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

 

 

Abstract ID: 65089

Category: JO7: HCV: Treatment

Assessment of ribavirin mutagenic properties in vivo and the influence of interferon alpha-induced reduction of hepatitis C virus RNA load upon therapy.

S. Chevaliez, Hopital Henri Mondor, Universite Paris 12, Creteil, France, R. Brillet, Hopital Henri Mondor, Universite Paris 12, Creteil, France, C. Hezode, Hopital Henri Mondor, Universite Paris 12, Creteil, France, D. Dhumeaux, Hopital Henri Mondor, Universite Paris 12, Creteil, France, J. Pawlotsky, Hopital Henri Mondor, Universite Paris 12, Creteil, France

 

In a recent report (Nature 2004;432:922-924), mathematical modeling of viral load decay during IFN alpha-ribavirin therapy was used to suggest that ribavirin primarily acts by making HCV virions produced during therapy less infectious. The hypotheses raised to explain this effect were that: (i) ribavirin, by being mutagenic, would accelerate the accumulation of genome mutations leading to the increased generation of non viable HCV variants (so-called ‘error catastrophe’); (ii) ribavirin’s mutagenic effect would appear only in patients with a low viral production related to a high antiviral efficacy of IFN.

 

OBJECTIVE:

To test these hypotheses in patients with chronic hepatitis C receiving IFN plus ribavirin.

 

METHODS:

The HCV genes encoding the full-length NS3 protease and full-length NS5A protein  were PCR-amplified 14 days before treatment, at baseline, at day 14 and at day 28 of therapy in 4 patients receiving ribavirin only and in 5 patients treated with IFN alpha 2b-ribavirin combination. Extensive quasispecies analysis was performed on the basis of 1360 clones generated and sequenced.

 

RESULTS:

(I) In the patients receiving ribavirin monotherapy, the rate of accumulation of mutations did not accelerate during ribavirin administration compared to the pretreatment period (natural genetic drift). In contrast, it tended to slow in 2 cases. (ii) In 4 of the 5 patients under IFN-ribavirin combination therapy, who all experienced a sharp reduction of viral replication over the study period, the rate of accumulation of mutations did not accelerate during the first 14 days of treatment compared to pretreatment, nor did it accelerate during the following 14 days when HCV RNA was consistently reduced by IFN. (iii) In one patient, however, the rate of accumulation of mutations exponentially accelerated during treatment, with a very high mutation rate between day 14 and day 28 when the HCV RNA load decreased from 45,000 down to 200 IU/ml (ie just before becoming negative). Two hypotheses can explain this finding: a- an artefact related to the selection of minor variants due to the very low viral load; b- an accelerated mutagenesis by ribavirin in the context of profound HCV RNA suppression as suggested by mathematical modeling. The latter hypothesis is currently being tested by analyzing the last HCV RNA-positive sample in each patient.

 

CONCLUSIONS:

Ribavirin does not appear to be a mutagenic agent in vivo, either in monotherapy or in combination with IFN alpha. However, this property could be revealed when HCV replication is reduced to very low levels by IFN, a hypothesis currently under study (these results will be presented).


Abstract ID: 65416

Category: JO7: HCV: Treatment

Clinical and Economic Implications of a 4-Week Viral Negative Response to Peginterferon Alfa-2b plus Ribavirin for Chronic Hepatitis C and Genotype 1 with Low Viral Load.

J. B. Wong, Tufts-New England Medical Center, Boston, MA, S. Zeuzem, Saarland University Hospital, Homburg/Saar, Germany, M. P. Manns, Medizinische Hochschule Hannover, Hannover, Germany, J. Harvey, Schering Plough Research Institute, Kenilworth, NJ, J. K. Albrecht, Schering Plough Research Institute, Kenilworth, NJ

 

Introduction:

For chronic hepatitis C infections with genotype 1, monitoring viral response at week 12 during treatment with peginterferon a-2b plus ribavirin has become the standard management algorithm, permitting discontinuation in those unlikely to achieve a sustained viral response (SVR). An earlier week 4 viral negative response to therapy identifies a subgroup of patients with genotype 1 and low viral load (£2 million copies/ml) who can be treated for just 24 weeks.

 

Aim:

To estimate the clinical and economic consequences of a 4-week viral negative response to peginterferon a-2b plus ribavirin for patients with genotype 1 and low viral load.

 

Methods:

We analyzed two trials of peginterferon a-2b plus ribavirin involving genotype 1 patients with low viral load (Manns Lancet 2001, Zeuzem EASL 2005). Although both trials dosed peginterferon a-2b at 1.5 mg/kg/week, they differed in the ribavirin dose and intended duration of therapy: ribavirin 800 mg/day (>10.6 mg/kg) for 48 weeks in Manns and ribavirin 800-1400 mg/day for 24 weeks in Zeuzem. We examined 4-week virologic and SVR outcomes. Drug costs were based on US average wholesale drug costs and observed dosages and duration of therapy in these trials.

 

Results:

The table shows the viral response data. For genotype 1 patients with low viral loads treated for 24 weeks, a 4-week viral negative response occured in 46% (95% CI: 39-54%) with an 89% (95% CI: 79-95%) likelihood of SVR (predictive value positive). The 4-week viral negative response should not be used as a stopping criteria because many sustained responders are not viral negative at week 4 (predictive value negative<100%).

 

24 weeks

48 weeks

Viral Negative Week

4 110/235 (46%)

13/38 (35%)

Likelihood of SVR

98/110 (89%)

11/13 (85%)

Predictive Value Negative

96/115 (83%)

9/25 (36%)

 

Drug costs for those viral negative at week 4 were $16,784 using the observed adherence to dosages and therapy duration in the 24 week study. Assuming the same adherence estimates for 48 weeks, drug costs would double to $33,567. If instead drug use matched that observed in the 48 week study, drug costs would equal $23,036 so that limiting treatment to 24 weeks would reduce costs by $6252, a 27% savings. Discontinuations (14% vs 3%) and dose reductions (49% vs 25%) were more frequent in the 48 week than in the 24 week trial, so the 27% likely represents a minimum savings.

 

Conclusion:

A viral negative response at week 4 in genotype 1 patients with low viral load identifies those who can be treated for just 24 weeks with a high likelihood of achieving a sustained viral response.


Abstract ID: 65792

Category: JO7: HCV: Treatment

INCIDENCE OF INFECTIONS DURING COMBINATION TREATMENT OF CHRONIC HEPATITIS C WITH PEGYLATED INTERFERONS ALFA 2B and 2A.

M. Antonini, University of Brescia, Brescia, Italy, M. Puoti, University of Brescia, Italy, Brescia, Italy, S. Babudieri, Clinica Malattie Infettive, Sassari, Italy, B. Zanini, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, P. Pagani, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, S. Rossi, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, I. Maida, Clinica di Malattie Infettive, University of Sassari, Sassari, Italy, V. Putzolu, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, C. Baiguera, Clinica di Malattie Infettive, University of Brescia, Brescia, L. Fenu, Clinica di Malattie Infettive, University of Sassari, Sassari, Italy, S. Zaltron, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, A. Spinetti, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, L. Biasi, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, S. Sassu, Clinica Di Malattie Infettive, University of Sassari, Sassari, Italy, K. Prestini, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, F. Zacchi, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, G. Carosi, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, M. Mura, Clinica di Malattie Infettive, University of Sassari, Sassari, Italy

 

To evaluate incidence and risk factors for neutropenia and infections occurring during combination therapy for chronic hepatitis C with pegylated interferons (PEGIFN)s and ribavirin we analysed longitudinal data from two Italian reference centres. Complete blood count was performed 1, 2 and 4 after starting treatment and then every 4 weeks thereafter but every week if neutrophils (N) counts<1000/mL. Dose adjustments for neutropenia were made according to manufacturers’ instructions. The analysis included all consecutive HCV infected patients without HIV co-infection who were prescribed PEGIFNs from June 1st 2001 to December 31st 2004. Mann-Whitney, Fisher’s exact test Log Rank test and Cox’s proportional model were used to assess statistical associations. We studied 319 patients treated for chronic hepatitis C with once weekly PEGIFNs: 2b 12 KDa at 1.5 mg/kg (162) or 2a 40KDa at 180 mg flat dose (157), in combination with ribavirin 10.6-13 mg/kg/d,. Patients treated with PEGIFNa2a had a significantly higher prevalence of F3-F4 stages at liver biopsy (62% vs. 33%; p<0.0001) showed a significantly higher body weight (72 vs 68 Kg p=0.03), significantly lower baseline N counts (2.97 vs. 3.3 x103 mL p=0.03) and were treated for a significantly longer time period (mean 190 vs 175 days p=0.006). We observed 73 infections: 38 in patients treated with PEGIFNa2b and 35 in patients treated with PEGIFNa2a. Twenty-three were respiratory infections, 17 cellulitis, 13 dental abscesses, 2 gastro-enteric infections and 18 infections involving other sites. Most of infections were mild; only four patients (1.2%) required hospitalisation. Proportion of treatment duration with N< 800/ mL were not significantly different in the two treatment groups (2.3% vs. 4%) Incidence of neutropenia and infections in persons treated with PEGIFNa2awere not related to body weight.. No statistically significant difference in the incidence of all infections and neutropenia was observed between patients treated with the two PEGIFNs. The incidence of all infections was significantly associated with age (HR 1.03 per year 95% CI 1.01- 1.05 p<0.001). Incidence of respiratory infection was related with duration of neutropenia (N< 800/mL) HR 1.013 per day (95% CI 1.0036-1.0225; p=0.0069) and with usage of PEGIFNa2b HR 2.45 (95% CI 1.001-6.01; p=0.041) but not with age. Incidence of severe infections was low. However 23% of treated patients suffered for infectious episodes with an increasing risk in aged subjects. Respiratory infections were related to the duration of neutropenia and there was a trend for an independent association between usage of PEGIFNa2b and respiratory infections.


Abstract ID: 65859

Category: JO7: HCV: Treatment

Does Hepatic Steatosis affect Sustained Virological Response in chronic Hepatitis C genotype 3 infected patients?

S. Rasool, Department of Medicine, Karachi, Pakistan, S. Hamid, The Aga Khan University,, Karachi, M. Zubair, Aga Khan University, Karachi, Pakistan, K. Mumtaz, Aga Khan University, Karachi, Pakistan, H. Shah, Aga Khan University, Karachi, Pakistan, W. Jafri, Aga Khan University, Karachi, Pakistan

 

Hepatic steatosis can be a prominent feature of chronic hepatitis C virus (HCV) infection, especially in genotype 3 patients, and is considered to be an independent factor for treatment failure. However, the association of this observation with different genotypes is not clear. Prevalence of genotype 3 is very high among chronic HCV patients in our community (in the range of 85%-90%).

 

Objectives:

The purpose of this study was to define the role of steatosis on sustained virological response (SVR) to antiviral therapy in chronic hepatitis C genotype 3 patients.

 

Methods:

We analyzed all naïve chronic HCV patients treated in our department during the last four years. Patients were included in the study only if a pretreatment liver histopathology was available, were infected with HCV Genotype 3 patients, completed 6 months of therapy with interferon-&#945; and ribavirin and had follow up available of at least 6 months. Liver biopsies were graded according to HAI and steatosis according to Brunt et al.

 

Results:

A total of 98 eligible patients were studied. Mean age was 38.09±9.02 years and sixty (61%) were males. Steatosis was present in 67/98(68.3 %) of patients. It was mild in 35/98 (35.7%) and moderate to severe in 32/98 (32.6%) of patients. End treatment response was achieved in 65/98 (66.3%) and SVR in 62/98 (63.3%) patients. SVR was associated with stage of fibrosis (p=0.02) and pre-treatment platelet count (p=0.05) but was not associated with age (p=0.92), gender (p=0.39), BMI (p=0.74), grade of inflammation (0.53) and grade of steatosis (0.28).

 

Conclusion:

Hepatic steatosis is present in a significant number of patients with chronic hepatitis C genotype 3 infection but does not affect sustained virological response.


Abstract ID: 65996

Category: JO7: HCV: Treatment

Evidence of saturable ribavirin absorption.

K. Lindahl, Div of Infectious Diseases, I 73, Stockholm, Sweden, R. Schvarcz, Div of Infectious Diseases, I73, Stockholm, Sweden, L. Ståhle, Dep of Clinical Pharmacology, Stockholm, Sweden

 

Aims:

Ribavirin is a nucleoside analogue most commonly used in combinations therapy with interferon for the treatment of chronic hepatitis C. Currently dose escalation studies are carried out and the aim of this study was to analyse the effect of dose on the bioavailability of ribavirin to study the possibility of saturable absorption. The authors also investigated the stability of ribavirin blood samples.

 

Methods:

Twenty-four patients treated for chronic hepatitis C were included in the study, 10 of which were obtained from a recent study of higher doses than used in current European guidelines. Ribavirin concentrations were analysed with a HPLC method. Relative bioavailability was defined as the observed concentration at steady state divided by the predicted concentration using a model previously described in a population pharmacokinetic analysis. Ribavirin stability was studied in whole blood samples obtained from four patients and stored under different conditions.

 

Results and conclusion:

Higher ribavirin doses were found to be linearly associated with a lower bioavailability (r2= 0.36; p<0.01). At the highest dose, the bioavailability was reduced by 50%. The main finding in this study is that the bioavailability of ribavirin gradually declines with increasing doses. These data suggests that ribavirin absorption is saturable and that ribavirin should be dosed at least thrice daily if higher doses, than recommended in most current guidelines, are used. It is also shown that there is a markedly increase of ribavirin concentration in whole blood samples stored for longer time at room temperature. The ribavirin concentration increased approximately five times when stored for one week at  room temperature before centrifuged and frozen, compared to ribavirin concentrations analysed within 3 hours. The recommended practice is to separate plasma and store samples frozen within 24 hours.


Abstract ID: 66252

Category: JO7: HCV: Treatment

Factors Associated with Liver Clinic Referral of Hepatitis C Virus (HCV)-Infected Patients.

H. Al-Hashem, Yale University/VA-CT Hepatitis C Resource Center, New Haven, CT, S. Wongcharatrawee, Yale University/VA CT- Hepatitis C Resource Center, New Haven, CT, J. Stratidis, Yale University/VA CT- Hepatitis C Resource Center, New Haven, CT, G. Garcia-Tsao, Yale University/VA CT- Hepatitis C Resource Center, West Haven, CT

 

Screening and testing for HCV is a priority at the VA Healthcare System with the ultimate goal of increasing the number of HCV patients who have appropriate information and timely access to medical evaluation, enabling them to reach a decision regarding antiviral therapy. Reaching this goal depends on appropriate referral to providers who treat HCV.

 

Objective:

To determine the rate of referral of HCV patients to the liver clinic and to determine predictors associated with referral.

 

Methods:

Retrospective cohort study of HCV-infected veterans identified in the period between September 1, 2003 and June 30, 2004 using the local HCV registry that contains data on patients with positive anti-HCV test or an HCV diagnosis. Prior to this period, several provider-training sessions regarding appropriate referral to liver clinic took place among local providers, particularly those from mental health clinics.

 

Results:

Of 235 patients identified, 34 were excluded because of a negative confirmatory test (prior to referral). The study comprises 201 HCV-infected patients with a median age of 52 years; 95% were male and 62% were Caucasian; 83% had a history of substance use and/or mental illness. Only 100 (50%) were referred to the liver clinic. Compared to non-referred patients, those referred were more likely to have an assigned primary care provider (PCP) (78% vs. 57%, p=0.002), be referred from a primary care clinic (PCC) (82% vs. 61%, p=0.002), have documented risk factors (89% vs. 62%, p<0.001) and have abnormal liver tests (LT) (66% vs. 34%, p<0.0001). There were no differences between groups regarding age, race, type of provider (MD vs. non-MD), and presence of medical or psychiatric co-morbidities. Independently predictive determinants of referral (stepwise logistic regression) were referral from PCC and abnormal LT. Analysis of the subgroup of patients with abnormal LT (n=102) reveals that only 66 (65%) were referred. Compared to non-referred patients, those referred were more likely to have an assigned PCP (82% vs. 50%, p=0.001), be referred from a PCC (82% vs. 56%, p=0.006) and have documented risk factors (91% vs. 75%, p=0.032). On multivariable analysis, the strongest predictor of referral of patients with abnormal LT was having an assigned PCP.

 

Conclusions:

At a VA facility, only half of HCV-infected patients are referred to liver clinic. The main predictors of referral (both in all HCV patients and in those with abnormal LT) were related to patient enrollment in the PCC. Future efforts should be aimed at ensuring enrollment of all veterans in a primary care clinic and at creating referral electronic reminders for primary care providers.


Abstract ID: 67446

Category: JO7: HCV: Treatment

Ribavirin plasma concentration is predictive of sustained virological response in HCV infected patients. A prospective study.

D. Breilh, Hopital Haut Leveque, Pessac, France, L. Castera, Hopital Haut-Leveque, Pessac, France, P. Trimoulet, Hopital Pellegrin, Bordeaux, France, J. Foucher, Hopital haut-Leveque, Pessac, France, S. Djabarouti, Hopital Haut Leveque, Pessac, France, P. Bernard, Hopital Saint-Andre, Bordeaux, France, J. Bertet, Hopital Haut Leveque, Pessac, France, P. Couzigou, Hopital Haut Leveque, Pessac, France, M. Saux, Hopital Haut-Leveque, Pessac, France, V. de Ledinghen, Hopital Haut-Leveque, Pessac, France

 

Background & aims:

Combination therapy with pegylated interferon and ribavirin is the standard treatment for chronic hepatitis C virus (HCV) infection. However, a relationship between virological response and ribavirin concentration has been previously reported. The aim of this prospective study was to define the target ribavirin concentration at week 12 associated with virological response at week 12, and 6 months after the end of treatment (sustained virological response, SVR).

 

Methods:

HCV infected naïve consecutive patients treated with standard regimen of pegylated interferon and ribavirin (800-1200 mg/day, according to genotype) were assessed for ribavirin plasma concentration at week 12. Residual plasma ribavirin concentration (12 hours after the previous dose) was obtained using a validated high performance liquid chromatography assay. Response at week 12 was defined as undetectable HCV-RNA or HCV-RNA drop ≥ 2 Log.

 

Results:

56 patients (19 males, mean age 50 ± 12 years, genotype 1 52%, mean viral load 912000 ± 1260000 UI/l) were included. Response at week 12, and SVR were observed in 80%, and 67.5% of patients, respectively. Median ribavirin plasma concentration at week 12 was 3.19 mg/l (range:0.41-7.23). Responders at week 12 and SVR had significantly higher plasma ribavirin concentration at week 12 than non responders: 3.29 vs 2.85 mg/l (p=0.005), and 3.47 vs 2.85 mg/l (p=0.023), respectively. A Chi2 step by step analysis indicated that the threshold of 3 mg/l at week 12 gave the best sensitivity (65.4%) and specificity (64.3%) for SVR. Using this threshold, ribavirin plasma concentration at week 12 had positive predictive value of 77% for SVR.

 

Conclusion.

Patients with SVR had higher ribavirin plasma concentration at week 12 than non-responders. Three in four patients with a concentration higher than 3 mg/l at week 12 were SVR. Therefore, early determination during treatment of plasma ribavirin concentration (with a target concentration of 3 mg/l at week 12) could be useful for monitoring HCV therapy. The impact of ribavirin dosage optimization, to obtain such a target concentration, on SVR rates should be further investigated.


Abstract ID: 67955

Category: JO7: HCV: Treatment

High Frequency of Anemia in HCV-HIV Coinfected Persons Receiving Weight-based Ribavirin and Zidovudine.

K. E. Sherman, University of Cincinnati College of Medicine, Cincinnati, OH

 

Among patients with HCV infection, treatment with Pegylated-Interferon (PEG-IFN) and Ribavirin (RBV) is often associated with anemia due to a combination of marrow suppression and ribavirin-induced hemolytic anemia. Anemia may lead to dose reduction and/or use of growth factors (e.g. epopoietin). Despite a tendency towards anemia among HCV/HIV coinfected subjects prior to PEG-IFN/RBV administration, previous studies suggested relatively good tolerability when ribavirin was administered at a dose of 800 mg/day. There is little data regarding treatment-associated anemia when weight-based ribavirin dosing is utilized. An unexpected degree of anemia in ACTG 5178 was observed and further analyses were performed.

 

METHODS:

ACTG 5178 is a PEG-IFN/RBV treatment trial for subjects with HCV/HIV coinfection.  Inclusion criteria mandated hemoglobin (HGB) of >11 g/dl for men and >10 g/dl for women. All patients must have been on stable ART for 8 weeks prior to entry. All subjects were treated with PEG-IFN alfa 2a 180 mcg q week + ribavirin 1000/1200 mg/day based upon body weight. Toxicity grade for change in HGB level was determined according to standard DAIDS/ACTG criteria.

 

RESULTS:

50 enrolled subjects had baseline and at least one subsequent on-treatment HGB determination. Following study drug initiation, twelve subjects (24.5%) had Grade 1 or greater anemia. Of these four reported Grade 2 anemia. Forty percent of subjects were on ART containing ZDV at entry. Among the 20 subjects actively receiving ZDV, eight (40%) had anemia meeting at least Grade 1 criteria. In contrast, only 4/30 (13.3%) of subjects not on concurrent ZDV had Grade 1 or greater anemia (P= 0.04). Dose modification of ribavirin was noted in 13 subjects. The majority (9) cited anemia as the reason for a change of ribavirin dosing.

 

CONCLUSION:

Unexpectedly high levels of anemia and ribavirin dose reduction were observed following initiation of ACTG 5178 compared to other treatment trials utilizing a lower dose of ribavirin. Data analysis suggests that concomitant ZDV use is highly associated with a higher frequency of Grade 1 or higher anemia compared to subjects on other drug-containing regimens. Increased early monitoring of HGB in these patients is recommended.


Abstract ID: 65345

Category: JO7: HCV: Treatment

Baseline neutralizing responses predict the virological response to pegylated interferon alpha-ribavirin combination therapy.

P. Woerther, Hopital Henri Mondor, Universite Paris 12, Creteil, France, Y. Morice, Hopital Henri Mondor, Universite Paris 12, Creteil, France, L. Barbotte, Hopital Henri Mondor, Universite Paris 12, Creteil, France, F. Montestruc, Roche Laboratories, Neuilly-sur-Seine, France, D. Lavillette, Ecole Normale Superieure, Lyon, France, M. Bouvier-Alias, Hopital Henri Mondor, Universite Paris 12, Creteil, France, J. Bronowicki, Hôpital Brabois, Nancy, France, C. Hezode, Hopital Henri Mondor, Universite Paris 12, Creteil, France, I. Lonjon-Domanec, Roche Laboratories, Neuillysur- Seine, France, B. Bartosch, Ecole Normale Superieure, Lyon, France, F. Cosset, Ecole Normale Superieure, Lyon, France, J. Pawlotsky, Hopital Henri Mondor, Universite Paris 12, Creteil, France

 

The mechanisms underlying the success or failure of pegylated interferon (PegIFN)-ribavirin combination therapy in chronic hepatitis C are multifactorial, intricate, and poorly understood. Virological and host factors have been studied, but the role of anti-HCV humoral responses (in particular the neutralizing response) remains unknown, mainly due to the lack of reliable assays.

 

OBJECTIVES:

To determine the relationship between anti-HCV neutralizing responses and baseline parameters and the virological responses to pegIFN-ribavirin therapy.

 

METHODS:

524 patients with genotype 1 chronic hepatitis C were treated with a combination of PegIFN-alpha 2a (Pegasys, Roche), 180microg qw, and ribavirin (Copegus,), 0.8 g/d. At week 24 the virological responders(HCV RNA negative) were randomized into continuing on combination therapy or on pegIFN alone. Serum neutralizing activity was measured at baseline by means of arecently developed in vitro neutralization assay based on the use of infectious retroviral pseudo-particles expressing the folded HCV envelope glycoproteins at their surface. This assay was optimized for high throughput and intrinsic performance.

 

RESULTS:

Results are available for 179 patients (the final results with the 524 patients will be presented). Neutralizing responses ranged from 0 (no detectable neutralizing response) to 100% (complete neutralization of HCV pseudoparticles infectivity in vitro by serum). Multivariate analysis showed a significant relationship between baseline neutralizing responses and the age (more or less than 44 years, p=0.0352) and the occurrence of a 2 log HCV RNA decrease at week 2 of therapy (p=0.0018). Both variables interacted, so that the relationship between baseline neutralizing response and the virological response at week 2 was stronger in the patients under 44 years of age (less than 44 years: 70.4% [65.0%-75.8%] in more than 2 log responders vs 85.0% [79.1%-91.0%] in less than 2 log responders; more than 44 years: 81.6% [76.9%-86.3%] vs 85.4% [78.9%-91.8%]). The baseline neutralizing response was also significantly related to the virological response (negative HCV RNA) at week 24 and to the sustained virological response in univariate analysis, but both responses were related to the virological response at week 2 which had the strongest relationship in multivariate analysis.

 

CONCLUSION:

Baseline neutralizing activity of HCV genotype 1-infected patients is significantly related to the age and the virological response to pegIFN-ribavirin therapy. A weaker neutralizing activity is associated with a more rapid HCV RNA decline and a greater likelihood of a sustained virological response.


Abstract ID: 63189

Category: JO7: HCV: Treatment

Expectant management of chronic hepatitis C infection – the patient perspective.

O. S. Khokhar, University of Illinois College of Medicine - Peoria, Peoria, IL, J. H. Lewis, Georgetown University Medical Center, Washington, DC

 

OBJECTIVE:

To assess patient satisfaction and the rationale behind the informed decision to be treated expectantly for chronic hepatitis C virus (CHC) infection.

 

METHODS:

A retrospective open access clinic-based chart review was completed on all patients with ICD-9 code 070.54 generated from hospital billing databases. Variables that were recorded included patient demographics, liver biopsy results, liver imaging results, peak alanine transaminase (ALT) level, comorbid conditions, source of infection, duration of infection, and rationale for expectant treatment by patient. A follow-up telephone communication consisting of a structured questionnaire was made at least one year after initial consultation was done. Patients were asked about their current health status, confirmation of expectant management, and awareness of pegylated interferon.

 

RESULTS:

A total of 446 patient charts were reviewed. Out of these, 115 (26%) patients made an informed choice for expectant management after consultation. Sixty-eight patients (59%) were genotype 1A, and 37 (32%) were genotype 1B. The remaining ten patients were genotype 3A, 3B, 2A, 2B, or 4. The major reasons for choosing expectant management were: the absence of any symptoms [n=51 (44.3%)]; concerns regarding adverse effects [n=25 (21.7%)]; medical contraindications [n=23 (20.0%)]; social circumstances interfering with effective treatment [n=11 (9.6%)]; and doubts regarding efficacy [n=5 (4.3%)]. A total of 75 patients were successfully contacted. Fifty-eight patients (77.3% [95% CI, 67.8% - 87.8%]) were comfortable with their initial decision and wished to remain expectantly followed. Eight patients (10.7% [95% CI, 3.7% - 17.7%]) stated that they were moderately satisfied, and six (8.0%) patients expressed dissatisfaction with their decision. Two patients (2.7%) had since chosen interferon treatment, while one patient died while awaiting transplant.

 

CONCLUSIONS:

A significant majority of patients with HCV infection choose to be followed expectantly. Reasons for this important decision include the asymptomatic nature of infection, concern of adverse effects and efficacy, medical contraindications, and social circumstances preventing optimal treatment. Furthermore, it is noted that the majority of patients remained satisfied with their initial informed decision to be followed expectantly. Based on our findings, we recommend that candidates for interferon treatment continue to be educated regarding efficacy and adverse effects. In addition, patients with changeable social conditions preventing treatment should be closely monitored for resolution of those issues and reevaluation.


Abstract ID: 63583

Category: JO7: HCV: Treatment

Efficacy of Peginterferon alfa-2a (40KD) and Ribavirin in patients with chronic hepatitis C in Germany – a contribution to health care research.

E. Zehnter, Centre of Gastroenterology Dortmund, Dortmund, Germany, S. Mauss, Centre of Gastroenterology and Hepatology, Düsseldorf, Germany, C. John , Centre of Gastroenterology Dr. John, Berlin, Germany, R. Heyne , Centre of Gastroenterology Dr. Heyne, Berlin, Germany, B. Möller , Centre of Gastroenterology, Dr. Möller, Berlin, Germany, B. Bokemeyer , Centre of Gastroenterology, Minden, Minden, Germany, G. Moog , Centre of Gastroenterology, Kassel, Kassel, Germany, U. Alshuth, Hoffmann-La Roche AG, Germany, Grenzach-Wyhlen, Germany, D. Hüppe, Centre of Gastroenterology Herne, Herne, Germany

 

Introduction

In an effort to measure the quality of treatment of patients with chronic hepatitis C the Association of German independent Gastroenterologists (bng) in cooperation with Hoffmann-La Roche, is conducting a nationwide observational study that consists of documenting screening and treatment data.

 

Methods

Between March 2003 and March 2005 data from >8000 patients has been documented at > 500 centres. A total of 7156 patient screenings have been completed and 2988 patients (41.8%) have been treated with peginterferon alfa-2a (40KD) and ribavirin. Results of treatment, compliance and side effects were recorded.

 

Results:

Demographic data are available for 2987 treated patients: mean age 41,5 y, 61.7% male, naive/relapser/unknown 84.3/12 .4/4.5% respectively, BMI 24.9 kg/m2, mean duration of infection: 11.4y, source of infection (>1 answer possible): iv drug abuse 44.8%, transfusion 17.8%, medical action 9.2%, contact to HCV infected person 81.%, tattoo/piercing 4.2%, accident/injury 1.1% (multiple answers possible) and unknown 22.6%.  The distribution of genotypes: GT1 59.6% (1780), GT2 7.2% (214), GT3 29.8% (889), GT4-6 3.5% (104).

 

ALT:  In 20.4% of the patients ALT was normal (male max 50 U/l; female max. 35 U/L)

 

Concomitant diseases were reported in 51.1% of the patients.  Important diseases were abuse of drugs/alcohol (31.7% of patients with concomitant disease), psychiatric diseases (17.9%), cardiac diseases (13.2%), diabetes mellitus (7.5%), HIV/HCV coinfection (7.0%), thrombocytopenia (3.9%) (multiple answers possible).

 

96% of patients were treated with a combination therapy. As of March 2005 925/1164 patients with GT1 (79.5%) and 594/634 with GT2/3 (93.7%) reached an Early Virological Response at week 12 ( EVR = ≥2-log10 drop in HCV RNA or HCV RNA undetectable).

 

To date, 76.1% GT-1 (N=547/719) and 95.6% GT2/3 (N=538/563) have achieved EOT Responses. Complete treatment data are available for 737 patients, who were treated according to consensus recommendations. Sustained Virological Response (SVR) were achieved by 234/381 GT-1/4/5/6 (61.4%) and 302/357 GT2/3-patients (84.6%). To date 147 GT1/4/5/6  and 55 GT2/3 were nonresponders.

 

Discontinuations:  A total of 443 (14.8%) patients have discontinued therapy: 40.5%, due to virological nonresponse 25.2% for poor tolerability, 13.8% were lost to follow-up, 9.0% for personal reasons and 9.7% for lack of compliance multiple answers possible).

 

The mean duration of absence from work was 11.4 days for genotype  1/4/5/6-patients and 8.8 days for genotype 2/3-patients.

 

Conclusion:

The results of this observational trial show that peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well tolerated in patients with chronic hepatitis C in real world clinical practice.

 

When treated according to current guidelines, patients achieved results similar to those achieved in controlled clinical trials. This observational study contributes importantly to health care research of patients with chronic hepatitis C.


Abstract ID: 64484

Category: JO7: HCV: Treatment

VIRAL FACTORS INFLUENCE SVR IN PTS WITH HCV-RELATED BRIDGING FIBROSIS BUT NOT CIRRHOSIS.

A. Mangia, GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy, G. Scotto, Infectious Diseases Division, Foggia, Italy, R. Cozzolongo, Gastroenterology Division, Castellana Grotte, Italy, D. Bacca, Internal Medicine Division, Casarano, Italy, N. Minerva, Internal Medicine Division, Canosa, Italy, V. Carretta, Internal Medicine Division, Venosa, Italy, F. Spirito, GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy, A. Andriulli, GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy

 

BACKGROUND:

In patients with HCV-related bridging fibrosis or cirrhosis, combination of RBV and PEG-IFN results in SVR rates which are 10-15% lower than in those with milder fibrosis. AIM: To investigate whether viral- or disease related factors, and adherence might account for these reduced rates.

 

PATIENTS AND METHODS:

Patients with either histologic or clinically apparent advanced hepatic damage underwent treatment with PEG-IFN α 2a or α 2b plus RBV (1000-1200 mg /daily) for standard duration depending on genotypes. Mean age was 57.5 yrs (range 18-70), 67% were males. Genotypes 1 or 4 were represented in 56% and viremia > 800.000 UI/ml in 60% of cases Platelets counts, splenomegaly, oesophageal varices, albumin and cholesterol levels, and prothrombin activity were recorded. Pts with ascites were excluded. Portal Hypertension. was defined as the occurrence of oesophageal varices and/or splenomegaly (>12 cm in size). Advanced disease was defined as presence of cirrhosis with or without PH. Adherence to therapy was evaluated from the number of pts with dose reduction of antiviral agents, and from the number of those withdrawn from therapy for side effects .

 

RESULTS:

250 patients completed so far 24 weeks follow up. SVR was achieved in 46% of pts overall (49% in F3 and in 44% in cirrhotic pts, P=0.44). At univariate analysis factors associated with SVR in pts with bridging fibrosis or cirrhosis are shown in the table. At multivariate analysis only genotype independently predicted SVR in pts with bridging fibrosis (p= 0.001; OR 3.9, 95% CI 2.1-7.1), whereas in advanced disease, platelets >110.000 μl (p=0.022, OR 2.4, 95% CI 2.1-5.1) and genotype (p=0.024, OR 2.4, 95% CI 1.1-5.3) were predictive of SVR.

 

CONCLUSIONS:

In pts with advanced disease high platelets counts and favourable genotypes are predictors of SVR, whereas signs of portal hypertension and suboptimal adherence are not.

 

Bridging fibrosis        P value     Advanced disease       P value

 


Abstract ID: 64866

Category: JO7: HCV: Treatment

RANDOMIZED, OPEN LABEL TRIAL COMPARING EFFICACY AND SAFETY OF PEGYLATED INTERFERON ALFA 2A VS ALFA 2B TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH NON 2/3 GENOTYPES – 12 WEEK VIROLOGICAL RESPONSE ANALYSIS.

H. Berak, Hospital of Infectious Diseases, Warsaw, Poland, A. Horban, Hospital of Infectious Diseases, Warsaw, Poland, M. Wasilewski, Hospital of Infectious Diseases, Warsaw, Poland, J. J. Stanczak, Hospital of infectious Diseases, Warsaw, Poland, A. Kolakowska- Rzadzka, Hospital of Infectious Diseases, Warsaw, Poland

 

Therapeutical efficiency of interferon alfa 2a (Pegasys, 40 KD) versus interferon alfa 2b (Pegintron, 12 KD) both in combination with ribavirin was analyzed at 12 week of treatment.

 

PATIENTS:

237 patients (pts) with chronic hepatitis C were consecutively divided into two groups. The A group (116 pts – 49%) was treated with interferon alfa 2a; the B group (121 – 51%) with interferon alfa 2b. There was no statistically significant difference in male/female ratios in both groups (p>1,0). Genotyping score was similar in both group (101 pts - 87% vs 111 pts - 92% non 2 or 3 genotype, respectively). The highest  percentage of patients in both groups were of staging 1 – 48,2% and 42,6%, followed by staging 2 – 34,5% and 31,3%, respectively.

 

METHODS:

Liver biopsies were analyzed according to the Knodell’s and Scheuer’s scores. Patients’ age and body weight were determined and their influence on treatment efficiency was analyzed. HCV genotypes were determined with VERSANT-LIPA HCV II Test (INNOGENETICS); HCV RNA was determined with HCV RNA ASSAY and viral load (VL) with CA HCV MONITOR TEST (both of ROCHE DIAGN SYS.). The levels of ALT activity were determined with routine tests. Treatment efficiency was estimated at 12 week. Early virologic response (ERV) was defined as decrease of VL >2 log or undetectable HCV RNA.

 

RESULTS:

During therapy 3 pts from each group were excluded due to side effects. 4 of them had genotype non 2/3 and they were included into the group with treatment failure. Efficiency of therapy was analyzed in 208 pts with genotype other than 2 or 3 – 98 pts in the A group and 110 pts in the B group. The overall EVR rate was 79,3% (168/212). The EVR rate for the A group was 85,1% (86/101) and 73,8% (82/111) in the B group. The difference is statistically significant.

 

Therapeutical efficacy after 12 weeks of treatment

 

THERAPEUTICAL EFFICACY TOTAL GROUP A GROUP B

 

CONCLUSIONS:

Early therapeutical efficiency of interferon alfa 2a is significantly higher comparing to those observed with interferon alfa 2b.


Abstract ID: 65337

Category: JO7: HCV: Treatment

Economic evaluation of standard-therapy (ST) for chronic hepatitis C (CHC) with Peginterferon alfa-2a (40KD) (PegIFN 2a) plus Ribavirin versus Peginterferon alfa-2b (12KD) (PegIFN 2b) plus Ribavirin: Ready-to-use syringe (SYR) versus Injector (INJ).

H. D. Janisch, Internistische Schwerpunktpraxen Erlangen, Erlangen, Germany, D. Hüppe, Centre of Gastroenterology Herne, Herne, Germany, B. Möller , Centre of Gastroenterology, Dr. Möller, Berlin, Germany, S. Mauss, Centre of Gastroenterology and Hepatology, Düsseldorf, Germany, M. Rössle, Centre of Gastroenterology Freiburg, Freiburg, Germany, S. Pape, Centre of Gastroenterology Paderborn, Paderborn, S. Christensen, Independent General Practice CIM, Münster, Germany, P. Hartmann, Centre of Gastroenterology Dr. Hartmann, Münster, Germany

 

Background:

PegIFN 2a and PegIFN 2b are approved for therapy of CHC in Europe. They have different pharmacological properties, which require different formulations for administration.

 

Objective:

Evaluate and compare economic and handling aspects of commercial formulations of PegIFN 2a (SYR) and PegIFN 2b (INJ) in the initial phase of CHC-ST in routine medical practice in Germany.

 

Methods:

Patients were allocated to therapy with PegIFN 2a or PegIFN 2b at the investigators discretion. During the first 8 weeks of CHC-ST a questionnaire was administered to physicians and nurses (at weeks 0, 2, 4, 8), and to patients (at weeks 2, 4, 8). The questionnaire was concerned with time required for patient education and drug administration, as well as documenting difficulties encountered with the two formulations.

 

Results:

95 patients were recruited. As of May 2005 complete data are available for 75 patients (37 SYR, 38 INJ). Mean total physician time consumed in the 8 week study period, including time required for initial patient education and drug administration (if necessary) plus additional patient education (if necessary), was 3.9 and 7.8 minutes per patient for SYR and INJ, respectively. A total of 13.0 and 17.6 minutes of nursing time was consumed by the use of SYR and INJ, respectively. On the basis of 75 €/h for physician time and 15 €/h for nursing time, total personnel costs per patient amounted to 8.2 € for SYR and 14.1 € for INJ, respectively. Problems with self-administration by patients occurred in 2.8% of SYR vs. 16.0% of INJ applications. The most frequent problem was related to preparation of the injection. Additional patient education for self-administration was necessary for 2.7% of SYR patients vs. 23.7% of INJ patients. From the physicians’ perspective self-administration led to problems in 14.3% of SYR applications and 45.8% of INJ applications. Self-administration of SYR was considered to be user friendly by 91.8% of patients, and of INJ by 71.3% of patients.

 

Conclusion:

In the initial phase of ST for CHC in routine medical practice, therapy with PegIFN 2a using SYR is less time consuming and less cost intensive with respect to handling than PegIFN 2b using INJ. The use of SYR is associated with less handling problems than INJ, and self-administration of SYR was judged to be more user friendly by the majority of physicians and patients.


Abstract ID: 65628

Category: JO7: HCV: Treatment

Peripheral insulin resistance during the treatment of chronic C hepatitis with pegylated interferon plus ribavirin.

V. B. Mello, Federal University of Bahia, Salvador, Brazil, R. Parana, Federal university of Bahia, Salvador, Brazil, M. Simões, Federal University of Bahia, Salvador, Brazil, G. R. Nuñez, Federal University of Bahia, Salvador, Brazil, T. R. Cruz, Federal university of Bahia, Salvador, Brazil, N. Fabrizio, Federal university of Bahia, Salvador, Brazil, M. Cruz, Federal university of Bahia, Salvador, Brazil

 

Patients with hepatitis C vírus (HCV) infection have a highaer risk of developing type 2 diabetes mellitus. However, the mechanism of this association and the role of antiviral treatment are still unclear. Our study aimed to investigate the relationship between the use of peguilated interferon and the development of insulin resistance on these patients.

 

Methods:

HOMA (homeostasis model assessment) was performed in 30 HCV-infected patients just before and during the first 6 months of treatment with peguilated interferon plus ribavirin. Antropometric parameters and glucose/cholesterol profile were also monitored.

 

Results:

There was no change in HOMA after 6 months of treatment. Glucose levels decreased but not significantly (p=0.059). Patients with higher HOMA index after 6 months of treatment also had higher aminotransferases levels (p=0.03), higher fat index on computed tomography (p=0.011), longer time of exposure to the virus (p=0.021), and a positive smoking history when compared to non-insulin resistant patients (p=0.045). There was no influence of fibrosis stage on liver biopsy in the insulin resistance development, even though insulin resistant patients had a greater necro-inflamatory index (p=0.02).

 

Conclusions:

There was no change in insulin resistance after six months of treatment. Insulin resistence is related to abdominal fat and antropometric parameters rather than antiviral treatment.


Abstract ID: 65944

Category: JO7: HCV: Treatment

Week 4 Virological Response with Peginterferon Alfa-2a (40KD) (PEGASYS®) Plus Ribavirin (RBV, COPEGUS®) Portends a Sustained Virological Response (SVR) After 24 Weeks in Genotype 1 Chronic Hepatitis C Patients with Persistently ‘Normal’ ALT Activity.

N. Gitlin, Emory University School of Medicine, Atlanta, GA, M. Manns, Medizinische Hochschule Hannover, Hannover, Germany, K. Sherman, Univ. of Cincinnati College of Medicine, Cincinnati, OH, T. Berg, Humboldt-Universitat zu Berlin Med Klinik, Berlin, Germany, P. Pockros, The Scripps Clinic, La Jolla, CA, C. Hézode, Hôpital Henri Mondor, Créteil, France, S. Roberts, The Alfred Hospital, Melbourne, Australia, S. Zeuzem, Saarland University Hospital, Homburg, Germany

 

Introducation

SVR rates in HCV genotype 1 patients with persistently ‘normal’ ALT activity were significantly higher after 48 than 24 wks of treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®) (40% vs 13%, p<0.001; Zeuzem et al. Gastroenterology 2004). We evaluated whether a rapid virological response (RVR) at week 4, defined as undetectable HCV RNA (<50 IU/mL) portended an SVR in patients treated for 24 wks in this study.

 

Methods

Treatment-naïve patients with persistently ‘normal’ ALT activity and quantifiable HCV RNA (>600 IU/mL) were randomized to 24 or 48 wks of treatment with peginterferon alfa-2a (40KD) 180 μg/wk + RBV 800 mg/d (the trial was initiated before the optimal regimen for genotype 1 was known: 48wks with an RBV dose of 1000/1200 mg/d). Multiple logistic regression (MLR) was used to identify baseline factors (sex, age, weight, HCV RNA level, ALT, histological diagnosis, fibrosis score and region) predictive of an SVR in patients treated for 24 wks.

 

Results

144 genotype 1 patients were randomized to 24 wks of treatment, 140 had a wk 4 virological test result and 130 completed therapy. Patients with an RVR had higher end of-treatment (EOT) virological response and SVR rates (table) and lower relapse rates between EOT and end of follow-up (25 vs 93%) than those without an RVR. MLR analysis revealed baseline HCV RNA level to be the only significant predictor of SVR in patients treated for 24 wks. Those with baseline HCV RNA ≤ 200,000 IU/mL (n=21) were significantly more likely to achieve an SVR than those with serum HCV RNA >200,000 IU/mL (n=123) [odds ratio (OR) 4.6; 95%CI 1.6-13.7, p=0.0057]. When the week 4 test result was included in the model, only SVR was a significant predictor of SVR [OR 39.2; 95%CI 10.9-144.8; p<.0001).

 

Conclusion

  • The proportion of genotype 1 patients who achieved an RVR with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) was similar, regardless of ALT activity, in multinational, randomized, phase III trials.  Overall, 39/276 patients (14%) with persistently ‘normal’ ALT and 181/1024 patients (18%) with elevated ALT achieved an RVR.
  • An RVR at week 4 is highly significant predictor of an SVR after 24 weeks’ treatment.
  • Nearly three quarters (12/17 (71%)) of genotype 1 patients with an RVR achieved an SVR after 24 weeks with peginterferon alfa-2a (40KD) plus ribavirin therapy.
  • Low baseline RNA was a significant predictor of SVR in genotype 1 patients treated for 24 weeks with peginterferon alfa -2a (40KD) plus ribavirin.  However, the week 4 test result was included in the analysis, RVR was the only significant predictive factor for an SVR.
  • Although virological relapse rates were higher in patients treated for 24 or 48 weeks without an RVR, relapse rates were lower in patients treated for 48 versus 24 weeks.  As such, further study is required before this criterion can be used as a guide to treatment duration in patients with HCV genotype 1 and persistently ‘normal’ levels.

 


Abstract ID: 66069

Category: JO7: HCV: Treatment

Specific mechanisms of HCV-3 on hypocholesterolemia. Long-term effect of sustained virological response.

C. M. Fernandez-Rodriguez, Fundacion Hospital Alcorcon, Madrid, P. Lopez Serrano, Fundacion Hospital Alcorcon, Madrid, Spain, M. Gutierrez Garcia, Fundacion Hospital Alcorcon, Madrid, Spain, J. Lledó Navarro, Fundacion Hospital Alcorcon, Madrid, Spain, M. Nevado, Fundacion Hospital Alcorcon, Madrid, Spain

 

Background:

Genotype-3 of hepatitis-C virus has been associated with hypocholesterolemia and liver steatosis. Reversal of these changes in patients with sustained virological response (SVR) has been reported. Yet, the long-term effect of this response is not known.

 

Objectives and methods:

To define baseline differences of serum cholesterol, its relationship with liver steatosis in patients infected with genotype 3 and in those infected with genotype 1 and its long-term time-course with treatment. A cohort of 215 patients with chronic hepatitis C referred to our unit was studied (genotype 1, n: 158; genotype 2, n: 4; genotypes 4 and 5, n: 12 and genotype 3, n: 41) and 25 patients with chronic hepatitis B. Covariates were age, body mass index (BMI), gender, alcohol intake, serum lipids, glycaemia, serum ALT, AST, GGT, grade and stage (metavir and scheuer), degree of liver steatosis and SVR.

 

Results:

Patients infected by genotype 3 had age-adjusted hypocholesterolemia and more frequent hepatic steatosis (p<0.001). Steatosis inversely correlated with serum cholesterol (p<0.01). In patients with genotype-3 and SVR, serum cholesterol raised from 140 mg/dl (CI 120-151) to 185 mg/dl (CI 171-199) twelve months after the end of treatment (p: 0.0001). By contrast, serum cholesterol did not change in non-responders with genotype-3 or in patients with genotype 1 regardless of virological response. Once excluded patients with genotype-3, there were not differences regarding serum cholesterol between patients with HCV and those with HBV.

 

Conclusions:

Besides causing hepatic steatosis, genotype-3 specifically decreases serum cholesterol. This interference with the metabolic lipid pathway reverses with SVR and it is sustained on a long-term basis.


Abstract ID: 66208

Category: JO7: HCV: Treatment

Persistence with Hepatitis C Therapy in African Americans and Patients with Depression in the Department of Veterans Affairs (VA).

F. Cunningham, Hines VA Hospital, Hines, IL, A. Lee, Boston University School of Public Health, Boston, MA, S. Usman Iqbal, 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

 

Introduction

Certain populations infected with Hepatitis C virus (HCV) have  been reported to have a decreased response to treatment. The African American (AA) population and those patients suffering from depression have been identified as two groups with a lower response to Hepatitis C treatment.

 

The specific reasons for a decrease in response have not been clearly identified. Moreover, persistence with prescribed HCV therapy has not been adequately studied in these populations. The goal of this study is to evaluate persistence in the AA and depressed patients undergoing treatment for HCV in the Department of Veterans Affairs.

 

Objective

To evaluate and compare treatment persistence in African American patients infected with HCV who received combination therapy with either peginterferon alfa-2a with ribavirin (peg-INF alpha–2a/Rib) or peginterferon alfa-2b with ribavirin (peg-INF alpha-2b/Rib)

 

To evaluate and compare treatment persistence in patients diagnosed with depression infected with HCV who received combination therapy with either peginterferon alfa-2a with ribavirin (peg-INF alpha–2a/Rib) or peginterferon alfa-2b with ribavirin (peg-INF alpha-2b/Rib)

 

Study Design

A retrospective inception cohort claims analysis on treatment naïve patients diagnosed with HCV.

 

Data Sources

The pharmacy databases (PBM v 3.0), the National Patient Files, and the Beneficiary Identification and Record Location (BIRLS) files of the Department of Veterans Affairs (VA) were utilized for the study.

 

Study Period

The study population included patients who had a diagnosis for hepatitis C virus between October 1, 2002 and September 30, 2004 (Fiscal Years 2003 - 2004) and a prescription for combination peginterferon (peg-IFN alpha-2a/Rib, PEG-IFN alpha-2b/Rib) during the same time period. The index date was defined as the date of the first claim of the specified drugs. The period of October 2000 to September 2002 (or 24 months prior to receiving treatment) was used to assess patients for comorbid conditions listed under the exclusion criteria.

 

Defining Variables

Persistence: A patient with a no-fill period of more than 60 days after a prescription of the study drugs was termed as discontinued. Persistence time was defined as the period from the date of first prescription to the date of discontinuation for the therapy initially prescribed.

Data Management and Analyses Plan:

Patient demographics were abstracted and analyzed from the VA administrative databases. Persistence rates were calculated for each of the two treatment groups using the Kaplan-Meier method.  Likelihood ratio test of equality between the two treatment groups was performed to detect any differences in persistence rates. Key variables for stratification included (1) race - white and African American and, (2) those diagnosed with depression.

Inclusion criteria

·       Male and female veterans > 18 years of age

·       At least one pharmacy claim for a 30-day supply of peginterferon alfa-2a, peginterferon alfa-2a/Rib, peginterferon alfa-2b, or peginterferon alfa-2b/Rib

·       An inpatient discharge diagnosis or at least 1 outpatient diagnosis for HCV in the 12 months prior to the index date.

·       Treatment-naïve as defined by no HCV treatment in the 12 months prior to the index date.

·       At least one clinic visit or inpatient diagnosis in the subsequent twelve months following the index date to assure contact with the VA system.

Exclusion Criteria

·       Presence of ICD-9 codes for any of the following comorbidities during the 24 months prior to the index date: HIV, Hepatitis B, Thrombocytopenia, Neutropenia, Anemia, Hemorrhage or active bleeding, Chronic renal failure, Bone marrow disorder, Cancer.

·       Patients with pharmacy claim(s) for a 60-day or 90-day supply of peginterferon alfa-2a, peginterferon alfa-2a/Rib, peginterferon alfa-2b, or peginterferon alfa-2b/Rib

Results

The study sample consisted of 816 (27%) AA patients and 1,984 (35%) patients with a history of depression.  Persistence with peginterferon alfa-2a/Rib was not significantly different (p=0.28) between AA and whites. The median duration of therapy was 5.3 months for whites vs. 4.7 months for blacks in the peginterferon alphs-2a/Rib group.  Persistence was significantly lower in AA compared to whites in the peginterferon alfa-2b/Rib group (p=0.0063). The median duration of therapy was 4.6 months for whites vs. 3.6 months for AA in the peginterferon alpha-2b/Rib group. There was no difference in persistence with either therapy

 

CONCLUSION

·       There was no difference in treatment in duration of therapy or persistence between AA and whites in the pegylated interferon alfa-2A/Rib treatment group.

·       The mean duration of therapy and persistence for pegylated interferon alfa-2B/Rib was significantly lower in the AA population compared to whites.

·       Further study is needed to determine if the differential persistence that exists between the two therapeutic groups is reflected in the response to treatment.

 


Abstract ID: 66238

Category: JO7: HCV: Treatment

Directly Observed Therapy (DOT) for the Treatment of Hepatitis C Virus (HCV) Infection in Injection Drug Users (IDUs) – An Interim Analysis.

J. Grebely, University of British Columbia, Vancouver, Canada, F. Duncan , Pender Community Health Centre, Vancouver, Canada, M. Viljoen, Pender Community Health Centre, Vancouver, Canada, C. Meagher, Coolaid Community Health Centre, Victoria, Canada, M. Khara, Pender Community Health Centre, Vancouver, Canada, J. Raffa, University of British Columbia, Vancouver, Canada, K. Genoway, University of British Columbia, Vancouver, Canada, C. Fraser, Coolaid Community Health Centre, Victoria, Canada, S. deVlaming, Pender Community Health Centre, Vancouver, Canada, B. Conway, University of British Columbia, Vancouver, Canada

 

Objective:

To document the safety and efficacy of treatment of HCV infection in IDUs who qualify for such treatment according to current clinical guidelines.

 

Methods:

HCV-infected IDUs attending our clinics who were viremic, non-cirrhotic, with ALT levels >1.5x ULN and in whom there was a reasonable expectation of adherence to therapy were offered 24-48 weeks (based on HCV genotype) of combination therapy with ribavirin (RBV, 800-1200 mg/day, based on weight) along with interferon-a2b (IFN--a2b, 1.5 mg/kg thrice-weekly) replaced by PEG- interferon-a2b (PEG-IFN-a2b, 1.5 mg/kg once weekly) as it became available. Staff administered all injections under direct observation. A physician evaluated patients weekly, with appropriate interventions for side effects or toxicity. For this interim analysis, success was defined as an end-of-treatment response (ETR) with normal ALT levels.

 

Results:

In total, 34 patients (28 males) received therapy

·       Standard interferon -IFN-a2b (12 patients) -6 patients (genotype 1); 2 patients (genotype 2), 3 patients genotype 3 and 1 patient with mixed genotypes (2 and 3).

·       Peginterferon alfa 2b – 10 patients (genotype 1); 2 patients (genotype 2) and 10 patients (genotype 3).

 

The mean baseline age, body weight, ALT and duration of infection were 43 years, 83 kg, 138 U/L and 12 years, and 13/34 (38%) reported illicit drug use in the past 6 months, 71% (24/34) reported previous anxiety or depression. Only 7 patients did not complete therapy, 3 due to toxicity (tinnitus, neutropenia, depression) and 4 due to nonadherence. Overall ETR was 65% (22/34), 78% (14/18) in subjects with genotype 2/3 infection. All 15 patients receiving the entire course of PEG-IFN-based therapy achieved an ETR, as did 58% (7/12) who experienced an addiction relapse on treatment.

 

Discussion

·       The overall ETR in IDUs receiving IFN-based therapy with ribavirin was 65% by ITT, 92% OT.

·       This was achieved in a population including 47% infected with genotype 1, 71% with a history of anxiety/depression and 35% with a relapse of drug use on therapy.

·       Drug use prior to and during HCV treatment did not reduce its overall efficacy.

·       5/7 premature treatment discontinuations were due to drug use relapse or depression.

·       The expansion of DOT programs for the treatment of HCV infection in a multi-disciplinary care clinics may provide us with an effective means of addressing the HCV epidemic in our inners cities.

·       Further studies are needed to evaluate sustained virologic response rates and the incidence of re-infection after treatment in inviduals with continued high-risk behaviour for HCV acquisition.


Abstract ID: 66695

Category: JO7: HCV: Treatment

Early Viral Response to Consensus Interferon plus Ribavirin Therapy in Patients who are Nonresponders or Relapsers to Prior PEG IFN plus Ribavirin Therapy.

R. Ghalib, Liver Institute at Methodist Dallas, Dallas, TX, C. D. Levine, Liver Institute at Methodist Dallas, Dallas, TX, M. Mouti, Liver Institute at Methodist Dallas, Dallas, TX, J. Weinstein, Liver Institute at Methodist Dallas, Dallas, TX, A. Schwartz, Liver Institute at Methodist Dallas, Dallas, TX, S. Cheng, Liver Institute at Methodist Dallas, Dallas, TX

 

Purpose:

To describe the early viral response to consensus interferon (CIFN) plus ribavirin combination therapy in patients who were nonresponders or relapsers to prior therapy with PEG IFN plus ribavirin therapy for chronic hepatitis C (HCV).

 

Methods:

This is an interim analysis of the first 12 weeks of retreatment in patients who failed prior therapy. Patients were started on CIFN 15 mcg daily plus weight based ribavirin therapy. HCV RNA was monitored at week 4, and every 3 months. Growth factors were allowed.

 

Results:

Sample included 45 patients with 27 (60%) prior nonresponders and 18 (40%) prior relapsers. Nonresponders had an age range of 35-56 years (mean 49.8 ± 4.2); 17 (63%) males and 10 (37%) females; genotype 1 in 93% and 2 in 7%; race with 15 (56%) White, Black 9 (33%), and 3 (11%) other; biopsy stage 1-2 in 10 (37%) and 3-4 in 17 (63%). Relapsers had an age range of 40-60 years (mean 49.5 ± 6.0); genotype 1 in 12 (67%), 2/3 in 4 (22%) and 4 in 29 (11%); race with 12 (67%) White, Black 0 (0%), and 6 (33%) other; biopsy stage 1-2 in 5 (28%) and 3-4 in 13 (72%). Patients currently at ≥12 weeks of treatment in 22 (81%) of nonresponders and 13 (72%) of relapsers. Discontinuations between week 4-12 for adverse events have occurred in 2 (7%) nonresponders and 1 (6%) relapsers. HCV RNA response at 4 weeks in nonresponders vs. relapsers was undetectable virus in 2 (7%) vs 6 (33%); ≥2 log decrease in 8 (30%) vs 14 (78%); 1 log decrease in 12 (44%) vs. 2 (11%); and <1 log decrease in 3 (11%) vs 1 (6%) with no data in 4 (15%) vs. 1 (6%), respectively. HCV RNA response at 12 weeks in nonresponders vs. relapsers was undetectable virus in 5 (23%) vs. 9 (69%); ≥2 log decrease in 17 (77%) vs. 13 (100%); and £1 log decrease in 5 (23%) vs. 0, respectively. Logistic regression for a ³2 log decrease in HCV RNA at week 4 identified prior response type and genotype as significant variables (-2 log likelihood 37.0; model Chisquare 16.8, df=2, p<.001).

 

Conclusions:

In nonresponders and relapsers to prior PEG IFN plus ribavirin therapy, the early virologic response rates (³2 log decrease) with CIFN 15 mcg daily plus weight based ribavirin therapy are 77% and 100%, respectively. Further investigation of predictive factors of sustained viral response is needed in the nonresponder and relapser population to guide selection of appropriate treatment candidates and therapies.


Abstract ID: 66875

Category: JO7: HCV: Treatment

Influence of Apolipoprotein E genotype on virologic response in HCV type 1-infected patients treated With Peg-IFNa plus Ribavirin

V. Weich, Charité, Campus Virchow, Berlin, Berlin, Germany, G. Teuber, Klinikum der Johann-W.-Goethe- Universität, Frankfurt, Germany, C. Sarrazin, Universitätsklinikum des Saarlandes, Homburg, Germany, H. Klinker, Klinikum der Universität Würzburg, Würzburg, Germany, P. Buggisch, Universitätsklinik Eppendorf, Hamburg, Germany, E. Schott, Charité,Campus Virchow, Berlin, Germany, A. Bergk, Charité,Campus Virchow, Berlin, Germany, H. Witt, Charité, Campus Virchow, Berlin, Germany, T. Berg, Charité, Campus Virchow, Berlin, Germany

 

Background:

Lipoproteins have been reported to be involved in the infection cycle of hepatitis C virus. A protective role of the apolipoprotein E4 (ApoE4) allele regarding the development of severe liver fibrosis was recently described in HCV-infected patients. Furthermore, reduced sustained response rates (SVR) after standard interferon alpha (IFNa) plus ribavirin combination therapy were found in HCV type 1-infected carriers of the Apo-E4 allele. The aim of the present study was to assess whether carriage of an Apo-E4 allele influences viral dynamics as well as SVR rates in a homogeneous group of HCV type 1-infected patients treated with pegylated IFNa plus ribavirin.

 

Patients and Methods:

295 treatment-naive patients with histologic proven chronic HCV type 1 infection (56% male, mean age 44 years) were analyzed. All patients received 1.5 μg/kg Peg-IFNa-2b plus 800-1400 mg ribavirin/day (according to body weight). HCV RNA was measured quantitatively and qualitatively at treatment week 1, 4, 8 ,12, 24 and 48 as well as 24 weeks after stopping therapy. The Apo-E polymorphism was determined by PCR amplification and melting curve analysis with FRET probes.

 

Results:

Neither early viral decline nor the frequency of a complete virologic on-reatmentresponse (HCV RNA negative by qualitative PCR) at week 4, 12 and 48 were significantly different between carriers or non-carriers of the Apo-E4 allele (31% vs. 30%, 78% vs. 67%, 75% vs. 72%). A sustained virologic response (SVR) was achieved in 61% of the Apo-E4 allele positive patients as compared to 52% of those patients not having an Apo-E4 allele (p=0.4). No single Apo-E genotype (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) could be associated with the dynamics of HCV RNA decline or SVR rates.

 

Conclusion:

Virologic response rates after combination therapy with Peg-IFNa-2b plus ribavirin are not influenced by the Apo-E genotype. The previously postulated disadvantage of treatment response in Apo-E4-allele carriers after standard combination therapy could not be confirmed. The more effective antiviral regimen given to our patients (i.e. Peg-IFNa plus ribavirin) may have overcome the unfavourable genetic background and might be an explanation for this discrepancy.

 

This work was supported in part by viRgil Network of Excellence and Hep-Net-Network

of Competence for Hepatitis.


Abstract ID: 67076

Category: JO7: HCV: Treatment

Clustering of Poor Prognostic Factors in Heavier Patients with Chronic Hepatitis C (CHC): Baseline Characteristics and Outcomes With Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (RBV, COPEGUS®) in Randomized, International, Phase III Trials.

M. G. Swain, University of Calgary, Calgary, Canada, G. Foster, Queen Mary College, The Royal London Hospital, London, United Kingdom (Great Britain), S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, J. Heathcote, University of Toronto, Toronto Western Hospital, Toronto, Canada, D. Jensen , Rush University Medical Center, Chicago, IL, S. Lee, Liver Unit, University of Calgary, Calgary, Canada, P. Pockros, The Scripps Clinic, La Jolla, CA, M. Sulkowski, Johns Hopkins University, Baltimore, MD, C. TREPO, HOTEL DIEU Hospital, Lyon, France

 

Sustained virological response (SVR) rates tend to decrease as body weight increases. This is apparent in a retrospective subanalysis of a Phase III trial of pegylated interferon alfa-2b (12KD)/RBV where the overall SVR of 54% increased to 61% when patients who weighed ≥75.5kg were excluded (Manns et al. 2001). Therefore, in this study, we assessed the complex relationship between body weight and baseline factors in patients enrolled in two phase III randomized international studies, and between weight and outcomes in patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®).

 

Methods:

Data from the two studies were combined (NEJM. 2002;347:975; Ann Intern Med 2004;140:346). Patients were classified by weight (≤75.5 or >75.5kg) and baseline characteristics of all patients were compared. Outcomes by weight in patients who were treated for 48 wk with peginterferon alfa-2a (40KD) plus RBV 1000/1200 mg/d in the two trials were also compared.

 

Results(table):

At baseline, significantly more patients in the >75.5 kg group were male, black, had cirrhosis, HCV genotype 1 infection or had acquired HCV through intravenous drug use (IVDU). Heavier patients also had significantly higher HCV RNA levels. Overall, SVR rates were significantly higher in the lighter patients with a body weight of ≤ 75.5 kg vs. > 75.5 kg  (Odds ratio 1.87, 95%CI, 1.42-2.45). Similarly, the SVR rate in patients infected with HCV genotype 1 was significantly higher in lighter than heavier patients (or 1.99; 95% CI 1.42-2.80; p=0.00006.  The incidence of serious adverse events (SAEs) was higher in the lighter patients, although there was generally no difference in withdrawal rates for AEs.

 

Conclusions:

·       Bodyweight has a complex relationship with a range of baseline characteristics and treatment outcomes in patients with chronic hepatitis C.

·       At baseline, patients with a heavier bodyweight (>75.5 kg) were significantly more likely to have a histological diagnosis of cirrhosis,  be infected with HCV genotype 1 and have higher HCV RNA levels than lighter patients (≤ 75.5 kg).  In addition, heavier patients were more likely than lighter patients to be male, older and black.

·       SVR rates with peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus) 1000/1200 mg/day for 48 weeks were higher in patients with bodyweight of ≤ 75.5 kg vs. > 75.5 kg.

·       In patients weighing ≤ 75.5 kg, the SVR rate was 67% overall and 59% in patients with genotype 1 infection.  This was compared with 52% and 41%, respectively, in patients weighing > 75.5 kg.

·       The clustering of poor prognostic factors in heavier patients may explain, in part, the lower SVR rates observed in these patients with all interferon-based treatments.

 


Abstract ID: 62002

Category: JO7: HCV: Treatment

Mutations in the HCV-p7 protein and sensitivity to antiviral therapy with amantadine in chronic hepatitis C.

U. Mihm, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, N. Grigorian, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, C. Welsch, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, E. Herrmann, Fachbereich Mathematik, Technische Universität Darmstadt, Darmstadt, Germany, B.  Kronenberger, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, G. Teuber, Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany, M. von Wagner, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, W. P. Hofmann, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, M. Albrecht, Max-Planck Institut für Informatik, Saarbrücken, Germany, T. Lengauer, Max-Planck Institut für Informatik, Saarbrücken, Germany, S. Zeuzem, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, C. Sarrazin, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

 

Introduction:

Formation of transmembrane ion channels by HCV-p7 and abrogation of channel function by amantadine was demonstrated in vitro. The clinical relevance of mutations in the HCV-p7 protein for response to antiviral therapies with and without amantadine is unknown.

 

Patients and Methods:

HCV-p7 was sequenced in 67 patients with chronic hepatitis C genotype 1 infection. Thirty-six (HCV-1a: n=12, HCV-1b: n=24) of 67 patients received amantadine in addition to an interferon-alfa-based therapy. Helical wheel modeling for HCV-p7 was performed by in silico analyses.

 

Results:

In patients with HCV-1b infection (n=42) a higher number of nonconserved mutations within the complete p7 protein and the transmembrane helix 2 as well as amino acid substitution L44F were associated with nonresponse to interferon based therapy independent of administration of amantadine (p<0.05). In patients with HCV-1b infection and combination therapy with amantadine amino acid substitution L20F was observed more frequently in virologic nonresponders compared with end-of treatment and sustained responders (5/9 vs. 3/15; p=0.099). By in silico modeling amino

acid position 20 was located towards the p7 channel lumen and mutation L20F might impair amantadine interaction due to changes in size and shape of the p7 ion channel pore. In patients with HCV-1a infection (n=25) no significant correlation of p7 mutations with treatment response or amantadine was found.

 

Conclusion:

In patients with HCV-1b infection, a higher number of amino acid mutations within HCV-p7 was associated with virologic nonresponse to interferon-alfa based therapy. Impaired antiviral activity of amantadine in patients with HCV-1b infection may be associated with substitution L20F in HCV-p7 helix 1.


Abstract ID: 64030

Category: JO7: HCV: Treatment

Predictive factors for histological response to long-term phlebotomy in patients with chronic hepatitis C.

M. Sartori, Azienda Ospedaliera Maggiore della Carita', Novara, Italy, S. Andorno, Azienda Ospedaliera Maggiore della Carita', Novara, Italy, S. Colombi, Azienda Ospedaliera Maggiore della Carita', Novara, Italy, C. Rigamonti, IRCCS Maggiore Hospital Milan, Gastroenterology Dept., Milan, Italy, R. Boldorini, Department of Medical Sciences. University of East Piedmont, Novara, Italy, G. B. Contessi, Hepatology Unit, A.O. Spedali Civili, Brescia, Italy, A. Rossini, Hepatology Unit, A.O. Spedali Civili, Brescia, Italy

 

Introduction:

Mild hepatic iron overload is common in patients with chronic hepatitis C (CHC) and may contribute to liver disease progression. Iron depletion reduces serum aminotransferase levels in most subjects with CHC and might improve liver histology in several patients. Our aim was to identify predictive factors for histological response (HR) to phlebotomy in CHC.

 

Methods:

Twenty-eight patients with CHC, 15 unsuitable for and 13 non responder to antiviral therapy (21 men, mean age 57±7 years), underwent iron depletion (achieving serum ferritin (SF) level < 35 μg/L by 200-450 mL phlebotomy every two weeks, then maintaining SF level < 70 μg/L by phlebotomy every 2-4 months). All patients underwent liver biopsy before iron depletion and after a period of 48±16 months. HR was defined, by two independent pathologists, as a one point reduction of staging score or, in case of unchanged staging score, as a two point reduction of grading score (Knodell). Pre-treatment factors putatively predictive for HR (age, sex, previous antiviral therapy, serum HCV-RNA level, HCV genotype, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), serum iron, SF, hepatic iron concentration (HIC), stainable liver iron, grading and staging scores) were evaluated by univariate and multivariate logistic analysis.

 

Results:

12/28 patients (43%) achieved HR, as previously defined (5 achieved both staging and grading score reduction). No woman was histological responder. In an univariate logistic analysis male sex, high pre-treatment histological grading (P=0.01) and HIC (P=0.04) predicted HR to phlebotomy. In a multivariate logistic analysis on male patients (females dropped due to estimability) only pre-treatment HIC (P=0.03; 95% CI=1.001-1.01) predicted HR. In fact, 12/17 men (71%) with HIC >= 1000 μg/g achieved HR, whereas 4/4 with HIC <1000 μg/g were not responder. HIC decreased in all patients after phlebotomy (1299±387 vs 447±313 μg/g; P<0.001). Furthermore, serum ALT decreased in all patients at the end of treatment (130±57 vs 70±39 U/L; P<0.001), AST in 27/28 patients (108±58 vs 64±45 U/L; P<0.001) and GGT in 22/28 patients (86±59 vs 56±56 U/L ; P=0.004). Finally, 7/28 patients (25%) achieved persistently normal aminotransferase levels during and at the end of phlebotomy. No side effects related to moderate iron depletion were reported.

 

Conclusions:

Male patients with CHC and HIC >= 1000 μg/g (17,91 μmol/g) are likely to achieve hepatic histological improvement by long-term phlebotomy. Therefore, iron depletion may be useful in such patients with CHC in whom antiviral therapy is contraindicated or proved to be ineffective.


Abstract ID: 64508

Category: JO7: HCV: Treatment

A significant association of the substitution in position 2209 of NS5A of hepatitis C virus 1b infection and the response to standard, consensus, or pegylated interferon plus ribavirin therapy.

H. Moriguchi, The University of Tokyo, Tokyo, Japan, T. Uemura, Keio University, Tokyo, Japan, C. Sato, Tokyo Medical and Dental University, Tokyo, Japan

 

Background:

The sustained virologic response (SVR) rate in patients with genotype HCV 1a/b isolates is insufficient (40 -50%) even with standard, consensus, or pegylated interferon plus ribavirin therapy (combination therapy). Furthemore, determinants for SVR or non -|response in the combination therapy for individual patients have not fully been understood despite extensive investigations with DNA microarray analyses.

 

Methods:

By using the PubMed data base from 1966 to May 2005, we analyzed the association between mutations in the nonstructural protein 5A gene (NS5A gene) and SVR to the combination therapy in the patients with HCV |1b infection (n=315). We analyzed the data by Spearman -fs rank correlation test and Mann-|Whitney-fs U test in the univariate analysis. Furthermore, a multiple logistic regression analysis was used to examine the influence of several factors on viral response.

 

Results:

In the univariate analysis, there was a significant positive correlation between the number of mutations in the NS5A 2209 -|2248 or the mutation at position 2209 in the NS5A gene and SVR to the combination therapy (P< 0.001 and P< 0.001, respectively). Furthermore, these results were confirmed with the multiple logistic regression analysis (regression coefficient:0.234, adjusted odds ratio:1.263 [95% CI: 1.056 -|1.511], P=0.011 and regression coefficient:1.871, adjusted odds ratio: 6.494 [95% CI: 1.485 |28.393], P=0.013, respectively). The SVR rate in the combination therapy in the patients with the mutation at position 2209 in the NS5A gene was 84.2 % (16/19), while that in those without the mutation was 31.8 % (94/296). Moreover, even though the patients with HCV-|1b infection had more than three mutations in the NS5A 2209-|2248, if they hadnot the mutation at position 2209 in the NS5A gene, the SVR rate in the combination therapy for them became significantly lower than those with the mutation at position 2209 in the NS5A gene (regression coefficient: -1.669, adjusted odds ratio: 0.188 [95% CI: 0.039 -0.921], P=0.039) using the multiple logistic regression analysis.

 

Conclusions:

The mutation of specific position 2209 in the NS5A gene plays an important role in obtaining SVR in the combination therapy for the patients with HCV-|b infection worldwide. This phenomenon could not be observed in the recent three published meta-analyses (n=675 1351) on interferon monotherapy.


Abstract ID: 64864

Category: JO7: HCV: Treatment

PEG-INTERFERON ± RIBAVIRIN IN ADVANCED HCV CIRRHOSIS.

V. Di Marco, V. Calvaruso, D. Ferraro, P.L. Almasio, G. Alaimo, M. Giglio, S. Peralta, R. Di Stefano, A. Craxì. Gastroenterology & Hepatology, University of Palermo, Italy

 

Background:

Treatment of advanced HCV cirrhosis with PEG-IFNs and ribavirin, either as pre-emptive strategy before OLT or as a way to slow down the disease progression toward decompensation, has received relatively scarce attention.

 

Aim:

To assess effectiveness and tolerability of PEG-IFN ± RBV in patients with advanced, compensated HCV cirrhosis.

 

Patients and method:

102 subjects with HCV cirrhosis (Child-Pugh < B7), age < 70 years, with platelets < 100,000/mm³ and/or F1/F2 gastroesophageal varices, 76 naives and 35 non-responders to previous alpha-IFN monotherapy, were randomized to receive 1 mcg/kg/week of PEG-IFN alpha2b as monotherapy (51 pts, mono group) or with RBV 800 mg/day (51 pts, combo group) ) for 52 weeks. Patients stopped therapy at 26 weeks if HCV-RNA positive.

 

Results:

Mono and combo groups were comparable for age (mean 56 ± 7.5 years), gender (64% males) body weight (mean 70 ± 11.2 Kg), previous IFN treatment and HCV-RNA load (mean MT 2.083.366 UI/ml vs CT 1.641.292 IU/ml, p=ns). By ITT analysis, 12 patients on mono and 21 patients on combo achieved an end-of treatment (ETR) viral response (23.5% vs 41.1%; p=0.057). After 6 months of follow-up 5 patients on mono and 10 patients on combo maintained a sustained virological response (SVR: 9.8% vs 19.6%, p=ns). Five out of 9 (55%) patients with genotypes 2 or 3, 10/88 (11.3%) of patients with genotype 1b, but none of 5 patients with genotype 4 had a SVR. Ten of 67 naïve patients and 5/35 of those previously treated achieved SVR (14.9% vs 14.2%, p ns). Thirty-four patients stopped therapy because of AE (20 mono vs 14 combo, p=ns). Causes of withdrawal were depression/intolerance (15%), leukopenia (10%), thrombocytopenia (4%), anaemia (3%), ALT flare (1%). One combo patient decompensated under treatment.

 

Conclusion:

PEG-IFN obtains profound suppression of HCV viraemia under treatment in 1/3 of patients with advanced cirrhosis, but SVR is obtained only by 15% of all patients. SVR was more common for genotypes 2 or 3, and comparable among naïves and nonresponders to previous monotherapy. A trend towards an increase in SVR was seen with RBV, but the trial groups were relatively small and the amount of RBV given probably insufficient. Treatment withdrawal due to intolerance and haematological toxicity was common, without life-threatening events.


Abstract ID: 65200

Category: JO7: HCV: Treatment

PREDICTED OUTCOMES IN PATIENTS WITH PERSISTENTLY ‘NORMAL’ ALT LEVELS AND HCV GENOTYPE 1 TREATED WITH PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) PLUS RIBAVIRIN (RBV, COPEGUS®) 1000/1200 MG/DAY FOR 48 WEEKS.

S. Zeuzem, Saarland University Hospital, Homburg, Germany, S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, C. Puoti, Marino Hospital, Rome, Italy, M. Swain, University of Calgary, Calgary, Canada, T. Berg, Universitatsklinikum Charité, Campus Virchow-Klinikum, Berlin, Germany, J. Zarski, Hôpital A Michallon, Grenoble, France, E. Snoeck, Exprimo NV, Lummen, Belgium, K. Jorga, F Hoffmann-La Roche, Basel, Switzerland, P. Marcellin, Hôpital Beaujon, Clichy, France

 

Introduction

In patients (pts) with ‘normal’ ALT, peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®) 800 mg/d for 48 wk produced an SVR in 52% of pts overall and in 40% of genotype 1 pts in a randomized, international trial (Zeuzem, Gastroenterology 2004). We modeled the probability of SVR and the incidence of anemia in these same genotype 1 pts if they had been treated with the currently recommended dosage of RBV (1000/1200 mg/d).

 

Methods

Baseline and outcome data from ‘normal’ ALT pts were incorporated into an existing generalized additive model established with data from elevated ALT pts treated for 48 wks with peginterferon alfa-2a (40KD) plus RBV 1000/1200 mg/day in two trials (Fried, NEJM 2002; Hadziyannis, Ann Intern Med 2004). The effect of RBV dose/kg and other prognostic factors for SVR rates and incidence of anemia (Hgb ≤10 g/dL) were analyzed. Simulations were run with the updated GAN models to predict SVR in genotype 1 normal ALT pts and the incidence of anemia in all normal ALT pts after treatment with peginterferon alfa-2a (40KD) + RBV 1000/1200 vs 800 mg/day. Model uncertainty was quantified by ‘bootstrapping’.

 

Results

·       Data from 38 HCV genotype 1-infected patients with persistently ‘normal’ ALT levels were used to update the SVR model, while data from 206 patients with persistently ‘normal’ ALT levels were used to update the anemia model.

·       The GAM analyses showed that, in patients infected with HCV genotype 1, the following prognostic factors in order of importance) were retained in the predictive model for an SVR:  baseline HCV RNA level; age; ribavirin dose per kilogram of bodyweight; baseline ALT quotient; histological diagnosis (cirrhotic vs. non-cirrhotic); and race (Caucasian vs. non-Caucasian).

·       Prognostic factors retained in the predictive model for anemia (in order of importance) included baseline hemoglobin level, ribavirin dose per kilogram of bodyweight, age, gender, baseline ALT and histological diagnosis.

·       Increasing the dose of ribavirin from 800 to 1000/1200 mg/day was predicted to increase the median probability of achieving an SVR by 9% in genotype 1 patients with persistently ‘normal’ ALT levels.  Moreover, the predicted SVR rate was similar to the predicted SVR rate in patients with elevated ALT activity treated with ribavirin 1000/1200 mg/day.

·       The incidence of anemia was predicted to rise when the dose of ribavirin was increased from 800 to 1000/1200 mg/day in patients with persistently ‘normal’ ALT activity (as has been seen in patients with elevated ALT activity).

·       From the model, the overall incidence of anemia in patients with persistently ‘normal’ ALT levels was predicted to be approximately double than in patients with elevated ALT.

·       However, further analyses demonstrated that the predicted differences in the incidence of anemia between patients with persistently ‘normal’ ALT levels were due prelimarily to the higher number of female patients with persistently ‘normal’ vs. elevated ALT activity (62% vs. 33%).  When the gender imbalance was taken into consideration, there was no significant difference in the incidence of anemia in patients with persistently ‘normal’ and elevated ALT.

 

Conclusion

·       Model simulations predict that SVR rates genotype 1 patients with persistently ‘normal’ ALT activity would be similar to those in patients elevated ALT activity following 48 weeks’ treatment with peginterferon alfa-2a (40KD) (PEGASYS) plus the standard approved dose of ribavirin (COPEGUS) (1000/1200 mg/day).

·       The predicted incidence of anemia in genotype 1 and non-1 patients treated with peginterferon alfa-2a (40KD) plus ribavirin 1000/1200 mg/day for 48 weeks was also independent of ALT status; for patients populations with a similar distribution of risk factors, such as gender and baseline haemoglobin, the risk of developing anemia should be the same in patients with persistently ‘normal’ and elevated ALT activity.

·       As such, the combination of peginterferon alfa-1a (40KD) plus the standard approved ribavirin dose of 1000/1200 mg/day for 48 weeks should be used in patients infected with HCV genotype 1, independent of ALT status at baseline;  this is reflected in the labeling for peginterferon alfa-2a (40KD).

 


Abstract ID: 66031

Category: JO7: HCV: Treatment

Efficacy and Cost-effectiveness of 24 Weeks of High-dose Induction Therapy with Consensus Interferon in Chronic Hepatitis C Patients with Genotype 2 Infection.

Y. Iwasaki, Okayama University Graduate School of Medicine and Dentistry, Okayama Japan, H. Tanaka, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, H. Ikeda, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, K. Yabushita, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, H. Kobashi, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, K. Takaguchi, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, T. Sakata, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, M. Ando, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, Y. Araki, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, R. Okamoto, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, M. Kawaguchi, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, M. Ohmoto, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, Y. Makino, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, J. Shimamura, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, K. Sakaguchi, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, Y. Shiratori, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

 

Background and Aims:

Several treatment strategies are currently available to patients with chronic hepatitis C. While these treatments have been compared in terms of their efficacy, the cost-effectiveness of treatment should be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus interferon therapy with high-dose induction for patients with chronic hepatitis C.

 

Methods:

We consecutively enrolled 104 patients with chronic hepatitis C; 62 men and 42 women, 38 with genotype 1 and 66 with genotype 2, with a mean age ± SD of 54 ± 12 years old. Patients were scheduled to receive 12 or 18 μg of consensus interferon daily for two weeks, then three times a week for twenty-two weeks. Efficacy, safety, and tolerance were assessed. A Markov model was constructed to evaluate cost-effectiveness simulating the natural history of patients with chronic hepatitis C. Transition probabilities were drawn from published data and US vital statistics. All cost data were obtained from published medical reimbursement data. Simulation and analysis were performed using TreeAge pro 2004.

 

Results:

Of 104 patients, a sustained virologic response was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2 (risk ratio, 95% CI: 8.85, 2.70-29.41), lower hepatitis C virus RNA levels (less than 200 KIU/ml) (12.82, 3.36-47.62), and patient age (6.25, 1.90-20.41) were independently associated with sustained virologic response. Sustained virologic response was achieved in 40% (15/38) of genotype 1 patients and 77% (51/66) of genotype 2 patients (P < 0.001). Discontinuation of therapy was required in 19 of 104 (18%) patients, and there was a tendency towards a higher discontinuation rate in older patient (≥55 vs. < 55) (24% (14/58) vs. 11% (5/46), P =0.082). Cost-effectiveness analysis revealed that the treatment increased life expectancy as assessed by quality-adjusted life years (QALYs) and it cost less than $17,000/QALY

in patients with genotype 2 infection.

 

 

QALY

Cost ($)/QALY

Consensus IFN (12 mg)

14.3

16,583

Consensus IFN (18 mg)

14.3

16,919

No treatment

11.8

25,765

 

Conclusions:

24-week consensus interferon therapy with high-dose induction shows high efficacy and is highly cost-effective in chronic hepatitis C patients with genotype 2 infection.


Abstract ID: 66153

Category: JO7: HCV: Treatment

Peginterferon a-2b 1 mcg/kg dose plus ribavirin 800-1200mg for 24-48 weeks, according to genotype, in naive patients with chronic hepatitis C: efficacy and cost-effectiveness evaluation.

M. Basso, Dpt Internal Medicine, University of Genova, Genoa, Italy, A. Grasso, Ospedale San Paolo, Savona, Italy, G. Percario, Ospedale San Carlo, Genoa, Italy, E. Azzola, Ospedale Santa Corona, Pietra Ligure, Italy, S. Artioli, Ospedale Civile S. Andrea, La Spezia, Italy, N. Pelli, Dpt Internal Medicine, University of Genova, Genoa, Italy, F. Torre, Dpt Internal Medicine, University of Genova, Genoa, Italy, A. Picciotto, Dpt Internal Medicine, University of Genova, Genoa, Italy

 

Background & Aims:

Dose finding study on monotherapy demonstrated no significant difference in sustained virological response (SVR) rate between peginterferon alpha-2b 1,5 mcg/kg/week and 1 mcg/kg/week in naive patients with chronic hepatitis C (Lindsay et al. Hepatology, 2001; 34:395-403). In the attempt to optimise efficacy and resources, we designed a multi-centre observational protocol, treating chronic hepatitis C naïve patients with peginterferon alpha-2b 1 mcg/kg/week and ribavirin 800-1200mg, according to body weight, for 24 weeks in genotype 2 or 3 and for 48 weeks for genotype 1 or 4 infected patients.

 

Methods:

148 consecutive, unselected naive patients (M/F: 87/61; median age: 49 yrs, range 19-67) were enrolled between 12/2001 and 6/2003 in five regional referring centres in Liguria, Italy. 51.4% had genotype 1/4. None of the patients had clinical sign of cirrhosis. HCV-RNA was assessed at week 2, 4, 12, end of treatment and at the end of follow up.

 

Results:

Six patients DO - dropped out (two due to intolerance after few injections, 4 due to non-compliance with the treatment). 142 patients were adherent to the protocol and follow-up. No statistically significant differences were presents between the genotype groups for age, sex, ALT levels. Overall, we achieve SVR in 59.4% of patients, with a 5.4% of relapse-responders (RRs) and a 35.2% of non-responders (NRs) (intention to treat). For genotype 1/4 (76 pts, 48 weeks treatment), we had 32.9% SVR, 7.9% RRs, 52.6% NRs and 6.6% DO. For genotype 2/3 (72 pts, 24 weeks treatment), we had 87.5% SVR, 2.8% RRs, 8.3% NRs and 1.4% DO. Week 2 and 4 HCV-RNA determinations did not prove to be reliable predictors of SVR. No major side effects or adverse events were reported. No dose reduction was needed for peginterferon alpha-2b, while a dose adjustment for anemia was necessary in 5% of the patients.

 

Conclusions:

·       Peginterferon alpha-2b 1 mcg/kg dose plus ribavirin 800-1200mg combination treatment was well tolerated in our group.

·       The overall SVR is comparable with the published data (54%, Manns et al, Lancet, 2001; 358:958-965).

·       Whilst in genotype 1/4 our results are slightly below the best-published results (32.9% vs 42%, Manns et al; peginterferon alpha-2b 1.5 mcg/kg plus 800mg ribavirin),

·       For genotype 2/3 we obtained identical results (87.5% vs 82%, Manns et al. with a 48 weeks treatment).

·       Our results suggest that this combination therapy for 24 weeks can be considered the best option in genotype 2/3 infected patients. With the same SVR ratio, we obtained to reduce significantly length of treatment and side effects, and to halve the costs. Clearly, genotypes 1/4 need more aggressive schedules.


Abstract ID: 66704

Category: JO7: HCV: Treatment

Reliability and Validity of the Beck Depression Inventory (BDI-II) in a Chronic Hepatitis C Population Undergoing PEG IFN plus Ribavirin Therapy

C. D. Levine, Liver Institute at Methodist Dallas, Dallas, TX, K. Sellman, John Peter Smith Hospital, Fort Worth, TX, R. Ghalib, Liver Institute at Methodist Dallas, Dallas,

TX

 

Purpose:

To determine the reliability and validity of the Beck Depression Inventory (BDI-II) in the chronic HCV population undergoing treatment with PEG IFN and ribavirin.

 

Methods:

The BDI-II is a self-report tool for depression with demonstrated reliability and validity in the normal and depressed populations. It was given to 182 subjects prior to office visits before beginning treatment, during treatment, and following completion of treatment. During interferon plus ribavirin therapy, subjects with signs of depression, anxiety or irritability were treated aggressively with antidepressants and referred for psychiatric evaluation as indicated.

 

Sample:

A total of 788 useable BDI-II tools were obtained with 119 (15%) prior to treatment, 586 (74%) during treatment, and 83 (11%) after treatment was discontinued. Age range was 18 to 74 (mean 48 ±7.4 yr) with 71 females (39%) and 111 males (61%). Ethnicity represented were Asian (9, 4.9%), Black (29, 15.9%), White (124, 68.1%), Hispanic (18, 9.9%), and Middle Eastern (2, 0.1%). BDI-II scores were slightly higher in the females vs. males prior to and during treatment. Scores returned to near baseline after treatment was discontinued. Most subjects were in the mild category of depression prior to (94%), during (72%) and after therapy (95%); however, 28% developed moderate or severe depression during therapy.

 

Results:

Factor analysis was used to determine construct validity in the HCV population. Principle component factor analysis with varimax rotation revealed 2 distinct factors (eigenvalues above .35) consistent with constructs identified in the depressed population. Factor 1 measured loss of pleasure, interest, and energy; indecisiveness; irritability; concentration difficulties; tiredness; and agitation. This factor represents the somatic affective dimension of depression. Factor 2 measured sadness, past failure, guilt feelings, self-dislike, self-criticalness, and worthlessness. Factor 2 reflects a cognitive dimension of self-reported depression. Variance explained by the two factors was 57.8%. Cronbach’s alpha levels above 0.8 demonstrate internal consistency reliability of the instrument. In this population the BDI had a Cronbach’s alpha of .911.

 

Conclusion:

BDI-II is an internally consistent and valid tool in measuring depression in the HCV patients during therapy. It is useful tool in identifying the presence and ongoing monitoring of changes in severity of depression during interferon plus ribavirin therapy.


Abstract ID: 66921

Category: JO7: HCV: Treatment

Efficacy of Daily Consensus Interferon and Ribavirin Compared to PEG-Interferon á-2b and Ribavirin in Non-Responders with chronic Hepatitis C.

M. M. Dollinger, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Y. Dridi, Martin-Luther-University Halle-Wittenberg, Halle, Germany, J. Lesske, Martin-Luther-University Halle-Wittenberg, Halle, Germany, S. Behl, Martin-Luther-University Halle-Wittenberg, Halle, Germany, W. E. Fleig, Martin-Luther-University Halle-Wittenberg, Halle, Germany

 

Consensus interferon is a synthetic type 1 interferon with enhanced in vitro efficacy compared to conventional interferon-α, but its use is limited by the acceptance of patients to tolerate the daily injections and the potential side-effects.

 

Objective:

To assess the efficacy, tolerability and safety of consensus interferon (CIFN) daily versus pegylated IFN a-2b (PEG-IFN) once weekly in combination with ribavirin (RBV) for HCV non-responders to previous combination treatment with IFN and RBV in a prospective, randomised, multicentre trial.

 

Patients/Methods:

40 patients with histologically proven chronic Hepatitis C, positive HCVRNA, elevated transaminases and previous non-response to treatment with combination therapy with IFN and RBV were randomised to 18 mcg/D CIFN for 6 weeks followed by 9 mcg/D CIFN for 42 weeks (CIFN + RBV: 18 patients) or 1.5 mcg/kg body weight of PEG-Interferon α-2b once a week for 48 weeks (PEG-IFN + RBV: 22 patients), each in combination with RBV (> 10.6 mg/kg body weight daily). There were no statistical differences between the two groups regarding sex, age, weight, or presence of cirrhosis, all patients had the HCV genotype 1b.

 

Results:

Based on an intent-to-treat analysis, the early response rate (ER, 24 weeks of treatment), the end-of-treatment response rate (ETR, 52 weeks of treatment) and the sustained response rate (SR, 6 months after treatment) are reported in Table 1. No significant difference was detected between the two groups.

 

 

There was no clinically significant difference in the incidence of adverse events between the two groups. However, there was a significant higher number of patients withdrawing within the first 6 months from CIFN + RBV than from PEG-IFN because of subjective side-effects (6/18 vs. 1/22, p<0.05, Figure 1). In contrast, the treatment was terminated because of primary non-response after 6 months in 8/22 patients treated with PEG-IFN + RBV versus only 2/18 patients treated with CIFN + RBV (p<0.05).

 

Figure 1: Patients on treatment

Conclusions:

Based on an intent-to-treat analysis, daily CIFN combined with ribavirin has the same antiviral efficacy and safety profile for the treatment of non-responders with chronic Hepatitis C as weight adjusted peg-IFNa2b. The daily regimen of CIFN is however less well tolerated by patients, a potential higher efficacy can therefore not be established in studies, and will be difficult or impossible to achieve outside of studies.

 

The study was supported by a grant of Yamanouchi and essex-pharma, Germany


Abstract ID: 66971

Category: JO7: HCV: Treatment

Sequential Treatment with Ribavirin and Low-Dose Pegylated (PEG) Interferon alfa 2b in Chronic Hepatitis C Patients with Normal ALT: A Pilot Study.

S. Schulte, Department of Gastroenterology, University of Cologne, Cologne, U. Toex, Department of Gastroenterology, University of Cologne, Cologne, Germany, J. Mertens, Department of Gastroenterology, University of Cologne, Cologne, Germany, I. Scheller, Department of Gastroenterology, University of Cologne, Cologne, Germany, N. Jaspers, Department of Gastroenterology, University of Cologne, Cologne, Germany, T. Goeser, Department of Gastroenterology, University of Cologne, Cologne, Germany, H. Steffen, Department of Gastroenterology, University of Cologne, Cologne, Germany

 

Objectives:

Patients with chronic hepatitis C and normal ALT show similar response rates after PEG-interferon ribavirin combination therapy compared to patients with elevated ALT. A ribavirin monotherapy prior to the PEG-interferon ribavirin combination therapy may be advantageous because of immune-modulating effects of ribivirin. The aim of this pilot study was, therefore, to evaluate a sequential therapy with ribavirin monotherapy followed by combination of low-dose PEG interferon alpha 2b and ribavirin in hepatitis C patients with normal ALT.

 

Methods:

20 HCV RNA positive patients (17 genotype 1 and 3 genotype 2 or 3) with histologically confirmed chronic viral hepatitis and normal ALT and AST for at least 6 months received ribavirin 1000 or 1200 mg/d for 4 weeks followed by 4 weeks combination therapy with PEG-interferon alpha 2b 100 μg/week and ribavirin followed by low-dose PEG-interferon (50 μg/week) plus ribavirin for 20 (non-responder) or 44 (responder) weeks. Follow up was 24 weeks.

 

Results:

At the end of therapy, 13 patients had become HCV-RNA negative, and 3 out of these had a relapse during follow up. Sustained virological response (SVR) was seen in 10 (50%), 7 (47%), and 3 (100%) patients for all genotypes, genotype 1, and genotype 2 or 3, resp. 5 patients were non-responders and 2 dropped out prematurely.

 

Conclusion:

Patients with chronic HCV infection and normal ALT treated with ribavirin monotherapy followed by a combination of low dose PEG-interferon alpha 2b and ribavirin have response rates similar to standard treatment. Further studies should be done to evaluate this protocol with potentially less side effects and expenses.


Abstract ID: 67504

Category: JO7: HCV: Treatment

Interim Analysis of the Safety and Efficacy of Peginterferon Alfa-2a plus Ribavirin in Chronic Hepatitis C Patients Unable to Tolerate or Nonresponsive to Treatment with Peginterferon Alfa-2b plus Ribavirin.

V. K. Rustgi, Georgetown University Medical Center, Fairfax, VA, S. Esposito, North Shore Hospital at Forest Hills, Bayside, NY, B. Freilich, Baptist Medical Center, Kansas City, MO, J. Lopez-Talavera, Roche Laboratories, Nutley, NJ, E. Lentz, Roche Laboratories, Inc, Nutley, NJ, M. L. Shiffman, Virginia Commonwealth University Medical Center, Richmond, VA

 

Introduction:

Phase III clinical trials have shown that hepatitis C virus (HCV)-infected patients treated with peginterferon alfa-2a plus ribavirin (PEG-2a/RBV) have a lower incidence of depression and flu-like symptoms than patients treated with standard interferon (IFN) plus RBV. In contrast, patients treated with peginterferon alfa-2b plus RBV (PEG-2b/RBV) have a side effect profile similar to those treated with IFN plus RBV. We have therefore tested the efficacy and safety of PEG-2a/RBV in patients intolerant (NT) of side effects or non-responders (NR) to treatment with PEG-2b/RBV.

 

Methods:

Patients infected with HCV genotype 1 treated with PEG-2b/RBV for a maximum of 12 weeks who were intolerant due to depression, fatigue, flu-like symptoms, or injection site reactions, or did not achieve early virologic response (EVR), defined as a 2-log decrease or undetectable HCV RNA after 12 weeks, were treated with PEG-2a/RBV. NTs and NRs with detectable HCV RNA after 12 weeks of treatment with PEG-2a/RBV were discontinued. Depression, fatigue, injection site reactions, and flu-like symptoms were evaluated by the Beck Depression Inventory, v2 (BDI-II), Fatigue Severity Scale (FSS), and Local Injection Site Reaction and Flu-like Symptom Questionnaires. HCV RNA was measured by Roche Amplicor (limit of detection, 60 IU/mL).

 

Results:

Table. Baseline characteristics at start and EVR at week 12 of PEG-2a/RBV treatment

 

Characteristic

Males

Blacks

Cirrhotics

Weight

HCV RNA

EVR n/N

On treatment

 

n (%)

n (%)

n (%)

kg*

log IU/mL*

(%)

after 12 weeks, n (%)**

NRs (N=32)

17 (53)

13 (41)

9 (28)

85.1 +3.8

5.29 + 0.19

4/29 (13.8)

4 (12.5)

NTs (N=25)

18 (72)

1 (4)

1 (4)

81.5 +3.7

2.99 + 0.12

23/24(95.8)

22 (88)

 

* Mean + SE

**through at least week 24

 

Only 4 of the NRs (12.5%) and none of the NTs were withdrawn due to adverse events or intercurrent illness. Only 2 and 4 NTs required dose adjustments of PEG-2a and RBV, respectively, for adverse events or laboratory abnormalities. In 21 NTs remaining on treatment at 24 weeks, relative to baseline, BDI-II score declined from 15.00 +1.48 (mean + SE) to 10.45 + 1.44, FSS visual analogue scale (VAS) score declined from 62.19 + 4.42 to 53.19 + 6.03, and the number of patients with injection site reaction declined from 10 (40%) at baseline to 2 (8%) at Week 24.

 

Conclusion:

Over 90% of patients intolerant of PEG-2b/RBV are tolerant of PEG-2a/RBV, allowing them to achieve EVR. In addition, 14% of patients unresponsive to PEG-2b/RBV have achieved EVR when converted to PEG-2a/RBV. Thus, based on a 12-week interim analysis, patients non-responsive or intolerant to treatment with PEG-2b/RBV can be successfully rescued with PEG-2a/RBV.


 Abstract ID: 67879

Category: JO7: HCV: Treatment

Eligibility for treatment of hepatitis C virus infection among young injection drug users in three US cities.

H. Hagan, NDRI, New York, NY, J. Campbell, Public Health Seattle and King County, Seattle, WA, R. Garfein, University of California San Diego School of Medicine, San Diego, CA, M. Latka, New York Academy of Medicine, New York, NY, S. Strathdee, University of California San Diego School of Medicine,, San Diego, CA, D. Thomas, Johns Hopkins University, Baltimore, MD, E. Golub, Johns Hopkins University, Baltimore, MD

 

Background:

Although recent studies have demonstrated feasibility and effectiveness of interferon with ribavirin as treatment for hepatitis C virus (HCV) infection in injection drug users (IDUs), treatment access has been low relative to other patients. We studied factors considered in determining treatment eligibility according to the 2002 NIH Consensus Guidelines for Management of HCV.

 

Methods:

Eligible subjects included HCV-antibody positive IDUs in Baltimore, New York and Seattle aged 18-35 who injected illicit drugs during the prior 6 months. We estimated the proportion of HCV-RNA positive young IDUs who may be considered ineligible for HCV-treatment according to measures of depression (Beck’s Depression Inventory (BDI) score >19), problem drinking (Alcohol Use Disorders Identification Test (AUDIT) score >8), and recent drug injection (last 30 days).

 

Results:

Of 404 HCV-RNA positive subjects, 45% had BDI scores >19 and 37% scored >8 on AUDIT; 89% had injected drugs at least once in the past 30 days. When both problem alcohol use and depression were considered together, 63% of subjects may be ineligible for treatment of HCV infection; when recent drug injection is also considered, 95% may be ineligible. African-Americans were somewhat less likely than other patients to be ineligible for HCV treatment when alcohol, depression and recent drug injection were considered together. However, there were no differences between men and women in the proportion having any of these contraindications to HCV treatment.

 

Discussion:

Applying multiple exclusion criteria may virtually eliminate access to treatment of HCV infection in IDUs. Particularly because younger patients are more likely to respond to treatment of HCV infection, screening for treatment eligibility should be limited to those factors demonstrated to be associated with reduced treatment success, such as excess alcohol use.


Abstract ID: 67941

Category: JO7: HCV: Treatment

Direct Costs of Medical Care for Treating Hepatitis C Patients in a Veterans Affairs Medical Center.

T. Adeniyi, Minneapolis VA Medical Center, Minneapolis , MN, Y. C. Jonk,

Minneapolis VA Medical Center, Minneapolis, MN, A. Knott Johnson, Minneapolis VA

Medical Center, Minneapolis, MN, E. Dieperink, Minneapolis VA Medical Center,

Minneapolis, MN, S. Ho, Minneapolis VA Medical Center, Minneapolis, MN

 

OBJECTIVES:

To identify the utilization and total direct cost of medical care, including outpatient and pharmaceutical care services associated with treatment and follow-up of Hepatitis C (HCV) patients. Our secondary objective is to determine the cost per patient cured.

 

METHODS:

99 patients with a positive HCV enzyme-linked immunoassay test conducted at the Minneapolis VA Medical Center in calendar years 2000 – 2001 and subsequently treated with pharmacotherapy were included in the study. This study takes the intent-to-treat perspective. Outpatient utilization and pharmacy data were extracted from VA administrative databases. Cost data for outpatient care were extracted from the Health Economics Resource Center’s outpatient average cost database. Cost data for the prescriptions medication were derived from the Veterans Health Information Systems and Technology Architecture database. Of the four strains of Hepatitis C, genotype 1 is the most prevalent and difficult to treat. Genotype 1 requires 48 weeks of therapy while genotypes 2-4 (non-genotype 1) require 24 weeks of therapy. Irrespective of genotype, prior to 2001, combination therapies consisted of interferon alfa 2B and ribavirin (IR). During 2001 interferon alfa 2B was replaced with peginterferon creating a new combination-therapy (PR). Thus, patients were transitioning from interferon alfa 2B to peginterferon and received all three antiviral medications during the course of their treatment (IPR).

 

RESULTS:

The data show that on average genotype 1 patients treated with IR (n=28), IPR (n=19), and PR (n=24) therapy, received 438.4, 796.5, and 223.5 days of antiviral medication treatment at a cost of $8,232 and $16,536 and $10,786 respectively. Non genotype 1 patients treated with IR (n=20), IPR (n=5), and PR (n=3) therapy received an average of 226.8, 690.4 and 141.7 days of antiviral medication treatment at a cost of $6,866, $12,695 and $9,237 respectively. Genotype 1 patients treated with IR, IPR, and PR therapy and followed for a year and a half to determine cure rates averaged 16.3, 19.2, and 6.4 Hepatitis C related clinic visits at a cost of $1,594, $1,812 and $636 respectively. Non-genotype 1 patients treated with IR, IPR, and PR averaged 12.3, 9.0 and 5.3 Hepatitis C related clinic visits at a cost of $1,184, $863 and $511 respectively.

 

CONCLUSIONS:

Largely due to treatment patterns, the cost of treating genotype 1 patients is more substantial than the cost of treating non-genotype 1 patients. The IPR group of patients is higher largely due to patients being non-responders and switching therapies, extending the length of treatment.


Abstract ID: 67976

Category: JO7: HCV: Treatment

Pegylated interferons (PEG-IFNs) do not present viral rebound after short-term administration of consensus interferon (CIFN) to IFN-naive patients (pts) with chronic hepatites C (CHC), genotype 1.

L. C. Da Silva, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, J. R. Pinho, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, S. K. Ono-Nita, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, C. L. Madruga, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, I. M. Mello, University of Sao Paulo School of Medicine, Sao Paulo, Brazil, F. J. Carrilho, University of Sao Paulo School of Medicine, Sao Paulo, Brazil

 

Introduction:

It is well known that genotype 1 and high viral load (> 800,000 U or > 5.9 log) are very important viral factors predictive of a poor response to combined therapy with PEG-IFN and ribavirin (RBV). According to three large trials, the rate of sustained response in such patients is below 50%. In an attempt to increase this rate through an improvement of early viral kinetics, a high dose of CIFN was given for two days just before starting a PEG-IFN.

 

Material and Methods:

Six consecutive CHC pts were given a 2-days induction treatment with 15mcg of CIFN every 12 hs. After 12 hs one of the PEG-IFN (3 pts with PEG-IFN-alpha-2a and 3 with PEG-IFN- alpha-2b) was administrated followed by one week dosing. Serum specimens were collected after pretreatment, 48hs, 2, 4, 8 and 12 weeks and submitted to a quantitative (Amplicor/Monitor, Roche, limit of detection (LD) 600 IU) or qualitative Amplicor/Monitor, Roche, LD 50 IU) when necessary. Results of viral load (VL) in induction group (Group B) were compared to those found in another group of patients also treated with PEG-IFN plus RBV but without induction treatment (Group A).

 

Results:

In the induction treatment groups, the following mean VL were observed: pre-treatment = 5.9 log, 48hs = 3.2 log, week 2 = 4.3 log, week 4 = 3.8 log, week 8 = 2.7 and week 12 = 2.3. A statistic analyses showed a significant difference between pre and 48hs (p < 0.0001) and between 48hs and week2 (p = 0.043). A comparison between the induction and non-induction group showed no difference among pre, week 2, 4, 8 and 12.

 

 

Discussion and conclusions:

Attempt to improve viral kinetics through a decrease of VL in phase 1 after a high-dose of CIFN did not change the viral patterns when compared to pts without induction treatment.


Abstract ID: 62985

Category: JO7: HCV: Treatment

Peginterferon Alfa-2a and Ribavirin in African American and Caucasian Patients with Chronic Hepatitis C, Genotype 1.

H. S. Conjeevaram, UNIVERSITY OF MICHIGAN, Ann Arbor, MI, M. W. Fried, University of North Carolina, Chapell Hill, NC, L. J. Jeffers, VA Medical Center, Miami, FL, N. Terrault, UCSF, San Francisco, CA, T. E. Wiley-Lucas, Rush University Medical Center, Chicago, IL, N. Afdhal, Beth Israel Deaconess Medical Center, Boston, MA, R. S. Brown Jr, New York Presbyterian-Columbia Presbyterian Center, New York, NY, S. H. Belle, University of Pittsburgh, Pittsburgh, PA, P. R. Robuck, NIDDK, NIH, Bethesda, MD, C. D. Howell, University of Maryland, Baltimore, MD

 

Background/Aims:

Compared to Caucasian Americans (CA), African Americans (AA) with chronic hepatitis C virus (HCV) infection are less likely to respond to interferon-based antiviral therapy. The biological bases for this racial difference in response are not known. Virahep-C is a prospective, multi-center clinical study, designed to compare the effects of peginterferon and ribavirin therapy between AA and CA pts and determine predictive factors for non-response to treatment.

 

Methods:

196 AA and 205 CA treatment-naïve pts with genotype 1 infection were treated with peginterferon alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). Pts who were HCV RNA negative at wk 24 were treated for an additional 24 wks and followed thereafter for evidence of SVR. Pts who were HCV RNA positive at wk 24 were considered nonresponders, and therapy stopped.

 

Results:

Baseline features were similar among AA and CA including age, gender, histologic severity but AA had higher average BMI, higher rates of diabetes and hypertension, and lower mean ALT, neutrophil, and hemoglobin levels (p< .001 for all). AA were also more likely to have HCV subtype 1b than CA (46% vs. 28%, p=.0004) and less likely to have 1a (47% vs. 58%, p=.04) but HCV RNA levels were similar. Virological response rates are shown below, representing final data on 94% of pts. Complete results are expected by October 2005.

 

 

Breakthrough responses between wk 24 and wk 48 occurred in 14% AA and 6% CA (p=.03). Relapse rates following treatment were similar between AA and CA (34% vs. 27%, p=.30). Frequencies of serious adverse events, dose reductions/discontinuations were similar among AA and CA. Multiple logistic regression analyses demonstrated that CA race was independently associated with a higher SVR rate compared to AA [OR 3.40 (95% CI 2.07-5.61)]. Other factors independently associated with lower SVR included male sex, higher baseline HCV RNA level, higher Ishak fibrosis score and compliance (< 80/80/80); none of these accounted for racial differences in response.

 

Summary/Conclusions:

In pts with HCV genotype 1 infection, AA have significantly lower rate of virological response to peginterferon and ribavirin therapy than CA. The differences in response are evident soon after starting therapy and persist. Analyses of other clinical, viral, immunological, and genetic differences between responders and non-responders in this cohort are ongoing.


Abstract ID: 61115

Category: JO7: HCV: Treatment

HEPATITIS C VIRUS PERSISTS AND REPLICATES IN THE LIVER OF THE MAJORITY OF SUSTAINED RESPONDER PATIENTS TO ANTIVIRAL TREATMENT.

V. Carreño, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, I. Castillo, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, E. Rodríguez-Iñigo, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain,  López-Alcorocho, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, J. Bartolomé, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, J. Quiroga, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, M. Pardo, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain

 

Recently it was demonstrated the presence of HCV-RNA in the liver of 3/11 (27%) sustained responders to antiviral therapy (serum HCV-RNA negative and persistently normal ALT levels), but HCV replication was not found in liver cells (1). We studied 20 patients (17 genotype 1 and the other 3 with genotype 2, 3 and 4) with a histological chronic hepatitis C who responded to antiviral therapy (pegylated or recombinant IFN ± ribavirin) with normalization of liver function tests and clearance of serum HCV-RNA and who remained so for 42.7±31.2 months after treatment. HCV-RNA-positive and negative strands were tested by strand-specific real-time RT-PCR and by in situ hybridization in the post-treatment liver biopsies obtained 35.3±35.0 months (range:8- 117 months) after the end of therapy. HCV-RNA strands were also studied in PBMC of the 20 patients. HCV-specific CD4+ and CD8+ T-cell responses were assessed by standard lymphoproliferative assays and HCV-tetramer analysis respectively. HCVRNA- positive strand was found in 19/20 (95%) liver biopsies (mean ± SEM: 1.9´105 ± 5.4´104  copies/mg total RNA). The HCV-RNA-negative strand was detected in 15/19 (79%) liver samples with HCV-RNA-positive strand (7.3´104 ± 3.1´104 copies/mg total RNA). The presence of HCV-RNA-positive and negative strands was confirmed in all cases by in situ hybridization. With respect to PBMC, 13/20 (65%) had HCV-RNA (9.5´105 ± 6.9´105 copies/mg total RNA). In addition, HCV-RNA-negative strand was detected in 12/13 (92%) of PBMC with HCV-RNA (1.6´105 ± 5.5´104 copies/mg total RNA). HCV-RNA was amplified from the liver of 4 patients with primers of the core region. PCR products were cloned and 4 clones from each patient were sequenced. Phylogenetic analysis showed higher genetic distances among patients than within patients, indicating that there was no cross-contamination among samples. Regarding cellular responses, 9/15 patients had a positive HCV-specific proliferative T-cell response. Moreover, NS3 tetramer-specific CD8+ T-cells positive for at least one epitope were detected in HLA-A2+ subjects. Finally, liver necroinflammation remained in the post-treatment liver biopsy of 15 patients and fibrosis was present in 7, although liver damage improved in all but 2 cases. In conclusion, HCV persists and replicates in the liver and PBMC of the majority of the patients with chronic hepatitis C after a sustained response to treatment, although they maintain HCV-specific cellular responses. As these responders have not cleared HCV infection and may maintain histological damage, they should be followed for years in spite of apparently clinical resolution of the disease.

 

(1) Hepatology 2005;41:106-14


Abstract ID: 65969

Category: JO7: HCV: Treatment

Rapid Virological Response at Week 4 (RVR) of Peginterferon alfa-2a (40KD) (PEGASYS®) plus Ribavirin (RBV, COPEGUS®) Treatment Predicts Sustained Virological Response (SVR) after 24 Weeks in Genotype 1 Patients.

D. Jensen, Rush University Medical Center, Chicago, IL, T. Morgan, VA Long Beach Healthcare System, Long Beach, CA, P. Marcellin, Hopital Beaujon, Clichy, France, P. Pockros, The Scripps Clinic, La Jolla, CA, R. Reddy, Hospital of the University of Pennsylvania, Philadelphia, S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, P. Ferenci, MedicalUniversity of Vienna, Internal Medicine IV, Vienna, Austria, B. Willems, Universite de Montreal, Montreal, Canada

 

Introduction

SVR rates were significantly higher in genotype (GT) 1 patients (pts) treated for 48 wks with peginterferon alfa-2a (40KD) (PEGASYS®) + RBV (COPEGUS®) 1000/1200mg/d than for 24 wks and/or with a lower RBV dose (800 mg/d) [52% vs 29–42%; Hadziyannis. Ann Intern Med 2004]. However, 78 of 219 (36%) GT1 pts randomized to peginterferon alfa-2a (40KD)/RBV for 24 wks achieved an SVR. Data was analyzed from this trial to identify factors that might predict which GT1 pts are likely to achieve an SVR after 24 wks of treatment.

 

Methods

Pts with chronic hepatitis C were randomized to 24 or 48 wks of peginterferon alfa-2a (40KD) + standard (1000/1200mg/d) or low dose RBV (800mg/d). SVR = HCV RNA <50IU/mL after 24wks of untreated follow-up. RVR = HCV RNA <50IU/mL after 4 wks. We used stepwise multiple regression analysis (MLR) to identify baseline factors predictive of SVR in GT1 pts treated for 24 or 48 wks with standard dose RBV.

 

Results

Data from 729 GT1 pts with week 4 results were analyzed of whom /729 patients had an RVR. Pts with an RVR had both higher end-of-treatment (EOT) and SVR rates than pts without an RVR (Figure). Pts with an RVR had lower relapse rates between EOT and follow-up, regardless of treatment duration or RBV dose. In contrast, relapse rates decreased with increasing duration of treatment and RBV dose in pts without an RVR. RVR was more likely in pts with a baseline HCV RNA level < 200,000 IU/mL (49 patients), < 200,000—600,000 IU/mL (26 patients) and > 600,000 IU/mL (9 patients)

 

Conclusion

This retrospective analysis of a large, randomized, phase III trial including 729 genotype 1 patients shows that:

·       Approximately 20% of patients with HCV genotype 1 infection achieved undetectable HCV RNA levels by qualitative PCR (i.e. an RVR) at week 4 of treatment with peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus).

·       Overall, 89% of patients with an RVR treated for only 24 weeks achieved an SVR.  Moreover, patients with an RVR treated for 48 weeks did not obtain a better SVR rate.

·       The SVR rate in patients without an RVR (44%) was obtained following treatment with peginterferon alfa-2a (40KD) plus ribavirin at the recommended dose (1000/1200 mg/day) for the recommended duration (48 weeks).

·       A lower baseline HCV RNA level was the only significant and independent factor associated with SVR.

·       An RVR at week 4 of treatment is the single best predictive factor for an SVR.

·       The use of RVR status to guide treatment duration in genotype 1 patients is appealing and should ideally be confirmed by prospective studies.

 

 


Abstract ID: 62020

 

Effect of Sertraline on Pruritus in Cholestatic Liver Disease: a Randomized Double Blind Placebo Controlled Crossover Study.

M. J. Mayo, University of Texas Southwestern at Dallas, Dallas, TX, I. Handem,

University of Texas Southwestern Medical Center at Dallas, Dallas, TX, S. Saldana,

University of Texa Southwestern Medical Center, Dallas, TX, H. Jacobe, University of

Texas Southwestern Medical Center, Dallas, TX, Y. Getachew, University of Texas

Southwestern Medical Center, Dallas, TX, A. J. Rush, University of Texas Southwestern

Medical Center, Dallas, TX

 

Background

Pruritus (severe itching) is frequently the most debilitating symptom of cholestatic liver diseases. Moreover, existing therapies are often not effective. Recent reports have suggested that serotonin reuptake inhibitors can improve pruritus, but all have been small, retrospective case series. The present study was designed to investigate the safety and efficacy of sertraline as a first-line treatment for cholestatic pruritus.

 

Methods

18 subjects with chronic pruritus due to liver disease were studied, including patients with primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C cirrhosis, and post-necrotic cirrhosis. Subjects were not allowed to take any other medication that might affect pruritus during the study, other than the study drug. In the first part of the study, subjects underwent an open-label dose escalation to determine the best dose of

sertraline that would optimize efficacy and tolerability. After a washout period, subjects were then randomized to either sertraline or placebo in a double blind fashion and treated for 6 weeks. After a second washout, they were crossed over to the other therapy for 6 weeks. Subjects made daily entries into a diary using a 0-10 visual analog scale to quantify their pruritus. At each study visit, a detailed assessment of pruritus was

documented, including distribution, timing, degree of disability, and physical evidence of  scratching. Depression inventories were also followed.

 

Results

The optimum dose was 100 mg for most subjects. One subject suffered unbearable dizziness with sertraline (12.5 mg) and withdrew from the study. All other subjects tolerated sertraline without difficulty, although higher doses were sometimes associated with drowsiness or diarrhea.

 

In the open-label portion of the study, pruritus improved a mean of -67% (range -36%to -97%). Improvement in pruritus with sertraline occurred in both depressed and nondepressed individuals.

 

In the controlled portion of the study, itch scores improved in patients taking sertraline (mean -30%, range -10% to -80%), whereas they worsened in

patients taking placebo (mean +24%, range +70% to -1%). The difference between the groups was statistically significant (p=.008). Changes in itch distribution, degree of disability, and physical evidence of scratching paralleled changes in the visual analog itch score.

 

Conclusion

·       Sertraline treatment significantly improves pruritus due to chronic liver disease and is well tolerated.

·       These findings imply that serotonergic pathways are important in the perception of itch and warrant further investigation.

Although few patients in the study had clinical depression at entry, "successful treatment of depression was not required for treatment of pruritus," Dr. Mayo said.