INFECTED, NOSOCOMIALLY, WITH HCV GENOTYPE 2.

E. Sikuler, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel, R. Tur Kaspa, Rabin Medical Center and Tel Aviv University, Petach Tiqva, Israel, Y. Shemer-Avni, Soroka Medical Center and Ben Gurion University, Beer-Sheva, Israel, J. Delgado, Soroka Medical Center and Ben Gurion University, Beer-Sheva, Israel, D. Zilberman, Soroka Medical Center and Ben Gurion University, Beer-Sheva, Israel, A. Fich, Soroka Medical Center and Ben Gurion University, Beer-Sheva, Y. Baruch, Rambam Medical Center and the Technion, Haifa, E. Hyam, Soroka Medical Center and Ben Gurion University, Beer-Sheva

 

In 2003, a cluster of HCV infected patients with a common history of a surgical procedure, performed during 2001-2003, was identified in a medical center. An epidemiological and a phylogenetic investigation linked a health provider, infected with HCV genotype 2, as the possible source of infection in 35 patients. HCV-RNA was isolated from sera of all patients and the double-stranded PePHD region, (correlating to amino acids 270 to 287 of the HCV E2 protein) was sequenced. After a routine clinical investigation 33 patients were offered anti viral therapy. The other 2 patients were not treatment candidates due to old age (82 and 84) and co morbidity.

 

Results:

Twenty two (66%) were women. The mean age was 48.5+16.9 years (18-75). ALT level was 117+135 I.U/L (15-757). Viral load was determined in 10 patients and was < 106 copies/ml in all. A liver biopsy performed in 13 patients, depicted a Metavir score ranging from A0,F0 to A2,F1. Thirty patients were treated with Pegylated interferon alpha 2a, 1 with Pegylated interferon alpha 2b and one with standard interferon. All the treated patients received ribavirin 800 mg daily. One patient refused to be treated and was lost for follow-up. Time from acquisition of disease to initiation of therapy was 14.8+4.9 month (5.5-26). Therapy duration was 24 weeks except for one patient who stopped therapy after 16 weeks. Sustained virological response (negative HCV-RNA by PCR at 48 weeks) was achieved in all 32 treated patients. It is of interest that the sequence motif of the PePHD region, studied in all patients, predicted good response to interferon.

 

Conclusion:

Although nosocomial HCV infection causes remarkable distress to patients and staff and can generate long and expensive legal claims, our results suggest a 100% sustained response of HCV genotype 2 infection, when anti-viral therapy is administrated 26 month or less after acquisition of infection. Our results also show correlation between the PePHD region sequence and the response to anti viral therapy.