The Liver Meeting
55th Annual Meeting of the American Association for the Study of
Liver Diseases

October 29 - November 2
Boston, Massachusetts
John B. Hynes Convention Center

 

Saturday Posters (10/30/2004)– HCV Treatment 1 – 5:30PM – 8:00PM

Topic:  Pegasys

Program#/Poster#: 348

QUANTITATIVE LIVER FUNCTION TESTS PREDICT SUSTAINED VIROLOGIC RESPONSE TO RETREATMENT WITH PEGINTERFERON ALFA-2A PLUS RIBAVIRIN: RESULTS OF THE LEAD-IN PHASE OF THE HALT-C TRIAL

 Gregory T. Everson, UCHSC, Denver, CO; Mitchell L. Shiffman, VCU, Richmond, VA; John C. Hoefs, UCI, Orange, CA; Marcelo Kugelmas, UCHSC, Denver, CO; Richard K. Sterling, VCU, Richmond, VA; Timothy R. Morgan, VAHLB, Long Beach, CA; Jennifer DeSanto, Carol McKinley, UCHSC, Denver, CO; Charlotte Hofmann, Paula Smith, VCU, Richmond, VA; William Rietkerk, UCI, Orange, CA; Shannon Lauriski, UCHSC, Denver, CO; Nora Milne, UCI, Orange, CA; David Wagner, Metabolic Solutions, Nashua, NH; Michael C. Doherty, Elizabeth C. Wright, NERI, Watertown, MD.

 

Introduction:

Patients with hepatitis C cirrhosis enrolled in HALT C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial) undergoing retreatment with peginterferon alfa-2a and ribavirin had lower SVR, 11%, than non-cirrhotics, 23% (P=.0005) (Gastro 2004;126:1015). Quantitative tests (QLFTs) correlate with cirrhosis (Hepat 2003; 38: abst 309), but also identify patients with poor function who lacking histologic cirrhosis.

 

Hypothesis:

Rate of SVR correlates better with liver function as predicted by QLFTs than liver biopsy. Patients: QLFTs were measured in 232 patients enrolled in HALT C prior to retreatment. Patients were divided into four quartiles for each QLFT, stratified from best to worst function, and SVR within each quartile was determined. Methods: Caffeine (Caf), antipyrine (AP), and 2,2,4,4-2H-cholate (CH) were taken orally and 24-13C-cholate and lidocaine were administered intravenously. These compounds or their metabolites (MEGX) were measured from timed serial samples of blood, saliva, and breath using standard techniques. Kinetic parameters (rate constant (kelim)), clearance (Cl), CH shunt and CH per oral clearance (CH PO Cl) were calculated. Perfused hepatic mass (PHM) was determined from SPECT liver scan.

 

Results:

Patient characteristics (mean+SD): age 49.8 + 7.2 yr, BMI 29.5 + 4.9, M:F 75:25, and HCV RNA 4.40 + 4.63 x 106 copies/ml. 40% had cirrhosis, 60% had bridging fibrosis, and 92% were infected with HCV genotype 1. Lab values: Bilirubin 0.7+0.4 mg/dl, albumin 3.8+0.4 g/dl, INR 1.0+0.1, and platelet count 169+66x1000/mm3. In this subgroup of HALT C, SVR was 5% in cirrhotics and 16% in noncirrhotics.

 

The table displays SVRs from best to worst functional quartile for each test. Significance (p value) was determined by Fishers Exact test and logistic regression.

 

QLFT

Quartile 1
(best)

Quartile 2

Quartile 3

Quartile 4
(worst)

Fisher
Exact

Logistic
Regression

CH PO Cl

22%

23%

10%

2%

.0009

.0253

CH Shunt

25%

17%

16%

2%

.0015

.0047

AP_Kelim

26%

24%

8%

0%

.0029

.0019

AP Cl

29%

22%

5%

4%

.0055

.0039

MEGX15min

18%

14%

23%

2%

.0101

.1138

PHM

18%

26%

14%

2%

.0119

.0053

Caf Kelim

26%

19%

10%

6%

.0150

.0086

 

On-treatment virological response (week 20) demonstrated even stronger correlations with results of QLFTs (data not shown). QLFTs correlated significantly with histological cirrhosis, but 23 to 61% of patients in the worst quartile for each test were noncirrhotic.

 

Conclusion:

Poor QLFTs better predict failure to achieve SVR than liver histology. Liver biopsy sampling error may fail to identify all patients with cirrhosis. Results of individual QLFTs may yield clues to metabolic pathways involved in viral clearance. This study was supported by contracts from NIDDK and gifts from Metabolic Solutions and Roche Pharmaceuticals

 

 

 

Topic:  Pegasys

Program#/Poster#: 349

THE IMPACT OF PEGINTERFERON (PEGIFN) AND RIBAVIRIN (RBV) DOSING ON SUSTAINED VIROLOGIC RESPONSE (SVR) IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS (HCV) UNDERGOING RETREATMENT IN THE HALT-C TRIAL

 Mitchell L. Shiffman, Virginia Commonwealth University, Richmond, VA; Timothy R. Morgan, University of California - Irvine, Irvine, CA; Marc G. Ghany, NIDDK, Bethesda, MD; Elizabeth C. Wright, New England Research Institutes, Watertown, MA; and the HALT-C Trial Group.

 

Introduction:

Several studies, including recent data from the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial (Gastroenterology 2004; 126:1015), have demonstrated that SVR was adversely affected when the dose of either PEGIFN and/or RBV were reduced during the first 12-20 weeks of therapy, particularly in patients with HCV genotype 1. Unfortunately, none of these prior studies contained a large enough sample size to evaluate the impact of dose reducing PEGIFN and/or RBV by variable amounts independent of the other or examined if the decline in SVR was due to reducing or discontinuing one or both of these agents. These issues were explored in the complete data set from the lead-in phase of the HALT-C trial.

 

Methods:

1145 genotype 1 HCV patients with non-response (NR) to prior treatment with IFN or IFN/RBV, bridging fibrosis or cirrhosis (FIB/CX) and no prior decompensation were evaluated. The target doses of PEGIFN alfa-2a and RBV utilized for treatment were 180 mcg/wk and 1,000-1,200 mg/day respectively. The total amount of PEGIFN and RBV taken by each patient during weeks 1-20 was expressed as a percentage of this target dose. Growth factors such as GMCSF or erythropoetin were not utilized. HCV RNA titer was measured by Roche Amplicor v.2 (lower limit: 100 IU/ml). Patients who were HCV RNA (-) at week 20 remained on treatment for 48 weeks and followed for SVR.

 

Results:

 

Effect of dose reduction or discontinuation during initial 20 weeks of therapy on SVR

 

                                                Peg alfa 2a dose

RBV Dose

81%-100%

61%-80%

<60%

Total

81%-100%

17% (88/511)

11% (8/74)

8% (5/66)

16% (101/651)

61%-80%

17% (16/96)

17% (6/36)

0% (0/20)

15% (22/152)

<60%

17% (6/35)

0% (0/10)

6% (1/17)

11% (7/62)

RBV stopped

0% (0/39)

0% (0/12)

0% (0/18)

0% (0/69)

Total

16% (110/681)

11% (14/132)

5% (6/121)

14% (131/934)

 

>80/80 = 17% SVR (88/511) vs. ≤ 80/80 = 10% SVR (42/423) p = 0.001 chi sq

 

 

Effect of dose reduction or discontinuation during weeks 20-48 on SVR

 

                                                Peg alfa 2a dose

RBV Dose

81%-100%

61%-80%

<60%

81%-100%

50 (62/125)

68 (17/25)

50 (9/18)

61%-80%

50 (12/24)

46 (6/13)

0 (0/8)

<60%

41 (7/17)

40 (4/10)

40 (4/10)

RBV stopped

32 (6/19)

0 (0/1)

75 (3/4)

 

 

Conclusion

 


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 350

PREVALENCE OF INSULIN RESISTANCE (IR) AND IMPACT ON TREATMENT IN CHRONIC HEPATITIS C (CHC)*

 Anna S. Lok, University of Michigan, Ann Arbor, MI; J. E. Everhart, NIDDK, NIH, Bethesda, MD; R. T. Chung, Massachusetts General Hospital, Boston, MA; L. Padmanabhan, New England Research Institute, Watertown, MA; M. L. Shiffman, Virginia Commonwealth University, Richmond, VA; G. T. Everson, University of Colorado, Denver, CO; K. L. Lindsay, University of Southern California, Los Angeles, CA; H. L. Bonkovsky, University of Connecticut, Farmington, CT; A. M. Di Bisceglie, St. Louis University, St. Louis, MO; W. M. Lee, University of Texas Southwestern, Dallas, TX; T. R. Morgan, University of California-Irvine, Irvine, CA; M. G. Ghany, NIDDK, NIH, Bethesda, MD; C. Morishima, University of Washington, Seattle, WA; HALT-C Trial Investigators, University of Michigan, Ann Arbor, MI.

 

Background:

Obesity and hepatic steatosis have been reported to be associated with lower rates of sustained virological response (SVR) to interferon (IFN) and ribavirin treatment of CHC. Obesity and hepatic steatosis are both strongly associated with IR.

 

Aim:

To determine the prevalence and predictive factors of IR and its effect on treatment response in CHC.

 

Methods:

Demographic, clinical, laboratory and histological data from non-diabetic patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial were analyzed. The HALT-C trial enrolled patients with CHC, Ishak fibrosis score >3 and prior nonresponse to IFN +/- ribavirin. All patients received pegIFN alfa 2a and ribavirin for 24 weeks. Patients with no detectable HCV RNA at week 20 continued combination treatment until week 48 and were observed for SVR. IR was estimated by HOMA (fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/l)/22.5)). For comparison, the mean HOMA in the adult, non-diabetic U.S. population is 2.4.

 

Results:

866 non-diabetic patients (36% with cirrhosis) were evaluated. Mean HOMA IR was 9.8 (SD 10.8), or 4 times the U.S. population mean, while the four quartile means were 3.0, 5.5, 8.5, and 22.2. In multivariate analysis, log10 HOMA was associated with black race, higher waist circumference, higher BMI, higher triglyceride, non current smoker, steatosis on biopsy, laboratory (platelet, AST), and histological (inflammatory and fibrosis scores) markers of advanced liver disease (p-values below).  Virological factors (genotype and HCV RNA level) were not associated with HOMA.

 

Predictors of Insulin Resistance

Variable

Log HOMA p-value

Black

<0.0001

BMI

<0.0001

Waist Circumference

0.0074

Triglyceride

<0.001

Platelet

0.02

Fibrosis Score

0.009

Hepatic Steatosis

0.0061

Current Smoker

0.0242

 

Predictors of antiviral response

Variable

Week 20 VR p value

SVR p value

Log HOMA

0.01

0.11

Hepatic Steatosis

0.004

0.04

Black

0.005

NS

AST/ALT ratio

<0.0001

<0.0001

Albumin

NS

0.0288

Platelet

<0.001

NS

Log HCV RNA

<0.0012

<0.0001

Genotype 1

<0.0001

<0.0001

Ishak Fibrosis

NS

0.002

Previous Combination Rx

<0.0001

0.0025

 

Conclusion:

 

* Supported by NIDDK, NIH and Hoffmann-La Roche, Inc.


TOPIC:  HIV/HCV Coinfection - PegIntron

 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 351

 

 

FINAL RESULTS OF ANRS HC02 - RIBAVIC: A RANDOMIZED CONTROLLED TRIAL OF PEGYLATED-INTERFERON ALFA-2B PLUS RIBAVIRIN VS INTERFERON ALFA-2B PLUS RIBAVIRIN FOR THE INITIAL TREATMENT OF CHRONIC HEPATITIS C IN HIV CO-INFECTED PATIENTS

 Stanislas POL Sr., Necker Hospital, Paris, France; Fabrice Carrat Sr., Firouzé Bani-Sadr, Saint-Antoine Hospital, Paris, France; Eric Rosenthal, Hospital de l'Archet, Nice, France; Françoise Lunel, Necker Hospital, Angers, France; Patrice Morand, CHU, Grenoble, France; Dominique Salmon, Cochin Hospital, Paris, France; Gilles Pialoux, Tenon Hospital, Paris, France; Cacoub Patrice, Pitié-Salpétrière Hospital, Paris, France; Perronne Christian, Raymond Poincaré Hospital, Garches, France; on behalf of the ANRS HC02-RIBAVIC group.

 

Background:

Hepatitis C may be severe in HIV-infected subjects evidencing the need to treat.

 

Aim:

 To compare the safety and efficacy of a 48 week-course of the standard (IFNa2b: 3 MIU x3/w, n=207) (INF group) to the pegylated (PEG-IFNa2b: 1.5 mg/kg x1/w, n=205) interferon (PEG group) both combined with ribavirin (800mg/d).

 

Methods:

A randomized, multicenter, parallel-group, open-label trial. Inclusion criteria were: HCV-RNA positive and abnormal liver histology, CD4 > 200, stable HIV-RNA, stable HAART or off HAART.

 

Results:

The 412 patients (39.5 ± 5.5 y, 77%M, 80% IVDU) were given ART in 83%. Mean CD4 cell count was 477/ml, HIV RNA < 400 in 69% (mean HIV load in others: 3.7 ± 0.7 logs). The mean pre-treatment Metavir score was A 1.8 ± 0.7, F 2.3 ± 1.0 and 39% of pts had F3-F4 of which 17% had sustained normal ALT. Baseline variables at entry were not different between groups. Treatment discontinuation occurred in 42% (86 IFN & 81 PEG) and severe adverse events in 31% (64 IFN & 63 PEG), including 6 mitochondriopathies. SVR was achieved in 20% of IFN pts vs 27% of PEG pts (p=0.03). In those who did not discontinue treatment, virological response rates were at W4 (12 vs 20%), W12 (34 vs 41%), W24 (41 vs 54%), (W48: 34 vs 52%) and W72 (6 vs 35%), respectively. Virologic response at W12 predicted SVR with 71% positive Predictive Value and its absence had a 99% Negative Predictive Value for Peg IFN.  SVR varied with genotypes 1 or 4 (11%) vs 3 or others (43%), but not with the Metavir score or the adjusted ribavirin dose. Response-associated pretreatment characteristics included genotypes other than 1 or 4 (OR=6.6), no concomitant protease-inhibitor therapy (OR=1.9), age 40 years or younger (OR=1.8) and and elevated alanine aminotransferase activity (OR=1.9). Necro-inflammation significantly decreased in the PEG pts (-0.20 vs 0.02, p =0.0008). Fibrosis stabilized in virological responders and worsened in non responders . Steatosis improved significantly in patients infected by HCV genotype 3 who had a sustained virological response (P= 0.017).

 

SVR by Histology

Fibrosis Score

SVR

F1, F2   44/51

36% Peg IFN vs. 31% IFN

F3, F4 (Bridging fibrosis/cirrhosis)  36/29

28% Peg IFN vs. 3% IFN

 

Conclusion:

In HIV-HCV coinfected pts, the combination of pegylated IFNa2b and ribavirin is associated with a superior HCV virologic response than standard combination with a quite similar adverse-event profile.


 

Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 352

 

PROXIMAL SPLENIC ARTERY EMBOLIZATION ALLOWS PEGYLATED INTERFERON AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS C WITH SEVERE THROMBOCYTOPENIA

Brigida Eleonora Annicchiarico, Massimo Siciliano, Antonella Franceschelli, Carmine Di Stasi, Giuseppe Bombardieri, Università Cattolica del Sacro Cuore, Rome, Italy.

 

Background:

Severe thrombocytopenia, a frequent complication of chronic hepatitis, is a major contraindication to interferon therapy in HCV infection. Previous studies indicate that splenic embolization procedures may lead to a significant increase of platelet count in splenomegalic patients with thrombocytopenia.

 

Patients and methods:

A group of seven naive patients (4 females, 47 to 63 year old) was selected on the basis of the following criteria: rapidly ongoing hepatitis C or compensated liver cirrhosis (Metavir grade ≥ 3 and score 2 to 4 at a liver biopsy obtained after platelet administation), splenomegaly (spleen diameter greater than 14 cm at ultrasonography) and severe thrombocytopenia (platelet count less than 60.000 units/μl). The HCV genotype was 1b in all patients. All subjects were submitted to proximal splenic artery embolization via a femoral artery approach, using Gianturco coils as embolization material. Pegylated alpha-2b interferon (1-1.5 μg/kg bw/week) and ribavirin (1000 to 1200 mg/day) were started about three months after the splenic artery embolization. All patients completed a twelve week course of treatment; in five of them an early virological response was obtained. Three patients completed 48 weeks of therapy. Two were HCV-RNA negative at the end of treatment and six months later. A written consent was obtained before each invasive procedure and before the beginning of the antiviral therapy. Statistical analysis was performed using the Student t test.

 

Results:

The baseline mean platelet count was 59000 units/μl ± 7400 SD. At the beginnig of combination therapy, about three months after splenic artery embolization, the mean platelet count was significantly higher than the baseline value (104000 units/μl ± 15900 SD; P<0.001) and a platelet count of at least 80000 units/μl was reached in all patients. After the first two months of combination therapy the mean platelet count was 93000 units/μl ± 12000 SD, significantly higher than the baseline value (P<0.001). The end-of-treatment platelet count of the two break-trough patients was 91000 units/μl and 104000 units/μl respectively. The end-of-treatment platelet count of the three patients who completed the 48 week course of therapy was 85000 units/μl, 94000 units/μl, and 88000 units/μl respectively. No any serious side effect was registered after the splenic artery embolization, nor during the combination therapy course.

 

Conclusions:

Proximal splenic artery embolization was safe and allowed pegylated interferon and ribavirin therapy in a group of thrombocytopenic subjects affected by severe hepatitis C. The improvement of platelet count obtained by this procedure persisted during the whole treatment course, that has been, in three subjects, 48 week long.


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 353

 

HISTOLOGIC BENEFIT OF PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) MONOTHERAPY IN PATIENTS WITH ADVANCED FIBROSIS OR CIRRHOSIS DUE TO CHRONIC HEPATITIS C

Greg Everson, University of Colorado Health Sciences Center, Denver, CO; J. Heathcote, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Stephen C. Pappas, St. Luke's Episcopal Hospital, Katy, TX; Sugantha Govindarajan, Rancho Los Amigos Medical Center, Downey, CA; Ellen Lentz, Juan- Carlos Lopez-Talavera, F. Hoffmann-La Roche Ltd., Nutley, NJ.

 

Introduction:

The primary goals of interferon (IFN)-based therapy for patients with chronic hepatitis C have been achieving sustained virologic response (SVR) and blockade of disease progression. Studies conducted noncirrhotic patients suggest that IFN slows fibrosis progression. We aimed to evaluate the benefit of IFN for the improvements in inflammation or fibrosis in patients with advanced fibrosis or cirrhosis.

 

Methods:

Data from patients with cirrhosis/bridging fibrosis who participated in a randomized controlled trial comparing 48 weeks of 90 (Peg-90) or 180 (Peg-180) ug/wk of peginterferon alfa-2a (40KD) and 3 MU/tiw IFN alfa-2a were analyzed (Heathcote, NEJM 2000;343:1673). Biopsies were graded and staged (Metavir criteria) by one pathologist (SG) blinded to treatment and time of biopsy. Primary endpoints were improvement in fibrosis stage (defined as ≥ 1 stage improvement) or inflammatory grade (defined as ≥ 1 grade improvement) from baseline. Wilcoxon Signed RanksTest was used in the analysis.

 

Results:

Data from 184 patients (68% of all patients) with paired liver biopsies obtained a median of 593 days apart were evaluated. At baseline, 76% had cirrhosis and 24% had extensive bridging. Demographics of patients with paired biopsies were similar to the intent to treat population. For those patients who had paired biopsies, SVRs were obtained in 9, 16, and 37% in the IFN, and Peg-90 and Peg-180 arms, respectively. Improvements in the inflammatory grade and fibrosis stage were seen in 23.9% and 29.3% of patients, respectively. Fibrosis improvement was 35% in the Peg-180 group, 25% in the Peg-90 group, and 27% for IFN. All measures of virologic response were highly correlated with inflammation and fibrosis improvement. There was a significant improvement (p<.05) in fibrosis from baseline when tested separately for all patients, SVRs, relapsers, and a trend of improvement was present for non-responders (p=.067).

 

Summary:

Pegylated interferon plus ribavirin is the current treatment standard for patients with chronic hepatitis C (CHC), including those with advanced fibrosis and compensated cirrhosis.

 

Patients with bridging fibrosis or cirrhosis can experience histological benefit after

interferon-based treatment.

 

Patients treated with peginterferon alfa-2a (40KD) 180 ug/week (27.9% vs 10.9%; P=0.0201) and 90 ug /week (31.1% vs 10.9%; P=0.0084) had significantly greater improvement in inflammatory grade than those treated with conventional interferon alfa-2a.

 

Peginterferon alfa-2a (40KD) 180 ug /week tended to be more effective than interferon alfa-2a in improving fibrosis stage (35.3% vs 27.3%; P=NS).

 

Patients with virological relapse and nonresponse also obtained moderate histological benefit.

 

The major predictor for fibrosis improvement was EVR.

 

EVR, baseline inflammatory grade (3 vs 2) and genotype (non-1 vs 1) were the three main predictors for the improvement of inflammatory grade.

 

Conclusions:

SVR is the primary goal of therapy in patients with CHC and advanced fibrosis.

However, this group of patients is more resistant to therapy.

 

Secondary benefits, including reduction in fibrosis and inflammation, are additional therapeutic objectives. Our findings of improvement in fibrosis and inflammation in this group of patients suggest that interferon-based therapies may delay disease progression, potentially reducing the rate of hepatic decompensation and the need for liver transplantation.

 

Although the greatest benefits were seen in patients with an SVR, patients with virological relapse and nonresponse also obtained moderate histologic benefit. Thus, it may be worthwhile to continue treatment in patients with bridging fibrosis or cirrhosis who do not have an EVR at week 12.

 

These results provide additional rationale for long-term maintenance therapy. In the Hepatitic C Antiviral Long Term Treatment Against Cirrhosis (HALT-C) trial peginterferon alfa-2a (40KD) (PEGASYS) 90 ug /week is currently being studied in patients with advanced liver fibrosis or cirrhosis.

 

 

Topic:  Experimental Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 354

 

EFFECT OF ONDANSETRON, A 5-HT3 RECEPTOR ANTAGONIST, ON FATIGUE IN CHRONIC HEPATITIS C: A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED STUDY

 Thierry Piche, Geoffroy Vanbiervliet, Hopital l'Archet 2, Hepatogastroentérologie, Nice Cedex 3, France; Christophe Renou, Centre hospitalier Hyères, Hyères, France; Zeina Antoun, GSK, Marly le Roi, France; Faredj Cherikh, Eve Gelsi, Daniel Bianchi, Hopital l'Archet 2, Hepatogastroentérologie, Nice Cedex 3, France; Sylvia Benzaken, Hopital l'Archet 2, Immunology, Nice Cedex 3, France; Marie-Christine Rigault, Hopital l'Archet 2, Pharmacy, Nice Cedex 3, France; Patrick Rampal, Hepatogastroentérologie, Monaco, Monaco; Pierre-Michel Huet, Albert Tran, Hopital l'Archet 2, Hepatogastroentérologie, Nice Cedex 3, France.

 

Background & aims:

There is a lack of available effective therapy for fatigue associated with chronic hepatitis C (CHC). The serotonin antagonist ondansetron has shown its efficacy in the chronic fatigue syndrome. The present randomized, placebo-controlled double blind trial investigated the effect of orally administered ondansetron on fatigue in CHC.

 

Methods:

Thirty six patients with CHC were included if fatigue was their predominant symptom and they scored more than 4 on a visual analog scale (0-10). During the study, fatigue and depression were measured at day 0, 15, 30 and 60 using validated self report questionnaire (Fatigue Impact Scale and Beck Depression Inventory). The patients were randomized to receive ondansetron tablets 4 mg bid or placebo for one month followed by an additional four weeks observation.

 

Results:

The fatigue score was 85.4±28.2 and 98.2±26.9 in the ondansetron and placebo group respectively (NS). Ondansetron significantly reduced the fatigue score with 30% improvement at day 15 (57.1±38.9, p<0.01), day 30 (54.5±37.6, p<0.01) and day 60 (60.8±37.3, p<0.01) whereas placebo did not. Compared to placebo, ondansetron significantly reduced the fatigue score at day 15 (p=0.03) and day 60 (p=0.04), whereas the difference reached statistical significance at day 30 (p=0.1). Ondansetron also significantly reduced the depression scores.

 

Conclusions:

The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has a significant positive effect on fatigue in CHC as compared to placebo. These observations support the concept that fatigue involves serotoninergic pathways and may encourage the further evaluation of the efficacy of ondansetron on fatigue in chronic liver diseases.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 355

 

RECENT ALCOHOL USE BUT NOT PRIOR ALCOHOL USE INFLUENCES HEPATITIS C ANTIVIRAL TREATMENT ADHERENCE AND OUTCOMES: RESULTS OF A NATIONAL MULTICENTER STUDY

 Bhupinderjit S. Anand, Houston VAMC, Houston, TX; Sue L. Currie, San Francisco VAMC, San Francisco, CA; Edmund J. Bini, VA NY Harbor Healthcare System, New York, NY; Samuel B. Ho, Eric Dieperink, Minneapolis VAMC, Minneapolis, MN; Hui Shen, University of California - San Francisco, San Francisco, CA; Teresa L. Wright, San Francisco VAMC, San Francisco, CA; for the VA-HCV-001 Study Group.

 

Background:

·      HCV infection has been detected in a high proportion (16% to over 40%) of alcoholics with or without liver disease.

 

·      Several studies have shown higher rates of cirrhosis in HCV patients who abuse alcohol compared to non drinking subjects.

 

·      Patients with HCV infection who abuse alcohol have typically    been excluded from clinical trials assessing anti-viral therapy.

 

·      Therefore, treatment compliance and outcomes is poorly understood in this group.

 

Method:

To determine the impact of past and recent alcohol use on HCV treatment candidacy, adherence and outcomes.

 

·      Patients with a positive HCV RNA test who completed a detailed questionnaire on the alcohol use were included in a prospective study.

·      Based on the questionnaire the subjects were categorized as follows:

§      Category 1: no alcohol vs. regular alcohol use

§      Category 2: quantity of alcohol consumed (none, <6 drinks/day, ³6       drinks/day)

§      Category 3: Cage score <2 or ³2

§      Category 4: Recent alcohol use (within the past 12 months).

§      Category 5: Subjects subdivided based on alcohol use over past 12 months:   nondrinkers, £ 2 drinks/day and >2 drinks/day

·      Patients considered eligible for treatment received interferon plus ribavirin by standardized criteria.

 

Results I:

 

Subjects

§       A total of 4,061 were enrolled from 25 V. A. Medical Centers    nationwide. 

§       Of these, 986 (24%) were considered eligible for treatment and 726 (18%) were started on therapy. 

 

Demographics

§       Mean Age: 50.3 ± 7.6 yr. 

§       Male: females: 701 (96.6%): 25 (3.4%) 

§       Whites 452 (62.5%), Blacks 166 (22.9%). Latinos 78 (10.7%) 

§       Duration of the infection:  25.8 ± 8.6 years.  

§       Liver biopsy: advanced fibrosis (stage 3 and 4) seen in 37.3% patients.  

§       Genotype 1: 74.8%. 

 

There was no statistical difference between patients who were offered and accepted treatment and those who were offered and did not accept treatment with respect to any of the above demographic features.

 

Results II:

Treatment Candidacy and Alcohol Use (n = 4,061)

§       Alcohol use (past and with the past 12 months) consistently reduced treatment    candidacy as judged by all criteria of alcohol abuse (Table 1, Fig 1).

 

Table 1: Alcohol Use and HCV Treatment Candidacy (n = 4,061)

Study Group

# Screened

Candidate
for Tx (%)

p value

Recent and/or Past Alcohol Use:

 

 

 

Alcohol use vs Non-alcohol use

 

 

 

  • Non drinker


721


199 (28)


0.01

  • Drinker


3,340


787 (23)

 

Amount of alcohol consumed:

 

 

 

  • Non drinker

721

199 (28)

0.04

  • <6 drinks/day - 893

213 (24)

213 (24)

 

  • ≥ 6 drinks/day – 2,447

563 (23)

563 (23)

 

Cage score

 

 

 

  • < 2

1,681

452 (27)

0.0003

  • ≥ 2

2,380

523 (22)

 

Recent Alcohol Use:

 

 

 

  • None

2,575

685 (27)

0.0001

  • Within past 12 months

1,486

290 (20)

 

 

 

Alcohol Use and Response to Therapy

 

§       There was no difference in the end-of-treatment responses between the different groups  

§       The sustained virologic response was lower in recent alcohol     users    compared to non drinkers but the difference was not           significant.  

§       Recent alcohol users had a higher treatment discontinuation rate compared to non drinkers

 

Table 2: Effect of Alcohol Use on HCV Treatment ( n = 726)

Study Group

# Treated

ETR (%)

SVR (%)

Early
D/C (%)

Recent and/or Past Alcohol Use:

 

 

 

 

Drinker vs. Non-Drinker

 

 

 

 

  • Non drinker

142

45 (32)

29 (20)

38 (27)

  • Drinker

584

173 (30)

104 (18)

177 (30)

Amount of alcohol consumed:

 

 

 

 

Non drinker

142

45 (32)

29 (20)

38 (27)

  • <6 drinks/day

178

49 (27)

27 (15)

58 (33)

  • ≥ 6 drinks/day

406

124 (31)

77 (19)

119 (29)

Cage score

 

 

 

 

  • < 2

339

97 (29)

57 (17)

96 (28)

  • ≥ 2

387

121 (31)

76 (20)

119 (31)

Recent Alcohol Use:

 

 

 

 

  • None

532

164 (31)

105 (20)

137 (26)

  • Within past 12 months

194

54 (28)

28 (14) *

78 (40)**

Values in parentheses indicate (%) rounded off to the closest value. Chi-Square = 2.6; p = 0.06. Chi-Square = 14.2; p = 0.0002.

 

Alcohol use and treatment candidacy


Results IV:

 


Effect of Alcohol Dose in Recent Drinkers

 

§       Recent drinkers were divided into three groups: nondrinkers, moderate (social) drinkers (£2 drinks/day) and heavy drinkers (>2 drinks/day).

 

§       The end-of-treatment response showed no significant difference  between the three groups. 

 

§       Sustained virologic response showed a trend towards inferior outcome based on the dose of alcohol intake but the differences failed to reach statistical significance.

 

§       Treatment discontinuation rates were higher in drinkers vs. abstinent subjects

 

Results V:

Effect of Alcohol Dose in Recent Drinkers

§       The trend in favor of nondrinkers for the sustained virologic response disappeared when patients who discontinued             treatment early were excluded from analysis.

§       Table shows ETR and SVR for persons who completed treatment.

Conclusion:

 

 

 

 

Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 356

 

PROGNOSTIC SIGNIFICANCE OF POSITIVE TMA FOR HCV RNA WITH NEGATIVE PCR AFTER 24 WEEKS OF PEGINTERFERON AND RIBAVIRIN FOR CHRONIC HEPATITIS C

 

Jaydeep S. Kadam, Stevan A. Gonzalez, Nicole L. Taylor, Deborah N. Rovner, Ira M. Jacobson, Center for the Study of Hepatitis C and Weill Medical College of Cornell University, New York, NY.

 

Background:

The lower limit of detection of most polymerase chain reaction (PCR) assays for hepatitis C virus (HCV) RNA is 50-100 IU/mL. The transcription-mediated amplification (TMA) method has the capability to detect ≥ 5 IU/mL. Studies have suggested that with interferon and ribavirin therapy, a positive TMA at the end of treatment is strongly associated with relapse, but the significance of TMA with peginterferon and ribavirin combination therapy requires further study.

 

Aim:

To assess the predictive value of TMA in patients who are PCR negative after 24 weeks or more of peginterferon and ribavirin therapy.

 

Methods:

A chart review was conducted to identify patients who had a qualitative TMA (Bayer) in the setting of negative PCR (Roche Amplicor) at 24 weeks of treatment or later. Patients had between 1 and 6 TMA determinations. All patients continued treatment after the first TMA+ result and were followed for at least 3 months after cessation of therapy. Patients were divided into 2 groups: (1) PCR-/TMA- and (2) PCR-/TMA+. The groups were analyzed for end of treatment (EOT) response, sustained virologic response (SVR), breakthrough, and post-treatment relapse, as defined by PCR testing.

 

Results:

Overall, 36 patients were included in this study. Twenty-six patients were PCR-/TMA- and 10 patients were PCR-/TMA+ at 24 weeks of treatment or later. Twenty-one patients (58%) were followed to ≥ 6 months following cessation of therapy (longer-term data will be presented). The rates of PCR negativity at ≥ 3 months following cessation of treatment were 20/26 (77%) in PCR-/TMA- and 3/10 (30%) in PCR-/TMA+ patients (p = 0.009). Of those followed to ≥ 6 months, the rates of SVR were 13/14 (93%) in PCR-/TMA- and 2/7 (29%) in PCR-/TMA+ patients (p = 0.002). Patients who were PCR-/TMA- at 24 weeks or beyond were less likely to have breakthrough at EOT (0/26, 0%) compared with PCR-/TMA+ patients (5/10, 50%; p < 0.001). Rates of relapse following therapy were similar in PCR-/TMA- (6/26, 20%) and PCR-/TMA+ patients (2/10, 23%; p = 0.84). In the breakthough group, only one of five patients had a medication dose reduction prior to breakthrough.

 

Conclusions:

(1) Patients who are PCR-/TMA+ at 24 weeks of treatment or later have a decreased rate of SVR compared with PCR-/TMA- patients. (2) Continued therapy in the setting of PCR-/TMA+ is commonly associated with recurrent HCV RNA detectability by PCR. (3) When treatment is continued in PCR-/TMA+, breakthrough is more common than post-treatment relapse. (4) Further studies are required on the management of PCR-/TMA+ patients.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 357

 

BONE MINERAL DENSITY IS IMPROVED AFTER 48 WEEKS COMBINATION THERAPY WITH INTERFERON-α AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C

 Eduardo Redondo-Cerezo, Hospital General Virgen de la Luz., Cuenca, Spain; Jorge González-Calvín, Universidad de Granada, Granada., Spain; Rafael Martín-Vivaldi, Flor Nogueras, Hospital Universitario Virgen de las Nieves, Granada, Spain; Rosaura Fernández-Pascual, Universidad de Jaen., Jaen, Spain; Fernando Escobar, Universidad de Granada, Granada., Spain.

 

Introduction:

In a previous study, we found that patients with chronic hepatitis C had low bone mineral density (BMD) and a high prevalence of osteopenia. Our aim is to further haracterize the effect of treatment with interferon plus ribavirin on bone mass and bone turnover in these patients.

 

Patients and methods:

34 chronic hepatitis C naïve patients (serologically and histologically demonstrated) were enrolled (mean age 41 years; range 25-55; 24 male, mean age 42, range 27-55; 10 female, mean age 40, range 25-51). All of them had elevated serum ALT levels, and they met the current criteria for therapy.

With a prospective design, patients were studied on three occasions: Before treatment with interferonα (3 MU thrice a week) and ribavirin (1000-1200 mg/d) (basal), 24 weeks and 48 weeks after starting therapy. The following examinations were performed each time: BMD, measured by dual x-ray absorciometry at lumbar spine (LS) and femoral neck (FN) (results were expressed as z-score values). Analysis were made for biochemical liver function tests, serum bone Gla-protein (BGP), insulin-like growth factor I, insulin-like growth factor binding globulin type 3, 25-hidroxivitamin D (25OHD), intact parathyroid hormone, free testosterone index, and urinary deoxypyridinoline excretion (D-Pyr).

Multivariate analysis was performed with a multiple linear regression test. Values were expressed as mean±SD.

 

Results:

BMD values before treatment (LS:-0,93±1,21;FN:-0,18±0,91) were significantly lower than values obtained after 48 weeks (LS:-0,62±0,92,p<0,0001; FN:0,16±0,73,p<0,0001). After 48 weeks of treatment, we also observed a significant reduction as compared with basal levels for serum levels of transaminases (AST:57,81±16,63 U/L vs 22,92±6,76;p<0,0001;ALT:103,54±33,58 vs 24,73±9,95;p<0,0001), alkaline phosphatase (176,00±50,35 vs 149,15±50,24;p<0,009), BGP (2,39±1,10 ng/mL vs 1,59±1,05;p<0,003) and urinary D-Pyr (6,07±1,93 nM/mM vs 5,29±3,57; p<0,05). We found no differences for the rest of parameters between basal values and after 48 weeks of therapy. Positive correlations were found between: BMD in LS and 25OHD (r:0,45;p<0,04), BGP and D-Pyr (r:0,58;p<0,005), D-Pyr and total alkaline phosphatase (r:0.39;p<0,05).

Inverse correlations were found between: BMD-FN and serum ALT levels (r:-0.36;p<0,04), BMD-LS and serum BGP (r<-0,40;p<0,04).

 

Conclusions:

Our study shows that interferon-α and ribavirin therapy in patients with chronic hepatitis C improves BMD in both LS and FN, and seems to reduce the high bone turnover found in these patients before treatment.


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 358

 

TOTAL CLEARANCE (CL/F) OF RIBAVIRIN IS THE FACTOR MOST INFLUENCING THE INCIDENCE OF HEMOLYTIC ANEMIA DURING IFN PLUS RIBAVIRIN THERAPY

 Yoshiyasu Karino, Tomohiro Kato, Tomohiro Arakawa, Shinichiro Matsumoto, Yasuaki Kuwata, Jun Akaike, Katsu Yamazaki, Takumi Ohmura, Takahiro Sato, Jouji Toyota, Sapporo Kosei General Hospital, Sapporo, Japan.

 

Background and Aim:

A major side effect of IFN plus ribavirin combination therapy for chronic hepatitis C is ribavirin-induced hemolytic anemia that often leads to the discontinuation of therapy and then to treatment failure. Although the severity of anemia depends mainly on the patient’s renal function, no recommendations currently exist for renal function based dosing of ribavirin. The aim of study was to obtain data which may provide insight on the appropriate maintenance dose of ribavirin.

 

Methods:

Ninety-five patients with chronic hepatitis C (56 males and 39 females, mean age: 51.6 years) who received IFN alfa-2b and ribavirin combination therapy were included in the analysis. These patients received ribavirin at the dose of 600, 800, or 1000 mg/day based on body weight, and the dose was reduced by 200 mg/day or discontinued depending on the decrease of hemoglobin levels. Total clearance (CL/F) of ribavirin was calculated according to the method described by Karmar et al. (Amer. J. of Kidney Disease 43:140-146, 2004) as follows: CL/F(L/hr) = 32.3 x body weight x (1-0.0094 x age) x (1-0.42 x sex)/serum creatinine (sex: 0 for males and 1 for females). Serum ribavirin levels were determined at Week 1, 2, 4, and 8 of treatment. For the analysis of factors affecting the reduction in hemoglobin levels, the dose of ribavirin by body weight, baseline hemoglobin level, baseline platelet level, baseline serum ALT, and CL/F were examined in multivariate analysis.

 

Results:

Of the 95 patients, 17 (17.9%) had the dose of ribavirin reduced and 7 (7.4%) discontinued ribavirin administration. CL/F was distributed widely, ranging from 5.2 to 62.9 L/hr (mean: 15.1 L/hr). Correlation (reverse) between serum ribavirin levels and CL/F was significant only at Week 4. All patients 60 years old or older had CL/F of less than 15 L/hr. The results of multiple regression analysis indicated that baseline hemoglobin level was the factor contributing most to the discontinuation of combination therapy (p=0.070), and CL/F was the only significant factor (p=0.001) associated with the reduction in the ribavirin dose. In fact, only 3 of 38 (7.8%) patients with CL/F of 15 L/hr or more compared to 11 of 20 (55%) patients with CL/F of less than 10 L/hr required a reduction of the ribavirin dose. Additionally, in patients with CL/F of less than 15 L/hr, a greater magnitude of change in hemoglobin levels was observed at Week 1 in patients requiring dose reduction (0.34 g/dl) than in those who did not (-0.09 g/dl).

 

Conclusions:

CL/F of ribavirin is the factor most influencing the incidence of hemolytic anemia. This suggests that the dose of ribavirin should also be determined based on CL/F. The results also indicate that attention should be paid to early decrease in hemoglobin levels to avoid discontinuation of therapy.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 359

 

DYNAMICS OF HCV FREE-VIRION AND IMMUNE-COMPLEX DURING INTERFERON THERAPY WITH AND WITHOUT RIBAVIRIN IN GENOTYPE-1B CHRONIC HEPATITIS C

 Naoki Fujita, Masahiko Kaito, Masaki Takeo, Ryusuke Sugimoto, Shinichiro Horiike, Hideaki Tanaka, Masayoshi Konishi, Mie University School of Medicine, Mie, Japan; Shozo Watanabe, Mie University, Mie, Japan; Yukihiko Adachi, Mie University School of Medicine, Mie, Japan.

 

Background:

Combination therapy of interferon (IFN) plus ribavirin for patients with chronic hepatitis C appears to be more effective than IFN alone and sustained virological responses (SVR) are substantially enhanced, but the mechanism(s) of this synergistic effect are currently unknown. We have previously reported that HCV circulated in infected hosts in various forms: free-virion (FV), nucleocapsid, and immune-complex (IC) with immunoglobulin and the serum dynamics patterns were different between FV- and IC-HCV RNA after initiation of IFN monotherapy (J Hepatol 2003;39:1013-1019).

 

Aim:

To analyze and compare FV- and IC-HCV dynamics during IFN alone and in combination with ribavirin and their relationships with treatment response in patients infected with HCV genotype-1b.

 

Methods:

Twenty-six patients [12 males and 14 females, mean age 50.3 (range 33-66) years] were treated with IFN-alfa 2b (6 MU daily for initial 2 weeks, followed by 6 MU 3 times a week for further 22 weeks) with (n = 15) or without (n = 11) ribavirin (600 or 800 mg/day). Only patients infected with genotype-1b were studied because viral kinetics is genotype dependent. Serial serum samples were obtained at 0, 3, 6, 9, and 12 hours, then 1, 2, 7, 14, and 28 days after the start of the therapy. Serum FV- and IC-HCV RNA were separated by immunoprecipitation using anti-human immunoglobulin and quantified using a highly sensitive real-time detection PCR (TaqMan). Mathematical modeling was employed to determine the patterns of viral kinetics during treatment.

 

Results:

At the 1st phase (days 0 to 2), the decline of FV- and IC-HCV RNA was similar between the two treatment groups. At the 2nd phase (days 2 to 28), the decline of IC was significantly faster in patients treated with IFN plus ribavirin compared with IFN alone (exponential decay slope = 0.079 +/- 0.036 vs. 0.048 +/- 0.027 log10/day, P = 0.0248; half-life = 81.1 +/- 21.4 vs. 135.1 +/- 61.4 hours, P = 0.0053), although the 2nd phase FV-decline was not significantly different between the 2 treatment groups. When the clinical variables were compared between the SVR (n = 6) and non-SVR (n = 9) patients in the combination therapy group, IC-decline at the 2nd phase were significantly faster in SVR patients than in non-SVR patients (exponential decay slope = 0.109 +/- 0.034 vs. 0.057 +/- 0.018 log10/day, P = 0.0067; half-life = 69.1 +/- 2.29 vs. 90.2 +/- 25.0 h, P = 0.0019).

 

Conclusions:

These results suggest that adding ribavirin to IFN act mainly on the IC-HCV at the 2nd phase, implying that ribavirin may modulate humoral immune response against HCV and lead a favorable response to IFN. Analysis of IC-HCV dynamics is useful for predicting the response to therapy and for understanding the mechanism of action of antiviral drugs in chronic hepatitis C patients.


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 361

 

PERMANENT HEARING LOSS IN PATIENTS TREATED WITH STANDARD AND PEGYLATED FORMS OF INTERFERON: A REVIEW OF THE FDA’S ADVERSE EVENT REPORTING SYSTEM (AERS)

 Russell Fleischer, Melissa Truffa, Food and Drug Administration, Rockville, MD.

 

Background:

Cases of transient and permanent sensorineural hearing loss in HCV-infected patients temporally related to treatment with standard and more recently pegylated forms of interferon (IFN, Peg-IFN) with or without ribavirin (RBV) have been reported. These events may be related to a direct ototoxic effect caused by IFN, autoimmunity, microvascular pathology, or an effect of the HCV virus itself. It is not clear whether individual reports represent rare associations or an important pattern of drug toxicity.

 

Methods:

The FDA Adverse Event Reporting System (AERS) was searched using the MedDRA grouping terms of Hearing Disorders NEC and Hearing Losses for reports of hearing loss associated with IFN or Peg-IFN+RBV.

 

Results:

We identified 110 unduplicated cases of hearing loss in patients receiving IFN or Peg-IFN+RBV for the treatment of HCV from 1993 to 2004; 66 with standard IFN and 44 with Peg-IFN; of those, 78 were in combination with RBV. Sixty-six were male, 39 female and 5 unknown with a mean age of 49 years (range, 29-72). 50 cases were from the US and 60 were non-US cases. Mean duration of therapy was 5 months (range, 1 day to 20 months). Unilateral hearing loss was reported in 43 cases and bilateral hearing loss was reported in 20 cases. Eleven patients had a previous history of hearing loss. Of the 110 patients, 29 reported some degree of permanent hearing loss following cessation of HCV therapy; of these 17 prematurely discontinued HCV therapy, 6 completed their course of HCV therapy, and 6 are unknown.

 

Conclusions:

 Although this retrospective analysis was based on spontaneously reported AEs with known limitations for determining causal relationships, these data suggest that non-reversible hearing loss may potentially be an important adverse event related to interferon-based anti-HCV therapy. Thus, the benefit to continued treatment should be balanced against the potential risk that any deficit in hearing may be permanent.


Topic: Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 362

 

EFFICACY OF IRON DEPLETION AND ANTIVIRAL THERAPY IN PATIENTS WITH PORPHYRIA CUTANEA TARDA (PCT) AND HEPATITIS C VIRUS (HCV) CHRONIC INFECTION

 Angelo Rossini Sr., Giovanni Battista Contessi Sr., Hepatology Unit, Brescia, Italy; Carla Leali Sr., Dermatology Unit, Brescia, Italy; Francesco Bozzetti, Hepatology Unit, Brescia, Italy; Elisabetta Cariani Sr., III Laboratory, Brescia, Italy.

 

Background/Aims:
Porphyria Cutanea Tarda (PCT) in our geographic area is frequently associated with hepatitis C virus (HCV) chronic infection and with hepatic iron overload. The aim of this study was to analyze if iron depletion may improve the rate of response to antiviral therapy.

 

Methods:

Twenty patients (19 male and 1 female; mean age 55.05±7.03 years) with PCT and histologically proven HCV chronic hepatitis were randomized to undergo (Group 1) or not (Group 2) phlebotomy for iron depletion before antiviral therapy. Patients in Group 1 received 450 ml phlebotomy every two weeks (mean 10.8 sessions, range 6-15) until iron deficiency was achieved as defined by two of three criteria: ferritin <10 ng/mL, transferrin saturation <20%, haemoglobin ≤ 11.5 g/dL. Patients in Group 1 (9 males and 1 female, mean age 51±2.1 years, range 36-57) had mean urinary porphyrin level 2106.7 ± 1870 μg/L (range 204-5263), and mean serum ferritin level 549 ± 374.9 ng/mL. All patients in Group 1 were infected by genotype 1b. Patients in Group 2 (10 males, mean age 59 ± 4.8 years, range 51 - 67) had mean urinary porphyrin level 1182 ± 1280 μg/L (range 177-4392), and mean serum ferritin level 690±352 ng/mL. Eight patients were infected by genotype 1b and 2 by genotype 2a. All patients received pegylated interferon plus ribavirin according to the body weight. The patients in Group 1 started antiviral therapy 3 months after the end of iron depletion.

 

Results:

In Group 1 basal porphyrin level (2106.7± 1870 microg/L) decreased after iron depletion to 518.4±370.8 microg/L (p<0.05). Baseline ALT levels (118±44.4 IU/L) dropped to 65.3 ± 26.8 IU/L (p<0.02), and GGT levels decreased from 112.9±35.7 IU/L to 71.1±31 IU/L (p<0.02) after iron depletion. Viral load was similar before (median 6.4, range 5.9-6.9 log copies/ml) and after (median 6.5, range 5.7-6.7) iron depletion. After iron depletion, one patient had porphyrin and GGT levels within the normal range, one patient had normal GGT and one normal ALT.

In no case interferon or ribavirin dosage had to be reduced. Sustained virological response was obtained in 3 (15%) of the 20 patients treated, 2 in group 1 and 1 in group 2, 1 patient in Group 1 showed a virological relapse three months after the end of therapy. All responder patients were infected by genotype 1b.

 

Conclusions:

1) Iron depletion in patients with PCT and chronic HCV infection has a favourable effect both on the metabolic defect and on liver enzyme levels. 2) The observation of similar viral titer before and after phlebotomy suggests that iron depletion does not affect significantly the rate of viral replication. 3) The rate of sustained response to antiviral teraphy is low in patients with PCT and HCV chronic hepatitis 4) Iron depletion doesn’t seem to improve the rate of response in these patients.

 


Topic:  Peg-Intron

  Presentation Time: 10/30/2004 5:30:00 PM                     Program#/Poster#: 365

 

EFFICACY AND SAFETY OF LOW DOSES OF INTERFERON (IFN) ALFA-2B PLUS RIBAVIRIN (RBV) IN ADVANCED HCV RELATED LIVER DISEASE

LUIGI ROFFI, Ospedale Civile, Sondrio, Italy; Guido Colloredo, Policlinico Ponte San Pietro, Ponte San Pietro (BG), Italy; Paolo Del Poggio, Ospedale di Treviglio, Treviglio, Italy; Giovanni Fornaciari, Elisabetta Castagnetti, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Roberto Ceriani, Ospedale Humanitas, Rozzano (MI), Italy; Renato Marin, Ospedale di Dolo, Dolo (VE), Italy; Massimo Pozzi, Alessandro Redaelli, Ospedale San Gerardo, Monza (MI), Italy; Giuliano Ramella, Ospedale Civile, Castiglione delle Stiviere (MN), Italy; Valentina Bellia, Pierpaolo Parravicini, Ospedale Civile, Sondrio, Italy; Sergio Casati, Chiara Corradi, Ospedale Sant’Anna, Como, Italy; Riccardo Bottelli, Ospedale di Angera, Angera (VA), Italy; Angelo Rossini, Spedali Civili, Brescia, Italy; Pietro Pioltelli, Ospedale San Gerardo, Monza (MI), Italy; Giorgio Bellati, Ospedale Sant’Anna, Como, Italy.

 

Introduction:

The efficacy of IFN plus RBV in chronic hepatitis C (CHC) has been evaluated in many clinical trials, genotype 1 and cirrhosis being the main independent prognostic factors of poor sustained response (SR). Long-term therapy and high doses of IFN/RBV have been used to reduce treatment failure. Unfortunately this therapeutic schedule accounts for a high rate of side effects leading to dropout and it is a limit for a widespread use in advanced liver disease.

 

Aims:

To evaluate the rate of virological End-of-Treatment (ETR) and SR in patients with advanced CHC treated with low doses of IFN alpha 2b plus RBV and the safety and tolerability of this therapeutic schedule.

 

Methods:

91 patients, 64 males, mean age 54 years (range 18 – 65) were consecutively enrolled in 11 hospitals and randomized in two groups.

·      Group A (55 patients, 31 genotype 1), induction phase: pegylated alpha IFN 100 mg once a week for 4 weeks followed by a maintenance phase with 50 mg once a week for up to 24 weeks plus RBV 800 mg daily. In patients with virological response, the maintenance phase continued for additional 6 months.

·      Group B (36 patients, 29 genotype 1), rIFNa2b 3MU three times a week plus RBV 800 mg daily for 24 weeks. In patients with virological response, the maintenance phase continued for additional 6 months.

 

Inclusion criteria:

CHC patients with liver biopsy performed within 12 months prior to entry to this protocol with a pathology report confirming a histological diagnosis of advanced disease: stage > 4 sec. Ishak; stage > 3 sec Knodell. Compensated liver disease with the following minimum biochemical criteria: Hemoglobin ³ 13 g/dL for males, ³ 12 g/dL for females, WBC > 3,000/mm3, Granulocyte > 1,500/mm3 , platelets > 80,000/mm3 , bilirubin within normal limits. Results were analyzed for intention to treat and by multivariate logistic regression analysis for factors influencing the response.

 

Results:

11 patients dropped out for side effects (6 in group A and 5 in group B). 19 patients reduced RBV doses for hematological toxicity. 50 (55%) of patients achieved virological ETR and 42 (46%) SR at 48 weeks after stopping therapy. Age, sex, HCV genotype, weight, type of treatment and RBV reduction was examined by logistic regression analysis. The SR was influenced only by age and genotype.

 

Conclusions

Low IFN doses, either recombinant or PEG, plus RBV are quite effective and safe in the treatment of patients with HCV related advanced liver disease.


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                        Program#/Poster#: 366

 

PEGINTERFERON-ALPHA2B AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS C GENOTYPE 4: IMPACT OF TREATMENT DURATION ON SUSTAINED VIROLOGIC RESPONSE

 Sanaa M. Kamal, Harvard Institutes of Medicine, Boston, MA; Ahmed El Tawil, Ain Shams University, Ain Shams Unversity, Ecuador; Qi He, Harvard Institutes of Medicine, Boston, MA; Khalifa El Sayed, Amr Hafez, Ain Shams University, Ain Shams Unversity, Egypt; Margaret James Koziel, Harvard Institutes of Medicine, Boston, MA; Alaa Ismail, Ain Shams University, Ain Shams Unversity, Ecuador; Jens Rasenack, University of Freiburg, Freiburg, Germany; Mohamed Ali Madwar, Ain Shams University, Ain Shams Unversity, Egypt.

 

Introduction:

Pegylated interferons have recently replaced conventional interferon for treatment of chronic hepatitis C due to their high efficacy in inducing sustained virological response.

 

Objective:

This randomized, parallel-group, double-blind trial is designed to assess the efficacy and safety of 24, 36 or 48 weeks of treatment with peginterferon-alpha2b in chronic hepatitis C genotype 4.

 

Patients and Methods

287 patients with chronic hepatitis C genotype 4 matched for age, gender, duration and stage of liver disease at enrollment were randomly assigned to receive peginterferon alfa-2b ( 1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight) for 24 (Group A: n=95), 36 (Group B=96) or 48 weeks (Group C: n=96). Liver functions, HCV-RNA titers and viral kinetics were evaluated before, during and after therapy. Liver biopsies and histopathological evaluation are performed before therapy induction and at end of follow-up. The primary treatment endpoint is to achieve sustained virologic response marked by undetectable HCV RNA concentration at the end of 24 weeks of follow-up after cessation of therapy. Secondary end-points are end of treatment virological responses and histological response.

 

Results:

Reported sustained virological response rates:

·      24 weeks – 29% (p=0.05)

·      36 weeks – 66% (p=0.02)

·      48 weeks – 69% (p=0.001)

Summary:

·      Significantly higher SVR rates were achieved with the 36- or 48-week schedules (66% and 69%, respectively) compared with the 24 week schedule (29%)

·      SVR rates were not significantly different between the 36- and 48-week regimens.

·      Treatment duration appears to be crucial in maintaining EVR and achieving SVR, and it should be at least 36 weeks with Peg IFNa-2b.

·      Histological improvement in HCV-4 was related t longer duration of therapy.

·      Viral kinetics of HCV-4 were more rapid for those reported in the literature for HCV-1 patients treated with Peg-IFNa-2b, but relatively slower than HCV-2 and HCV-3.

·      Peg-IFNa-2b plus ribavirin for 36 weeks was better tolerated than 48 weeks and induced reasonable SVR and histological response.

 

Conclusion:

·      Chronic HCV-4 responds favorably to Peg-IFNa-2b plus ribavirin

·      The 48- and 36- week treatment regimens were statistically superior to 24 weeks so the mandated treatment of HCV-4 patients is at least 36 weeks or more

·      We observed good tolerance to the 36-week regimen for HCV-4 and similar SVR rates to the 48-week regimen.  This may have important clinical implications for:

§       Increased adherence to therapy

§       Decreased adverse events

§       Increased cost effectiveness


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 367

 

PEG-IFN α2B 1.0 μG/KG/WK + RIBAVIRIN IS EQUALLY EFFECTIVE AS PEG-IFN α2B 1.5 μG/KG/WK + RIBAVIRIN: PRELIMINARY SVR RESULTS FROM A PROSPECTIVE, RANDOMIZED, CONTROLLED MULTI-CENTER TRIAL

 Steven L. Flamm, Northwestern University Medical School, Chicago, IL; Jeffrey Goldman, Gastro. Assoc. of Olympia Fields, Hazel Crest, IL; Joel Cahan, Consultants in Gastro., Munster, IN; Gregory Nelligan, Rockford Clinic, Rockford, IL; David Chua, Summit Dig. and Liv. Dis. Specialists, Oakbrook Terrace, IL; Bradley Shapiro, Northwest Healthcare, Hoffman Estates, IL; Muhammad Bawani, Gastroenterologists, Ltd., Libertyville, IL; Rockford Yapp, Digestive Health Services, SC, Downers Grove, IL; Edward Jurkovic, Digestive Dis. Consultants, Kankakee, IL; Robert Brown, Columbia University Medical Center, New York, NY; Sarah Skahen, Tina Jackson, Northwestern University Medical School, Chicago, IL.

 

Background:

PEG-IFN α2b (1.5 mcg/kg/wk) + ribavirin (800mg/d) is effective for patients with chronic hepatitis C virus (HCV). The medications have many side effects and frequently require dose reduction or discontinuation. Data comparing PEG-IFN α 2b (1.0 mcg/kg/wk) monotherapy yield equivalent SVR in comparison to PEG-IFN α 2b (1.5 mcg/kg/wk) monotherapy. SVR and tolerability of PEG-IFN α2b (1.0 mcg/kg/wk) + ribavirin are unknown.

 

Aim:

We sought to determine the efficacy and tolerability of PEG-IFN α 2b [1.0 mcg/kg/wk vs 1.5 mcg/kg/wk] in combination with ribavirin. We speculate that lower dose PEG-IFN α 2b may be equally effective as the standard dose. Methods: Patients with chronic HCV (+ HCV RNA) were evaluated within the context of a prospective, randomized, controlled, multi-center trial comparing PEG-IFNα2b (1.0 mcg/kg/wk) [LD] + ribavirin (800-1400mg/d) vs. PEG-IFN α2b (1.5 mcg/kg/wk) [SD] + ribavirin (800-1400mg/d). Demographic, serological (ALT), virological (HCV RNA level and genotype) and histological data were obtained. Medications were administered for 24 WKS (HCV GT 2/3) or 48 WKS (HCV GT 1). Tolerability (side effect profile and drop out rate) was determined. Preliminary ETR and SVR data are reported.

 

Results:

281 patients have been enrolled and received at least one dose of medication. 272 patients (141 in LD and 131 in the SD) have received the medications for at least 48 WKS. 91/141 (65%) in LD are GT1 in comparison to 102/131 (78%) in SD. There are no significant differences between the groups at baseline. 72/141 (51%) in LD are HCV RNA - at WK 48 [38/94 (40%) GT 1 and 34/47 (72%) GT 2/3] in comparison to 70/131 (53%) in SD [47/102 (46%) GT 1 and 23/29 (79%) GT 2/3]. 223 patients have reached F/U WK 24. There are no significant differences in SVR between the LD 46/119 (39%) and SD 46/104 (44%) and none within genotype [LD GT 1 22/78 (28%), SD GT 1 28/80 (35%), LD GT 2/3 24/41 (59%), SD GT 2/3 18/24 (75%). 32/141 (23%) in LD discontinued the regimen prior to WK 48 in comparison to 25/131 (19%) in SD. There is no difference in adverse events in LD (159) in comparison to SD (168).

 

Conclusion:

  1. PEG-IFN α2b (1.0 mcg/kg/wk) + ribavirin are equally as effective as PEG-IFN α2b (1.5 mcg/kg/wk) + ribavirin in regards to ETR and SVR. This is true in GT 1 and GT non-1 patients.
  2. Medication discontinuations were equal between the two groups.

Topic:  Interferon Based Therapies

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 368

 

EFFECT OF SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON PLUS RIBAVIRIN ON THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HCV CIRRHOTIC PATIENTS

Hugo Cheinquer, UFRGS and FFFCMPA, Porto Alegre, RS, Brazil; Nelson Cheinquer, Silvia Coelho-Borges, Christina Schmitt Juruena, Decio Sampaio Peres, Fernando Wolff, UFRGS, Porto Alegre, RS, Brazil.

 

Background/Aim:

There is evidence of decreased incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C treated with interferon (IFN). However, there is a lack of reports considering this endpoint in HCV patients treated with IFN plus ribavirin (RBV). The aim of this study was to compare the rate of HCC among HCV cirrhotic patients treated with IFN + RBV in relation to sustained virological response (SVR) status.

 

Methods:

In this retrospective cohort study, 86 biopsy proven cirrhotic patients with HCV infection, without any other form of liver disease, were treated with IFN (conventional or pegylated) + RBV for at least 24 weeks (genotype 2,3) or 48 weeks (genotype 1). Treatment was stopped in all patients with positive HCV-RNA at week 24. Only those treated with >80% of the expected medication dosage were included. Of the 86 patients, 22 (26%) received more than one course of treatment. At baseline all patients were Child-Pugh A with no previous history of hepatic decompensation and no evidence of HCC on abdominal ultrasound (US). SVR was defined as negative HCV-RNA 24 weeks after end of treatment measured by qualitative PCR with a limit of detection of 50 IU/ml. Only patients followed every 6 months with US for more than 12 months after the end of the last course of therapy were included. HCC was diagnosed by liver biopsy and/or coincident findings of focal lesion >2 cm on US and spiral CT with arterial hypervascularization. The protocol was approved by the Institution Ethics Comittee. All patients signed informed consent. Statistical analysis was based on Fisher’s Exact Test and Kruskall-Wallis (alpha<0.05).

 

Results:

There were 42 (49%) SVR and 44 (51%) non-SVR. Mean follow-up was 33.6 ± 20.2 months (range:12-84 months) in SVR versus 26.4 ± 16.3 months (range:12-84 months) in non-SVR (P=0.07). During follow-up, no SVR and 3 non-SVR patients underwent OLT, 2 of them with HCC. Of the 42 patients with SVR, HCC was diagnosed in 1 (2.4%) versus 7 (15.9%) of 44 without SVR (P=0.03; RR:0.86, 95% CI: 0.75-0.99). Baseline characteristics among SVR versus non-SVR patients were the following, respectively: age 51.6 ± 8.7 years versus 52.8 ± 10.6 years (P=0.58); male sex 59.5% versus 61.4% (P=0.52); mean ALT 4.2 ± 2.4 xULN versus 3.6 ± 2.3 xULN (P=0.28); genotype 1 16.7% versus 40.5% (P=0.04); estimated disease time from exposure to last treatment course was 22.9 ± 7 years versus 22.5 ± 6.6 years (P=0.82).

 

Conclusion:

Among an homogeneous group of HCV cirrhotics treated with IFN + RBV we have found a lower incidence of HCC in patients who achieved SVR. This finding may indicate that either eradication of HCV by itself confers relative protection against HCC, or that SVR functions as a surrogate marker to identify cirrhotics with a low probability of HCC development.


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM           Program#/Poster#: 369

 

EFFECTS OF PEG-IFN-α2A (40KD) DOSE REDUCTION, RIBAVIRIN DOSE REDUCTION AND RIBAVIRIN INTERRUPTION ON HEPATITIS C VIRAL KINETICS AND ITS CORRELATION TO SVR IN THE DITTO-HCV STUDY

 Harel Dahari, Yonit Homburger, Bar-Ilan University, Ramat-Gan, Israel; Elke Verheij-Hart, Erasmus Medical Center, Rotterdam, Netherlands; Michael von Wagner, Saarland University Hospital, Homburg/Saar, Germany; Ioannis Goulis, Aristotle University of Thessaloniki, Thessaloniki, Greece; Yoav Lurie, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel; Gabriele Missale, Azienda Ospedaliera di Parma, Parma, Italy; Jan-Maarten Vrolijk, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Juan I. Esteban, Hospital General Vall d’Hebron, Barcelona, Spain; Cristophe Hezode, Hopital Henri Mondor – Universite Paris XII, Creteil, France; Martin Lagging, University of Goeteborg, Goetoborg, Sweden; Francesco Negro, Hospital University of Geneve, Geneve, Switzerland; Alexandre Soulier, Hopital Henri Mondor – Universite Paris XII, Creteil, France; Carlo Ferrari, Azienda Ospedaliera di Parma, Parma, Italy; Solko W. Schalm, University Hospital Rotterdam Dijkzigt, Rotterdam, Netherlands; Jean-Michel Pawlotsky, Hopital Henri Mondor – Universite Paris XII, Creteil, France; Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Avidan U. Neumann, Bar-Ilan University, Ramat-Gan, Israel; for the DITTO-HCV group.

 

Background:

Combination therapy with pegIFN alfa and ribavirin achieves sustained virologic response rates (SVR) of 54-61% in patients with chronic hepatitis C. It has been shown that SVR rates vary as function of compliance to protocol and early viral decline.

 

Objectives:

Verify if interruption or dose reduction of ribavirin (RBV) (1000-1200 mg qd) or peginterferon alfa-2a (40KD) (PEG-IFN) (180 μg qw) is related to viral breakthrough or to blips in viremia during treatment, and how it affects SVR.

 

Methods:

A number of comparator sub-groups were selected based on dosage of PEG-IFN or RBV and early viral kinetics out of the 270 patients studied. Patients with early rapid viral response (RVR) and full dose of both drugs for 48 weeks (N=28 gen 1, N=15 gen 2-3); RVR patients who only discontinued RBV per protocol at 6 weeks (N=18 gen 1, N=10 gen 2-3); patients who had only dose reduction of RBV to 600-800 mg qd (N=10 gen 1, N=4 gen 2-3); patients who had only dose reduction of PEG-IFN to 135, 90 or 45 ug qw (N=10 gen 1, N=5 gen 2-3). HCV RNA (Cobas Amplicor v2, Roche) was measured frequently in the first month, every 2 weeks until week 12 and every 6 weeks until week 48. Viral breakthrough (VB) during treatment was defined as positive RNA for at least 2 consecutive visits. Viral blips during treatment were defined as 1 time increase in viremia from negative to positive. Fisher’s exact test was used for testing statistical significance (P<0.05).

 

Results:

Among gen 2-3 patients there was no effect of RBV interruption or RBV dose reduction, as well as reduction of PEG-IFN to doses down to 90 ug qw on VB, blips, relapse or SVR rates.

Among gen 1 RVR patients who interrupted RBV at 6 weeks there was no increase compared to the RVR full dose group in blips (16% vs 28%) or VB (5% vs 4%). However, relapse rate was significantly higher for patients who interrupted RBV resulting in lower SVR rates (65% vs 93%, P<0.04).

Among genotype 1 patients who reduced RBV dose there was no increase compared to the RVR full dose group in blips (20% vs 26%) or VB (0% vs 5%). Relapse rates in RVR patients did not increase with RBV dose reduction.

The 3 gen 1 patients who reduced PEG-IFN dose to 45 ug had a resulting viral breakthrough and no SVR. Those who reduced dose to 90 ug or higher had shown no increased viral blips (30% vs 26%) or VB (0% vs 5%). Relapse rates in RVR patients did not increase with PEG-IFN dose reduction.

 

Conclusion:

In rapid viral responders, RBV interruption or dose reduction, as well as PEG-IFN reduction down to 90 ug, does not affect viral kinetics within the limitations of detection level of 50 IU/ml. Relapse rate of rapid viral responders is increased when RBV is completely interrupted but not when RBV or PEG-IFN dose is reduced by half.


Topic:  HIV/HCV Coinfection  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 372

 

SAFETY AND EFFICACY OF PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) PLUS RIBAVIRIN (COPEGUS®) IN HIV-HCV CO-INFECTED PATIENTS WITH CIRRHOSIS/BRIDGING FIBROSIS: RESULTS OF THE AIDS PEGASYS RIBAVIRIN INTERNATIONAL CO-INFECTION TRIAL (APRICOT)

Joe Sasadeusz, Alfred Hospital, Melbourne, Victoria, Australia; E Godofsky, Bach & Godofsky, Bradenton, FL; Richard Sterling, Virginia Commonwealth University Health System, Richmond, VA; Bonaventura Clotet, Hospital Universitari Germans Trias i Pujo, Barcelona, Spain; Vincente Soriano, Calle Nueva Zelanda, Madrid, Spain; Armin Rieger, AKH Wien, Vienna, Austria; Francesca Torriani, UCSD Treatment Center, San Diego, CA; Jean DePamphilis, F. Hoffmann-La Roche Ltd, Nutley, NJ.

 

Background:  

Effective HCV treatment is urgently needed for HIV-HCV co-infected patients. In this population, Pegasys plus Copegus produced higher overall sustained virological response (SVR) rates than in patients randomized to conventional interferon/ribavirin or Pegasys monotherapy (40% vs. 12% and 20%, respectively, p < 0.001). However, the safety of combination therapy in coinfected patients with advanced fibrosis remains unclear. We investigated the efficacy and safety of Pegasys plus Copegus in patients with cirrhosis or bridging fibrosis enrolled in this trial.

 

Methods:

Eligible HIV-HCV co-infected patients were naïve to interferon and ribavirin, had detectable HCV RNA (>600 IU/mL), elevated ALT levels, compensated liver disease and stable HIV disease. Cirrhosis/bridging fibrosis was determined by local pathologists at each site (Ishak modified Histological Activity Index) based on a biopsy obtained ≤15 months prior to treatment. Data from patients treated for 48 weeks with Pegasys 180 μg/wk and Copegus 800 mg/d, are included in this analysis. SVR was defined as undetectable HCV RNA (<50 IU/mL) at the end of follow-up (week 72).

 

Results:

Among patients with cirrhosis 13/44 (30%) treated with Pegasys plus Copegus, 9/45 (20%) treated with Pegasys monotherapy and 5/45 (11%) treated with interferon/ribavirin had SVRs. These results are generally consistent with those in the overall patient population. There was no difference in the incidence of death or hepatic decompensation between the three treatment groups. Five patients with cirrhosis experienced hepatic decompensation during treatment with Pegasys plus Copegus. Two of three deaths in cirrhotic patients were due to hepatic decompensation. These individuals had evidence of advanced liver disease at baseline (Child Pugh ≥6).

 

Conclusion:

Peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus) was generally well tolerated in HIV-HCV coinfected patients with compensated cirrhosis or bridging fibrosis.  However, because of the potential for rapid progression of liver disease in this subgroup, HIV-HCV coinfected patients with advanced fibrosis should be carefully evaluated before initiating treatment and carefully monitored during treatment with interferon-based therapies.  Didanosine should be avoided in patients with advanced liver disease, particularly when alternative antiretroviral treatment options are available.

 

Peginterferon alfa-2a (40KD) plus ribavirin produced an SVR rate of 30% in cirrhotic patients, which, although somewhat lower than that in the overall treatment group (40%), demonstrates that eradicative treatment for HCV has a favorable benefit-top-risk ratio in this important subgroup. 

 


Topic:  HIV/HCV Coinfection – Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                               Program#/Poster#: 374

 

ACUTE HCV IN A COHORT OF HIV-POSITIVE MEN - OUTCOMES AND RESPONSE TO PEGYLATED INTERFERON-ALPHA 2B AND RIBAVIRIN

Mark Danta, Chris Hui, Gabrielle Slapak, Geoff Dusheiko, Margaret Johnson, Sanjay Bhagani, Royal Free Hospital, London, United Kingdom.

 

Background:

An epidemic of acute HCV has recently been recognised amongst HIV-positive men in London. We describe their virological outcomes and initial response to early treatment.

Treatment protocol: All patients with a persistently positive HCV RNA by RT-PCR twelve weeks after presentation were offered PegIFN-alpha 2b (1.5 µg/kg) and ribavirin (>10.6 mg/kg) for 48 weeks.

 

Results:

Since October 2002, 36 cases of acute HCV have been identified (mean age 30.5 years, median CD4 514 cells/µl). 17 were on HAART. Genotype 1 infection was noted in 21(58%), genotype 3 in 7 (19%), genotype 4 in 4 (11%) and 4 were un-typable. 9 (25%) have spontaneously cleared HCV. Treatment has been started in 16 patients (median CD4 514 cells/µl, median HCV viral load (vl) 5.86 logs, 12 genotype 1, 3 genotype 3, 1 genotype 4). At week 12, of the 15 patients evaluated, 11 (73%) have achieved an early virological response (HCV vl <50 iu/l or > 2 log decrease), 2 are non-responders, 1 has stopped therapy due to intolerance and 1 patient has been lost to follow-up. Of the 9 patients followed through to week 24, 6 (66%) have an undetectable HCV-RNA, 2 remain non-responders and 1 stopped. 2 patients stopped therapy between 24-48 weeks and remain undetectable. At week 48, 3 patients have achieved end of therapy response and 2 are non-responders.

 

Conclusions:

Spontaneous clearance of HCV is possible despite HIV co-infection. Initial results suggest a favourable response to early treatment despite unfavourable genotypes and high HCV viral loads.


Topic:  HIV/HCV Coinfection – Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 376

 

BODY COMPOSITION AND METABOLIC EFFECTS OF ANTIVIRAL TREATMENT OF HEPATITIS C INFECTION

 Irina Kaplounov, Ellen S. Engelson, St. Luke's-Roosevelt Hospital, New York, NY; Safak Reka, SUNY Downstate Hospital Center, Brooklyn, NY; Donald P. Kotler, St. Luke's-Roosevelt Hospital, New York, NY.

 

Background:

Previous studies have documented body composition and metabolic alterations in chronic hepatitis C infection, in the presence or absence of HIV co-infection, but have not systematically looked at the response to therapy with Interferon and Ribavirin.

Methods:

We examined the effects of 3 months of pegylated interferon + ribavirin on body weight, body composition, glucose metabolism and lipid metabolism in 9 mono-infected (4 female) and 9 co-infected (3 female) subjects, and examined the influence of HIV status and the relationship to HCV antiviral effects. Measurements at baseline and after 12 weeks of therapy included body composition by anthropometry and BIA, fasting glucose and insulin plus calculation of HOMA and QUICKI indices, fasting triglycerides, cholesterol, and HDL, and HCV RNA.

 

Results:

Mean body weight fell by 2.7 kg (p<0.001), with a significant loss of 2.1 kg fat (p<0.001) but not fat-free mass. Waist (p<0.05) and hip circumferences (p<0.005) fell, while mean waist-to-hip ratio was unchanged. Subjects became less insulin resistant (mean HOMA 8.7 vs. 6.1, p<0.05). Total cholesterol (183 vs. 163 mg/dl, p<0.05) and HDL (40 vs. 30 mg/dl, p=0.005) concentrations fell, while LDL cholesterol and triglycerides did not change. Therapy was also associated with increased serum soluble TNF receptors I (1187 to 1680 pg/ml) and II (3941 to 5263 pg/ml), both p<0.001. The changes were quantitatively similar in mono-infected and co-infected subjects. Fourteen of the 18 subjects had a >2 log decrease in plasma HCV RNA content. The nutritional and metabolic changes were similar in patients who did and did not have a viral response, except responders lost significantly more fat than non-responders (1.8 kg vs. 0.3 kg, p<0.01).

 

Summary:

Therapy with interferon and ribavirin promotes lipoatrophy and dyslipidemia, but decreases insulin resistance. These alterations are not affected by HIV serostatus.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 377

 

PRELIMINARY ANALYSIS OF THE EFFECT OF INSULIN RESISTANCE UPON TREATMENT RESPONSE RATES IN HEPATITIS C INFECTED PATIENTS

 Monica M. Pradhan, William M. Cassidy Sr., LSU-HSC, Baton Rouge, LA.

 

Introduction:

20 to 60% of patients treated for HCV do not achieve SVR. Factors associated with non-response are also associated with insulin resistance (IR). This is an interim report of a study evaluating the role of IR.

 

Methods:

Non diabetic, HCV positive patients between the 18 & 70 positive were enrolled. Liver biopsy was performed within 36 months prior to therapy. Fasting blood sugar (FBS), fasting insulin level (FIL), waist measurement, and weight, was collected at several points during therapy to determine if any could be used to predict sustained viral response (SVR). HOMA score was calculated as (FBS * FIL)/22.5. HCV RNA was measured at baseline (BL), and at Week 12 of therapy. Patients were treated with pegylated-interferon alpha 2b and weight-based ribavirin. Fisher’s exact test was used to determine if HOMA score predicted who achieved early virologic response (EVR).

 

Results:

220 (67% M, 33% F) have been enrolled. 74% were GT-1. Results are given for GT-1 patients. 100 patients have reached Week 12 of therapy. Mean stage of fibrosis was 1.81. Lab data was categorized into quartiles, with those in the lowest quartile indicating least insulin resistance. Mean HOMA score was 15.5 and mean fibrosis stage was 1.27 for those in the lowest quartile of HOMA score (63.5 and 2.0 in the highest quartile, respectively). 23% were African-American in the lowest quartile, and 30% were African American in the highest quartile. 79% of those whose BL HOMA score was in the lowest quartile achieved EVR, whereas 66% of those in the highest three quartiles of BL HOMA scores achieved EVR (p=0.164). 68% of those whose BL weight was in the lowest quartile of weight achieved EVR, and 68% of those in the highest three quartiles of BL weight achieved EVR (p=0.582). 58% of those whose BL waist measurement was in the lowest quartile achieved SVR, whereas 72% of those whose waist measurement was in the highest three quartiles achieved EVR (p=0.144).

 

Discussion:

Among the common correlates with increasing insulin resistance and decreased responsiveness to interferon/ribavirin therapy include age, race, weight, fibrosis stage. Previous work has indicated that insulin resistance is associated with decreased T-cell responsiveness. The question arises is insulin resistance the underlying factor or are these other factors surrogates for the effect of insulin resistance upon T-cells. At this early stage, those who are most insulin sensitive have a trend towards more frequent EVR. This study excludes diabetics and therefore, does not include the most insulin resistant patients. This preliminary data suggests a role for insulin resistance but must be confirmed with complete enrollment with comparisons to other factors known to decrease SVR.

 


Topic:  Interferon Based Therapy

 Presentation Time: 10/30/2004 5:30:00 PM                      Program#/Poster#: 379

 

IMPROVEMENT IN COGNITIVE FUNCTIONS IN PATIENTS WITH CHRONIC HEPATITIS C UNDER TREATMENT WITH PEG. INTERFERON+RIBAVIRIN

Doron L. Zamir, Barzilai Hospital, Ashkelon, Israel; Kerzman Simion, Anima Scan, Ashdod, Israel; Steven Melnik, Melzer Ehud, Kaplan Hospital, Rehovot, Israel; Vaneli Maguli, Barzilai Hospital, Ashkelon, Israel; Meir Aladjem, Electrical and Computer Engineering, Beer-Sheva, Israel; Ron Milo, Zoya Aladjem, Barzilai Hospital, Ashkelon, Israel.

 

Background:

Cognitive deficit was reported in hepatic cirrhosis even in early stages and lately in patients with chronic hepatitis C. A recent study demonstrated better cognitive function in patients that were successfully treated with pegylated interferon and ribavirin than in patients with active HCV infection.

 

Aims:

  1. to check whether there is cognitive impairment in patients with chronic HCV hepatitis.
  2. To check if successful treatment improves cognitive impairment.

 

Methods:

A group of 31 patients with active chronic hepatitis C all planned for treatment with PEG interferon + Ribavirin was evaluated. Patients with impaired Mini Mental State Examination or with major depression were excluded previously. Volunteers with the same demographic parameters were chosen as a control group. Both groups underwent a computerized neuropsychological assessment “CogScan” which included 15 psychologic tests: Finger Tapping Test (FTT), Inspection time (IT), Motion Perception Test (MPT), Simple Reaction Time (SRT), Choice Reaction Time, Immediate and Delayed Memory for Pictures, Words and Faces, Stroop test, Time-Accuracy Tradeoff test (TATT), Digit Symbol Substitution Test (DSST), and Continuous Performance test (CPT). Statistical analysis was performed using t-test for Equality of Means. Probability was estimated (p value<0.05). A similar cognitive test was done within 3-6 month of treatment.

 

Results:

The patients with hepatitis C were found to be cognitively impaired in all subtests, except sustained attention (CPT) versus control subjects. Most impairments were subtests of motor output, selective attention (Stroop test, accuracy), working memory and pair-associated learning (DSST test). However significant improvement (p<0.05) was found in the second evaluation in some cognitive functions. These patients will be evaluated once again after a year of treatment.

 

The HCV patients treated (until 10/2004) were found to be cognitively improved (significantly0 during treatment on the stoop test.

 

Conclusions:

  1. Patients with chronic HCV hepatitis have significant impairment in all stages of information processing. Deficits in performance on tests of selective attention, working memory and learning ability suggests an impairment in fronto-subcortical circuits, especially in anterior cingulated girus.
  2. However some of these function tend to show significant improvement after 3-6 months of treatment.
  3. After the next evaluation we will try to find out whether there is some cognitive improvement in the group of patients with failure of treatment, and a few months after finishing treatment.

 

 


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 380

 

PROSPECTIVE ASSESSMENT OF THE INCIDENCE OF INFECTIONS DURING PEGYLATED INTERFERON (PEG-IFN) PLUS RIBAVIRIN (RBV) TREATMENT FOR CHRONIC HEPATITIS C (CHC)

Massimo Zuin, Alessia Giorgini, Pier Maria Battezzati, Ana Lleo, Francesca Cardani, Mauro Podda, University of Milan, Milan, Italy.

 

Background:

A 30-50% decrease of eutrophil count is expected in CHC patients receiving PEG-IFN plus RBV, leading to increased risk of infection. Despite potential impact on survival, available evidence on such adverse events only comes from retrospective studies or from RCTs on highly selected patients.

 

Aim:

To assess prospectively incidence and risk factors for infections during PEG-IFN plus RBV treatment for CHC in an outpatient setting.

 

Methods:

Between October 2002 and April 2004 in our centre we offered PEG-IFN α-2a (180 µg/wk) plus RBV (800-1200 mg/day) treatment to 188 consecutive outpatients with histologically-proven CHC fulfilling NIH criteria. 174 patients (age 53±11 yr, range 28-70; 63% men; 31% with cirrhosis) accepted to enter the trial. Presence of infection was serially assessed by clinical, radiologic, microbiologic criteria and graded severe if required hospitalization, bed rest, i.v. therapy or study treatment discontinuation.

 

Results:

After 21±12 wk (4-48), 47 patients developed 51 mild (17 upper respiratory tract, 14 genito-urinary, 11 muco-cutaneous, 9 viral) and 10 severe infections (3 pneumonia, 2 large abscess, 1 discitis, pericarditis, meningo-encephalitis, tuberculosis and sepsis). Incidence rate of all infections was 5.2% (n of cases per 100 patient-mo), cumulative incidence was 47%. The corresponding figures for severe infections were 1.1% and 14.3%. Incidence of all infections was higher in the 86 patients with eutrophil counts below sex-specific median value (1330 or 1200 cells/µL, male/female patients) on treatment wk 4 (7.2% vs 2.9%, P=0.006), in the 41 in the upper age quartile (≥64 yr) (8.8% vs 4.4%, P=0.014), with a borderline significance in women (7.3% vs 4.2%, P=0.062). Low eutrophil count on wk 4 (hazard ratio 2.63, 95%CI 1.37-5.05; P=0.019) and old age (2.21, 1.14-4.28; P=0.019) independently predicted infections at Cox regression analysis.

 

Conclusions:

In a “real world” setting of CHC patients, incidence of infectious adverse events to a PEG-IFN plus RBV regimen appears to be more frequent than reported so far. Cumulative incidence of severe, sometimes life-threatening infections may be as high as 14%. Careful clinical monitoring is recommended in older patients and in those with low eutrophil counts after 4-wk treatment.


        Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 381

 

EPIDEMIOLOGY AND RESPONSE TO TREATMENT IN PATIENTS INFECTED BY HCV GENOTYPE 4 IN FRANCE COMPARED TO IMMIGRANTS PATIENTS INFECTED IN EGYPT

 Author Block: Dominique Roulot, Valerie Bourcier, hopital Jean Verdier, Bondy, France; Helene Fontaine, hopital Necker, Paris, France; Francois Bailly, hopital Hotel Dieu, Lyon, France; Laurent Castera, hopital St Andre, Bordeaux, France; Marie Pierre Ripault, hopital Beaujon, Clichy, France; Raoul Poupon, hopital St Antoine, Paris, France; Francoise Roudot-Thoraval, hopital Henri Mondor, Creteil, France; Observational VHC4 study group.

 

Background:

Infection by hepatitis C virus genotype 4 (HCV 4) is frequent in Egypt, where a high rate of sustained virological response (SVR) (61 to 68%) is observed after treatment with pegylated interferon alpha plus ribavirin (PEG-IFNα +RBV). Prevalence of HCV 4 infection is increasing in France and Europe but epidemiological and therapeutic data are missing.

 

Methods:

Epidemiology, histological features and responses to treatment were compared between patients infected by HCV 4 in France (the French group) and immigrants infected in Egypt (the Egyptian group). 1596 patients, referred to 19 French centres between 1995 and 2004 for HCV genotype 4 infection were studied, 69% belonging to the French group, 15% to the Egyptian group and 16% being infected in sub-saharian Africa. Histological data were available for 617 patients of the French group and 198 patients of the Egyptian group. A total of 772 naive patients were treated: 45% with interferon alpha alone (IFNα), 18.6% with interferon alpha plus ribavirine (IFNα+RBV) and 34.3% with PEG-IFNα +RBV for 48 weeks. In the last group, a follow-up 24 weeks after the end of treatment was available for 214 patients.

 

Results:

The mean age was the same in French and Egyptian groups (43.8 +10 vs 44.7+10 yrs). Patients were predominantly male, particularly in the Egyptian group (93.4 and 64.6%). The contamination mode was iatrogenic (following shistosomiasis treatment) or of unknown origin in 93% of the Egyptian group, whereas 56% of patients of the French group were exposed through IV drug use. When known, duration of contamination was longer in the Egyptian group (27.0+9.8 vs 20.0+6.5 yrs).

Liver histological lesions were more severe in the Egyptian group compared to the French group: moderate to severe activity (A2,A3 of the METAVIR score) was found in 51.3 and 37.0% of the cases, respectively (<0.0002) and cirrhosis in 29.8 and 10.8% of the cases, respectively (p<0.0001).

Globally, the rates of SVR were low in patients treated with IFN alone (5.8%) or with IFN+RBV (24.4%). The rate of SVR was 36.8%. in all patients receiving PEG-IFNα +RBV, higher in patients without cirrhosis (41.7%) than in patients with cirrhosis (24.3%). After adjustment for the presence of cirrhosis, sustained virological response was significantly higher in the Egyptian than in the French group: 57,.0 and 39.4 %, respectively, in non cirrhotic patients and 38.1 and 15.4%, respectively, in cirrhotic patients (Mantel-Haenszel test, p<0.04).

 

Conclusion:

Although liver histological lesions appears to be more severe in immigrants infected by HCV 4 in Egypt than in patients infected in France, the SVR to PEG-IFNα plus ribavirin was higher in the former group. Different HCV 4 subtypes types and/or genetic factors may explain this difference.


Topic:  Treatment  Side Effects 

Presentation Time: 10/30/2004 5:30:00                  PM Program#/Poster#: 382

 

SEVERE INTRAOCULAR COMPLICATIONS OF INTERFERON-ALPHA AND RIBAVIRIN THERAPY IN PATIENTS WITH CHRONIC VIRAL HEPATITIS C

 Damien Sène, Bahram Bodaghi, David Saadoun, Valérie Touitou, Pitié-Salpêtrière Hospital, Paris, France; Gabriel Perlemuter, Hôpital Antoine Béclère, Clamart, France; Nathalie Cassoux, Jean Charles Piette, Phuc Le Hoang, Patrice Cacoub, Pitié-Salpêtrière Hospital, Paris, France.

 

Background:

Ophthalmologic monitoring of patients with viral hepatitis C who require interferon alpha-therapy (IFN) is a major issue but its modalities are still controversial. Although severe posterior segment involvement is a rare complication, it may lead to permanent visual loss in the absence of appropriate therapy.

 

Aim of the study:

To describe clinical and therapeutic features of IFN -associated intraocular disorders in patients with chronic hepatitis C.

 

Patients and methods:

Records of 10 patients who presented ophthalmologic complication under course of IFN + ribavirin for chronic hepatitis (9 viral hepatitis C and 1 idiopathic hepatitis), retrospectively analyzed. IFN was discontinued in all cases. Clinical and angiographic findings were cautiously monitored.

 

Results:

Ocular complications included : central retinal vein occlusion (2 cases), central retinal artery occlusion (1 case), diffuse occlusive vasculopathy (1 case), severe hypertensive retinopathy (1 case), bilateral ischemic optic neuropathy (1 case) and Vogt-Koyanagi-Harada like (VKH) disease with bilateral serous retinal detachment (3 cases). Unless for VKH disease, the appearance was not influenced by the type of IFN (Peg or standard) but by vascular or immunological risk factors such as diabetes, hypertension and cryoglobulinemia. Despite IFN discontinuation, patients presenting with VKH disease needed high dose corticosteroids to control serous retinal detachment and to achieve a visual improvement in all cases. After a 6 month-period, IFN was reinitiated in 2 patients under close ophthalmologic monitoring. Reinitiation was performed after significant improvement of retinal or choroidal disorders and major control of other systemic vascular risk factors. Ocular relapses have not been noted after a follow-up of 8 months.

 

Conclusion:

Occlusion of retinal, choroidal or optic nerve vessels is the major ocular complication associated with IFN in patients with hepatitis C. Close ophthalmologic monitoring and efficient control of systemic or ocular vascular risk factors seem mandatory before further IFN reinitiation.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00                  PM Program#/Poster#: 383

 

NECESSITY OF EARLY RE-TREATMENT FOR PATIENTS WITH CHRONIC HEPATITIS C WHO DO NOT ACHIEVE SUSTAINED RESPONSE BY INTERFERON MONOTHERAPY

 Naoki Hiramatsu, Akinori Kasahara, Shinjiro Yamaguchi, Shuji Ishii, Masanori Miyazaki, Takashi Toyama, Masakazu Yasumaru, Tatsuya Kanto, Tetsuo Takehara, Norio Hayashi, Osaka university graduate school of medicine, Suita, Osaka, Japan.

 

Background and Aim:

Recently, the risk of liver carcinogenesis has been reported to decrease in transient responders as well as sustained responders from analysis of patients with chronic hepatitis C treated by interferon (IFN) therapy. In this study, we attempted to predict the risk ratio of HCC in individual patients with chronic hepatitis C who received IFN therapy to enable comprehensive judgment on the necessity of early re-treatment.

 

Methods:

This study included 742 chronic hepatitis C patients who received IFN monotherapy. Patients with genotype 1 and a high viral load (1H group, n = 348) and the others (non-1H group, n = 394) were analyzed separately. Multivariate analysis was performed using Cox proportional hazards regression. Patients were categorized into eight groups according to the risk factors (age, gender, fibrosis) identified by multivariate analysis, and the risk ratio and incidence of HCC were calculated in comparison with the mean incidence of HCC in nonresponders.

 

Results:

In the 1H group, the only significant risk factor for HCC was age; patients ≥55 years of age had a significantly higher risk ratio (3.77) than did those under 55 years (p = .0002). The risk ratio of HCC (λ) in each category was calculated from the parameter estimate and the mean value of various factors; logeλ= -0.57170 x (SR) -0.52261 x (TR) + 1.32647 x (Age – 0.49375) -0.60046 x (Sex – 1.26875) + 0.62044 x (Fibrosis – 0.56563) (IFN effect: not suitable = 0, suitable = 1; Age: < 55 yo = 0, ≥ 55 yo = 1; Sex: male = 1, female = 2; Fibrosis: < F2 = 0, ≥ F2 = 1). The formula for the third-year cumulative incidence of HCC in each category was calculated as (1 – (1 – 0.02729)λ) x 100 (%). Patients in the category of ≥ 55 yo, male, ≥ F2 had the highest third-year appearance rate of HCC, which was 4.6% in sustained responders, 4.8% in transient responders and 8.0% in nonresponders. In the non-1H group, significant risk factors for HCC were age (risk ratio 4.37, p = .002), gender (risk ratio 5.59, p = .005), and the degree of fibrosis (risk ratio 10.03, p = .002). Patients in the category of ≥ 55yo, male, ≥ F2 had the highest third-year appearance rate of HCC, which was predicted to be 5.2% in sustained responders, 13.5% in transient responders and 39.3% in nonresponders. The HCC incidence of transient responders and nonresponders in the non-1H group was much higher than that in the 1H group although almost the same values were obtained among sustained responders in both groups.

 

Conclusions:

Our results indicate that the non-1H patients who do not achieve SR by interferon monotherapy should be treated at an early stage by interferon and ribavirin combination therapy, especially aged male patients with advanced fibrosis. Only 24-week combination therapy can free them of HCC to a high proportion of 80%.


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                        Program#/Poster#: 384

 

TREATMENT WITH PEG-INTERFERON ALFA-2B IN PATIENTS AFFECTED BY ACUTE HEPATITIS C: A PILOT STUDY

 GAETANO SCOTTO Sr., EMILIO PALUMBO Sr., CLINIC OF INFECTIOUS DISEASE, Foggia, Italy; VINCENZINA FAZIO, DEPARTMENT OF LABORATORY, Foggia, Italy; DONATELLA CONCETTA CIBELLI Sr., ANNALISA SARACINO, GIOACCHINO ANGARANO, CLINIC OF INFECTIOUS DISEASE, Foggia, Italy.

 

Background:

Acute hepatitis C often progresses to chronic infection (70%). In this study we evaluated if early treatment with Peg-Interferon alfa-2b can prevent chronic evolution in acute hepatitis C.

 

Methods:

 A total of ten patients (6 males and 4 females, mean age 38.4 ys) with diagnosis of acute hepatitis C, based on well-documented HCV seroconversion, with high ALT levels and persistent HCV RNA titers after 3 months from disease onset, were consecutively treated with Peg-Interferon alfa-2b 1,5 μg/Kg once a week subcutaneous for 52 weeks. Patients were HBsAg and anti-HIV negative. Six patients had genotype 1b, two 3a and two 2a/2c.Viral load was quantified by commercial PCR assay (Amplicor HCV-Monitor, Roche Diagnostic Systems, sensitivity >600 IU/ml). During therapy all patients were monthly examined and monitored for blood count, transaminases and HCV RNA levels and, in patients with undetectable viremia, HCV RNA was evaluated by qualitative PRC (Amplicor Roche, sensitivity >50 IU/ml). Anti-HCV antibodies were measured by a III generation ELISA (Ortho-Clinical Diagnostic) every six months. Follow-up was performed for at least 6 months (range 6-14 months). Response was defined as HCV RNA less than 50 IU/ml and normal ALT levels at the end of therapy (primary response) and at the end of a 6-month follow-up (sustained response).

 

Results: 

All patients completed therapy. At the end of treatment, 8/10 (80%) patients responded and during follow-up any case of relapse was evidenced. Anti-HCV antibodies decreased in three patients. No correlation with response was found for pre-treatment viral load, genotype and interval between acute infection and start of therapy.

 

Conclusions:

Our data show that treatment with Peg-Interferon alfa-2b prevent chronic evolution in most cases.

 


Topic:  HIV/HCV Coinfection – Management Patterns

 Presentation Time: 10/30/2004 5:30:00 PM                      Program#/Poster#: 386

 

LOW PHYSICIAN REFERRAL RATES AND HIGH NO-SHOW RATES ARE MAJOR BARRIERS TO HCV THERAPY AMONG PATIENTS COINFECTED WITH HIV AND HCV

Michael Shim, Inessa Khaykis, James Park, Edmund J. Bini, VA New York Harbor Healthcare System & NYU School of Medicine, New York, NY.

 

Background:

HCV is a leading cause of morbidity and mortality among patients with HIV infection. However, HIV/HCV coinfected patients are less likely to be treated for HCV than those with HCV monoinfection. The aims of this study were to determine the proportion of HIV/HCV coinfected persons that were referred for HCV treatment and to determine barriers to HCV therapy in this population.

 

Methods:

Consecutive patients with newly diagnosed HCV infection over a 1-year period from 1/1/00 through 12/31/00 were identified by using the computerized patient record system at our medical center. Demographic and follow-up data through 6/30/02 were collected by reviewing electronic medical records. The follow-up time was calculated from the time of diagnosis of HCV until the time of the last follow-up visit. At our medical center, all HCV treatment is performed by the GI service and ID physicians do not treat HCV infection.

 

Results:

During the 1-year study period, 8,203 patients were tested for HCV antibodies and 1,363 (16.6%) were positive. Among the 1,363 patients with HCV, 170 (12.5%) were coinfected with HIV and 1193 (87.5%) had no known HIV infection. The median follow-up time was 590 days (IQR, 167 – 734 days) in the HIV/HCV coinfected patients and 599 days (IQR, 267 – 722 days) in those with HCV monoinfection (p = 0.57). HIV/HCV coinfected patients were significantly less likely to be referred for HCV treatment compared to those with HCV alone (42.4% vs. 59.9%; p < 0.001). After adjusting for age, sex, race/ethnicity, being homeless, active substance abuse, active psychiatric disease, and the number of comorbid medical disorders, HIV/HCV coinfected patients were still significantly less likely to be referred for HCV treatment (OR = 0.47; 95% CI, 0.33 – 0.66; p < 0.001). Of those who were referred for HCV treatment evaluation, only 41.7% of the HIV/HCV coinfected patients showed up for their clinic appointment compared with 65.6% of those with HCV monoinfection (p < 0.001). After adjusting for all of the potential confounding variables listed above, HIV/HCV coinfected patients were still significantly less likely to show for their clinic appointment compared to those with HCV monoinfection (OR = 0.29; 95% CI, 0.17 – 0.50; p < 0.001).

 

Conclusions:

Low physician referral rates and high no-show rates are major barriers to successful HCV therapy in patients coinfected with HIV/HCV. Strategies to overcome these barriers are needed in order to increase the number of coinfected patients that are treated for HCV infection.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00                  PM Program#/Poster#: 387

 

DYNAMIC DECISION ANALYSIS TO DETERMINE OPTIMAL TREATMENT DURATION IN CHRONIC HEPATITIS C

 Bart J. Veldt, Bettina E. Hansen, Marinus J. C. Eijkemans, Robert J. de Knegt, Theo Stijnen, J. Dik F. Habbema, Solko W. Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.

 

Background:

The side effects and costs accompanying the 24 to 48 week’s treatment of chronic hepatitis C can be limited if the treatment is stopped early in patients unlikely to respond. Current stopping rules are based on HCV-RNA measurements.

 

Aims:

To determine whether individualized recommendations for stopping treatment can be based on a simple alanine aminotransferase test, also taking into account the cost-per-cure.

 

Method:

Individual patient data from 13 randomised controlled trials with interferon alone or combined with ribavirin were analysed. We used multiple logistic regression to investigate the increase in probability of sustained virological response by prolonging treatment from 24 to 48 weeks. This analysis was performed for different patient types, using the following explanatory variables: alanine aminotransferase levels during treatment, age, sex, genotype and presence of cirrhosis.

Decisions to continue treatment were based on an increase in sustained virological response of 10% or more, in view of its clinical relevance. If the increase was less than 10%, the cost-per-cure became decisive with a limit of €50,000.

 

Results:

The probability of sustained virological response increased by less than 10% if treatment was continued up to 48 weeks in patients with genotype 1 or 4 without cirrhosis who had elevated alanine aminotransferase at week 4. The cost-per-cure would exceed €50,000 for these patients. Sustained virological response rates in cirrhotic patients increased by 14-47% if treatment was continued up to 48 weeks. Non-cirrhotics with genotype 2 or 3 did not benefit when treatment continued beyond 24 weeks.

 

Conclusion:

Dynamics of alanine aminotransferase and cost-per cure are proposed as useful components for medical decision making about the duration of therapy in chronic hepatitis C.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 388

 

PATIENTS WITH CHRONIC HEPATITIS C AND CHRONIC RENAL INSUFFICIENCY OR END STAGE RENAL DISEASE RESPOND POORLY TO INTERFERON MONOTHERAPY

 Swati Pawa, Milton Mutchnick, Murray Ehrinpreis, Ravi Dhar, Julia Greer, Firdous Anjum Siddiqui, Wayne State University, Detroit, MI.

 

Background:

Chronic hepatitis C (CHC) infection is the leading cause of liver disease post renal transplant. Renal transplantation is associated with a significant worsening of liver disease in recipients who are positive for hepatitis C virus antibody (anti-HCV) prior to transplantation. This is an important clinical problem since the prevalence of CHC in patients on long-term hemodialysis ranges from 10% - 60%. Moreover, treatment after transplantation is associated with an increased risk of graft rejection. Futhermore, ribavirin is contraindicated in these prior to transplant. Effective treatment of CHC is needed in these patients to prevent the progression of liver disease, particularly in renal allograft recipients and to lower the risk of potential transmission of HCV within hemodialysis (HD) units.

 

Objectives:

To determine the treatment responses to interferon (IFN) monotherapy in CHC patients with chronic renal insufficiency (CRI) (creatinine ≥ 1.6) or end stage renal disease (ESRD).

 

Methods:

Thirty-six patients with CRI and 136 patients with ESRD were identified from a computer database of more than 2500 patients with HCV infection seen at our institution since January 1993. Thirteen of the 36 patients with CRI and 25 of the 136 patients with ESRD underwent treatment with IFN. The outcomes measured were end of treatment response (ETR) and sustained viral response (SVR). Of the 28 patients with ESRD, 23 patients were on hemodialysis and 5 on peritoneal dialysis.

 

Results:

The mean age of the patients was 50 years; 68% were male. African-Americans (AA) constituted 97% and Caucasians 3%. The mean pretreatment serum HCV RNA by PCR was 844,542 IU/ml and the mean pretreatment ALT was 64 U/L. Information on genotype was available in 32 patients. Genotype 1 accounted for 97% of the patients and one patient was genotype 2a. Thirty-seven patients underwent liver biopsy. In 62% no (stage 0) or early fibrosis (stage 1 and 2) was noted; 14% had stage 3 and 24% showed cirrhosis. This was an intention to treat analysis. Twenty-nine patients were treated with standard IFN and 6 patients with pegylated-IFN. Two patients (5%), one treated with standard IFN and one treated with PEG-IFN, achieved ETR but relapsed after 48 weeks. None of the patients achieved an SVR. Eight patients discontinued therapy because of side effects and 5 patients were non-compliant and lost to follow-up after 4 weeks of therapy. Hence the drop out rate was about 39%.

 

Conclusions:

Our data suggest that CHC patients with ESRD and CRI respond poorly to IFN monotherapy in contrast to the observation made by other institutions where the response was as good as in non-renal failure patients. A higher prevalence of AA patient population and predominance of genotype 1 at our institution could explain this poor


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 389

 

GAMMA-GLUTAMYLTRANSPEPTIDASE (GGT) IS THE MOST RELIABLE PREDICTIVE SINGLE PARAMETER FOR TREATMENT OUTCOME IN HCV TYPE 1-INFECTED PATIENTS

 Viola Weich, Charité, Campus Virchow, Berlin, Germany; Eva Herrmann, Christoph Sarrazin, Universität des Saarlandes, Homburg, Germany; Holger Hinrichsen, Universitätsklinikum Schleswig-Holstein, Kiel, Germany; Peter Buggisch, Universitätsklinikum Eppendorf, Hamburg, Germany; Tilmann Gerlach, Klinikum Grosshadern, München, Germany; Hartwig Klinker, Universität Würzburg, Würzburg, Germany; Ulrich Spengler, Universitätsklinik Bonn, Bonn, Germany; Alexandra Bergk, Bertram Wiedenmann, Charité, Campus Virchow, Berlin, Germany; Stefan Zeuzem, Universität des Saarlandes, Berlin, Germany; Thomas Berg, Charité, Campus Virchow, Berlin, Germany.

 

Introduction:

In earlier studies we already could demonstrate a significant correlation between GGT level and treatment response in HCV-infected patients receiving combination therapy. The aim of the present study was to establish in large group of patients whether GGT can be taken as an independent predictive factor beyond the other already established predictive parameters (as for instance, viral load, fibrosis stage, and age).

 

Patients and methods:

961 treatment-naïve patients were retrospectively analyzed (HCV type 1, 4-6 (n=784), HCV genotype 2 and 3 (n=136); unknown (n=41)). In all patients GGT levels were determined before start of therapy. 422 patients (44%) had GGT levels below or even upper limit of normal (ULN). Antiviral response to combination therapy with standard (n=204) as well as PEG IFNa (n=650) plus ribavirin could be determined in 854 patients (89%) 24 weeks after end of therapy.

 

Results:

In the presence of an elevated GGT (> ULN), a sustained virologic response (SVR) was only achieved in 40% as compared to 66% of those patients showing normal GGT levels (<=ULN) at start of therapy (p< 0.0001). This association was restricted to HCV type 1 (4-6)-infected patients (63% in GGT <=ULN vs. 35% in GGT > ULN; p< 0.0001). Interestingly there was a clear significant association between elevated GGT levels and the frequency of virologic nonresponse and relapse rates. Thus, the rate of nonresponse was 82% vs.17% (p< 0.0001), and the relapse rate was 33% vs. 21%; p=0.004). Factors which were significantly associated with a GGT elevation were age (p<0.0001), BMI (p< 0.0001), ferritin (p< 0.0001), triglyceride (p<0.0001), platelets (p=0.001), IgA (p=0.002), bilirubin (p=0.047) as well as fibrosis stage (p=0.001) and steatosis (p=0.01), while sex, viral load, HCV type, cholesterol, glucose, albumin, and reatinine did not influence GGT levels. Multivariate analysis confirmed GGT as the most important independent predictor for treatment outcome in HCV type 1 infection.

 

Conclusion:

This study on a large cohort of HCV-infected patients convincingly demonstrates that GGT is the most important independent predictor for treatment outcome in HCV type 1 infection. Thus, analysis of GGT levels before therapy is an interesting approach to stratify HCV genotype 1-infected patients with respect to their prognosis of treatment outcome.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM           Program#/Poster#: 391

 

BRIDGING HIGH-RISK HEROIN USERS TO HEPATITIS C TREATMENT USING BUPRENORPHINE

 Diana L. Sylvestre, University of CA, San Francisco, Oakland, CA; Laphyne Barrett, Alice Asher, OASIS, Oakland, CA; Lisa Hartfield, Beth Klem, Judith B. Cohen, East Bay Community Recovery Project, Oakland, CA.

 

Abstract Body: Background:

Although 50-70% of the 1 million active heroin users in the US have been exposed to HCV, the majority are excluded from HCV treatment due to concerns about adherence, psychosocial instability, and reinfection. The approval of buprenorphine (BPN) as a primary care-based medication for opiate addiction offers a new, one-stop means of reducing or eliminating problematic drug use while simultaneously providing treatment for HCV.

 

Methods:

We are conducting a prospective pilot study of the use of BPN to bridge street-recruited heroin users to hepatitis C treatment. Eligible participants initially receive 12-24 weeks of on-site BPN monotherapy; they subsequently undergo combined BPN/HCV treatment for 24-48 weeks. A 24-week BPN taper is undertaken after HCV treatment is complete.

 

Results:

To date, 337 heroin users have been screened at syringe exchanges; their median age is 45 years, 71% are male, and 35% are Caucasian, 36% are African-American, and 23% are Latino. 74% have been eligible for study; the majority are ineligible because of spontaneous viral clearance. To date, 96 have initiated BPN treatment. Their estimated median duration of HCV exposure is 28 years, 70% have genotype 1, and 30% have genotypes 2 or 3. At the time of initial engagement, 45 of the 96 (47%) were additionally using cocaine or methamphetamine and 53 (55%) admitted to current alcohol ingestion.

Sixteen patients have initiated combined BPN/HCV treatment. Twelve week viral loads are available on 9 patients; 7 are undetectable, one showed >2-log reduction, and one patient is a nonresponder. To date, there have been no HCV treatment discontinuations.

 

Conclusions:

Developing effective strategies to engage active heroin injectors in HCV treatment is the key to mitigating the scope and consequences of this disease. Although the findings are preliminary, it appears that BPN may provide a novel and effective engagement option.

Funding source: NIDA R01 DA015629


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 393

 

PREVALENCE OF THYROID DYSFUNCTION DURING INTERFERON-BASED THERAPY IN CHRONIC HEPATITIS C

Samer Nasser, Heiner Moenig, Martin Brzank, Ullrich Foelsch, Holger M. Hinrichsen, University of Kiel, Kiel, Germany.

 

Background:

Thyroid dysfunction is frequently seen during interferon therapy in patients treated for hepatitis C or malignant melanoma. Both hypothyroidism and hyperthyroidism might occur. Thus TSH monitoring is required during the course of therapy and discontinuation of the drugs is often necessary.During interferon monotherapy the prevalence of thyroid dysfunction was < 10%. After introduction of the combination therapy of interferon and ribavirin and more recently of PEG-interferon and ribavirin the prevalence raised. The aim of the study was to determine the prevalence and the clinical relevance of thyroid dysfunction in patient treated for hepatitis C with different treatment regimes. Furthermore associations of thyroid dysfunction with treatment response, viral genotype and preexisting thyroid autoantibodies were analysed.

 

Patients and Methods:

245 patients treated for hepatitis C in clinical trials with prospective determinations of thyroid function were enrolled. 6 therapeutic regimes were included: Interferon alpha (IFN), IFN + Ribavirin ( IFN + Riba), Consensus interferon (CIFN), CIFN + Riba, PEG-Interferon (PEG-IFN) und PEG-IFN + Riba. In all cases thyroid function was determined prior, during and after therapy. Thyroid autoantibodies were analysed before therapy and in all cases of thyroid dysfunction during therapy. The results were correlated with the virological response and viral genotype.

 

Results:

In 39 out of 245 treated patients (15,9%) thyroid etermined was seen. 16 cases with primary eterminedism, 13 cases with hyperthyroidism and a biphasic dysfunction in 10 cases. Thyroid dysfunction was seen more frequently during PEG-IFN and ribavirin combination therapy (26%). In all treatment regimes sustained virological response was positively associated with the onset of thyroid disease during treatment (p < 0.05). The probability of thyroid disease raised from 20% to 50% if preexisting thyroid autoantibodies were present prior to the antiviral therapy. Only in 2 out of 39 cases the antiviral therapy has to be stopped due to significant thyroid disease. In both cases classical Graves disease with was diagnosed. Long term thyroid etermi substitution was necessary in 14 out of 39 cases.

 

Conclusions:

The current antiviral combination therapy of hepatitis C is frequently associated with thyroid dysfunction. Thyroid dysfunction is more often seen if preexisting thyroid autoantibodies are etermined. On the other hand is the sustained virological response to antiviral therapy positive correlated with thyroid dysfunction. Discontinuation of antiviral therpy is rarely necessary, except in Graves disease


Topic:  Treatment – Pegasys

 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 394

 

RIBAVIRIN (RBV) DOSE REDUCTION IN PATIENTS WITH HCV GENOTYPE 1 INFECTION RECEIVING COMBINATION TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) PLUS RBV (COPEGUS®)

 Janet S. Lee, Sylvia Hu, Juan Carlos Lopez-Talavera, F. Hoffmann-La Roche Ltd., Nutley, NJ.

 

 

Introduction:

Pegylated interferon in combination with RBV is the standard treatment for patients with chronic HCV infection. Decreasing RBV exposure has been suggested to have a negative influence on sustained virologic response (SVR) rates. Here we present analysis of the relationship between the reasons and timing of reductions in RBV dose and SVR rates.

 

Methods:

Pooled data from 569 patients with HCV genotype 1 from 2 phase III trials (ITT population) randomized to 48wk of PEGASYS 180mcg/wk and RBV 1000 mg/d (body weight <75 kg) or 1200 mg/d (body weight ≥75 kg) were analyzed. Use of erythropoietin to manage adverse events (AE) was prohibited. The RBV dose was reduced to 600 mg/d for adverse events (AE) or laboratory abnormalities (LA). 4 categories of RBV exposure during the 48 wk treatment period were created for this analysis: early (before wk 12) and late (after wk 12) reductions due to AE/LA, reductions for reasons other than AE/LA, and no dose reduction.

 

Results (Table):

The table shows the timing, reasons for RBV dose modification, viral response rates and cumulative Pegasys and RBV dose according to the 4 categories. Patients aged >40yr were more likely to receive early and late dose reductions for AE/LA (P=.0001). In addition, a significantly greater proportion of US patients (25% early, 24% late) had dose reductions for safety reasons than non-US patients (17% early, 20% late), and smaller proportion of US patients without modification due to safety reason (37% other reasons, 13% no modification) versus non-US patients (47% other reasons, 16% no modification) (P<0.05). Other reasons included primarily missed doses. Patients with dose reductions for safety received less cumulative RBV exposure than patients with RBV reductions for other reasons.

 

Conclusions:

Reductions of ribavirin dose were relatively common in these studies of the combination of peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus), but peginterferon dose reductions were less common.  Of the 247 patients who completed treatment, 313 (73%) were able to maintain ≥97% of the peginterferon alfa-2a (40KD) dose, and 255 (57%) were able to maintain ≥97% ribavirin dose.

 

Reductions in the ribavirin dose during the first 12 weeks of therapy were associated with reduced SVR. 

 

Patients who had an early ribavirin dose reductions due to AE/lab abnormalities had lower ribavirin exposure for the duration of the trial, were also more likely to have lower peginterferon alfa-2a (40KD) exposure, and to discontinue treatment.  All of these factors are likely to compromise the response to therapy.  Avoiding ribavirin dose reductions and dose discontinuations will likely improve overall SVR, althought the magnitude of this benefit remains to be determined.

 

Fewer US patients maintained a full ribavirin dose during the treatment period compared with non-US patients.

 

These results support further evaluation of optimal dose and, if necessary, dose reduction strategy for ribavirin in the setting of combination therapy.

 

Patients With RBV Dose Modification

No RBV Modification

 

For AE or LA

For Other Reasons

 

Before wk 12

After wk 12

 

 

n

116

124

244

85

EVR – n (%)

91 (78)

110 (89)

197 (81%)

59 (69%)

SVR – n (%)

39 (34)

66 (53)

130 (53%)

44 (52%)

Actual PEGASYS dose before wk 12
(mean % ± SE)

93% ± 1

98% ± 1

96% ± 1

92% ± 2

Actual RBV dose before Wk 12
(mean % ± SE)

76% ± 2

99% ± .3

97% ± 1

93% ± 2

Actual PEGASYS dose (mean % ± SE)

75% ± 3

88% ± 2

86% ± 1

77% ± 4

Actual RBV dose
(mean % ± SE)

53% ± 2

80% ± 2

88% ± 1

79% ± 4

Reason – n (%)

 

 

 

 

Anemia

63 (54)

53 (43)

 

 

AE only

50 (43)

67 (54)

 

 

EVR = minimum 2-log reduction or undetectable HCV RNA at week 12

 

 


Topic:  Experimental Therapy

 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 396

 

A PILOT TRIAL OF THYMALFASIN (THYMOSIN ALPHA-1) IN COMBINATION WITH PEGINTERFERON ALPHA-2A (PEG-IFN2A) AND RIBAVIRIN IN HCV NON-RESPONDERS: 48-WEEK (END OF THERAPY) RESULTS

 Jorge L. Poo, Francisco Sanchez-Avila, Medica Sur Clinical Foundation, Mexico City, Mexico; David Kershenobich, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Xochitl Garcia Samper, Hospital Adolfo Lopez Mateos, Mexico City, Mexico; Julieta Gongora, Medica Sur Clinical Foundation, Mexico City, Mexico; Martha Garcia Sandoval, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Jose A. Chavez Oest, Hospital Adolfo Lopez Mateos, Mexico City, Mexico; Eduardo B. Martins, SciClone Pharmaceuticals, San Mateo, CA; Misael Uribe, Medica Sur Clinical Foundation, Mexico City, Mexico.

 

Introduction:

Virological response rates for retreatment of combination interferon (IFN) plus ribavirin HCV non-responders with PEG-IFN plus ribavirin have been disappointing. Thymalfasin in combination with PEG-IFN2a and ribavirin has previously been suggested to increase early virological response rates in HCV non-responder patients.

 

Objectives:

To investigate the effects of thymalfasin in combination with PEG-IFN2a and ribavirin in patients that did not respond to a previous course of IFN plus ribavirin.

 

Methods:

Hepatitis C patients who were non-responders to a previous course of at least 24 weeks of combination therapy were enrolled. Non-response was defined as a documented positive HCV RNA at the end of the previous course of therapy. Study treatment was thymalfasin 1.6 mg twice a week plus PEG-IFN2a 180µg/week plus ribavirin 800-1,000 mg/day. For inclusion, subjects were required to have HCV RNA positive by PCR, elevated ALT and no evidence of decompensated cirrhosis. The end of treatment endpoint efficacy was assessed by HCV RNA clearance by PCR after 48 weeks.

 

Reesults:

25 patients were enrolled (9 male, 16 female; mean age 56.9 yrs [range 27-65]). 2 patients discontinued treatment at week 24, when both had positive HCV RNA. Genotype 1 HCV was present in 21 patients, and genotype 2 in 4 patients. At the end of treatment (week 48), 12/25 (48%) subjects had undetectable HCV RNA. The HCV RNA response as per protocol analysis was 52% (12/23). Of the genotype 1- and genotype 2-infected patients, 10/21 (47.8%) and 2/4 (50%) had undetectable HCV RNA, respectively. Normal ALT was seen in 11/23 (47.8%) patients. Thymalfasin was well tolerated with no obvious side effects and no need for dose modifications. PEG-IFN2a or ribavirin required dose modification in 36% and 13% of patients, respectively; 1 patient required dose interruption.

 

Conclusions:

These data suggest that thymalfasin adds to the efficacy of PEG-IFN2a plus ribavirin in inducing an end of treatment response in patients with HCV who are non-responders to previous combination therapy.


Topic:  HIV/HCV Coinfection – Treatment  Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 397

 

PREDICTORS OF ANEMIA IN A COHORT OF HIV/HCV INFECTED PATIENTS ON INTERFERON AND RIBAVIRIN INCLUDE AGE AND SEX, BUT NOT CD4 COUNT

 Lev Ginzburg, Alison J. Uriel, Mount Sinai Medical Center, New York, NY; Carol Bodian, Mount Sinai School of Medicine, New York, NY; Douglas T. Dieterich, Mount Sinai Medical Center, New York, NY.

 

Background:

Treatment of chronic hepatitis C (HCV) is an important issue to address in HIV/HCV co-infected individuals. The current recommended anti-HCV treatment regimen of peg-interferon (IFN) and ribavirin (RBV) is frequently complicated by RBV-induced hemolytic anemia. Management of anemia may require RBV dose reduction, which can be associated with decreased treatment efficacy. There are currently no models to predict which individuals are at increased risk of developing anemia during anti-HCV therapy.

 

Purpose:

To identify the risk factors associated with the development of anemia [hemoglobin (Hgb) <12 g/dL] by week 8 of IFN/RBV therapy in a cohort of 91 HIV/HCV co-infected patients (pts).

 

Methods:

Baseline demographic and clinical data, including CD4 lymphocyte count, antiretroviral (ART) regimen, iron indices, liver histology and RBV dosage (in mg/kg) were extracted retrospectively from patient charts. Hgb’s up to week 8 of anti-HCV therapy were recorded. A multivariable logistic regression analysis was performed to determine the odds ratios for developing Hgb < 12 g/dL.

 

Results:

Baseline characteristics of the cohort were as follows: mean age was 43 years (33 – 70), 72.5 % (66/91) were male. Mean baseline CD4 count was 547 (119 – 612), 29% (26/91) were on AZT. Mean baseline Hgb was 14.2 g/dl (10.4 – 18.0), 8% had Hgb < 12 g/dL, and 10% (9/91) were iron deficient. Cirrhosis was present in 23% (21/91). Hgb fell to <12 g/dL in 50 % (46/91) during IFN/RBV therapy; erythropoietin (EPO) was instituted in these pts. Mean baseline RBV dose was 12.45 mg/kg in pts that developed anemia vs. 12.27 mg/kg in those that did not. Multivariable logistic regression analysis revealed that two variables had statistically significant, and clinically relevant, odds ratios for developing anemia – age and sex. The odds ratio for male sex was 0.128. The odds ratio for age was 1.045 for every year over 55 (i.e. 1.3 for age 60, 1.6 for age 65). Pts with CD4 counts ≤ 200 cells/mm3 did not develop anemia more frequently than those with CD4 counts > 200 (45% vs. 49%). AZT use and RBV dose were also not independently associated with increased risk of anemia.

 

Conclusion:

In our HCV/HIV cohort, two variables were found to correlate with development of anemia: age > 55 and female gender. An independent clinically relevant association with baseline CD4 count, Hgb, iron status, presence of cirrhosis, mean RBV dose or concurrent use of AZT was not identified. There was no correlation between CD4 ≤ 200 and increased risk of anemia. Further research is needed in order to validate a model to identify a subset of pts at increased risk of developing significant anemia on IFN/RBV, and to determine if supportive therapy with EPO to prevent anemia and subsequent RBV dose reduction will result in improved sustained viral response rates.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 398

 

CONTROLLED THERAPY INTERRUPTION, CTI: A NOVEL APPROACH HARNESSING MEMORY CD8 T-CELL RESPONSE IN CHRONIC HCV THERAPY

 Gerond Lake-Bakaar, Weill Cornell University Medical Center, New York, NY.

 

Introduction:

Memory cells are virus specific T cells that survive acute infection. They rapidly re-acquire cytotoxic activity on re-exposure to antigen. In chronic viral infections, high antigen load or poor CD4 help, cause memory cells to become partially exhausted or deleted. HAART, followed by intermittent re-exposure to virus through structured therapy interruptions (STI), has induced modest immune control in early HIV disease, though CD4 is impaired. HCV does not directly cause CD4 cell destruction. Thus, controlled therapy interruption, CTI, might generate clinically significant protective immunity in chronic HCV infection.

 

CTI Protocol:

CTI cycle #1 starts with initiation of pegylated interferon and ribavirin (P+R) therapy when viral load is at steady state and is continued until HCV RNA becomes undetectable (TMA <5 iu/ml), and then stopped. If virological relapse ensues, Cycle #1 is considered complete when a new HCV steady state is reached. Cycle #2 can be started. Cycling continues until SVR is achieved.

 

Results:

We report on CTI in two consecutive cases of previous interferon failures. Pat BB, 52y male with genotype 1, cirrhosis and mild ascites, relapsed after 15 months of therapy with P+R. HCV RNA was undetectable at EoT. Total bilirubin was normal during treatment, but increased slightly with viral relapse. CTI (cycle #1) was started and continued until HCV RNA became negative by TMA at week 6. ALT fell to 30 and bilirubin to 1.8. On therapy interruption HCV RNA promptly increased to 760,000 iu/ml and ALT to 89. CTI (cycle #2) was initiated. HCV RNA became undetectable by TMA within eight weeks, while paradoxically total serum bilirubin increased to 5.7 and ALT to 204. No drug, alcohol, viral or autoimmune cause was found for the hepatitis flare. After three months on no therapy, virus remains undetectable and both total bilirubin and ALT are normal.

Patient DG, 48 m with genotype 1, stage 2 fibrosis had relapsed after I+R two years earlier. Steady state HCV RNA was around 2 million iu/ml. After three months of P+R, HCV RNA became undetectable by TMA. DG stopped treatment. Consecutive HCV levels two weeks apart were 6700 and 6600 iu/ml at weeks 6 and 8 respectively. CTI (cycle # 1) was started. HCV fell slowly, becoming undetectable by TMA at week 10. Treatment was stopped. HCV remains undetectable at three months after just one cycle.

 

Conclusion:

The severe hepatitis flare in patient BB, reflecting reduced hepatic reserve in cirrhosis, supports increased CTL activity possibly augmented by P+R. Prolonged aviremia during extended therapy interruption in DG, indicates clinically significant protective immunity. Undetectable viral load after 3-months on no therapy has been associated with a high probability of SVR. This novel mode of treatment may prove useful in CHC patients.


Topic:  Pegasys

 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 401

 

EFFECT OF AMANTADINE ON QUALITY OF LIFE AND FATIGUE IN PATIENTS WITH CHRONIC HEPATITIS C PARTICIPATING IN A PROSPECTIVE, DOUBLE BLIND, PLACEBO CONTROLLED, RANDOMIZED TRIAL OF TREATMENT WITH PEGYLATED INTERFERON ALFA2A/RIBAVIRIN

 Elisabeth Formann, University of Vienna, Vienna, Austria; Wolfgang Jessner, University of Innsbruck, Innsbruck, Austria; Rainer Hubmann, General Hospital Linz, Linz, Austria; Christian Datz, Krankenhaus Oberndorf, Oberndorf, Austria; Petra Munda-Steindl, University of Vienna, Vienna, Austria; Anton Klingler, Medical University of Innsbruck, Innsbruck, Austria; Gabriele Moser, Peter Ferenci, University of Vienna, Vienna, Austria.

 

Introduction:

Fatigue, reduced qualtity of life (QoL) and depression are frequent in patients with chronic hepatitis C (CHC). These symptoms increase during interferon (IFN)/ribavirin(RBV) therapy.

 

Aims:

To evaluate the influence of amantadine (AMA) on fatigue and QoL in patients on treatment with PEG-IFN alfa and ribavirin participating in a prospective, double blind, placebo controlled, randomized trial. This trial compared AMA to placebo in patients with CHC, genotype 1.

 

Methods:

210 de novo patients with CHC genotype 1 were treated with 180µg PEG-IFN α2a (PEGASYS®, Roche, Basel, CH)/week and 1-1.2 g ribavirin/d (COPEGUS®, Roche, Basel, CH) and 200mg AMA/d (group A) or an identical looking placebo (group B) for 48 weeks in patients. QoL and fatigue were assessed using standard questionnaires before, during (at weeks 24, 48) and after antiviral treatment (follow up week 24) including the Fatigue-Severity Score (FSS) (9 items plus a visual analogue scale (VAS)) and the Short Form 36 Health Survey. Analysis of covariance with terms for sex, age, group, stage of fibrosis, initial response and baseline value has been applied to evaluate their influence on the last observed value.

 

Results:

192 of the 210 patients (63% males, 37% females, age 45 ± 10.3 years, 105 group A, 87 group B, fibrosis 0-2: 75%, fibrosis 3-4: 25%) completed questionnairies at the given time points. Baseline characteristics, as well as QoL (at baseline and on treatment) did not differ between the two treatment groups. Endpoint analysis (last observed minus baseline value) revealed worsening of mean FFS by 0.1 ± 1.8 and by 0.5 ± 1.9 scorepoints in group A and B, respectively. An improvement of -0.2 ± 3.0 for group A and worsening of 1.0 ± 3.3 for group B was observed for the Fatigue VAS. Analysis of covariance revealed a significant influence of baseline value (p=0.001) and group (p=0.04) on both, endpoint mean FSS and VAS. VAS was also influenced by the stage of fibrosis (p=0.04) and sex (p=0.03).

 

Conclusion:

AMA alleviates fatigue severity and may thereby enable patients to adhere to PEG-IFN/RBV therapy.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 402

 

LONG-TERM FOLLOW UP OF CHRONIC HEPATITS C PATIENTS WITH SUSTAINED VIROLOGICAL RESPONSE TO VARIOUS FORMS OF INTERFERON BASED ANTIVIRAL THERAPY

 Elisabeth Formann, Petra Munda-Steindl, Harald Hofer, University of Vienna, Vienna, Austria; Wolfgang Jessner, University of Innsbruck, Innsbruck, Austria; Melitta Penz, Christoph Oesterreicher, Ulrike Czizek, Peter Ferenci, University of Vienna, Vienna, Austria.

 

Introduction:

To date, combination therapy with pegylated interferon alfa (IFN) and ribavirin is the therapy of choice in patients with chronic hepatitis C infection. A sustained virological response (SVR), defined as HCV PCR negativity at the end of therapy and six month later, can be achieved in 42%-52% of patients with genotype 1 infection and in 80% in patients infected with genotype 2 or 3. Nevertheless, little is known about long term maintainence of HCV-PCR negativity.

 

Aim:

The aim of the study was to evaluate durabilitity of virologic response in patients with SVR to antiviral therapy treated at a single center.

 

Methods:

Follow-up data of sustained virologic responders to antiviral therapy treated at the General Hospital Vienna between 1987 and 2002 were obtained. Six of these patients received monotherapy with standard IFN-alfa2a or 2b (Roferon® , Roche, Basel, CH, IntronA®, AESCA, Traiskirchen, Austria) and 65 standard IFN-alfa in combination with ribavirin. Sixty-one patients were treated with pegylated IFN- alfa2a or PEG-INFalfa2b in combination with ribavirin. Usually, patients are seen at least once yearly at the outpatient clinic. Patients not seen since May 2002 were contacted and asked to come for testing. Qualitative serum HCV RNA was tested by the COBAS AMPLICOR® HCV test, v2.0 (lower detection limit: 50 IU/mL; Roche Diagnostics, Vienna, Austria).

 

Results:

A total of 194 patients treated in our unit achieved an SVR (53.6% genotype 1, 36.6% genotype 2 or 3, 8.8% genotype 4; 15.5% with cirrhosis). Out of these patients 132 were followed for more than 1 year after end of treatment. 17 of these patients were retested in 2004. No recent information (2 years or longer) was obtained in 12 patients. In these patients, the last follow-up date was used.

 

Conclusion:

No recurrence of HCV infection was seen in any patient. Thus, long-term prognosis in chronic hepatitis C patients with a SVR to therapy with (PEG-)IFN+/-Ribavirin is excellent.

 

Table 1, *not all patients had pretreatment liver biopsy/genotype testing 

Treatment

N (GT1/non1)*

Fibrosis 0-3/4*

Years of follow-up, median (range)

HCV-PCR positive

ALT normal (%)

IFN

6 (1/3)

4/0

3.20 (1.94-6.68)

0

100

IFN/RIBA

65 (22/43)

53/8

3.44 (1.02-5.86)

0

81.5

PEG-IFN/RIBA

61 (40/21)

50/11

1.32 (1.01-4.15)

0

98.4

 


Topic:  Special Populations- Treatment

Presentation Time: 10/30/2004 5:30:00 PM Program#/Poster#: 403

 

THE ASSOCIATION OF RACE AND TREATMENT FOR HEPATITIS C

Christine M. Rousseau, University of Washington, Seattle, WA; George N. Ioannou, Jeffrey A. Todd-Stenberg, Kevin L. Sloan, Jason A. Dominitz, VA Puget Sound Health Care System, Seattle, WA.

 

Introduction:

Although anti-viral therapy is available for hepatitis C infection, only a minority of patients undergo treatment. Race has been shown to be associated with receipt of medical care for a variety of conditions.

 

Aim:

To examine the association between race and treatment of hepatitis C, a retrospective cohort study was conducted in eight Department of Veterans Affairs Medical Centers. The subjects included a consecutive sample of 5460 patients with chronic hepatitis C infection. After excluding those with absolute contraindications to anti-viral therapy, 4263 patients remained. The principal outcome was antiviral treatment for hepatitis C. Secondary outcomes, representing steps in the treatment decision-making process, included referral to specialty clinic, complete laboratory evaluation, genotype testing, and liver biopsy. Multiple logistic regression was used to adjust for clinical and socio-demographic factors.

 

Results:

 

Blacks were significantly less likely than Whites to receive anti-viral therapy (adjusted odds ratio[OR].38; 95% confidence interval [CI], .23 - .62). Among those whose virus was genotyped, Blacks remained significantly less likely to be treated, independent of genotype (adjusted OR, .51; 95% CI .27 - .96). Blacks and Whites had similar odds of referral to specialty clinics and liver biopsy. However, Blacks were significantly less likely to have complete laboratory evaluation (adjusted OR, .68; 95% CI, .52 - .88) and viral genotyping (adjusted OR, .68; 95% CI, .53 - .89).

 

Race as a Predictor of Anti-Viral Treatment after Adjusting for Genotype among the Subjects Who had a Genoype Available (N=1340)

Anti-Viral Treatment

Viriable

N(%)

Adjusted OR* (95% CI)

White

345 (13.7)

1.0

Black

19 (4.5)

0.51 (0.27 to 0.96)

Hispanic / Other

18 (13.6)

1.79 (0.85 to 3.75)

Genotype 2 or 3

162 (40.0)

1.0

Genotype 1 or 4

248 (27.5)

0.50 (0.38 to 0.67)

*Adjusted for age, sex, facility, homeleness, marital status, priority, poverty, year, appointments (log transformed), psychiatric diagnoses, alcohol/drug abuse, comorbidity, human immunodeficiency virus, cirrhosis, each laboratory test (white blood cell count, hemoglobin, platelet count, creatinine, bilirubin, alanine aminotransferease, prothrombin time international normalized ratio, albumin.)  No laboratory test was adjusted for when complete laboratory evaluation was the outcome.  Unknown race is not shown.

 

Conclusion:

We conclude that Blacks were less likely than Whites to be evaluated and receive treatment for hepatitis C. Provider bias, patient preference, or residual confounding are possible explanations for the observed difference in treatment rates.  Future studies should evaluate whether provider bias, patient preference, or residual confounding are possible explanations for the observed difference in treatment rates.


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 404

EARLY VIRAL KINETICS DURING TREATMENT WITH LOW DOSES OF PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH GENOTYPES 2 AND 3

 Bahman Bozorg, Avidan U. Neumann, Theo Heller, Marc Ghany, National Institutes of Health, Bethesda, MD; David E. Kleiner, National Cancer Institute, Bethesda, MD; Jean-Michel Pawlotsky, Hopital Henri Mondor, Creteil, France; Stefan Zeuzem, Saarland University Hospital, Homburg/Saar, Germany; Solko W. Schalm, Eramus Medical Center, Rotterdam, Netherlands; Glen Lutchman, Yoon Park, Cheryl Rymer, T Jake Liang, Jay H. Hoofnagle, National Institutes of Health, Bethesda, MD.

 

Background:

Patients infected with HCV genotype (gt) 2 and 3 have a high rate of sustained virological response to pegIFN and ribavirin therapy, averaging 75%. Studies of early viral kinetics have shown a biphasic decline of viral load during IFN therapy; the first phase due to inhibition of viral production and the second phase compatible with loss of infected cells. A dose-response effect on viral kinetics was shown for standard IFN and for pegIFN alfa -2b in patients with gt 1, but not for pegIFN alfa -2a and not for patients infected with gt 2 and 3.

 

Aim:

Early viral kinetics in patients infected with HCV gt 2 or 3 treated with low-doses of pegIFN-alfa -2a (90mcg/w) and ribavirin (800 mg/d) were analyzed and compared to historical controls with standard-doses of therapy.

 

Methods:

19 patients (male 58%, gt 2/3=14/5, mean age =48, mean log baseline viral level= 6.0) were treated. All had chronic hepatitis on pretreatment liver biopsy. Virological results were compared to those from patients participating in the DITTO-HCV trial (Neumann et al, EASL, J Hep 2002) who received 180mcg/w of pegIFN alfa-2a and 1000-1200 mg/d of ribavirin (N=77, male 62%, Gt 2/3= 24/53, mean age= 43, mean log baseline viral level = 6.1). HCV RNA levels were quantified in both groups by COBAS Amplicor v2 with limit of detection of 50 IU/ml. Differences between the groups were tested for statistical significance using the non-parametric Mann-Whitney U-test and Fisher’s exact test and significance was set at P<0.03.

 

Results:

The 1st phase decrease was significantly (P<0.001) lower in the low-dose group (mean 1.2 ± 0.8 log IU/ml) as compared to normal dose (2.4 ± 1.0). However, the pattern of viral decline during the 1st week was similar in both groups (null response: 4% vs 6% respectively, rebound: 4% vs 6%, bi-phasic decline 92% vs 88%). Moreover, there were no differences in the 2nd phase slope between the dose groups (mean 0.9 ± 0.5 log/w vs 0.9± 0.45). There were no significant differences between the low and standard dose groups in percentage of patients who were HCV-RNA negative at week 1 (6% vs 8% p =NS), week 4 (53% vs 70% p=NS) or week 12 (88% vs 97% p=NS).

 

Conclusions:

Patients with gt 2 and 3 demonstrated typical HCV kinetic responses upon initiation of therapy with low doses of pegIFN and ribavirin. The first phase demonstrated a clear dose response whereas the second phase did not. Based on these results we predict that low dose therapy will be as effective as full dose in clearance of HCV by the end of treatment. Nevertheless, the results of sustained virological response are required to determine if low dose of pegIFN alfa-2a and ribavirin is as effective as standard doses for treatment of patients infected with gt 2 or 3.


Topic:  Pegasys 

 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 405

 

RIBAVIRIN PHARMACOKINETIC STUDY WILL LEAD TO INDIVIDUAL DOSE ADJUSTMENT IN CHRONIC HEPATITIS C PATIENTS

Véronique Loustaud-Ratti Sr., Sophie Alain Sr., Lydie Lemonnier Jr., Pierre Marquet Sr., François Denis Sr., CHU Dupuytren, Limoges, France; Françoise Lunel Sr., CHU Angers, Angers, France; Annie Lefebvre Sr., Eric Liozon Sr., Elisabeth Vidal Sr., CHU Dupuytren, Limoges, France.

 

Introduction:

The benefit of body weight dose adjustment (BWDA) of ribavirin (Riba) has been suggested in clinical therapeutic trials. However, Riba has a large volume of distribution and its concentrations display a great inter-individual variability. Larrat et al. did not find any correlation between BWDA and serum Riba concentrations. Moreover, patients with low serum concentrations did not have a virological response (1). The aim of our study is to establish population pharmacokinetics (PK) and pharmacodynamics (PD) of Riba and amantadine (Ama) in association with peginterferon.

 

Method:

Phase II pilot study of difficult-to-treat hepatitis C patients (genotype 1) who received peginterferon α 2a (40KD) and Riba [BWDA: <75 kg 1000 mg/d, >75 kg 1200 mg/d] alone for 3 months and then associated with Ama (200 mg/d) for the next 9 months. PK curves were performed at D0, W12, W24 for Riba and W12, W24 for Ama. Virological follow up included W2, W4, and monthly evaluation of viral load until W24 (PCR Amplicor Cobas and branched bDNA).

 

Results:

We give the preliminary Riba PK and PD results for the first 13 patients who have reached W24. Nine males and 4 females were included, mean age 47.5+/-8.02, mean viral load 676645 +/- 419943 UI/ml, body weight 67.9+/-15.4 kg , BMI 25.3+/-4.05, fibrosis score <3 (METAVIR scoring system). Nine patients have a virological response at W24. The Riba AUC0-10h are widely distributed between the 13 patients with a mean of 3236 ng.h.ml-1 at D0 (range 1143-5424), 25067 ng.h.ml-1 at W12 (range 17000-38708), 23874 ng.h.ml-1 at W24 (range 16368-39928). We define two populations at each PK period i.e. patients with a low AUC and patients with a high AUC. The Kaplan Meier curve shows that patients with a high AUC (n=6) at D0 (but not at W12 or W24), have a trend for a quicker virological response (negative qualitative PCR), compared to those with low AUC (n=7) (p=0.11). At D0, the mean AUC values of responders (negative qualitative PCR at W12) are significantly higher than those of non responders (3802 and 2332 ng.h.ml-1 respectively with p=0.025). Preliminary results show that introduction of Ama has no impact on Riba PK curves.

 

Conclusion:

The PK curves of Riba are widely distributed in spite of a BWDA of the drug. Patients with a high AUC at D0 are likely to have a quicker virological response. This population PK analysis of Riba could allow early individual dose adjustment of the drug in order to improve efficacy.

(1)Larrat et al. Antimicrob Agents Chemother.2003;47:124-9.

Acknowledgments: this work was supported by Roche, Fr

 


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 406

 

OUTCOME OF COMMUNITY BASED HEPATITIS C TREATMENT IN INTRAVENOUS DRUG USERS RECEIVING NALTREXONE IMPLANTS

 Gary P. Jeffrey, University of Western Australia, Nedlands, Western Australia, Australia; Fern Chua, Australian Medical Procedures Research Foundation, Perth, Australia; Emma Young, Western Australian Liver Transplantation Service, Perth, Australia; Gary Hulse, University of Western Australia, Nedlands, Western Australia, Australia; George O’Neil, Australian Medical Procedures Research Foundation, Perth, Australia.

 

Introduction:

The effectiveness of HCV antiviral therapy in patients who have undergone drug dependency treatment and continue to inject drugs is presently unknown. In particular the ability to tolerate and comply with therapy and to avoid re-infection after completion of therapy needs further study.

 

Methods:

Patients attending a drug rehabilitation and naltexone implant clinic (AMPRF) from October 2002 until May 2004 were screened for HCV infection and offered further assessment and treatment. A shared-care model was developed with an AMPRF GP and nurse educator screening patients and providing initial education and testing. A Hepatologist attended the clinic on a fortnightly basis and reviewed patients before a liver biopsy was performed. Treatment was either Rebetron (alpha interferon and ribavirin, n=12) or pegylated interferon and ribavirin (n=15) for 6 months (genotype 2/3) or 12 months (genotype1). Treatment was started and monitored by the GP and nurse educator at the clinic. Viral and host factors influencing sustained irological response (SVR, PCR negative 6 months after therapy) were studied.

 

Results:

47 patients had a liver biopsy performed. Metavir fibrosis scores were: 16 with F0, 24 with F1, 4 with F2, and 3 with F3. 20 patients did not meet Australian S100 biopsy criteria guidelines and were not eligible for government funded therapy. 27 patients have been started on therapy. Only 2 eligible patients were unable to start therapy due to ongoing excessive IDU. HCV genotypes were: 20/47 genotype 1, 1/47 genotype 2 and 26/47 genotype 3. End of treatment response (ETR, PCR negative) was 22/26 (85%) and the SVR was 11/16 (69%). Four patients stopped therapy early, 2 for depression and 2 for flu-like symptoms. Only two patients having an ETR re-infected due to unsafe injection practices. 12/25 reported no further IDU, 11/25 occasional or rare IDU and 2/25 regular use of IDU. 16/25 received antidepressant and/or antipsychotic medication.

 

Conclusion:

This pilot study of HCV treatment in a shared care naltrexone implant clinic found antiviral therapy resulted in a 69% SVR. This result is comparable to that reported in hospital based clinics in non IDU patients. If further studies confirm these findings HCV antiviral therapy should be offered to this large and currently under treated group.


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 407

 

BASELINE CES-D SCORE AS A PREDICTOR OF DEPRESSION DURING TREATMENT WITH INTERFERON PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C

Cheryl D. Levine, Reem Ghalib, Liver Institute at Methodist Dallas, Dallas, TX; Cordelia Martin, University of Texas School of Public Health, Houston, TX; Ahmad Abo Kayass, Fay Simon, Liver Institute at Methodist Dallas, Dallas, TX.

 

Purpose:

To evaluate the level of depression in chronic hepatitis C (HCV) patients at initiation of interferon plus ribavirin therapy as a predictor of depression during therapy.

 

Methods:

This retrospective cohort study included subjects treated for HCV between June 2000 and June 2003. The sample included 70 HCV patients without prior history of diagnosed depression being treated with PEG INF alfa-2b plus ribavirin therapy. There were 48 females ages 17-77 years and 22 males ages 25-70 years. All patients have completed therapy with screening for depression using the Center for Epidemiologic Studies Depression Scale (CES-D) prior to treatment, and at weeks 2, 4, 8, 12, 16, 24, 32, 36, 48 during therapy. Patients were divided into 3 groups based on baseline CES-D Score: group 1 with <6, group 2 with 6-15, and group 3 with >15. Antidepressant medications were initiated at the discretion of the clinician with patient concurrence.

 

Results:

CES-D scores at initiation of therapy had a mean of 4.6 ± 6.1 in females and 5.3 ± 5.6 in males. Group 1 had 29 females and 16 males; Group 2 had 15 females and 5 males; and Group 3 had 4 females and 1 male. Group 1 had 3 start antidepressants at the screening visit, 15 during the first month, 5 in the second or third month, for a total of 21/45 (47%) during HCV therapy. Group 2 had 3 start antidepressants at the screening visit, 6 during the first month, 3 during the second or third month, for a total of 18/20 (90%). In Group 3 all 5 patients started antidepressants at the screening visit. The CES-D scores for treatment weeks 2 through 24 were lower in Group 1 vs. Groups 2 and 3 (p<.005). CES-D scores for weeks 32 to 48 were not different. However, the average CES-D scores during the total treatment were lower in Group 1 vs. Groups 2 and 3 (F=13.7, p<.001).

 

Conclusions:

Evaluation of depression during treatment revealed that patients who were less depressed (Group 1) at initiation of interferon plus ribavirin therapy had significantly less depression during treatment than those with higher levels of depression at initiation of therapy (Groups 2 and 3). Increased depression in Group 3 occurred despite initiation of antidepressant therapy at the screening visit. Patients with higher CES-D scores prior to HCV therapy developed more severe depression earlier in therapy when compliance with therapy is critical to efficacy. Therefore, consideration should be given to delaying therapy until depression is under control. Close monitoring for depression is important throughout HCV therapy in all groups. Screening for depression prior to interferon plus ribavirin therapy is important in identifying patients at greater risk of depression. Strategies for use of antidepressants and delay of treatment to minimize treatment-related depression in this population needs further study.

 


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 408

 

LONG-TERM EFFECT OF INTERFERON ALFA-2B PLUS RIBAVIRIN THERAPY ON INCIDENCE OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH HEPATITIS C VIRUS-RELATED CIRRHOSIS

 Chao-Hung Hung, Chuan-Mo Lee, Sheng-Nan Lu, Jing-Houng Wang, Hung-Da Tung, Chien-Hung Chen, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Republic of China.

 

Objective:

To assess the treatment efficacy of interferon (IFN) alfa-2b plus ribavirin therapy and to determine whether these therapies influence the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis.

 

Methods:

One hundred twenty-five patients with HCV-related cirrhosis who received IFN alfa-2b (3 or 5 MU thrice weekly) and oral ribavirin (1000-1200 mg per day) for 24 or 48 weeks were analyzed. Sustained virological response (SVR) was defined as negative HCV RNA at 6 months after therapy. Any other pattern of response was defined as non-response (NR).

 

Results:

A total of 111 patients completed therapy. Forty-eight % of patients were of genotype 1b. Seventy-two (58%) achieved a SVR. Multivariate analysis of the factors (age, gender, genotype, viral load and IFN dosage) revealed that non-genotype 1b (p=0.000) and low viral load (p=0.000) were independent variables of treatment efficacy. Over a median follow-up of 37 (12-60) months, HCC developed in 10 patients with NR and 5 with SVR. The incidence was significantly higher in patients with NR than that of sustained responders (p=0.0281).

 

Conclusion:

These results suggest that successful HCV eradication by using IFN alfa-2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV-related cirrhosis.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 409

 

DURABILITY OF SUSTAINED VIROLOGICAL RESPONSE IN HEPATITIS C TREATED PATIENTS

 CHRISTOPHER P. DESMOND, STUART ROBERTS, SHARA NGUYEN, FRANCIS DUDLEY, JOANNE MITCHELL, CAROLINE DAY, MICHAEL BAILEY, STEPHEN PIANKO, ALFRED HOSPITAL, Melbourne, Australia.

 

Background and Aims:

Late relapse after a treatment induced sustained virologic response is known to be uncommon in hepatitis C virus infection. The optimal follow-up of these patients is unclear. Our aim was to examine long term virologic outcome in a group of sustained virologic responders.

 

Methods:

We retrospectively identified 147 patients treated at our hospital who had achieved a sustained virological response. We analysed baseline demographics, risk factors for infection, genotypes and treatments received. The durability of virologic response was assessed for all patients.

 

Results:

Of 147 patients, 67% were male; 83% Caucasian, 7% Asian and the median age was 39 years. Risk factors included: IVDU (54%); blood transfusion (22%). Genotype was determined in 134 patients: gt 1 (34%); gt 2 (8%); gt 3 (54%); gt 4 (2%) and gt 6 (1%). Therapy included 1 treatment course in 127 (86%) patients; 2 in 16 patients (10%); 3 in  6 patients (4%). Treatment consisted of: interferon alone 32 patients; Peg-interferon alone 3 patients; interferon/ ribavirin 68 patients and Peg-interferon/ ribavirin patients. Mean duration of therapy was 34 weeks. After a mean follow-up of 119 weeks (range 24-537 weeks) post sustained virologic response, there was no evidence of virologic relapse in 146/147 patients (99%). One patient experienced a virologic relapse at some time between 24- 94 weeks after an end of treatment response.

 

Conclusions:

Virologic relapse after a sustained virologic response in hepatitis C virus infection is rare. We have shown that, irrespective of genotype and treatment(s) received, the response is maintained up to 10 years with virtually no late relapse. The critical outcome is achieving a sustained response. Virologic follow-up in these patients is of low yield and largely unnecessary.


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 410

 

COMPARISON OF 2 DOSES OF PEG-INTERFERON ALFA-2B PLUS WEIGHT BASED RIBAVIRIN FOR TREATMENT OF PREVIOUSLY UNTREATED PATIENTS WITH GENOTYPE 1 HCV INFECTION

 Paula P. Cox, Hao Do, Robert L. Carithers Jr., University of Washington, Seattle, WA; Pacific Northwest Hepatology Research Consortium.

 

Background:

Patients who receive > 10.6 mg/kg of ribavirin plus 1.5 mg/kg of PEG Intron have sustained virological response rates > 60% Manns et al. Lancet (2001). However, patients with HCV genotype 1 infection have not fared as well. Even with optimum doses of PEG Intron and ribavirin, fewer than 50% of patients achieve a sustained response to treatment. This is a problem of increasing importance since 70% of U.S. patients with chronic hepatitis C have genotype 1 infection.

 

Patient population and study design:

104 previously untreated patients with genotype 1 infection were randomized to receive either either Group 1: PEG-Intron 1.5 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 48 wk or Group 2: PEG-Intron 3.0 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 24 wks then PEG-Intron 1.5 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 24 wk. Patients were stratified by the presence or absence of cirrhosis and study region. Treatment was discontinued in patients who had detectable HCV RNA after 24 weeks of therapy. Virological response was defined as absence of detectable HCV RNA by PCR.

 

Results:

To date, 49 and 48 patients have been randomized to groups1 and 2 respectively. 70 patients have completed 12 weeks and 36 patients have completed 48 weeks of treatment. Virologic response at week 12 was observed in 72% of patients in group 1 and 82% in group 2. Virological response after 48 weeks of therapy was seen in 65% of patients in group1 and 75% in group 2. 19 patients (13 in group 1 and 6 in group 2) have discontinued therapy due to adverse events or noncompliance. 27% of patients in group 1 and 13% of patients in group 2 have had grade 3 or 4 adverse events. Patient enrollment and follow-up of these patients is ongoing.

 

Conclusions:

High dose PEG-Interferon plus weight based ribavirin therapy is tolerated as well as standard doses of PEG-Interferon plus weight based ribavirin. However, there appears to be only a slight increase in efficacy after 12 and 48 weeks of therapy with the higher dose regimen.

 


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 411

 

FACTORS AFFECTING HCV VIRAL LOAD IN PATIENTS WITH GENOTYPE 1 INFECTION

 John Ticehurst, Johns Hopkins University School of Medicine, Baltimore, MD; Sylvia Hu, Fayez Hamzeh, F. Hoffmann-La Roche Ltd., Nutley, NJ; David Thomas, Johns Hopkins University School of Medicine, Baltimore, MD.

 

Introduction:

Hepatitis C virus (HCV) RNA can be detected in the blood of chronically infected patients. The quantity of HCV RNA predicts treatment response, but what determines the HCV RNA level (VL) itself is unknown. This exploratory data analysis describes the correlation between HCV VL and various baseline demographic characteristics of patients enrolled in six pivotal trials for peginterferon α-2a (PEGASYS®) and ribavirin (COPEGUS®).

 

Methods:

This analysis was restricted to HCV genotype 1 (n = 2474) patients with baseline VL assessment. HCV RNA VL was measured by Cobas Amplicor HCV Monitor Test, version 2.0 (Roche Diagnostics). The baseline factors evaluated were age, sex, race (white vs black vs other), weight, BMI, hepatic inflammation, hepatic fibrosis. Baseline characteristics were first summarized for each of the three HCV RNA categories as determined by distributions along a continuum: <0.3, 0.3-1.0, and >1.0 million copies per mL. Differences in baseline characteristics among the groups were tested using Cochran-Armitage Trend Test. The correlation coefficients were provided along with the p-value for testing R2≠0.

 

Results:

Statistically significant correlations were detected between baseline HCV RNA VL and age, weight and BMI . However, the strength of these correlations was low, correlation coefficients (R) ranged from 0.16 for age, 0.11 for gender, 0.10 for fibrosis, 0.09 for inflammation, 0.07 for weight, and 0.05 for BMI. Even when all of these factors were incorporated into a linear regression model, less than 10% of the person to person variability in HCV RNA level was explained, R 0.214.

 

Conclusions:

HCV RNA levels are higher in persons who are older, male, have more fibrosis and inflammation on biopsy, are heavier and have higher BMI. Nonetheless, most of the person to person differences in HCV RNA levels cannot be explained by sociodemographic and histologic factors. Further research is needed to understand the biologic basis for HCV RNA set points and their role in predicting treatment response.

 

Table 1 Summary of Baseline Characteristics By Baseline HCV RNA

 

Baseline HCV RNA (million copies/mL)

 

≤0.3

0.3 - 1

> 1

P-Value

n

243

524

1707

 

Weight ≤ 85 kg

181 ( 74.5%)

356 ( 67.9%)

1101 ( 64.5%)

0.0015

Age ≤ 40 years

123 ( 50.6%)

238 ( 45.4%)

584 ( 34.2%)

<.0001

BMI ≤ 27 kg/m2

167 ( 68.7%)

317 ( 60.5%)

941 ( 55.1%)

<.0001

 


Topic:  Interferon Based Therapy 

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 412

 

REGRESSION OF LYMPHOPROLIFERATIVE DISORDERS AFTER TREATMENT FOR HEPATITIS C INFECTION? A SYSTEMATIC REVIEW

 Javier P. Gisbert, Luisa Garcia-Buey, Jose M. Pajares, Ricardo Moreno-Otero, La Princesa University Hospital, Madrid, Spain.

 

Aim:

To systematically review the experience of therapeutic studies where antiviral regimen, with alfa-interferon (IFN) with or without ribavirin (RBV), was administered to patients with lymphoproliferative disorders, trying to answer the question whether eradication of HCV may induce regression of lymphoproliferative disorders.

 

Methods:

Bibliographical searches were performed in several electronic databases and in the Cochrane Controlled Trials Register up to April 2004, looking for several key words related with “Hepatitis C” and “Lymphoma”. Abstracts of the articles selected in each of these multiple searches were reviewed, and those meeting the inclusion criteria were recorded. Reference list from trials selected by electronic searching were hand searched to identify further relevant trials. Articles published in any language were included. Patients with only mixed cryoglobulinemia but with no other associated lymphoproliferative disorders were not included.

 

Results:

Sixteen therapeutic studies where antiviral regimen (with IFN with or without RBV) was administered to HCV-infected patients with lymphoproliferative disorders (mainly low-grade, but also intermediate/high grade non-Hodgkin’s lymphomas) have been performed, including a total of 65 patients. Complete remission of the lymphoproliferative disorder was achieved in 75% (95% confidence interval, 64-84%) of the cases. In contrast with infected patients, HCV-negative subjects did not respond to IFN therapy, indicating that the response observed in the HCV-infected patients is not merely due to the antiproliferative effect of IFN. Remission of lymphoproliferative disorders after HCV eradication with IFN was maintained, provided that HCV infection did not reappear; however, viral relapse was usually followed by recurrence of lymphoma. Several studies demonstrated a similar response to chemotherapy in non-Hodgkin’s lymphoma patients infected and non-infected with HCV. It was reported that in HCV-infected patients with non-Hodgkin’s lymphoma treated with corticoids and chemotherapy liver function tests deterioration did not occur, thus indicating that immunosuppressive therapy does not, apparently, increase HCV replication. Some studies suggest that the addition of IFN to standard CHOP may decrease hepatic side effects of chemotherapy.

 

Conclusion:

Although it is evident that larger therapeutical trials of antiviral therapy are needed to determine the role of this strategy in HCV-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that IFN (plus RBV) is an attractive therapeutic option for some HCV-related low-grade lymphomas. Multicenter controlled studies with pegylated IFN plus RBV are eagerly awaited.


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 413

 

SUSTAINED VIRAL RESPONSE (SVR) WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) WHO WERE NON RESPONDERS (NR) TO PEGINTERFERON ALFA-2B AND RIBAVIRIN

 Norman Gitlin, Kristina D. Muther, Emory University, Atlanta, GA.

 

Introduction:

Sustained viral response rates in patients with naïve CHC treated with Peginterferon alfa-2b (“PEGINTRON”) and ribavirin have been reported in registration studies to vary from 42% for genotype 1 to 81% for genotypes 2 or 3. Retreatment of patients with pegylated interferon and ribavirin who failed simple interferon and ribavirin, has resulted in a SVR varying from 10 to 18%.

 

We report our initial SVR results in 31 patients who were NR to peginterferon alfa-2b and ribavirin at 12 to 24 weeks of therapy and then retreated with peginterferon alfa-2a and ribavirin, using fixed dose peginterferon alfa-2a, 180 microg/week and body weight dosing of ribavirin 1000 or 1200mg daily.

 

Patient Demographics:

Of the 31 patients, 17 were Caucasian (11 males), and 14 were African American (8 males). Cirrhosis was present in 11 patients (32%). Genotype 1 was present in 29 patients, the other 2 patients were genotype 2. All the patients had failed to eliminate their HCV viral loads by 12 to 24 weeks of therapy with peginterferon alfa-2b and ribavirin.

 

Results:

A SVR was achieved in 10 of the 31 (32%) patients. This consisted of 8 out of 17 (47%) Caucasian and 2 of 14 (14%) African Americans. A total of 3 of 11 (27%) with cirrhosis achieved a SVR. Withdrawal or relapse during therapy occurred in 1 patient (3%) in each category. Adverse reactions required the use of erythropoietin and/or granulocyte stimulating factor in 6 (19%) patients; irritability, depression or fatigue in 8 (26%) and systemic features (flu, fever, weight loss, insomnia) in 7 (23%).

 

Conclusion:

Retreatment of patients who failed peginterferon alfa-2b and ribavirin with peginterferon alfa-2a and ribavirin resulted in an overall SVR of 32%. It was well tolerated. Better outcomes occurred in Caucasian patients than African American. Pre-existing cirrhosis did not preclude a successful response.


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 414

 

PEG-INTERFERON-ALPHA-2B AND RIBAVIRIN TREATMENT IN CHILDREN AND ADOLESCENTS WITH CHRONIC HEPATITIS C

Stefan Wirth, HELIOS Klinikum, Wuppertal, Germany; Antje Ballauff, Children' Hospital, University, Essen, Germany; Ulrike Kullmer, Children's Hospital, University, Mainz, Germany; Thomas Lang, Children's Hospital University, Munic, Germany; Philip Wintermeyer, Patrick Gerner, HELIOS Klinikum, Wuppertal, Germany.

 

Background and aims:

Treatment with recombinant alfa-interferon-2b three times a week and daily ribavirin yielded encouraging results with an overall response rate of around 50% in our pediatric population with chronic hepatitis C. However, the administration of PEG-interferon in the combination treatment has the considerable advantage of weekly dosage and moreover improved the response rate in adults. Therefore, the aim of the study was to evaluate the efficacy and tolerability of PEG-alfa-Interferon-2b in combination with ribavirin in chronic infected children with various routes of viral transmission.

 

Methods:

In an open label pilot study 62 children (33 female, 29 male) aging from 2 to 17 years (mean 11) were treated with subcutaneous PEG-alfa-interferon-2b at a dose of 1.5 µg/kg body weight once a week in combination with oral ribavirin (15 mg/kg x day) for 12 months. Mode of infection was parenteral in 24, vertical in 25 and unknown in 13 children.. Genotype 1 was present in 49 (79 %) and type 2 and 3 in 13 (21 %) patients. Due to protocol children, who remained HCV RNA positive after six month therapy, discontinued treatment.

 

Results:

61 children completed the study. At the end of treatment 37 (60,7 %) patients were HCV RNA negative and liver enzymes had normalized. Response was documented in 19 (82,6 %) children with parenteral, in 13 (52 %) with vertical, and in 5 (38,5 %) with unknown route of infection. 24/48 (50 %) of individuals with genotype 1 and 13/13 with genotyp 2, 3 were HCV RNA negative. 11,1 % had HCV RNA breakthrough during the 6. - 12. months of treatment and the relaps rate was 12,5 %, indicating to date a sustained response rate of 44 % in genotype 1. Overall, the treatment was well tolerated. Nevertheless, considerable side effects were present in 20 %.

 

Conclusion:

Due to our results combination of PEG-alfa-interferon with ribavirin seems to be well tolerated in children and adolescents with chronic hepatitis C. Compared to parenterally infected children patients with vertical transmission displayed a lower response. Overall, it seems doubtful, if PEG-interferon is actually able to improve the response rate in comparison with non-pegylated interferon in this age group.


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 416

 

ELEVATED ALT AND AST DUE TO PEGYLATED INTERFERON –α INDUCED POLYMYOSITIS IN TREATED PATIENTS WITH UNDETECTABLE HEPATITIS C VIRAL LOAD

Michael P. Curry, Simon C. Robinson, Sean Savitz, Beth Israel Deaconess Medical Center, Boston, MA; Cathey Williams, Norman Gitlin, Emory University, Atlanta, GA.

 

Introduction:

Polymyositis has been documented to occur in minority of patients infected with hepatitis C virus infection (HCV). The etiology of HCV related polymyositis in unknown. In addition, interferon therapy of HBV, melanoma and renal cell carcinomas has been reported to cause polymyositis. Interferon is contraindicated in patients with autoimmune diseases and caution is indicated in treating patients with myositis. Myositis occurred in less than 1% of patients in registration studies. We report the development of polmyositis in 9 patients (7 males) treated with combination pegylated interferon and ribavirin therapy for chronic HCV infection.

 

Patients:

These patients (mean age ± SD: 48 ± 8y) were treated with Ribavirin in combination with Pegylated Interferon-α 2b (n=6) or Pegylated Interferon-α 2a (n=3). Eight patients had genotype 1 and 1 had genotype 3 HCV infection. Mean pre-treatment HCV RNA was 3.5x 106 IU/ml.

 

Results:

Polymyositis was suspected in 5 patients with negative viral load after they developed asymptomatic elevations in AST and ALT and subsequently had a CPK checked. Polymyositis was symptomatic in 4 patients with elevation of AST and ALT, 3 of whom had undetectable HCV RNA at presentation. Polymyositis was confirmed by elevations of CPK, aldolase and physical exam in 6 patients, 3 patients had confirmatory muscle biopsy and electromyography. The mean time from start of treatment to diagnosis of polymyositis was 24 weeks (range 5-44weeks). CPK was elevated in all patients with a mean value of 584U/ml. Eight patients completed combination anti-viral treatment. EVR and SVR was 78% and 67% respectively. One patient discontinued anti-viral therapy at week 5 because of symptoms of polymyositis. Polymyositis resolved in 6 patients. One patient was treated with steroids and azathioprine with resolution and 3 patients have mild residual symptoms not requiring treatment.

 

Conclusion:

Polymyositis is recognized side effect of pegylated interferon-α 2a and –α 2b therapies for HCV. It should be suspected in patients with elevation in AST/ALT during interferon therapy with a negative viral load or if patients develop skeletal muscle weakness. Diagnosis can be confirmed by measurement of CPK, EMG and muscle biopsy when indicated. Most patients can continue treatment under close scrutiny with favorable virological outcomes.


Topic:  Complementary Therapies

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 418

 

COMPLEMENTARY AND ALTERNATIVE MEDICINE: A SURVEY FOR PEOPLE DIAGNOSED WITH HEPATITIS C

 Andrea L. Mulkins, Natalie R. Rock, Lori Lee Walston, Paula Cramer, Frank H. Anderson, Vancouver Hospital, Vancouver, BC, Canada.

 

Objective:

To provide quantitative measures of the prevalence, patterns, reasons for use and perceived benefits from complementary therapies (CAM) among individuals with Hepatitis C (HCV).

 

Methods:

A self-administered questionnaire was given to 300 HCV patients attending a community based outpatient clinic at Vancouver Hospital. The questionnaire included 19 questions regarding demographics, conventional treatments received, specific CAM therapies used, reasons for use, perceived benefit, disclosure to physician and utilization of CAM information resources. Data was entered into SPSS 10.0 and analyzed primarily for descriptives including frequencies and summary measures. Users of CAM and non-users were compared by demographics (age, gender, marital status, education, employment status and ethnicity) and medical (time since diagnosis, type of conventional treatment) characteristics. Contingency analysis between CAM use and potential determinants was performed to select variables to be included in modeling. A multiple logistic regression analysis including all the significant independent variables was then conducted to determine the strongest independent predictors of CAM use.

 

Results:

Fifty-nine percent of patients used CAM therapies with the most common being the herbal supplement, milk thistle, exercise and multivitamins. The most common reasons given for choosing to use CAM therapies were to (1) improve quality of life (2) boost the immune system and (3) slow disease progression. Most patients felt that CAM therapies had improved their energy levels, reduced stress, and gave them a sense of control over the illness whereas only 43.9% felt that CAM therapies improved liver function. The majority of those using CAM (81%) had told their physician(s) about their CAM use, but few utilized either their family physician (15%) or their specialist (7%) as sources of CAM information. CAM users most commonly consulted friends or family (39%) for information about CAM. CAM users were more likely than nonusers to delay or decline conventional treatment. Respondents who had never used CAM had typically never thought about it or did not have enough information about the treatments.

 

Conclusions:

More than one half of recently diagnosed HCV patients utilize some form of CAM therapy, and the majority, disclose their use to their physician(s). However, they tend to rely on anecdotal information for their CAM decision making. Dissemination of reliable CAM information is one key to helping patients navigate this difficult arena.


                              Topic: Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 419

 

PEG-IFN ALFA-2B AND RIBAVIRIN FOR CHRONIC HEPATITIS C IN DAILY PRACTICE. THE ITALIAN MULTICENTER HIT STUDY

Giovanni B. Gaeta, Davude F. Precone, Gianfranca Stornaiuolo, Anna Amato, Novella Carannante, Maria Stanzione, Marcello Persico, Felice Piccinino, Second University of Naples, Napoli, Italy; Nicola Caporaso, Federico II University, Napoli, Italy; Piero L. Almasio, University of Palermo, Palermo, Italy; HIT Study Group (Hepatitis C In-the-field Treatment.

 

Introduction:

We prospectively evaluated the patients starting treatment (Tx) for chronic hepatitis C in 92 units, during the period December 1, 2001- March 30, 2002. No indications on selection criteria or choice of Tx were provided.

 

Methods and patients:

1288 consecutive patients were included. Males were 59.2%, median age was 58 years (range 18-74), body weight 72 Kg (42-120), 57.6% had BMI <25 and 4% >30. Intravenous drug use and blood transfusion were recorded in 11.5% and 10%, respectively; 59% were IFN naïve. 43 centres enrolling 694 patients agreed to complete follow-up: treated naïve patients were 425 (61.2%) and 291 of them received Peg IFN alfa2b plus ribavirin; 72.6% were genotype 1 and 10% had cirrhosis, 68.5% fulfilled the admission criteria used in Manns trial. All the patients were scheduled to receive 48 week Tx and were followed-up for at least 24 weeks after stopping Tx.

 

Results:

On ITT analysis, overall SVR was 47.1%; response rates by genotype are reported in the Table. 80% of the patients were treated with Peg IFN dose >1 mcg/Kg and RBV dose >10.6 mg/Kg; the dose received was not associated to SVR. Age and genotype were the only independent response predictive factors. Premature discontinuation of Tx for adverse events occurred in 17.9% of the cases. SVR occurred in 30.4% of the cases who discontinued, 41.9% of those who reduced dose and in 53.9% of those who maintained the initial dose.

 

 

SVR and ETR by HCV genotype 

 

SVR

ETR

All

137/291 (47.1%)

185/291 (63.6%)

Genotype 1

63/162 (38.9%)

98/162 (60.5%)

Genotype 2

22/39 (56.4%)

30/39 (76.9%)

Genotype 3

11/16 (68.8%)

12/16 (75%)

Other and Unknown

41/74 (55.4%)

45/74 (60.8%)

 

Conclusion:

The persons treated in daily practice for chronic hepatitis C were older, had a lower body weight and had more frequent comorbidities than those treated in RCTs; moreover, in one third of the cases the admission criteria used in Manna trials were not fulfilled.  Overall, the sustained response rate of 47.1% indicates that a greater variety of patients than in RCTs can be successfully treated with combination of Peg-FIN alfa 2b and ribavirin.

 

The strong independent predictive value of age suggests that a policy aimed to an early identification of treatable patients is warranted.

 

 


Topic:  Interferon Based Therapy – Special Populations – Prisons

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 420

 

TREATMENT FOR HEPATITIS C IN JAILHOUSES IS DOABLE AND SUCCESSFUL: DEFINITIVE DATA OF FIRST NATIONAL FRENCH STUDY

 Author Block: REMY andre jean, hepatology unit, Perpignan, France; POPHEC investigators group.

 

Background: A French survey in 85 jailhouses in 2000 yielded disappointing results regarding diagnosis and treatment of hepatitis C (HCV) in inmates: serology was available for 2/3 of the patients but only 36% had undergone liver biopsies (LB) and 4% had been treated. LB access was identified as a an obstacle to therapy. This prospective study (POPHEC) was designed to increase treatment access in this population. Methods: 37 medical units in French jailhouses participated. LBs were optional. Biochemical, virologic and clinical data were collected . Therapy and data collection continued for patients transferred. When final data are not available, patients have been included in none responders.

 

Results:

As of June 1st 02, 200 patients were analyzed: 94% men, mean age 37 years, contamination route IVDU in 78%, transfusion in 3%. Genotype was 1a, 1b, 3a and 4 in 28%, 11%, 36% and 7%, respectively; 12% were also infected with HIV; 37% were treated by methadone or buprénorphine. The average viral load was 1227689 IU/mL; 33% had LB before treatment with an mean Metavir score of A1.8 F1.73. The mean treatment duration ranged from 4 months in patients with early termination due to non-medical reasons to 7 months for patients completing therapy ; 95 patients (47.5%) experienced complete sustained response ).

 

Conclusion:

Treatment for HCV in jailhouses is feasible and uccessful; limitation in indications for LBs, as recommended by the 2002 French consensus conference, specifically apply to the inmate population and facilitate access to HCV therapy, as well as initiatives such as POPHEC.


Topic:  Disease Management – Special Populations

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 422

 

BARRIERS TO TREATMENT OF HEPATITIS C IN ALASKA NATIVES

 Carol Christensen, Alaska Native Tribal Health Consortium, Anchorage, AK; Dana Bruden, Artic Investigations Program, CDC, Anchorage, AK; Steve Livingston, James Williams, Chriss Homan, Alaska Native Tribal Health Consortium, Anchorage, AK; Thomas Hennessy, Artic Investigations Program, CDC, Anchorage, AK; Heike Deubner, Daniel Sullivan, David Gretch, University of Washington, Seattle, WA; Brian McMahon, Alaska Native Tribal Health Consortium, Anchorage, AK.

 

Background:

Effective antiviral treatment is available for Hepatitis C infection, though ethnic differences in response rates may exist. The purpose of this study was to determine barriers to treatment in Alaska Natives with HCV who receive their care in a managed care system and to determine if there is any difference between patients who are treated vs. those who are not treated.

 

Methods:

All Alaska Natives with HCV are sent a letter biannually reminding them to have their liver function tests performed by either a primary care provider or the Hepatology clinic. We retrospectively reviewed charts of patients receiving antiviral treatment between 1992-2003. We prospectively evaluated patients in the Hepatology Clinic at the Alaska Native Medical Center for eligibility for treatment over a one-year period and documented a primary reason why treatment was not given. We performed statistical analysis comparing those patients who were treated, not treated, and those not keeping their appointments.

 

Results:

·      Of 750 Alaska Natives identified statewide who are HCV RNA positive, 52 (7%) have received antiviral therapy since 1992.

·      Of the 445 Alaska Natives who are HCV RNA positive living in the Anchorage area, 130 treatment naïve patients had 196 appointments scheduled in 2003 and 58 (45%) of those patients did not keep their appointment.

 

Treatment was not given in 69 patients (96%) for the following reasons:

·      15 current alcohol or drug abuse,

·      14 normal ALT levels,

·      15 patients’ decision to defer treatment,

·      5 concurrent medical conditions,

·      5 decompensated cirrhosis,

·      4 severe psychiatric condition,

·      2 mild fibrosis on liver biopsy, 2 not competent,

·      5 other reasons.

 

Three patients (4%) began treatment. Patients treated had a significantly longer estimated length of infection (p<0.01) and were more likely to have a Knodell Fibrosis score > 1 (p=0.03) compared to not treated patients. No significant differences were found in sex, mean age, genotype, elevated ALT, risk factors, and alcohol consumption at the time of study entry.

There was no significant difference in patients who kept their appointments but were not treated vs. those not keeping their appointments in the following variables; sex, mean age, mean number of years since diagnosis, genotype, elevated ALT, Knodell Fibrosis score > 1 on liver biopsy, risk factors, and alcohol consumption at the time of study entry.

 

Conclusions:

·      A significant number of Alaska Native patients with HCV remain untreated for a variety of reasons, similar to what has been in found in other groups.

·      No significant differences were found in patients who attended vs. those who did not keep clinic appointments.

·      Future studies are needed to examine how to improve clinic attendance by analyzing the reasons why patients do no keep appointment.

·      Heath education tools need to be developed to inform patients about the hepatitis C disease process and treatment options.


Topic:  Pegasys

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 423

 

COMPARATIVE SAFETY OF PEGINTERFERON ALFA-2A (40 KD) (PEGASYS®) AND PEGASYS PLUS RIBAVIRIN (COPEGUS®): RESULTS OF THE PROSPECTIVE, RANDOMIZED, MULTICENTER, OPEN LABEL WINGS™ SAFETY TRIAL

Maribel Rodriguez-Torres, Fundacion de Investigation de Diego, Santurce, Puerto Rico; Linsay Philip, PrimaCare, Fall River, MA; Mitchell L. Shiffman, Virginia Commonwealth University Health System, Richmond, VA; Edward Brettholz, Concord Medical Center, New York, NY; Michael Ryan, Gastrointestinal & Liver Specialists of Tidewater, Norfolk, VA; Sylvia Hu, Mary Beth Layton, Salvatore Badalamenti, F. Hoffmann-La Roche Ltd., Nutley, NJ.

 

Introduction:

Treatment of chronic hepatitis C with PEGASYS and PEGASYS/COPEGUS, achieves sustained virological responses in a substantial number of patients. Both agents have been associated with adverse effects (AE) that may impact compliance and efficacy. We compared the safety of PEGASYS with PEGASYS/COPEGUS in patients enrolled in the WINGS trial.

 

Methods:

1280 patients with chronic hepatitis C were randomized 1:3 to 48 weeks of treatment with PEGASYS or PEGASYS/COPEGUS at 223 US centers. When results from multicenter clinical trials showed superior efficacy of PEGASYS/COPEGUS compared with monotherapy, an additional 602 patients were enrolled in the combination therapy arms (Fried NEJM 2002, Hadziyannis Ann Intern Med 2004). The primary objective was the relative risk (RR) between the 2 randomized groups of fatigue (Fatigue Severity Scale ≥4), depression (BDI-II ≥22), anemia (hgb <10 g/dL or ≥3 g/dL decrease), neutrophils <0.5 x 109/L, or clinically significant infections (CSI) requiring treatment through week 12.

 

Results:

Patients were predominantly male (69%), Caucasian (82%), aged >40 yrs (82%) with HCV genotype 1 infection (62%, non-1 18%, unknown 20%) and had most commonly acquired HCV through intravenous drug use (41%). 47% of patients were treatment-naïve, 29% had received prior treatment (i.e. had relapse/breakthrough/nonresponse) and the previous treatment status of 24% is unknown.

During the first 12 weeks of treatment in randomized patients, the RR of anemia (2.3, 95CI: 1.9-2.8) and neutropenia (3.1: 1.2-8.2) were significantly higher in recipients of PEGASYS/COPEGUS than PEGASYS. The RR of fatigue (1.1: 0.95-1.3), depression (1.0: 0.7-1.5), CSI (1.1: 0.9-1.4) and serious CSI (0.8: 0.3-2.1) were similar between the 2 groups. Comparative safety of treatment in all enrolled patients through week 48 is presented in the table.

 

Conclusion:

The safety profile of PEGASYS and PEGASYS/COPEGUS was similar, except for the incidence of anemia and neutropenia during the first 12 weeks of treatment. In the study, AEs generally occurred early in treatment and were managed mainly without treatment discontinuation. The results of WINGS confirm the excellent safety profile of PEGASYS/COPEGUS.

Adverse events during 48 weeks of treatment in all patients

Event – N (%)

PEGASYS N=301a

PEGASYS/COPEGUS N = 1549

Fatigue (FSS score ≥4)

214 (71)

1077 (70)

Depression (BDI-II ≥22)

29 (10)

167 (11)

Hgb <10 g/dL

17 (6)

100 (6)

Neutrophils <0.5 x 109/L

6 (2)

45 (3)

CSI

74 (24)

420 (29)

Serious CSI

5 (2)

37 (3)

Dose Modifications

90 (31)

618 (40)

Discontinuations for Lab abnormalities or AE

34 (11)

180 (12)

Deaths (possibly treatment-related)b

1

1

a140 of 301 patients added COPEGUS therapy at wk 12 or later. b1 death was attributed to suicide and the second occurred in a patient lost to follow-up so causality could not be ruled out

 


Topic:  HIV/HCV Coinfection – Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 424

 

BASELINE INSULIN RESISTANCE DEMONSTRATES NEGATIVE PREDICTIVE VALUE FOR WEEK 12 EARLY VIROLOGICAL RESPONSE TO ANTIVIRAL THERAPY IN HEPATITIS C AND HIV CO-INFECTED PATIENTS

 Kaushik Agarwal, Alison J. Uriel, Lisa Moorehead, MariaIsabel Fiel, Nikolas Kontorinis, Mount Sinai Medical Center, New York, NY; Mark Sulkowski, Johns Hopkins Medical Institute, Baltimore, MD; Douglas T. Dieterich, Mount Sinai Medical Center, New York, NY; Hepatitis Resource Network.

 

Introduction:

Evidence suggests an important role for steatosis in response to antiviral therapy in Hepatitis C monoinfection (HCV). Dyslipidemia and abnormal insulin metabolism are common in HIV infection and often related to anti-retroviral therapy (ART). Thus HIV/ HCV patients are at increased risk of non-alcoholic fatty liver disease (NAFLD), which may also negatively impact response to antiviral therapy.

 

Aim:

To investigate the role of insulin resistance (IR) in early virological response (EVR) to combination therapy in HCV/ HIV co-infected patients.

 

Methods: Baseline characteristics of 102 co-infected individuals who were enrolled into a re-treatment study with pegylated interferon α-2a and ribavirin (HRN004) were assessed. IR was calculated via the homeostasis model assessment (HOMA-IR). Liver biopsies were scored using the modified HAI for HCV. Univariate analyses and multivariate logistic regression were utilized.

 

Results:

84 patients began treatment, 19 patients discontinued therapy prior to 12 weeks. 84 patients entered this cohort, 43% demonstrated EVR. 70 (83%) were male, 70 (83%) genotype 1, 35 (42%) were Hispanic, 25 (30%) were African-American and 24 (28%) Caucasian. Mean age was 48.6 years (± 6.2SD), median BMI 25.9 (IQR 24.0-30.0); 40 (47%) were on a protease inhibitor, 81 (96%) had a CD4 count > 200, 60 (71%) had undetectable HIV viral load, median HCV-RNA was 657x103 IU/ml (IQR 438-5011x103). 27 (42%) (viral load information not updated ) Histological analysis demonstrated that 70 (96%) patients had HAI grade 0-9 and (56%) had HAI fibrosis stage 0-3.

 

 

Conclusions:

Our data demonstrate that HOMA-IR and cholesterol are significant predictors of EVR in HCV/ HIV co-infected patients undergoing antiviral therapy. Mechanisms underlying these findings warrant further investigation.

 


Topic:  Interferon Based Therapy- Special Populations

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 425

 

HISPANIC PATIENTS HAVE A DIFFERENT RESPONSE TO INTERFERON/RIBAVIRIN THERAPY FOR HEPATITIS C THAN NON-HISPANIC WHITE PATIENTS

John Goff, Patricia Branch, Lisa Thomsen, Rocky Mountain Gastroenterology Associates, Arvada, CO; Rocky Mountain Clinical Research.

 

Introduction:

There is ample evidence for differences in the response of hepatitis C (HCV) to treatment with interferon (IFN) and ribavirin between ethnic groups, but there is little information on whether the Hispanic population has any unique treatment response issues. We did a retrospective review of concurrently treated with IFN and ribavirin non-Hispanic white (NHW) patients and Hispanic patients with HCV to determine if there were any differences.

 

Methods:

50 NHW (36M, 14F) and 28 Hispanic (21M, 10F) were included. The avg age = 48 yr NHW, 53 yr Hispanic. 44% of the NHW were stage 3 or 4. 64% of the Hispanic were stage 3 or 4. The NHW genotypes were 74%=1, 10%=2, 10%=3, 4%=unknown. The Hispanic genotypes were 43%=1, 18%=2, 18%=3, 21%=unknown. Genotype 1 patients received 12 months of therapy with IFN and ribavirin. Genotype 2/3 patients received 6 months of therapy with IFN and ribavirin. 92% of the patients received pegylated IFN with ribavirin. The other 8% had IFN and ribavirin.

 

Results:

NHW end of treatment response (ETR) = 46% and Hispanic ETR = 54%, but the sustained viral response (SVR) was 78% and 60% of the ETR for the NHW and Hispanic groups respectively. The ETR for genotype 1 = 32% NHW and 43% Hispanic, while the ETR for genotype 2/3 = 100% NHW and 80% Hispanic. The SVR for genotype 1 = 58% NHW and 75% Hispanic, while the SVR for genotype 2/3 was 100% NHW and 50% Hispanic of the ETR groups respectively.

 

Conclusions:

The Hispanic patients had a higher %ETR compared to NHW patients, but they had a lower %SVR. The major difference occurred in the higher loss of response for the Hispanic patients in the genotype 2/3 group. The better %SVR in the Hispanic genotype 1 group is despite them being older and having more fibrosis than the NHW group. These findings raise the question as to whether Hispanic patients with genotype 2/3 might benefit from 12 months of treatment rather than 6 months.


Topic:  Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 426

THREE MONTH HCV RNA BY PCR POST IFN AND RIBAVIRIN THERAPY FOR SUCCESSFULLY TREATED CHRONIC ACTIVE HEPATITIS C (HCV) CAN BE USED TO DETERMINE SUSTAINED VIROLOGICAL RESPONSE (SVR)

 Lino J. De Guzman, Bradley Collins, Inland Empire Digestive Diseases & Liver Center, Redlands, CA.

 

AIM:

The purpose of this trial was to evaluate the earliest time point (one or three months) before patients (pts) can be classified as having a SVR after a complete response (CR) to HCV treatment (TX). Currently, the standard is to wait 6 months after TX before identifying pts with a SVR. It is estimated that 98% of pts with a SVR at 6 months will remain virus free indefinitely unless re-exposed and infected.

 

Methods:

A total of 60 HCV pts who had a CR had quantitative HCV RNA by PCR collected at the end of TX and at 1, 3 and 6 month intervals thereafter. There were 33 males, 35 pts were Genotype (G)1, 11 pts G 2 and 14 pts G 3. In order to qualify, pts must have completed 24 weeks if G2 or G3 or 48 weeks if G1 of either PEG IFN or standard IFN plus ribavirin. Metavir scores were the following: F0 (7 pts), F1 (22 pts), F2 (14 pts ), F3 (11 pts) and F4 (6 pts). This trial also examined if any underlying relationship existed between a pts total white blood cell count (WBC) and amino alanine transferase (ALT) levels after cessation of therapy to predict ultimate response or relapse.

 

Results:

HCV RNA by PCR taken at 1 and 3 months after completing TX correlated highly with viral loads obtained at 6 months. A total of 13 of the 60 pts (21.6%) with CR relapsed. All of the 3 month HCV RNA measurements were in exact agreement with those taken at 6 months (100% specificity). Only one (G 3) pt who had a CR after 24 weeks of TX became HCV RNA(+) between the 1 and 3 month blood draws (98% specificity).

 

Conclusion:

The specificity of the HCV RNA by PCR at 1 and 3 months post HCV TX for pts with a CR is similar to the viral load at 6 months. Based on the results of this data, we feel that SVR can be made with assurance at 3 months post HCV TX. and perhaps as early as 1 month after the end of TX. There was no significant relationships between WBC or ALT levels in predicting SVR.


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 427

 

BUDGET IMPACT ANALYSIS OF TWO DIFFERENT METHODS OF EVALUATING EVR TO PEGINTERFERON ALFA-2B (PEGINTRON®) PLUS RIBAVIRIN (REBETOL) THERAPY IN GENOTYPE 1 NAÏVE PATIENTS WITH CHRONIC HEPATITIS C

 MARIA BUTI, RAFAEL ESTEBAN, HOSPITAL UNIVERSITARIO VALLE HEBRON, Barcelona, Spain; LESLIE FOSBROOK, SCHERING-PLOUGH, Madrid, Spain; Miguel angel CASADO, PHARMACOECONOMICS & OUTCOMES RESEARCH IBERIA, Madrid, Spain.

 

Background/Aims:

Genotype 1 patients with chronic hepatitis C are the least responsive to peginterferon and ribavirin therapy and therefore monitoring early virologic response (EVR) is an important tool for identifying non-responders quickly, permitting therapy discontinuation and avoiding side effects and costs.

 

Objective:

To analyze the financial impact of two different measurement techniques for evaluating the EVR during peginterferon alfa-2b plus ribavirin therapy and to compare the results with the full 48 week course of therapy in genotype 1 naïve patients with chronic hepatitis C.

 

Methods:

A financial impact model was developed to compare two different strategies of determining EVR and the resultant impact on treatment costs compared with standard 48 weeks course of therapy. Strategy 1: peginterferon alfa-2b plus ribavirin for 12 weeks. Patients with a decline in HCV-RNA >2 logs continue therapy to complete 48 weeks. Strategy 2: peginterferon alfa-2b plus ribavirin for 12 weeks. Patients with HCV Core Ag negative continue therapy to complete 48 weeks.

 

EVR

PPV (EVR and SVR)

Strategy 1

74%

86%

Strategy 2

82%

84%

 

EVR was defined at week 12 as either a decline of >2 logs in HCV RNA levels tested with a quantitative HCV RNA assay (total 2 tests: baseline / week12) or undetectable HCV Core Ag at week 12 (1 HCV Core Ag test). Clinical data was taken from multi-center trials[JP1] , while costs were taken from published literature based on the perspective of the Spanish Health Care System. The base-case scenario assumed that a potential study population of 85,000 people with genotype 1 would be eligible for treatment in Spain.

 

Results:

For genotype 1 patients with chronic hepatitis C, testing EVR by HCV Core Ag was the most effective strategy resulting in 58,548 patients reaching SVR and an overall budget of US$1,338 million (US$22,858 per successfully treated patients). Conversely, evaluating EVR by means of quantitative HCV-RNA resulted in 54,094 patients and an investment of US$1,276 million (US$23,589 per successfully treated patient). The incremental cost per successfully treated patient with strategy 2 versus strategy 1 therefore represents US$13,988.

 

Conclusion:

Assessment of EVR, specifically by HCV Core Ag test, in genotype 1 chronic hepatitis C patients treated with peginterferon alfa-2b and ribavirin provides an accurate tool for identifying patients with SVR resulting in a lower overall cost. This strategy should be recommended in current clinical practice.


Topic:  HIV/HCV Coinfection – Interferon Based Therapy

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 428

 

EARLY PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE (SVR) IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) AND HIV INFECTION TREATED WITH IFN+RBV

 Manel Crespo, Juan I. Esteban, Silvia Sauleda, Alberto Juarez, Vicenç Falco, Esteban Ribera, Isabel Ruiz, Imma Ocaña, Victor Vargas, Maria Buti, Albert Pahissa, Rafael Esteban, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

 

Background:

HCV viral dynamics during the first weeks of treatment with interferon + RBV is useful to identify poor viral response in monoinfected patients. Patients showing an HCV RNA decrease < 2 log at week 12 have a minimal chance to eradicate HCV infection and are therefore considered non responders.

 

Aim:

To assess the predictive value of HCV viral dynamics in HCV-HIV coinfected patients treated with interferon + RBV

 

Methods:

From an ongoing randomised trial, in patients with CHC and stable HIV infection, aimed to compare the efficacy and safety of pegIFN alfa-2b (1.5 mcg/Kg/week) versus IFN standard (3 MIU/tiw), both in combination with RBV (800 mg/d), we assessed the virological response at week 4,8 and 12 of treatment in the first 61-consecutive-enrolled patients who have finished treatment and follow-up periods, and constructed ROC plots with the RNA decreases from baseline at these time points (ΔRNA 4, 8 and 12) to define the best cut-off point of predicted probability for SVR. The duration of treatment was 24 (genotype 2/3) or 48 weeks (genotype 1/4, in case HCV-RNA < 100 IU/mL at week 24). SVR was defined as HCV-RNA < 100 IU/mL 24 weeks after the end of treatment.

Results: In an intent-to-treat analyses, SVR was 53% (16/30) in the pegIFN+RBV group and 35% (11/31) in the IFN+RBV group (p=ns). For genotype 1/4 SVR was 37% (7/19) versus 19% (4/21), whereas for genotype 2/3 SVR was 82% (9/11) and 70% (7/10), respectively. As summarised in the table, sensitivity peaks with 100% negative predictive value for SVR were observed for HCV- RNA decrease > 1 log at week 4 and > 3 log at week 12 of treatment. In a stepwise logistic regression analyses also including baseline parameters (HCV RNA, genotype, treatment arm, sex, age, BMI), HCV-RNA decrease at week 12 was the most powerful predictor of SVR.

 

Conclusion:

SVR can be early predicted in HCV-HIV coinfected patients and the rule of 2-log decrease at week 12 is also useful. Monitoring the early response make special sense in this population both to avoid toxicity in non responders and to ensure adherence in all eventual responders.

 

Notes. ΔHCV RNA: viral load decrease from baseline; PPV: positive predictive value; NPV: negative predictive 

 

Week

Δ HCV RNA

Sensitivity

Specificity

PPV

NPV

4

> 1 log

100% (27/27)

42% (14/33)

59% (27/46)

100% (14/14)

8

>= 1.9 logs

100% (26/26)

61% (20/33)

64% (23/36)

96% (22/23)

12

> 3 logs

100% (27/27)

70% (23/33)

73% (27/37)

100% (23/23

 


Topic:  Treatment Side Effects

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 429

 

PREVALENT MANIC SYMPTOMS IN PEGINTERFERON-INDUCED MOOD DISORDERS IN PATIENTS WITH CHRONIC HEPATITIS C: THERAPEUTIC IMPLICATIONS

Laurent Castera, Services d'Hepato-Gastroenterologie, Hopital Haut Leveque et St-Andre, Bordeaux, France; Aymery Constant, Laboratoire de Psychologie de la Sante EA 526, Université Victor Segalen Bordeaux 2, Bordeaux, France; Jacques Demotes-Mainard, Centre d'Investigation Clinique, Hopital Haut Leveque, Pessac, France; Patrice Couzigou, Service d'Hepato-Gastroenterologie, Hopital Haut Leveque, Pessac, France; Chantal Henry, Services de Psychiatrie, Hopital Charles Perrens, Bordeaux, France.

 

Background:

Interferon (IFN)-induced mood disorders are common and often responsible for treatment discontinuation. Most studies reported these disorders as depressive episodes and thus recommended antidepressant treatment. However, in clinical practice, patients frequently complain of irritability and hostility and cases of mania and bipolar syndromes have been reported with IFN.

 

Aims:

To characterize mood disorders (incidence, time course, nature, risk factors and management) occurring during peginterferon plus ribavirin treatment of chronic hepatitis C.

 

Methods:

98 naive patients with chronic hepatitis C (57 males, mean age 42±12 yrs) treated with peginterferon-alpha (1.5µg/kg/week) plus ribavirin (800-1200 mg/d) for 24 to 48 weeks were enrolled in a longitudinal study of mood assessment. They were systematically screened for mood disorders at baseline and during treatment (at week 4, W12, W24, and W48) by a trained psychologist using the MINI (Mini-International Neuropsychiatric Interview, a semi-structured interview that assess psychiatric disorders according to DSM-IV criteria) and MADRS (Montgomery-Asberg Depression Scale, that measures intensity of depressive symptoms). In case of the occurrence of psychiatric side effects, patients were refered to a psychiatrist for diagnosis and management.

 

Results:

38 patients (39%) developed mood disorders (33 (87%) between baseline and W12, 5 (13%) between W12 and W24 and none after W24), consisting of major depression with manic features in 17 cases (45%) and irritable mania/hypomania in 21 cases (55%). Their occurrence was significantly associated with a past history of depression (p<0.04) and intravenous drug use (p<0.006). 24 patients needed to be referred to a psychiatrist. Given the predominance of manic symptoms (mean number of maniac vs depressive symptoms: 5.33 vs 3.83, respectively; Wilcoxon test; t=31.5; z=3.08; p=0.002), patients were treated with an antipsychotic (amisulpride) at a low to moderate dosage (mean dose 160 mg, range 100-600 mg) (19 as initial treatment and 5 after failure of antidepressant treatment). Improvement was observed within 1 to 2 weeks in most patients, allowing the continuation of antiviral therapy in all patients but one (96%).

 

Conclusions:

Our findings, showing that IFN-induced mood disorders consist of a mixture of manic/hypomanic and depressive symptoms, differ substantially from those of studies published so far identifying depression as a hallmark of IFN-induced mood disorders. They may have important therapeutic implications : when manic symptoms are prevalent, antidepressant may exacerbate these symptoms. Antipsychotic such as amisulpride should rather be used, allowing the continuation of antiviral therapy in the majority of patients.


Topic:  Treatment Side Effects        

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 430

 

OCULAR SIDE EFFECTS IN CHRONIC HEPATITIS C PATIENTS RECEIVING PEGYLATED INTERFERON (PEG-INF) ARE RELATED WITH SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) LEVELS

 Raul Andrade, F Jesus Gonzalez, Luis Vazquez, Angel Cilvetti, R Camargo, M Garcia-Cortes, MI Lucena, Hospital Clinico Universitario, Malaga, Spain.

 

Introduction:

PEG-INF associated with ribavirin is currently the standard therapy for chronic hepatitis C. Side effects with combination therapy may be severe and often leads to premature discontinuation. Ocular features in patients treated with interferons appear to be common but usually asymptomatic although severe retinal changes and loss of visual acuity has been described.

 

Aim:

The aim of this study was to determine the presence of ocular alterations during PEG-INF therapy and its possible relationship with the main pro-angiogenic growth factor (VEGF).

 

Methods:

Thirty four chronic hepatitis C patients [(18 men/16 women; median age 44.3 years (17-67)] were prospectively assessed during routine treatment with PEG-INF (18 patients with PEG-INF α2a, 180 μg/w and 16 with PEG-INFα2b, 1.5 μg/kg/w). Complete ophthalmologic evaluation was performed before and at the end of therapy as was serum VEGF levels using a commercially available kit of ELISA (R&D system).

 

Results:

Thirteen out of 34 (38.2%) patients were found to develop ocular side effects considered to be of vascular pathogenesis (intraretinal haemorrhage and cotton wool patches; the OSE group). The presence of OSE was irrespective of the type of PEG-INF employed as well as of the response to therapy. The OSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects (NOSE group) (281 (106-386) vs 117 (83-225) pg/ml; p=0.05). These differences increased when VEGF values were corrected by platelet count (1.656 (1.021-2.653) vs 0.820 (0.533-1.217) pg/106 platelets; p=0.008). In the OSE group baseline VEGF and VEGF/platelet values were significantly higher than those observed in the other group (164 (55-260) vs 64 (21-172) pg/ml; p= 0.046 and 0.920 (0.217-1.543) vs 0.320 (0.100-0.661) pg/106 platelets; 0.024 respectively).

 

Conclusions:

In chronic hepatitis C patients treated with PEG-INF, the OSE presumed to be of vascular pathogenic origin, are related to circulating VEGF levels. High baseline serum VEGF levels may predict these particular adverse effects and could be useful to select the population that deserve a close follow-up.

 

Saturday Poster Session 10/30/2004 5:30 pm – 8:00pm

Viral Hepatitis and Liver Transplantation

 

 

Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM              Program#/Poster#: 440

 

IMPACT OF DONOR AGE ON SURVIVAL AND FIBROSIS IN HCV PATIENTS TRANSPLANTED WITH HCV(+) LIVERS

 Asma Poonawala Khapra, Kaushik Agarwal, Maria Isabel Fiel, Nickolas Kontorinis, Sabera Hossain, Thomas D. Schiano, Mount Sinai Medical Center, New York, NY.

 

Introduction:

The use of hepatitis C virus antibody positive (HCV(+)) donor organs in liver transplantation (LT) for HCV has become a widespread strategy to increase the donor pool. However, there is no data on severity of histological fibrosis secondary to HCV post-LT recurrence in this population.

 

Aim:

To evaluate clinical outcome and histological fibrosis in a cohort of HCV patients transplanted with HCV(+) grafts matched to HCV patients transplanted with HCV(-) grafts.

 

Methods:

A retrospective database review of all patients transplanted for HCV at MSMC from 1988 to 2004 was undertaken. Thirty-nine patients were identified as having received HCV(+) grafts while 580 patients received HCV(-) grafts. Kaplan-Meier survival curves compared graft and patient survival in the two groups. In assessing histological fibrosis, each case (HCV(+)) was matched to a control from the pool of HCV(-) graft recipients utilizing criteria of donor age, transplant year, UNOS/MELD score, recipient age, and post-LT survival. All liver biopsies were reviewed by one blinded liver pathologist and, using the Knodell modified histological activity index (HAI), analyzed for fibrosis due to HCV recurrence.

 

Results:

No significant difference in patient and graft survival was seen between recipients of HCV(+) donor organs and controls. Yet, a statistically significant decrease in both graft and patient survival was found in patients who received HCV(+) grafts from older donors (>50); with a higher rate of graft failure (hazard ratio, 2.74; 95% CI, 1.34-5.61) and increased rate of death (hazard ratio, 2.63; 95% CI, 1.23-5.6) as compared to HCV(-) graft recipients who also received older donor organs (see fig). Matched case-control analysis of histology data revealed that recipients of HCV(+) grafts had more severe fibrosis post-LT for equal length of survival than recipients of HCV(-) livers, with a median of difference in maximum fibrosis of 1 among the two groups (p=0.008). Also, more advanced fibrosis was seen in patients who received HCV(+) grafts from older donors as compared to those who received HCV(+) grafts from younger donors (p= 0.012).

 

Conclusion:

Our data suggests that HCV(+) graft recipients from older donors (>50) have higher death rates, graft failures, and more extensive fibrosis post-LT than HCV(-) graft recipients from older donors. Furthermore, we demonstrate that all HCV(+) graft recipients, regardless of donor age, have more advanced fibrosis and thus, worse histological outcomes post-LT, than HCV(-) graft recipients.

 

 


 

Topic:  Transplantation – Diagnostic Tools

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 441

 

THE RELIABILITY OF LIVER BIOPSY TO DIAGNOSE ACUTE REJECTION? THE IMPACT OF RECURRENT HEPATITIS C

 Ryan A. McTaggart, Linda Ferrell, University of California, San Francisco, San Francisco, CA; Charles R. Lassman, University of California, Los Angeles, Los Angeles, CA; John P. Roberts, Norah A. Terrault, Sandy Feng, University of California, San Francisco, San Francisco, CA.

 

Introduction:

Historically, liver biopsy has proven reproducibility and reliability to diagnose acute rejection (AR) after liver transplantation (LTx). We hypothesized that the context of recurrent hepatitis C (R-HCV) would significantly erode the diagnostic reliability of liver biopsy for AR.

 

Methods:

Two LTx pathologists (P1 and P2) from two large volume centers reviewed four sets of blinded slides representing 88 liver biopsies, all of which carried historical diagnoses of mild or moderate AR, R-HCV, or both. Pathologists were informed that all biopsies were obtained between 4 weeks and 6 months after transplantation and given blinded sets, labeled by the transplant era (1993-1994 = 50 biopsies or 2000-2001 = 38 biopsies) and the recipients’ HCV status (HCV+ = 38 biopsies and HCV- recipients = 50 biopsies). Readings were transcribed into a database and, after a hiatus of one month or more, each pathologist was asked to score his/her blinded readings for the diagnosis of AR using the following scale: 1=Unlikely; 2=Possible; 3=Probably; 4=Likely. An experienced clinician © also scored blinded printouts of the current readings of both pathologists and of historical readings. The C’s scores were then used to compare current interrater agreement and agreement between current versus historical diagnoses. Agreement was assessed by determining frequencies of relative (difference ≤ 1) and exact agreement (RelAg and ExAg, respectively) and by weighted kappa statistics (wκ).

 

Results:

C was an excellent interpreter of both P1 and P2 (wκ P1 = 0.92; wκ P2 = 0.90) (Table 1a). There was good agreement between pathologists regarding the diagnosis of AR for HCV- recipients (wκ = 0.55) but poor agreement for HCV + recipients (wκ = 0.18) (Table 1b). Comparison of current to historical readings similarly showed substantially better agreement for HCV- recipients (wκ current vs. 93/94 = 0.58; wκ current vs. 00/01= 0.39) than for HCV+ recipients (wκ current vs. 93/94 = 0.021; wκ current vs. 00/01 = -0.037) (Table 1c).

 

Conclusions:

The clinical context of HCV dramatically affects the reproducibility and reliability of liver biopsy to diagnose AR early after LTx. Presumably, histologic features of recurrent HCV which overlap with those of AR compromises the ability of even highly experienced LTx pathologists to make the diagnosis. If increased intensity of immunosuppression is associated with accelerated post-transplant HCV progression, our results suggest that a decision to treat AR based upon biopsy results alone may be ill-advised. 

 

 

 

 

 


 

Topic:  HIV/HCV Coinfection – Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                    Program#/Poster#: 442

 

INDICATIONS AND TIMING FOR LIVER TRANSPLANTATION IN HIV CO-INFECTED PATIENTS

Isabelle Pache, Jean-Charles Duclos-Vallee, Elina Teicher, Henri Bismuth, Denis Castaing, Daniel Vittecoq, Didier Samuel, Paul Brousse Hospital, Villejuif, France.

 

Introduction:

Patients with a chronic viral hepatitis have a faster evolution to cirrhosis when co-infected with HIV. Since 1998, these patients have been evaluated for liver transplantation.

 

Aim:

To determine at what time of their liver disease these patients are referred.

 

Results:

Between 1.1.1998 and 30.6.2003, 102 patients with cirrhosis due to chronic hepatitis B, C and/or D and co-infected with HIV have been seen at our Hepatology Unit. Mean age was 41.6±7.3 years. Eighty six (84.3%) patients were male. HIV infection was known for 11.4±4.3 years. Contamination was most frequently due to drug injections. Mean CD4 count was 389±298. Seventy one (69.8%) patients have a chronic hepatitis C, 21 (20.5%) a chronic hepatitis B, 6 (5.8%) a delta co-infection, and 4 (3.9%) a BC coinfection. Thirty (29.4%) patients were Child-Pugh A, 30 (29.4%) Child-Pugh B and 42 (41.2%) Child-Pugh C. The mean MELD score was 17.6±6.5. Among the 59 patients who were considered as possible candidates for liver transplantation, 17 (28.8%, mean MELD score: 23.4±5.7) died before evaluation or on waiting list, 4 (6.8%) reached again a Child-Pugh A score and were withdrawn from waiting list (no death during follow up) and a diagnosis of advanced hepatocellular carcinoma was made in 1 patient. Fourteen (23.7%) patients had a liver transplantation, Their mean MELD score was 19.4±6.5. 23 patients are still waiting transplantation. Forty-nine (48%) patients did not meet criteria for a liver transplantation. The most frequent reasons (>100%) were: Child-Pugh A cirrhosis (69.4%), current alcohol abuse (24.5%), non compliance (18.4%), advanced hepatocarcinoma in 5 patients (10.2%).

 

Conclusions:

Among the 102 HIV infected patients referred for cirrhosis due to chronic viral hepatitis, 57.8% met the criteria for a liver transplantation, but in 29%, the liver disease was too advanced and these patients died before evaluation or on the waiting list. The Meld score as prognosis indicator should be evaluated, but more specific and sensitive criteria for liver transplantation should be defined in HCV-HIV co-infected patients. HIV coinfected patients should be referred early in the course of the liver disease to a liver transplantation unit.

 

 


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                 Program#/Poster#: 443

 

DONOR PREDICTIVE FACTORS OF HCV RECURRENCE AFTER LIVER TRANSPLANTATION (OLTX)

 Sara Boninsegna, Padua University, Italy, Padova, Italy.

 

Background/Aim:

Post-OLTx HCV recurrence is virtually universal but rate and severity of graft disease and the identification of the factors influencing recurrence are still under debate. Aim of this study was to evaluate donor predictive factors of recurrent HCV disease in patients transplanted for HCV-related cirrhosis.

 

Methods:

187 consecutive patients transplanted for HCV-related ESLD were evaluated (147 M/37 F, mean age 51±9.2, mean follow-up 75.9 ± 32.5). Donor’s factors evaluated: age, sex, [Na]serum, ICU stay, use of vasoactive drugs, graft ischemia time, AST/ALT.

 

Results:

1, 5, 7-year survival rate were 84%, 76%, 75% respectively. Patients with peri-operative mortality (11%) were excluded from the analysis. HCV recurrence, defined as HCV-RNA positivity and biopsy-proven hepatitis, was found in 136/164 (83%) overall. Median time of HCV recurrence was 10±2 months. Biochemical hepatitis (presence of ALT >2 nv) during first 6 post-OLT months occurred in 73/164 (44.5%). Recurrent HCV cirrhosis developed in 28/164 (17%) in a median time of 39±3 months. The following donor factors influencing time of histological recurrence (HEP) and development of recurrent cirrhosis (Cirrh) were evaluated:

 

 

X2

Logistic Regression

Donor’s Factors

HEP

CCirrh

HEP

Ccirrh

< 12 mths

<6 mths

< 12 mths

<6 mths

p

p

p

p

p

p

age

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

sex

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

[Na]serum

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

ICU stay

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

AST/ALT

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

>1 Vasoactive drug

0,01

0,0001

n.s.

0,02

0,001

n.s.

Cold ischemia time

n.s.

n.s.

0,03

n.s.

n.s.

n.s.

Tot ischemia time

n.s.

n.s.

0,005

n.s.

n.s.

0,03

 

Conclusions:

1)Strong vasoactive therapy in the management of the donor is related with early HCV recurrence. 2)Total ischemia time is related with recurrent HCV cirrhosis (in particular: cold ischemia time seems related with recurrent HCV cirrhosis)

 


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                       Program#/Poster#: 444

 

HCV QUASI-SPECIES IN LIVER TRANSPLANT PATIENTS OUTCOME

 Javier Moreno Sr., Rafael Barcena Sr., Santos Del Campo Sr., Miguel Garcia Jr., Jesus Nuño Sr., Jesus Fortun Sr., Gloria Moraleda Sr., Hospital Ramon Y Cajal, Madrid, Spain.

 

Background:

It has been showed that HCV quasispecies in patients who receive a orthotropic liver transplantation (OLT) is more homogeneous with respect to control patients (1). The fibrosis outcome and relapse severity could be determinated by the quasispecies distribution after OLT.

 

Aim:

To evaluate whether disease development could have been influenced by the quasispecies distribution in patients who did receive an OLT. Patients and

 

Methods:

Fifteen patients undergoing liver transplantation divided into two groups according to fibrosis stage. Group I: 7 patients who developed a mild fibrosis (I-II); group II: 8 patients who developed a severe fibrosis (III-IV). Liver histology was done after 34.07±9.08 months in group I and 26.52±15.07 months in group II. The mean age of the patients was 59.14±3.34 in group I and 49±10.32 in roupie. HCV quasispecies diversity was analysed in the hypervariable region 1 (HVR1) of the viral genome and assessed by RT-PCR, cloning and sequencing in pretransplantation and posttransplantation serum samples. MEGA2(2) and SPSS were used to analize the data obtained.

 

Results:

There were not statistically differences in the groups when HVR1 nonsynonymous substitutions were compared between pretranspalnt and posttranplant serum samples (p=0.39 in group I, p=0.062 in group II). Neither, significant differences were observed when roupieplant serum samples were compared between group I and II (0.066±0.051 vs 0.060±0.050, respectively; p=0.82). However, a significant decrease in the HVR1 nonsynonymous substitutions was found in posttransplant serum samples in group II when compared with group I (0.025±0.015 vs 0.052±0.029, respectively; p=0.038,). Finally, a statistically significant difference was also observed when the mean age of the patients was compared (59.14±3.34 in group I vs 49±10.32 in roupie, p=0.028).

 

Conclusion:

The mutation appearance that give rise nonsynonymous substitutions in the viral genome seems to indicate the outcome of the fibrosis severity.

1. Moreno GJ, del Campo TS, Moraleda GG, Garcia GM, de Vicente LE, Nuno Vazquez-Garza J et al. Analysis of hepatitis C viral quasispecies in liver transplantation. Transplant Proc 2003; 35(5):1838-1840.

2. MEGA2: Molecular Evolutionary Genetics Analysis software, Bioinformatics. 2001.

 


Topic:  Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                   Program#/Poster#: 446

 

FACTORS PREDICTIVE OF 24 WEEK VIRAL RESPONSE TO PEG IFN ALFA-2B PLUS RIBAVIRIN IN PATIENTS WITH RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION

Reem Ghalib, Cheryl Levine, Tricia McClelland, Liver Institute at Methodist Dallas, Dallas, TX; Blaine Hollinger, Rise Stribling, Baylor College of Medicine, Houston, TX; Terry Box, William Hutson, University of Utah, Salt Lake City, UT; Anthony Post, University Hospitals of Cleveland, Cleveland, OH; Fredric Regenstein, Shoba Goshi, Tulane University, New Orleans, LA; Jeffrey Weinstein, Ahmad Abo Kayass, Fay Simon, Liver Institute at Methodist Dallas, Dallas, TX; Ayman Zubi, John Goss, Baylor College of Medicine, Houston, TX; Stephen Cheng, Bo Husberg, Liver Institute at Methodist Dallas, Dallas, TX.

 

Introduction/Aim:

To identify factors predictive of 24 week viral response to PEG IFN alfa-2b plus ribavirin in the post transplant patient with recurrent hepatitis C.

 

Methods:

This multi-center randomized clinical trial of OLT patients with histologic recurrent HCV started with PEG IFN alfa-2b 0.5 mcg/kg/week plus ribavirin 600 mg/day. At week 4, patients tolerating therapy were increased to ribavirin 800 mg/day and according to baseline randomization either remained at 0.5 mcg/kg/wk (low dose arm) or increased to 1.5 mcg/kg/week (high dose arm). Therapy continued for 48 more weeks unless HCV RNA was positive at week 24.

 

Results:

Currently 59 patients are enrolled (age 37-67 years; mean 51.5 ± 6.0) (20 females; 39 males) with a range of 0.3-4.8 years post OLT (mean 1.5 ± 1.0). HCV was genotype 1/4 in 45 patients (76%). Mean HCV RNA at baseline was 3.9 million IU/mL (range 0.04-15.5 million IU/mL). Analysis was done on 50 patients who have either completed >24 weeks or discontinued therapy. By treatment week 12, 27 patients had undetectable virus which continued to week 24, 2 patients had ≥ 2 log decrease in virus with having undetectable virus at week 24; and 22 patients had <2 log decrease in virus with one having undetectable virus at week 24. Significantly more patients were HCV RNA negative at 24 weeks in the high dose arm compared to low dose arm with 21/24 (88%) vs. 8/26 (31%), respectively (p<.001). HCV RNA was negative in 20/41 (49%) genotype 1/4 vs. 9/9 (100%) genotype 2/3 (p <.004). HCV RNA viral clearance by gender and race was noted at 11/17 (65%) male and 18/33 (55%) female (p<.4); and 26/40 (65%) White, 0/2 (0%) Black, 2/7 (29%) Hispanic, 1/1 (100%) Asian (p<.09). Analysis of patients by weight revealed viral clearance in 13/21 (62%) with <80 kg vs. 16/29 (55%) ≥ 80 kg (p<.4). Virologic response by ribavirin dose was 7/12 (58%) with >10.6 mg/Kg vs. 22/38 (58%) with <10.6 mg/kg (p<.9). HCV RNA 24 week viral clearance by level of baseline viral load was <1 million/mL with 8/14 (55%), 1 to 5 million/mL with 11/17 (65%), 5-10 million/mL with 8/16 (50%), and >10 million/mL with 2/1 (67%) (p <.8)

 

Conclusions:

Analysis of this ongoing study of treatment of recurrent hepatitis C in liver transplant patients shows that the most predictive factor of 24 week viral clearance was dose of PEG IFN alfa-2b comparing 1.5 mcg/kg/week to 0.5 mcg/kg/week (87% and 31%, respectively). As in the non-transplant population, patients with genotype 2/3 and White race had higher on treatment response rates at week 24. No significant relationship was found for gender, body weight, ribavirin dose (mg/kg), or baseline viral load. Further investigation of predictive factors of viral response are needed in the liver transplant population to guide selection of appropriate treatment candidates and therapies.


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                Program#/Poster#: 445

 

DISPARATE MEASURES FOR DISPARATE PATIENTS: THE BENEFITS OF TOPICAL TESTOSTERONE REPLACEMENT (TTR) IN TRANSPLANT RECIPIENTS WITH CHRONIC HEPATITIS C VIRUS AND ALLOGRAFT FAILURE

Guy W. Neff, University of Cincinnati, Cincinnati, OH; Christopher B. O’Brien, Kamran Safdar, Antonette Demanno, Seigo Nishida, Eric Rideman, Andreas Tzakis, Juan Madariaga, University of Miami, Miami, OH; Steve M. Rudich, University of Cincinnati, Cincinnati, OH.

 

Introduction:

Liver transplant recipients suffering chronic allograft failure due to recurrent HCV often develop marked muscle wasting followed by ascites prior to succumbing to death. Topical testosterone replacement (TTR) has been shown to effectively improve muscle mass and overall well being in patients with HIV.

 

Aims:

Determine if TTR could improve muscle mass, well being and survival in patients post liver transplant with impending allograft loss due to recurrent HCV.

 

Methods:

A retrospective review of patients treated for at least 6 months from January 2000 to October 2003 with testosterone gel 1% (5 grams per day) therapy for muscle wasting (MW) (Group 1). Pre and post treatment albumin, pre-albumin, ransferring, testosterone (free and total), estrogen and luteal hormone (LH) were performed. Drug safety analysis included frequency of acute rejection, cholestasis, malignancy, patient and/or graft loss. Group 2 consisted of patients not treated with testosterone with a similar clinical setting during the same time frame.

 

Results:

14 patients were identified with stage 3 or 4 fibrosis and MW and allograft failure due to recurrent HCV. Group 1 (n=9) included 6 males & 3 females, mean age 51 years. Group 2 (n=5) included 3 males & 2 female, mean age 53 years. Group 1 9/9 pts had subjective improvement in muscle strength, and overall well being. Group 1 had an increase in mean serum albumin from day 1, 30, 90 and 180 (2.5, 2.7, 3.1, 3.5, g/dL, respectively) while those in Group 2 decreased from 2.6 to 2.1 g/dL (p=0.0002) over the 6 months. MELD scores in Group 1 improved from 14 to 10 (aver) while those in Group 2 worsened from 14 to 22 (p=0.001). CTP scores improved from 9.0 to 7.0 in group 1 while worsening in group 2 9.1 to 10.4 (p=0.04). There were no differences in pretreatment ransferring; however serum testosterone (% free (0.8 to 1.2) and total (255 to 745 ng/dl)) and estriol (35 to 45 ng/ml) increased while luteal hormone (12 to 5.1 mIU/ml) returned to normal values. 2/9 patients in group 1 and none in group 2 were treated with pegylated interferon alfa 2a with ribavirin. One of the treated patients has become serum HCV PCR nondetectable. There were no deaths in Group 1, while 4/5 patients in Group 2 died on average 84 days (range 14 to 144) post transplant. Complications in Group 1 included: 2 women with lower extremity lymph edema, (both cases resolved with lowering of TTS to 2.5 grams per day), 1 case of hypertension, (treatment stopped at month 6), 1 case of pruritus (treatment stopped at month 6).

 

Conclusions:

These results suggest that TTR increases muscle strength (subjective measures), stimulates albumin synthesis and most importantly improves survival in post liver transplant recipients with HCV and allograft failure.

 


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                        Program#/Poster#: 447

 

EXCESS WEIGHT GAIN AFTER LIVER TRANSPLANTATION AND EARLY FIBROSIS PROGRESSION OF RECURRENT HEPATITIS C

Pierluigi Toniutto, Carlo Fabris, Luca Apollonio, Elisabetta Fumo, Maja Caldato, Internal Medicine, University of Udine, Udine, Italy; Carlo Smirne, Rosalba Minisini, Mario Pirisi, University of East Piedmont, Novara, Italy.

 

Introduction/Aim:

Early progression to fibrosis is observed in many patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (OLT). It has been suggested that, in immunocompetent patients with hepatitis C, obesity leads to more rapid fibrotic changes in the liver. Overweight and obesity are frequent and early complications of OLT; thus, the aim of this study was to verify the impact of excess weight gain after OLT in relationship to the course of recurrent HCV.

 

Methods:

Eighty consecutive patients (54 males; median age 54 years, range 23-67) were studied; minimum follow-up after OLT was 2 years. Forty-eight patients were HCV positive: 27 of them received antiviral treatment with interferon plus ribavirin, started a median of 404 days after OLT. In the remaining 32 patients, disease etiologies were: hepatitis B (N. = 12), alcohol (N. = 10), autoimmune or cholestatic liver disease (N. = 10). The speed of fibrosis development, expressed in fibrosis units per month (FU/mo), was calculated dividing the staging score at the last follow-up liver biopsy (final staging score), by the time interval (median 28 months, range 3-74) elapsed after OLT. Body mass index (BMI) values were calculated one and two years after OLT; the ratio of triglyceride to cholesterol serum levels (TCR) was calculated one year after OLT.

 

Results:

Median (75th percentile) BMI values were 25.5 (27.5) kg/m2 and 26.0 (28.5) kg/m2, at one and two years, respectively. The median final staging score was 1 (range 0-6), the median speed of fibrosis development was 0.05 FU/mo (range 0-1.25); however, 16 patients reached a final staging score >2 (of them, 11 belonged to the HCV group). Earlier recurrent hepatitis C (within 180 days after OLT) was associated with a BMI <27.5 kg/m2 one year post OLT (25/28 Vs 13/20; p <0.05) and with TCR >1.0 (11/28 Vs 1/20; p <0.01). In HCV positive patients, a speed of fibrosis development = 0.10 FU/mo or lower was significantly more common when donor age was = 45 years or younger (23/36 Vs 3/12; p<0.02), and recipient BMI two years post-OLT was 28.5 kg/m2 or higher (12/36 Vs 0/12; p<0.05). Time to event analysis showed that a low BMI value at 1 year was associated with shorter time to reach a staging score >2 in HCV positive patients (p<0.05) but not in HCV negative patients (p = NS).

 

Conclusions:

In the first years post-OLT, fibrosis progression of recurrent HCV is not hastened by post-OLT excess weight gain; on the contrary, grafts of overweight and obese HCV recipients undergo less fibrotic deposition, possibly due to later hepatitis recurrence. Since HCV adsorption is known to be inhibited by low density lipoproteins, the metabolic profile associated with overweight might interfere with HCV binding and entry into the hepatocytes.

 


Topic:  Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                     Program#/Poster#: 448

 

SUSTAINED VIROLOGICAL RESPONSE OF 65% IN PATIENTS TREATED WITH COMBINATION ANTIVIRAL THERAPY FOR RECURRENT HCV FOLLOWING LIVER TRANSPLANTATION

 Abduljaleel J. Al Alwan, N Girgrah, B McQuarrie, M Cattral, N Baker, PD Greig, A Humar, D Grant, I McGilvray, G A Levy, L Lilly, University Health Network, University of Toronto., Toronto, ON, Canada.

 

Background:

HCV infection is the leading indication for liver transplantation worldwide. Although short-term patient and graft survival for HCV patients is similar to other indications, long-term results are inferior. Here we report the results of treatment for recurrent HCV infection at our centre.

 

Methods:

Sixty-one patients with HCV recurrence (75% Genotype 1) were treated between Aug 1999 and Dec 2003 with interferon-α 2b or pegylated interferon-α 2b in combination with ribavirin (400-1000mg p.o. daily) for 3 to 38 months. Serum aminotransferases, HCV RNA levels and histology were followed.

 

Results:

Three patients discontinued therapy before 3 months and were excluded from analysis. Of the 58 patients treated for at least 6 months, 31/58 (53%) lost HCV RNA. Of these 58 patients, 23 completed treatments, while 35 still on treatment. 15/23 (65%) remained HCV RNA negative more than six months off treatment (SVR). All patients who became HCV RNA negative normalized their serum aminotransferases. On follow-up biopsy of patients completed treatment, which was available in 15/23, 9/15 (60%) demonstrated histological improvement. Of the 35 pts continuing on therapy for at least 6 months, 15/35 (43%) have now become HCV RNA negative. The virologic response rate was 20/28 (71%) in patients on Neoral versus 11/30 (37%) in patients on tacrolimus (p= 0.025). More eural patients achieved an SVR (10/12) than those treated with tacrolimus (5/11) although this did not reach statistical significance (p= 0.09).Of treated patients; the incidence of biopsy proven rejection was 7%. Growth factors used in 48% of our patients

 

Conclusions:

Combination therapy can be used safely and effectively for recurrent HCV, although dose reduction/discontinuation or requirements for growth factors are common. Interestingly the response rate in patients treated with eural is better than in those patients treated with tacrolimus compatible with a recent report suggesting that neural inhibits HCV viral replication in vitro. The response rate of 65% is superior to previously reported results, which may reflect longer treatment, use of growth factors and may be eural as primary immunosuppression.

 


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                        Program#/Poster#: 449

 

NATURAL HISTORY AND PREDICTORS OF THE SEVERITY OF RECURRENT HEPATITIS C FOLLOWING LIVER TRANSPLANTATION: A PROTOCOL BIOPSY STUDY

 Valeria Ines Descalzi, Liver Unit, Fundacion Favaloro, Buenos Aires, Argentina; Santiago Perez Lloret, Sonia Marcela Soria, Andres Eduardo Ruf, Silvina Eveleyn Yantorno, Oscar Claudio Andriani, Luis Gustavo Podesta, Federico Guillermo Villamil, Fundacion Favaloro, Buenos Aires, Argentina.

 

Introduction:

Recurrence of HCV infection following liver transplantation (OLT) is characterized by an accelerated fibrogenesis. However, outcome of HCV- disease in OLT recipients has marked individual variations and remains mostly unpredictable.

 

Aim:

To investigate the natural history of recurrent HCV infection and identify variables associated with the severity of allograft injury.

 

Methods:

The study included 53 consecutive patients with non-cholestatic HCV-recurrence and at least 1 year of follow up. Liver biopsies were performed by protocol every 6-12 months and when clinically indicated. The METAVIR score was used for grading and staging. Severe recurrence was defined as fibrosis >F2 at 1 year or ≥F3 at 3 years of OLT. Statistical tests included Kaplan-Meier and univariate and multivariate analysis by logistic regression. Variables studied included donor and recipients demographics, source of HCV infection, metabolic conditions, OLT for HCC, alcohol history, severity of illness, type of donor, pre- and post-OLT virologic factors, ischemia times, type and intensity of immunosuppression, incidence of cellular rejection and time to recurrence.

 

Results:

A total of 206 biopsies where obtained (4±2 per patient).Actuarial risk of histological chronic hepatitis was 67.5% at 1 year, 87.5% at 3 years and 90% at 6 years of OLT.Activity grade increased from 1.4±0.9 at 1 year to 2.3±0.9 at 6 years.Actuarial risk of fibrosis at 1 and 6 years was 14%/70% for F2, 8%/46% for F3 and 0%/18% for F4.Mean fibrosis score increased from 1.2 at 1 year to 1.8 and 2.2 at 3 and 6 years respectively. HCV-recurrence was diagnosed as mild in 27 patients (51%) and severe in 26 (49%). Donor age (mild:34±1 years, severe:43±12 years) was the only variable significantly associated (p=0.01) with the severity of recurrence on univariate analysis, even after exclusion of living donors. Independent predictors of severe recurrence (Cox&Snell R²=0.427) were donor age (OR:1.11, p=0.004), immunosuppression with cyclosporine (mild: 19%, severe: 81%;OR: 25.7, p=0.003), and OLT for HCC (mild:35%, severe: 65%; OR:14.07, p=0.01).

 

Conclusions:

1) Assessment of HCV recurrence with protocol biopsies showed that 6 years after OLT chronic hepatitis is almost universal and that the majority of patients have fibrosis≥F2; 2) In agreement with previous reports, this study showed that donor age is an independent predictor of severe disease. In contrast, our study did not show a significant association regarding others variables considered to be predictors of severe HCV-disease such as pre-OLT viremia, number of treated rejections, or intensity of immunosupression; 3) Further studies are required to confirm whether use of cyclosporine and OLT for HCC have a negative impact on HCV recurrence

 


Topic:  Liver Transplantation Peg-Intron

Presentation Time: 10/30/2004 5:30:00 PM                    Program#/Poster#: 450

 

A TRIAL OF PEGYLATED INTERFERON AND RIBAVIRIN AMONG LIVER TRANSPLANT RECIPIENTS WITH HEPATITIS C: REASONS FOR SCREENING FAILURE AND LOW ENROLLMENT

 A.Obaid Shakil, Shahid Habib, Brian Berk, Bijan Eghtesad, Amadeo Marcos, John J. Fung, University of Pittsburgh, Pittsburgh, PA.

 

Introduction:

Despite concerted efforts, most interferon treatment studies in transplant recipients with hepatitis C have enrolled few patients. The reasons for low enrollment have not yet been fully elucidated. We initiated a randomized study of pegylated interferon alfa2b with or without ribavirin among liver transplant recipients with recurrent hepatitis C who were at least 3 months post-transplantation. The aim of our current analysis was to determine the reasons for screening failure among study candidates.

 

Methods:

Liver recipients who attended the transplant clinic were screened for the Treatment of Recurrent C Hepatitis (TORCH) study. We analyzed the study database for failure of fulfillment of the individual inclusion and exclusion criteria. The study had 17 inclusion and 17 exclusion criteria that included age, biochemical, virologic and histologic features, and conditions that could compromise graft or patient survival.

 

Results:

Among 244 patients screened, 18 (7%) were enrolled. The most frequently failed criteria are depicted in the Table. Prior post-transplant treatment with interferon, low blood counts and elevated serum creatinine were the most frequent reasons for screening failure. Among 226 patients who failed screening, two patients did not fulfill seven criteria, nine failed six criteria, and seven failed five criteria. Seventy-five (33%) patients failed to fulfill at least three criteria whereas 142 (63%) failed to fulfill at least two criteria. The mean interval between transplantation and screening in patients who received prior interferon treatment was 51 months compared to 25 months among those who had not received prior interferon therapy (p=ns). Thirty-nine of the 149 patients (26%) who had not been on interferon prior to screening received interferon subsequently, during a mean follow up of 12 months. Thus, 116 of the 226 (51%) patients who failed screening received interferon outside the study protocol.

 

Conclusions:

Liver transplant recipients who are at least 3 months post-transplantation continue to have sub-optimal laboratory values that compromise their enrollment in interferon based treatment studies. Many such patients receive treatment outside study protocols. Further liberalization of enrollment criteria is needed in this population to ensure adequate recruitment.

 

This study was funded in part by Integrated Therapeutics Research, New Jersey.


 

Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                             Program#/Poster#: 452

 

PRETREATMENT IDENTIFICATION OF PATIENTS AT RISK FOR DEVELOPING RIBAVIRIN ASSOCIATED ANEMIA DURING TREATMENT OF POSTTRANSPLANT HCV INFECTION – THE RBV ANEMIA RISK SCORE

 Mohamed Hassan, Narayanan Menon, Walter Kremers, John Poterucha, Michael R. Charlton, Mayo Clinic, Rochester, MN.

 

Background/Aims:

Recurrence of HCV infection is almost universal following liver transplantation (LT), frequently leading to important allograft injury. Efficacy of post-LT antiviral therapy is limited by the high frequency of ribavirin (RBV) dose reductions, most commonly due to anemia. The aim of our study was to determine whether pre-treatment variables, singly or in combination, could be used to identify patients at risk for ribavirin intolerance.

 

Methods:

Fifty-four consecutive patients (36 men) with histologically confirmed post-LT HCV recurrence, who were treated with combination interferon and RBV, were prospectively studied. Discontinuation of RBV therapy and indications for discontinuation were recorded. Patient and virus specific variables were also recorded. Model building for outcomes was carried out using logistic regression. Receiver operating characteristic (ROC) curves for different models were created and compared.

 

Results:

Pretreatment characteristics of patients who required discontinuation of RBV and patients who tolerated RBV are shown in the table. RBV dosing was similar in both groups. Twenty-five (46%) patients discontinued RBV treatment. Patients who tolerated RBV were, on average, younger and had higher creatinine clearances than patients requiring RBV discontinuation. Sustained virological response (SVR) was higher for patients who tolerated RBV (27.5 Vs 18%). The most common reason for discontinuation of RBV was anemia (71%). A model (RBV Anemia Risk Score) incorporating pre-treatment creatinine clearance and baseline hemoglobin (scaled for creatinine clearance and weight: Hb/(CrCl/wt)) was the best predictor of RBV discontinuation. The concordance for this model (area under ROC) was 0.73, (p=0.0007).

 

Conclusions:

Discontinuation of RBV adversely impacts SVR. RBV associated anemia is the major indication for RBV discontinuation. Patients at risk for developing anemia that requires cessation of RBV therapy can be identified by a simple model incorporating pretreatment hemoglobin, creatinine clearance and weight. The potential for the RBV Anemia Risk Score to preemptively target erythropoiesis stimulating therapy to patients at greatest risk for RBV intolerance should be explored.

 

Variable

Tolerated RBV

RBV Discontinued

Overall Mean

Age (years)

51 (+/-6)

56 (+/-8)

54 (+/-6)

Weight (kgs)

93 (+/-20)

84 (+/-22)

88 (+/-20)

BMI

30 (+/-5.7)

28 (+/-6.7)

29 (+/-6)

Pre-Rx Creatinine Clearance (mL/Min)

71 (+/-16)

55 (+/-24)

65 (+/-21)

Pre-Rx Creatinine

1.2 (+/-0.4)

1.3 (+/-0.4)

1.27 (+/-0.4)

Pre-Rx Hemoglobin (g/dL)

13.3 (+/-1.4)

12 (+/-1.6)

13 (+/-1.6)

Pre-Rx viral load (IU x 10(6)/mL)

3.4 (+/-0.4)

5.1 (+/-0.9)

3.9 (+/-0.6)

RBV dose (mg/d)

900 (+/-206)

895 (+/-196)

900 (+/-200)

RBV dose (Wt)

10 (+/-3.8)

11 (+/-3.7)

10.7 (+/-3.6)

 

 


Topic:  Transplantation– Pegasys

 

Presentation Time: 10/30/2004 5:30:00 PM              Program/Poster# 453

 

IMPACT OF PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN ON HEPATIC FIBROSIS FOR RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION- A SINGLE CENTER EXPERIENCE

Sandeep Mukherjee, Joyce Rogge, Lynne Weaver, Daniel Frances Schafer, Rowen Zetterman, University of Nebraska Medical Center, Omaha, NE.


Background:

Recurrent hepatitis C (HCV) is universal after liver transplantation (OLT) and is often treated with interferon. We describe our experience with pegylated interferon and ribavirin combination therapy on 29 patients from a single transplant program.

Methods:

Between October 2002 and June 2004, patients with recurrent HCV were screened to determine if they were eligible for treatment. Recurrent HCV was defined as the presence of elevated transaminases in the presence of HCVRNA viremia with a biopsy demonstrating recurrent hepatitis or steatosis. This cohort was followed prospectively after starting a treatment protocol of pegylated interferon alfa-2a 180mcg qweekly and ribavirin 1000-1200mg qd (Roche, Nutley, NJ) with folic acid 1mg per day. Patients with genotypes 1 and 4 were treated for 12 months and other genotypes for 6 months. HCVRNA was repeated at 3 months, end of treatment (EOT) and six months after EOT for patients HCVRNA negative at EOT. Liver biopsies were repeated at EOT and scored according to the Batts and Ludwig methodology.

Results:

33 patients were screened and 29 eligible for treatment. There were19 males and 10 females. Median age was 49.8 years. 21 patients were genotype 1, 5 were genotype 2, 2 were genotype 2 and one was genotype 4. Median pre-treatment viral load was 2.8 million iu/ml. Median interval between OLT and treatment was 16 months. 15 patients have completed treatment, 11 remain on therapy and 3 were intolerant. Of the patients who completed treatment, 11 were HCVRNA negative at 3 months and remain negative at EOT. 6 months after EOT, 5 remain HCVRNA negative (pending in 6). Of the 11 patients on treatment, 7 were HCVRNA negative at 3 months, 1 was RNA positive and pending in 3. Interestingly, 2 of the 3 intolerant patients developed a sustained response to HCV eradication after 2 months of treatment (both were genotype 2). Improved fibrosis scores, defined as a downstaging of the EOT biopsy by at least 1 stage, occurred in only 1 patient, were unchanged in 3 and worse in 8 patients, of whom 6 were sustained responders. Decompensated liver disease occurred in 3 of these 6 patients of whom 2 were retransplanted and remain HCVRNA negative after a mean follow up of 8 months.

Conclusions:

Pegylated interferon alfa-2a and ribavirin were well tolerated in this series of patients. Only 11.3% of patients withdrew from therapy. In an intention to treat analysis, sustained HCV eradication occurred in at least 24.1% of patients. However, progressive fibrosis occurred in 75% of sustained responders. This suggests that mechanisms other than recurrent HCV may be responsible for cirrhosis in these patients who, despite successful HCV eradication, remain at risk of developing decompensated liver disease requiring retransplantation.


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                    Program#/Poster#: 454

 

IMPACT OF DONOR AGE AND YEAR OF TRANSPLANTATION ON GRAFT AND PATIENT SURVIVAL FOLLOWING LIVER TRANSPLANTATION FOR HEPATITIS C

 David J. Mutimer, Bridget K. Gunson, Queen Elizabeth Hospital, Birmingham, United Kingdom; John Chen, Flinders Medical Centre, Adelaide, Australia; Joaquin Berenguer, Hospital Universitario La Fe, Valencia, Spain; Peter Neuhaus, Charité Campus – Virchow Klinikum, Berlin, Germany; Denis Castaing, Hôpital Paul Brousse, Paris, France; Juan C. Garcia-Valdecasas, Hospital Clinic, Barcelona, Spain; Mauro Salizzoni, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy; Rene Adam, Hôpital Paul Brousse, Paris, France; Darius F. Mirza, Queen Elizabeth Hospital, Birmingham, United Kingdom; on behalf of centres contributing to the European, Liver Transplant Registry (ELTR).

 

Introduction:

Hepatitis C virus (HCV) infection has become the most common indication for liver transplantation (LT). Graft and patient survival are adversely affected by recurrent infection of the graft. Recent publications have described an inferior outcome for recently transplanted HCV patients and have highlighted the impact of advancing donor age on severity of recurrent HCV. The donor age at which a measurable impact on graft and patient outcome can be observed has not clearly been defined. In addition, the impact of donor age on graft and patient survival for non-HCV patients needs to be examined.

 

Methods:

We have examined the ELTR to examine the impact of transplantation date and donor age on graft and patient survival for HCV patients (n=4736) and for a comparison group of transplanted alcoholic liver disease patients (ALD, n=5406).

 

Results:

For the entire cohort, graft and patient survival of HCV patients was inferior to ALD patients. Since 1987 there has been a steady improvement in the outcome of transplanted ALD patients, an improvement not observed for HCV patients. Liver donor age has increased year on year since 1989. Graft and patient survival for both ALD and HCV cohorts was adversely affected by advancing donor age. Comparison of graft and patient survival for HCV and ALD cohorts was made according to donor age (donor age sub-grouped <20, 20-30, 30-40, 40-50, 50-60 and > 60 years of age). For donors younger than 40 years of age, HCV and ALD recipient graft and patient survival are not significantly different. For donors older than 40, HCV recipient graft survival is inferior to ALD graft survival, an inferiority that increases for each advancing decade of donor age. For donors older than 50, HCV recipient patient survival is inferior to ALD patient survival, an inferiority that increases when the donor age is greater than 60.

Conclusion:

The results of liver transplantation for European HCV patients are inferior to a comparison group of ALD patients, and have not improved during the past 15 years. Liver donor age has increased significantly during that period. Advancing donor age has an adverse influence on graft and patient survival for ALD and HCV patients, but a significantly greater impact is observed for HCV patients when the donor is older than 40 years.


Topic:  Liver Transplantation

Presentation Time: 10/30/2004 5:30:00 PM                  Program#/Poster#: 456

 

PROSPECTIVE STUDY OF RECURRENT HEPATITIS C: FACTORS INFLUENCING DISEASE SEVERITY AT ONE YEAR POST-TRANSPLANTATION

 A.Obaid Shakil, Shahid Habib, A. Jake Demetris, Mordechai Rabinovitz, Thomas Shaw-Stiffel, Amadeo Marcos, John J. Fung, University of Pittsburgh, Pittsburgh, PA.

 

Background/Aims:

Hepatitis C viral (HCV) infection in the transplant recipient has an accelerated course. The aim of our study was to determine host, donor and virologic factors that influence disease severity in the liver allograft.

 

Methods:

We initiated a prospective follow up study of liver transplant recipients with hepatitis C. The primary end point of our current analysis was the stage of liver allograft fibrosis at one year (± 3 months) post-transplantation. Demographic, laboratory and virologic factors were analyzed by univariate and multivariate analyses to determine their association with severe disease.

 

Results:

Among 265 HCV positive patients transplanted during the study period, 179 were enrolled. One hundred and twenty one had at least one year of post-transplantation follow up and among them 87 had liver allograft biopsies performed at one year. Twelve patients died within the first year of follow up. Histology revealed mild disease (modified fibrosis stage 0-2) in 38 patients and severe disease (stage 3-6) in 29 patients. The mean recipient age was similar in the two groups, but recipients with severe disease were more likely to have received organs from older donors. Although most patients were men, recipients with severe disease were more likely to be women and more likely to have gender mismatch. Pre-transplant MELD score was lower in patients with severe disease but Child-Pugh score was similar. The proportion of patients who received T cell depletion therapy as induction immunosuppression (anti-thymocyte globulin or alemtuzumab) was similar in the two groups. Pre-transplant serum HCV RNA levels and HCV genotype distribution was also similar in the two groups. There was no difference in the warm and cold ischemia times and blood product usage. The results did not change when we repeated the analysis after including in the severe group, an additional 9 patients who died between 12 and 48 weeks following transplantation. Older donor age was the only factor found predictive of severe disease on multi-variate analysis.

 

Conclusions:

Donor age appears to be the most important determinant of severe disease in liver transplant recipients with recurrent hepatitis C. Induction T cell depletive therapy and pre-transplant serum HCV RNA levels and genotype did not influence severity of disease in the short term.

 

This study was funded in part by NIH grant DK060619-02. 

 

 


 Sunday Poster Session—October 31 – 8:00 to 5:00PM – Hepatitis C: Virology, Epidemiology and Natural History

 

Topic:  Interferon Based Therapy

 

Presentation Time: 10/31/2004 12:30:00 PM                     Program#/Poster#: 544

 

GENOTYPE 1 VERSUS 3 AND CIRRHOSIS STATUS HAVE STRONGER EFFECT ON HEPATITIS C VIRAL KINETICS DURING COMBINATION TREATMENT THAN INTERFERON DOSAGE

Jose E. M. Medeiros Filho, University of Paraiba, Joao Pessoa – Paraiba, Brazil; Avidan U. Neumann, Bar Ilan University, Ramat Gan, Israel; Isabel MVG C. Mello, Joao R. R. Pinho, Fernanda M. Malta, Adolfo Lutz Institute, Sao Paulo – SP, Brazil; Luiz C. da Silva, Flair J. Carrilho, University of Sao Paulo, Sao Paulo – SP, Brazil.

 

Introduction:

Chronic HCV infection is a major health problem worldwide, and is the most common indication of liver transplantation due to decompensated cirrhosis and/or hepatocellular carcinoma. Although the progress on therapy, sustained virological response (SVR) is inferior to 55% in genotype 1 infected patients, despite use of pegylated IFN. Previous data regarding IFN (with/out ribavirin) demonstrated that fibrosis status is an important factor that impacts SVR rates; advanced fibrosis has been related to lower SVR rates.

 

Aim:

To evaluate the role of cirrhosis status in early viral kinetics (VK).

 

Methods:

We have recently analysed 46 naïve patients, 28 genotype 1 (7 cirrhotics – LC; 21 chronic hepatitis – CH), and 18 genotype 3 (5 LC; 13 CH) treated with IFN 9MU daily vs. 9MU at first day followed by 3 MU daily, both associated with ribavirin, with frequent viral load (VL) determinations.

 

Results:

First phase decline was compared in genotype 1 and 3, with a mean decline of 1 and 1.7 IU/mL (p<0.001). At day 2 VL determination demonstrated a statistically significant higher decline in gen 3 (p<0.001), and also a higher second phase slope for gen 3 (0.33) vs. gen1 (0.06) (p<0.001). Gen 1 LC patients showed a less intense 1st. phase when compared to gen 3 LC ones (p<0.005). The same was observed for second phase slope. Gen1 LC were compared to gen 1 CH ones and only second phase slope showed significant difference (p=0.04; 0.02 vs 0.06). No difference was observed between gen 3 LC or CH. The effect of IFN regimen on liver histology was evaluated, and a faster second phase was demonstrated for non-cirrhotic in all IFN regimens (p<0.01 for 9 MU qd; p<0,05 for 3 MU qd).

 

Conclusions:

We demonstrated that liver cirrhosis and genotype (1 vs. 3) adversely affects early VK parameters, explaining the worst SVR rates observed in cirrhotic patients. Also, the mechanisms that explain these data are still poorly understood, but may be related to the relative excess of fibrous tissue – and consequent relative deficiency of liver parenchyma and immune cells, resulting in an impaired immune response and infected cells clearance.


Topic:  HIV/HCV Coinfection- Pegasys

Presentation Time: 10/31/2004 12:30:00 PM     Program#/Poster#: 548

EARLY HCV-RNA CLEARANCE IN HIV/HCV-COINFECTED PATIENTS TREATED WITH PEGYLATED INTERFERON ALFA-2A PLUS RIBAVIRIN

 Nuria Camino, Marina Nuñez, Miriam Romero, Pablo Barreiro, Carlos III Hospital, Madrid, Spain; Antonio Ocampo, Celia Miralles, Xeral-Cies Hospital, Vigo, Spain; Luz Martín-Carbonero, Carlos III Hospital, Madrid, Spain; Alvaro Fernández, Arquitecto Marcide Hospital, Ferrol, Spain; Javier García-Samaniego, Vicente Soriano, Carlos III Hospital, Madrid, Spain.

 

Background:

Combination therapy with pegylated interferon (pegIFN) plus ribavirin (RBV) has become the standard treatment for chronic hepatitis C. Recent reports have claimed that responses are lower in HIV-coinfected patients. While viral kinetics has become the basis for predicting treatment outcome in HCV-monoinfected individuals, data from HIV+ patients are still scarce.

 

Aim:

The aim of this study was to assess the early virological response (EVR) at different time points across HCV genotypes in HIV/HCV-coinfected patients.

 

Methods:

PRESCO is an ongoing multicenter, prospective, comparative trial, in which HIV/HCV-coinfected patients from Spain with elevated ALT, CD4 >300 cells/mm3, no Child B/C cirrhosis, nor ddI use, were invited to participate. Patients received pegIFN-α 2a 180 mcg/wk + RBV 1000-1200 mg/day. Plasma samples were collected at weeks 4 and 12.

 

Results:

A total of 306 patients have been recruited up to May 2004. Virologic data were available from 138 patients at week 4, and from 147 at week 12:

WK 4
< 1 log

WK 4
1-2 log

WK 4
> 2 log

WK12
< 1 log

WK 12
1-2 log

WK 12
> 2 log

Genotype 1

22/71 (30%)

18/71 (25%)

32/71 (45%)

10/71
(14%)

4/71
(6%)

57/71
(80%)

Genotype 2/3

5/52
(10%)

2/52
(4%)

45/52 (86%)

1/59
(2%)

1/59
(2%)

57/59
(96%)

Genotype 4

5/15
(33%)

4/15 (13%)

8/15
(53%)

2/17
(12%)

3/17
(18%)

12/17
(70%)

Total

32/138 (23%)

21/138
(15%)

85/138 (62%)

13/147
(9%)

8/147
(5%)

126/147 (86%)

 

Conclusions:

In this immunologically preserved HIV/HCV population, only 14% of patients treated with pegIFN-α 2a +RBV did not attain 2 log reduction in HCV-RNA at week 12. This is the same rate described in HCV monoinfected individuals. Furthermore, >95% of HIV/HCV patients with genotypes 2/3 reached >2 log HCV-RNA reduction at week 12. Therefore, stopping rules recommended for HCV monoinfected patients seems to be equally valid in HIV-HCV coinfected patients.


Topic:  Epi- Special Populations

Presentation Time: 10/31/2004 1:45:00 PM    Program#/Poster#: 549

DETERMINANTS OF HEPATITIS C VIRAL RNA LEVELS AMONG A COHORT OF INJECTION DRUG USERS WITH AND WITHOUT HUMAN IMMUNODEFICIENCY VIRUS COINFECTION

 Karen H. Seal, Alex Monto, University of California, San Francisco, San Francisco, CA; Lorna Dove, Columbia University Medical Center, New York, NY; Eric Vittinghoff, Hui Shen, Daniel Tracy, Erica Miller, Teresa Wright, University of California, San Francisco, San Francisco, CA.

 

Background/Aims:

Higher hepatitis C virus (HCV) RNA levels have been associated with poorer response to HCV anti-viral therapy and higher likelihood of HCV viral transmission. The aim of this study is to identify factors associated with serum HCV RNA levels among injection drug users (IDUs) with and without human immunodeficiency virus (HIV) coinfection.

 

Methods:

Between 1997 and 2003, 418 patients with a history of IDU were recruited from methadone, liver, and HIV clinics at 2 inner-city hospitals. Participants were included in the cohort if they had a positive HCV antibody, were HCV treatment-naïve, and if HIV antibody and viral load, CD4 lymphocyte counts and HIV antiretroviral therapy could be confirmed at enrollment through chart review. Participants were invited to return for evaluation at semi-annual intervals. Sociodemographic, clinical, and drug and sexual risk behavior information were collected through standardized interviews. Quantitative HCV RNA levels were determined by polymerase chain reaction (PCR) at each study visit and HCV RNA levels were log transformed to approximate a normal distribution. Independent associations with log10 HCV RNA levels were assessed using multivariate mixed models.

 

Results:

Of 283 eligible participants, the mean length of follow up was 29 months (range 4-51 months) and the mean number of study visits was 3.3 (range 1-5 visits). At enrollment, HCV RNA was detected in 241 (85%) participants yielding a total of 799 observations during the study period. Overall, the median serum HCV RNA level in the cohort was 1.4 million copies/ml [interquartile range (IQR) = .69- 2.4 million copies/ml.] The median HCV RNA level was significantly higher among 126 HIV coinfected participants [1.6 million copies/ml (IQR=.82- 2.6 million copies/ml)] than among 115 HCV moninfected participants [1.2 million copies/ml (IQR=.63 – 2.4 million copies/ml); p=0.004]. There were no significant associations between HCV RNA levels and HIV viral load, CD4 lymphocyte count or HIV anti-retroviral therapy after adjusting for age, age at HCV infection, race, sex and HCV genotype.

 

Conclusions:

HCV RNA viral levels are significantly higher in IDUs coinfected with HIV than in HCV moninfected patients. Markers and determinants of immune status in HIV patients, namely HIV viral load, CD4 lymphocyte count and HIV anti-retroviral therapy were not found to be associated with HCV viral levels, but we were also unable to rule out potentially important effects. Further research is needed to determine how HIV infection might increase HCV viremia. This, in turn, could influence HCV treatment response and HCV transmission among HIV coinfected patients.


Topic:  Epi

Presentation Time: 10/31/2004 12:30:00 PM            Program#/Poster#: 550

HIGH PREVALENCE OF HCV REPLICATION IN LYMPH NODE TISSUES FROM PATIENTS WITH ADVANCED HEPATITIS C

 S Pal, M Chang, D G. Sullivan, K K-Y Lai, W Fausch, J Kae, R L. Carithers Jr., J D. Perkins, D R. Gretch, University of Washington, Seattle, WA.

 

Background:

Hepatitis C virus (HCV) is a positive-strand RNA virus that chronically infects an estimated 170 to 350 million people worldwide. Up to one-fifth of the individuals with chronic hepatitis C progress to cirrhosis, and a significant subset of these patients require liver transplantation to survive. One focus of our research is to characterize HCV replication in human liver transplant patients to better understand hepatitis C pathogenesis.

 

Hypothesis:

Although the liver is the main site of HCV replication, there is an increasing body of evidence for virus propagation in extrahepatic locations. Using tissues obtained from patients with end-stage hepatitis C undergoing liver transplantation, we tested the hypothesis of extrahepatic HCV replication using a highly sensitive and strand specific in situ hybridization (ISH) assay which is able to detect and differentiate between genomic (G) and replicative intermediate (RI) HCV RNAs.

 

Methods:

We analyzed proximal lymph node tissues from 14 liver transplant patients with hepatitis C, genotypes 1a or 1b, as well as tissues from control non-infected patients. Quantifiable control cell lines for ISH experiments were generated by cloning HCV subgenomes behind a etracycline regulated promoter, which allowed inducible expression of G and RI RNAs in HeLa cells.

 

Results:

HCV G RNAs were detected in lymph node specimens from all 14 patients with advanced hepatitis C, compared to 0% of specimens from noninfected controls. Positive signals were widely distributed in both T cell and B cell rich regions, and in the majority of cases signals were strongly positive indicating widespread viral infection. Active replication of HCV was documented in 9/14 (64%) lymph node specimens with low to moderate intensity of RI signal primarily restricted to CD19 positive B cell follicles. Molecular analysis of HCV envelope 2 hypervariable regions cloned from infected tissue confirmed different quasispecies populations in lymph node compared to liver compartments.

 

Summary:

HCV infection was present in 100% of lymph node biopsy specimens from patients with end-stage hepatitis C. Active HCV replication was confirmed in B cell rich follicles. Conclusion: These results confirm the hypothesis that extrahepatic infection is a common occurrence in patients with hepatitis C and suggest viral replication is most active in B lymphocytes. The clinical significance of this finding requires further investigation.Table1. HCV infection and replication in human lymph node tissues.

Table1. HCV infection and replication in human lymph node tissues. 

 

G only

RI only

Either G or RI

Both G and RI

Number (%) cases
Positive for HCV RNA
by ISH

5/14 (36%)

0/14 (0%)

14/14 (100%)

9/14 (64%)

 


Topics:  Occult HCV

 

Presentation Time: 10/31/2004 1:45:00 PM                            Program#/Poster#: 551

 

PATIENTS WITH OCCULT HEPATITIS C VIRUS INFECTION IN LIVER ARE POTENTIALLY INFECTIOUS

 Inmaculada Castillo, Elena Rodriguez-Iñigo, Javier Bartolomé, Susana de Lucas, Nuria Ortíz-Movilla, Margarita Pardo, Vicente Carreño, Fundacion Estudio Hepatitis Virales, Madrid, Spain.

 

Background:

Occult HCV infection is characterized by the presence of HCV-RNA in liver in the absence of anti-HCV and of serum HCV-RNA. Up to 70% of patients with occult HCV infection have also HCV-RNA in their peripheral blood mononuclear cells (PBMC) (1). However, it is unknown if HCV is replicating in the PBMC of these patients.

 

Methods:

To study this issue we included 18 patients with an occult HCV infection. These patients had abnormal values of ALT and/or GGTP, were anti-HCV and serum HCV-RNA negative and had viral RNA in liver, as detected by RT-PCR and by in situ hybridization. In addition, all 18 patients were HCV-RNA positive in their PBMC and aliquots of these PBMC stored in liquid nitrogen, were available. Detection of the positive and negative HCV-RNA strand in PBMC was done by strand-specific RT-PCR, performing cDNA synthesis at high temperature using the thermostable enzyme rTth. Moreover, detection of HCV-RNA strands of both polarities was also performed by in situ hybridization of the PBMC samples.

 

Results:

The presence of the positive HCV-RNA strand in PBMC was confirmed in all the 18 patients with occult HCV infection by strand-specific RT-PCR and by in situ hybridization. The mean percentage of PBMC presenting the positive HCV-RNA strand was 3.2 ± 2.3 %. The negative HCV-RNA strand was found in the PBMC of 11/18 (61%) patients by strand-specific RT-PCR. The presence of the negative HCV-RNA strand was confirmed in the 11 patients by in situ hybridization, being the percentage of PBMC harboring the negative HCV-RNA strand of 3.13 ± 3.51 %.

 

Conclusion:

In conclusion, HCV replicates in the PBMC of patients with occult HCV infection and so, although these patients do not have serum HCV-RNA they are potentially infectious.

(1)J Infect Dis 2004; 189: 7-14


Topic:  Experimental Therapy

Presentation Time: 10/31/2004 12:30:00 PM              Program#/Poster#: 552

IN VITRO RESISTANCE MUTATIONS AGAINST VX-950 AND BILN 2061, TWO HCV PROTEASE INHIBITOR CLINICAL CANDIDATES: SINGLE-RESISTANCE, CROSS-RESISTANCE, AND FITNESS

 Chao Lin, B. Govinda Rao, Yu-Ping Luong, John R. Fulghum, Debra L. Brennan, Yun-Yi Wei, J. Daniel Frantz, Judith Lippke, Hsun-Mei Hsiao, Sue Ma, Kai Lin, John P. Maxwell, Kevin M. Cottrell, Cynthia A. Gates, Robert B. Perni, Ann D. Kwong, Vertex Pharmaceuticals Incorporated, Cambridge, MA.

 

Introduction:

VX-950, a small molecule inhibitor of the HCV NS3•4A protease, was optimized using a structure-based drug design approach. In this report, we describe in vitro resistance studies on VX-950 and another HCV protease inhibitor, BILN 2061, using a sub-genomic replicon system. The primary resistance mutation against VX-950 remains sensitive to BILN 2061, and the dominant BILN 2061-resistant mutations remain fully susceptible to VX-950.

 

Results:

Our structural analysis suggests that these dominant resistance mutations develop in response to VX-950 or BILN 2061 via different mechanisms. In addition, cross-resistance mutations were identified under selection with both HCV protease inhibitors. Steric hindrance appears to be the primary cause for loss of drug susceptibility for the primary VX-950-resistant mutation as well as the cross-resistance mutations. Fitness studies indicate that these resistance mutations are compromised in their ability to support HCV replication in the replicon system.

 

Conclusion:

 

 


 

Topic:  Epidemiology

Presentation Time: 10/31/2004 12:30:00 PM                      Program#/Poster#: 556

FACTORS ASSOCIATED WITH SPONTANEOUS RESOLUTION OF HEPATITIS C VIREMIA AMONG INJECTION DRUG USERS WITH AND WITHOUT HUMAN IMMUNODEFICIENCY VIRUS COINFECTION

 Karen H. Seal, Alex Monto, University of California, San Francisco, San Francisco, CA; Lorna Dove, Columbia University Medical Center, New York, NY; Eric Vittinghoff, Hui Shen, Daniel Tracy, Erica Miller, Teresa Wright, University of California, San Francisco, San Francisco, CA.

 

Background and Aims:

·      Of patients acutely infected with hepatitis C (HCV), a minority will spontaneously resolve HCV viremia, generally within the first years.

·      Due to shared routes of transmission through contaminated injection equipment, 5-10% of HCV-infected persons are coinfected with HIV.

·      There is conflicting data regarding the impact of HIV infection on the spontaneous resolution of HCV.

·      The aim of this study was to identify factors independently associated with spontaneous resolution of HCV viremia among anti-HCV (+) injection drug users (IDUs) with and with HIV coinfection.

 

Methods:

·      Between February 1997 and July 2003, 390 patients were recruited by flyers from methadone, liver and HIV clinics at San Francisco VA Medical Center and San Francisco General Hospital.

·      Participants were included if they met the following inclusion criteria:\

§       >18 years of age

§       Reported past and/or ongoing injection drug use

§       Anti-HCV (+) by enzyme immunoassay (EIA) HCV antibody testing

§       HCV treatment-naïve

 

Data Collection/Laboratory Testing

·      Participants underwent in-dept interviews using standardized questionnaires to collect sociodemographic, clinical, and drug and sexual risk behavior data.

·      Age at time of HCV infection was defined as age at initiation if IDU.

·      HIV-related data at enrollment including HIV antibody, HIV viral load, CD4 lymphocyte count, and HIV antiretroviral medication history were collected through chart extraction at each of the hospitals.

·      Quantitative HCV RNA virus was measured by polymerase chain reaction (PCR).

·      Specimens with undetectable HCV RNA underwent confirmatory testing using a more sensitive quantitative PCR test (lower limit of detection=50 IU/ml).  Positive HCV antibody status was confirmed using recombinant immunoblot assay (RIBA). 

 

Statistical Methods

·      Spontaneous HCV viral resolution was examined as a dichotomous outcome in a cross-sectional univariate analysis using chi-square and Fischer’s exact tests as indicated. 

·      Independent predictors of HCV viral reolution were assessed using a multiple logistic regression model in which predictors significant at p<0.1 were trained. 

Results:

·      Of 390 study participants, 354 met inclusion criteria and were included in this analysis.

·      Median age was 46 years (interquartile range=41-49) and estimated median age at HCV infection was 22 years (interquartile range=18-28).

·      Less than half, 165 (47%) were infected with HCV alone (HCV monoifected) and 186 (53%) were coinfected with HIV.

·      HCV RNA was undetectable by PCR in 44 (12%) participants.

·      We could detect no significant difference in spontaneous resolution of HCV viremia between participants with HCV monoinfection (n=24) compared to those with HIV coinfection (n=20) (odds ratio (OR) = 1.41; 95% Confidence Interval (CI)=0.75-2.66;  p=0.28.

·      Moreover, among HIV coinfected participants, neither HIV viral load, CD4 lymphocyte count, nor HIV antiretroviral mediation history was significantly associated with spontaneous HCV viral resolution.

·      In multivariate analysis, spontaneous HCV resolution was independently associated with female sex (OR=3.62, (CI=1.68-7.81) p=0.001) and age at infection (per 10 years) (OR=0.59, (CI=0.36-0.99; p=0.04).

 

Conclusions:

 

·      Among HCV (+) IDU with HIV coinfection, HIV infection was not associated with spontaneous resolution of HCV viremia.

·      In this aging population of IDUs, almost all participants were infected with HCV prior to the first cases of HIV infection reported in 1981.  Thus, HCV infection and resolution likely predated the acquisition of HIV infection.

·      This study may have been limited by the small number of HIV resolvers, reducing our power to detect the impact of HIV infection on spontaneous resolution of HCV viremia.

·      Female sex and younger age at infection were both independently associated with spontaneous HCV resolution among IDUs.

·      Future prospective studies might examine acute HCV seroconversion in HIV-infected patients to establish whether and how concurrent HIV infection impacts resolution of HCV viremia.

·      More work is needed to explain why women and younger persons are more likely to resolve HCV infection or possibly resist subsequent reinfection through injection drug use.

 


Topic:  HIV/HCV Coinfection

Presentation Time: 10/31/2004 1:45:00 PM                  Program#/Poster#: 563

 

DETECTION OF HEPATITIS C VIRUS (HCV) IN SERUM AND PERIPHERAL BLOOD COMPARTMENTS OF HIV-/HCV+ AND HIV+/HCV+ WOMEN

 Jason T. Blackard, Massachusetts General Hospital, Boston, MA; Laura Smeaton, Harvard School of Public Health, Boston, MA; Yoichi Hiasa, Norio Horiike, Morikazu Onji, Ehime University School of Medicine, Ehime, Japan; Irma Rodriguez, Miriam Hospital, Providence, RI; Kenneth H. Mayer, Miriam Hospital & Brown Univerity, Providence, RI; Raymond T. Chung, Massachusetts General Hospital, Boston, MA.

 

Background:

In the U.S., 150,000 to 300,000 people are infected with both HCV and HIV. Multiple studies have demonstrated the adverse effects of HIV co-infection on HCV disease progression and treatment response. We previously investigated serum HCV diversity in co-infected persons initiating antiretroviral therapy (ART) for HIV infection (J Inf Dis. 2004. 189:1472). However, few studies have addressed the effects of ART on HCV in HIV+/HCV+ persons in compartments other than the serum. Whether extrahepatic HCV replication occurs is a critical question to transmission and pathogenesis. Conflicting data regarding HCV replication in peripheral blood mononuclear cells (PBMCs) have been reported, although PBMCs may represent a critical site for interactions between HIV and HCV.

 

Methods:

Representative samples collected as part of the HIV Epidemiologic Research Study – to evaluate the natural history of HIV in women – were utilized. We analyzed PBMC and serum compartments of 28 HIV-/HCV+ and 20 HIV+/HCV+ women. A strand-specific RT-PCR approach was used to detect positive- and negative-strand (i.e., replicative intermediates indicative of viral replication) HCV at two time points (before and within 6 months after initiating ART for the HIV+ group).

 

Results:

Positive-strand HCV RNA was detected in the serum from 42 (89%) women at the initial time point. Positive- or negative-strand HCV RNA was detected in PBMCs from 21 (44%) and 12 (60%) women, respectively. The detection frequency of positive- and negative-strand HCV was similar between HIV+/HCV+ and HIV-/HCV+ women. Even after initiating ART, positive- and negative-strand HCV were detected more frequently in HIV+/HCV+ than HIV-/HCV+ women [+strand: 12 (60%) vs. 7 (25%), p = 0.02; -strand: 12 (60%) vs. 7 (25%), p = 0.01]. Serum HIV RNA levels were not correlated with HCV RNA levels in either compartment. Serum and PBMC HCV RNA levels were not correlated.

 

Conclusions:

We found that the detection frequency of positive- and negative-strand (i.e., the replicative intermediate indicative of viral replication) HCV RNA in the PBMC compartment was significantly higher for HIV+/HCV+ women.. While higher serum levels of HCV RNA were found in HIV+/HCV+ women, HCV RNA levels in the serum and PBMCs were not significantly correlated, suggesting differential regulation of HCV replication in these distinct compartments.  HIV RNA levels and HCV RNA levels were not correlated with either compartment, and treatment of HIV appeared to have minimal effect on HCV detection rates and RNA levels.  Taken together, our findings may partially explain the limited HCV antiviral response rates observed among co-infected persons, as low levels of HCV replication in the PBMC compartment would not likely be controlled by current HCV therapies.


Topic:  HIV/HCV Coinfection-Interferon Based Therapy

Presentation Time: 10/31/2004 12:30:00 PM                          Program#/Poster#: 564

 

PRESENCE OF MULTIPLE HCV GENOTYPES AND RESPONSE TO INTERFERON-RIBAVIRIN THERAPY HIV/HCV CO-INFECTED PATIENTS

 Maurizio Bonacini, Natalie Bzowej, Yume Phuong, California Pacific Medical Center, San Francisco, CA.

 

Background:

Commercial genotyping methods used in HCV studies detect the dominant genotype but are not sensitive enough to detect those present in lower proportions. Reasons for unsatisfactory virological response rates may be due to infection with multiple genotypes.

 

Hypothesis:

The presence of multiple genotypes is associated with nonresponse to interferon-ribavirin therapy in HIV/HCV (coinfected) patients.

 

Methods:

Baseline and end-of-therapy sera were analyzed from 6 sustained responders (SVR), 3 relapsers and 3 non responders who had sufficient serum. Patients had been enrolled in a published AmfAR study [Hepatology 2004;39:989-998]. Patients were treated with a combination of interferon-α2b and ribavirin for up to 48 weeks. Commercial genotyping (gt) was performed using Inno-lipa probe on baseline specimens. For additional gt determination, viral RNA was extracted and reverse transcribed. Primer pairs specific for each of 6 gt and 9 subtypes were used to amplify the core region [modified from Mizokami, Virus Research. 52:221-30, 1997]. Extended PCR (45 cycles) was used to increase sensitivity of viral detection and was compared to PCR (30 cycles). Genotypes were identified by comparison of visible bands on ethidium bromide gels with known standards. Negative controls were used for each PCR reaction.

 

Results:

Commercial gt was confirmed in 11/12 pts. In one patient we found gt 2a/3a (3a dominant) vs. gt 2 by Inno-lipa. At baseline, we found an additional gt in 5 of 12 patients using 30 cycles RT-PCR. Using 45 cycles we were able to detect multiple genotypes in 11/12 patients (see table). The 7 pts with 3 or more gt had lower CD4 counts (mean=430) than those with 1-2 gt (mean=574, p=NS). Gt 1a (not necessarily dominant) was found at baseline in 2/6 SVR and in 6/6 relapsers and nonresponders (33% v. 100%, p=0.06).

 

Conclusions:

1. Commercial assays detect only the dominant genotype in HIV/HCV coinfected patients, 2. 45-cycle PCR allows detection of multiple genotypes, 3. gt 1a may be associated with a lack of SVR in coinfected patients.

Acknowledgement:

We wish to thank the amfAR investigators for their support of this work.

NA=not available

Patient

Inno-lipa

Baseline gt 30X PCR

Baseline gt 45X PCR

On therapy gt
45X PCR

Follow-up gt 45X PCR

SVR1

3

3a

1a,2a,3a

Na

Na

SVR1

2

3a

2a,3a

Na

Na

SVR1

1

1a

1a,1b,2a,2b,3b

Na

Na

SVR1

3

2a,3a

2a,3a

NA

NA

SVR1

3

2a,3a

2a,3a

NA

NA

SVR1

3

2a,3a

2a,3a

NA

NA

Rel1

2

2a,2b

1a,2a,2b

Neg

1a,2b

Rel2

3

2a,3a

1a,2a,3a

Neg

1a,2a,3a

Rel3

3

3a

1a,2a,3a

Neg

1a,2a,3a

NR1

1

1a

1a,1b,2a

1a,1b,2a

1a,2a

NR2

1

1b

1a,1b,2a

1b,2a,3a

1a,1b,2a,3a

NR3

1

1a

1a

1a,2a

1a,2a

 

 


Topic:  Diabetes

Presentation Time: 10/31/2004 12:30:00 PM              Program#/Poster#: 566

CAUSAL RELATIONSHIP BETWEEN HEPATITIS C VIRUS INFECTION AND THE DEVELOPMENT OF TYPE 2 DIABETES MELLITUS IN A HEPATITIS C VIRUS HYPERENDEMIC AREA

 Takumi Kawaguchi, Yumiko Nagao, Takafumi Yoshida, Kazuo Tanaka, Tatsuya Ide, Masaru Harada, Ryukichi Kumashiro, Michio Sata, Kurume University School of Medicine, Kurume, Japan.

 

Backgrounds:

Hepatitis C virus (HCV) infection antedates insulin resistance. However, this association at the population level including asymptomatic HCV carriers remains unclear. Furthermore, the involvement of HCV core, showing many biological properties, in the development of type 2 diabetes mellitus (DM) has never been examined.

Aims: The aims of this study are to examine an association between HCV infection and insulin resistance, and a causal relationship between HCV infection and the development of type 2 DM in an HCV hyperendemic area.

 

Methods:

In an HCV hyperendemic area (adult population is 7,389 and 23.6% residents are anti-HCV positive), randomly selected subjects with anti-HCV positive (n = 31) and subjects with anti-HCV negative (n = 44) were enrolled in this study. An association between HCV infection and insulin resistance was examined in 1995. Insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR). After 7 years follow-up, we examined the relative risk of the development of type 2 DM by a case-cohort analysis.

 

Results:

There was no significant difference in age, sex, BMI, alcohol intake, and γ-glutamyltranspeptidase between the subjects with anti-HCV positive and negative. Although alanine aminotransferase level showed significant increase in anti-HCV positive subjects, mean value was within normal range. Anti-HCV-positive subjects showed increased HOMA-IR values compared to anti-HCV negative subjects (6.8 ± 1.4 vs 3.8 ± 0.6; p = .04). Moreover, stratification of the anti-HCV-positive group according to serum HCV core titer revealed an association between HCV core and insulin resistance. HOMA-IR values (9.3 ± 2.7) was significantly increased in subjects with high titer (≥ 300 fmol/L) of HCV core compared to those (4.5 ± 1.0; p = .03) in subjects with low titer (< 300 fmol/L) of HCV core and those (3.8 ± 0.6; p = .004) in subjects with anti-HCV negative. Among 71 subjects free of DM in 1995, 8 subjects developed type 2 DM over 7 years of follow-up evaluation. Overall, anti-HCV-positive subjects were 3-fold as likely as anti-HCV-negative subjects to develop type 2 DM, but this difference was not significant (p = .11; relative hazard, 3.62; 95% CI, 0.45 – 1.05). After stratification of the anti-HCV-positive group according to serum HCV core titer, a significant increase in the incidence of type 2 DM was seen in subjects with high titer of HCV core compared to anti-HCV-negative subjects (p = .04; relative hazard, 5.25; 95% CI, 0.49 – 0.95).

 

Conclusions:

We report here for the first time community-based evidence for an association between HCV infection and insulin resistance, and a causal relationship between HCV infection and the development of type 2 DM. We also showed the involvement of HCV core in the development of type 2 DM.

 


Topic:  Epidemiology

Presentation Time: 10/31/2004 1:45:00 PM                    Program#/Poster#: 567

IDENTIFICATION OF CLUSTERS OF HEPATITIS C USING GEOSPATIAL ANALYSIS

 Simona Rossi, Steven K. Herrine, Stacey B. Trooskin, Thomas Jefferson University Hospital, Philadelphia, PA; C Victor Spain, Mindy J. Perilla, Philadelphia Department of Public Health, Philadelphia, PA; Victor J. Navarro, Thomas Jefferson University Hospital, Philadelphia, PA.

 

Background:

Geospatial analysis (GA) can identify disease clusters, defined as geographic areas where cases reside closer to one another than would be expected by chance alone. Historically used to link diseases to environmental risk factors, GA can also identify areas with high disease report rates. Using GA to identify high hepatitis C virus (HCV) report rates can help focus intervention and prevention strategies. In Pennsylvania, positive HCV tests are reported by mandate to public health agencies.

Aims: To use GA to identify clusters of HCV in Philadelphia County, and to describe the demographics of each cluster.

 

Methods:

Reported HCV cases (ELISA, RIBA, or nucleic acid) for 2003, were mapped by each case’s address; addresses with >2 reports were excluded as possible institutions or clinics. GA was performed to identify statistically significant HCV clusters using SaTScan v4.0 software following a Poisson model; US Census tract data (2000) were used to describe the demographics of each cluster.

 

Results:

GA identified 11 clusters in which the rate of HCV reports was higher than expected (p<0.05) [Table]. Most clusters consisted of predominantly African American communities and all had a median income below that of the county, consistent with the known epidemiology of HCV. Three clusters had a predominantly Hispanic ethnicity.

 

Clusters

Cases/
100,000

RR*

Race (%)

Ethnicity
(%)

Median
Household
Income
($)

African American

Caucasian

Hispanic
%

Philadelphia

253.9

 

43.2

45.0

8.5

30,746

1

1331.2

5.2

97.2

0.8

1.15

22,043

2

620.5

2.4

12.4

68.2

21.8

22,489

3

574.6

2.3

23.8

39.0

46.1

15,240

4

560.2

2.2

95.7

1.6

1.8

20,573

5

525.1

2.1

78.3

11.6

7.9

18,244

6

511.1

2.0

97.1

0.7

1.4

17,212

7

507.5

2.0

45.8

14.5

52.9

14,090

8

488.2

1.9

91.5

4.9

1.7

21,484

9

467.6

1.8

34.6

52.6

12.5

28,594

10

390.4

1.5

45.9

15.9

50.5

19,267

11

383.6

1.5

11.1

68.6

4.8

24,931

*RR = risk of having a positive report in a cluster relative to the risk of having a positive report in all other Philadelphia census tracts

 

Conclusion:

GA can be used to identify clusters of HCV. When linked with census tract data, GA can facilitate description of each cluster’s demographics. Once validation demonstrates that clusters of HCV reports represent areas of clinical disease, appropriate intervention, prevention, and research strategies can be targeted.


Topic:  Epidemiology

Presentation Time: 10/31/2004 1:45:00 PM                            Program#/Poster#: 569

HEPATITIS C IN HISPANICS: A DESCRIPTIVE ANALYSIS AND COMPARISON WITH OTHER RACES

 Rita Lepe, Jennifer Layden, Scott Cotler, University of Illinois at Chicago, Chicago, IL.

 

Background:

Hispanics comprise 13% of the population in the United States and are the fastest growing minority group. The NHANES III study showed that 2.1% of Hispanics have evidence of hepatitis C virus (HCV) infection (N Engl J Med 1999;341:556-562). Race or ethnicity has been identified as a factor that might affect disease progression. Features of HCV in Hispanics have not been well characterized. Aims: To compare features of HCV among Hispanics, Whites, and African Americans and to characterize HCV in Hispanics.

 

Methods:

A retrospective analysis was preformed on data collected from consecutive patients seen at the University of Illinois at Chicago hepatology outpatient clinic from 1/98 to 8/03. Patients who were anti-HCV seropositive with detectable HCV RNA and were seronegative for HbsAg and HIV were included. A total of 1225 patients were identified; 227 Hispanics, 508 Whites, and 490 African Americans. Patients were identified as Hispanic according to the definition of the United States Census Bureau. Data collection included patient race, age, gender, risk factor for HCV, laboratory parameters, and histological activity index (HAI). A history of alcohol use was noted but not quantified.

 

Results:

Comparison among races showed that Hispanics had the highest prevalence of cirrhosis and the greatest amount of portal inflammation on liver biopsy. Pairwise comparisons showed that Hispanics had significantly more cirrhosis than African Americans (p<0.001) and a trend toward more cirrhosis than Whites (p=0.17). These findings persisted when controlling for sex and age. Furthermore, Hispanics had significantly more portal inflammation than both African Americans (p=0.002) and Whites (p=0.04). Hispanics had the highest ALT levels (p <0.001). History of injection drug use was higher in African Americans (p= 0.001). A history of alcohol use was comparable among the races. There was a trend toward a higher prevalence of cirrhosis in Hispanic women (56%) than in Hispanic men (45%) [p=0.14]. Hispanic women were more likely to have acquired HCV by blood transfusion than men (p<0.001). History of ETOH use, injection drug use and tattooing was more common in Hispanic men than in Hispanic women (all p<0.05).

 

Conclusions:

In this cross-sectional analysis of HCV infected individuals, there were differences in the prevalence of cirrhosis among races. Hispanics had the highest portal inflammation scores. Further studies are needed to evaluate potential causes for differences in histologic progression of HCV among races.


Topic:  HIV/HCV Coinfection

Presentation Time: 10/31/2004 1:45:00 PM                 Program#/Poster#: 571

 

HEPATITIS C AND HUMAN IMMUNODEFICIENCY VIRUS: CO-INFECTION RATES AND CO-TESTING PATTERNS AMONG VETERANS

 Marilyn S. Huckans, Aaron D. Blackwell, Todd A. Harms, David W. Indest, Peter Hauser, Portland VA Medical Center, Portland, OR.

 

Introduction/Aim:

The purposes of this study were to determine hepatitis C (HCV) and human immunodeficiency virus (HIV) infection and co-infection rates and examine HCV and HIV testing and co-testing patterns.

 

Methods:

Using a comprehensive database system, we retrospectively reviewed data from the medical records of all 319, 762 patients seen over a six-year period at any facility in the Northwest Veterans Affairs Healthcare System (NWVA): 8 medical centers and 17 outpatient clinics in Alaska, Washington, Oregon, and Idaho. Patients were predominantly male (88.4%), Caucasian (86.3%), and middle age (Mean age = 59.8 years, SD = 16.0).

 

Results:

Within the total sample (319,762), 31.0% (99,002) were tested for HCV, and 5.2% (16,695) were tested for HIV. Only 4.1% (13,110) were co-tested. Of those tested, 12.1% (11,979/99,002) tested HCV positive (3.8% of the total sample), and 5.2% (4514/86,814) tested HIV positive (0.3% of the total sample). Of those co-tested for both diseases, 1.5% (197/13,110) were co-infected (0.1% of the total sample). 35.3% (4628/13,110) of those co-tested, tested positive for at least one infection. 79.1% (692/875) of HIV positive patients were tested for HCV, 29.2% (202/692) of whom tested positive. Compared with HIV negative patients, HIV positive patients were no more likely to receive HCV testing (OR = 8.45; CI, 7.20-9.99). In contrast, only 34.6% (4,152/11,999) of HCV positive patients were tested for HIV, 4.9% (202/4,152) of whom tested positive. Compared with HCV negative patients, HCV positive patients were significantly more likely to receive HIV testing (OR = 4.58; CI, 4.38-4.78).

 

Conclusions:

 


Topic:  HIV/HCV Coinfection

Presentation Time: 10/31/2004 12:30:00 PM                   Program#/Poster#: 572

 

LIVER-RELATED MORTALITY IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS IN FRANCE (GERMIVIC COHORT STUDY, 1995-2003)

 Eric Rosenthal, Centre Hospitalier Universitaire, Nice, France; Gilles Pialoux, Hôpital Tenon, Paris, France; Noëlle Bernard, Hôpital Saint-André, Bordeaux, France; Marina Karmochkine, Hôpital Européen Georges Pompidou, Paris, France; David Rey, Centre Hospitalier Universitaire, Strasbourg, France; Christian Pradier, Centre Hospitalier Universitaire, Nice, France; Michèle Bentata, Hôpital Avicenne, Paris, France; Françoise Borsa-Lebas, Hôpital Charles Nicolle, Rouen, France; Christian Michelet, Hôpital Pontchaillou, Rennes, France; Yann Quertainmont, Hôpital Kremlin-Bicêtre, Paris, France; Catherine Leport, Groupe Hospitalier Bichat-Claude Bernard, Paris, France; Stanislas Pol, Hôpital Necker, Paris, France; Christian Perronne, Hôpital Raymond Poincaré, Garches, France; Patrice Cacoub, Groupe Hospitalier Pitié Salpêtrière, Paris, France; GERMIVIC Joint Study Group.

 

Introduction/Aim:

To determine mortality due to end-stage liver disease (ESLD) in a nationwide cohort of HIV-infected patients seven years following the introduction of HAART and to compare this with that observed before and during the early years of HAART.

 

Methods:

All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2003. Sixty-five departments, following a total of 20,940 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995, 1997 and 2001 (Cacoub et al, CID 2001; Rosenthal et al, AIDS 2003).

 

Results:

Among 215 deaths observed during 2003, 101 (47.0%) were related to AIDS, 27 (12.6%) to ESLD, and 87 (40.4%) to other causes. Mortality due to ESLD represented 23.7% of non AIDS-related deaths; 25 of the 27 patients dying from ESLD had chronic hepatitis due to isolated HCV infection. In 2003, deaths due to ESLD (12.6%) remained stable compared with 2001 (14.3%) and were significantly more frequent than in 1995 (1.5%) and 1997 (6.6%). As in Mortavic 2001 study, the prevalence of hepatocellular carcinoma as a cause of death remained high (1995, 4.7%; 1997, 11%; 2001, 25%; 2003, 14.8%), as did alcohol consumption.

 

Conclusions:

In the post-HAART era, ESLD due to HCV is a growing cause of mortality in HIV-infected patients. Increased longevity attributable to HAART, and a higher prevalence of alcohol consumption, are likely involved in this trend.


Topic:  HIV/HCV Coinfection

Presentation Time: 10/31/2004 12:30:00 PM                      Program#/Poster#: 574

 

PREVALENCE AND FACTORS ASSOCIATED WITH HEPATIC STEATOSIS IN HCV-HIV CO-INFECTED PATIENTS

Laurent Castera, Service d’Hepato-Gastroenterologie, CHU Bordeaux, Bordeaux, France; Didier Neau, Service de Maladies Infectieuses, Hôpital Pellegrin, Bordeaux, France; Maria Winnock, INSERM U593 ISPED, Université Victor Segalen Bordeaux2, Bordeaux, France; Brigitte Le Bail, Service d’Anatomo-pathologie, Hopital Pellegrin, Bordeaux, France; Laurent Geraut, Michel Dupon, Service de Maladies Infectieuses, Hôpital Pellegrin, Bordeaux, France; Denis Lacoste, Service de Medecine Interne, Hopital St-Andre, Bordeaux, France; Jean-Luc Pellegrin, Service de Medecine Interne, Hopital Haut Leveque, Pessac, France; Helene Trouette, Service d’Anatomo-Pathologie, ospital Haut Leveque, Pessac, France; Victor de Ledinghen, Service d’Hepato-Gastroenterologie, CHU Bordeaux, Bordeaux, France; Mari-Edith Lafon, Laboratoire de Virologie, Universite Bordeaux2, Bordeaux, France; Paulette Bioulac-Sage, Service d’Anatomo-pathologie, Hopital Pellegrin, Bordeaux, France; Francois Dabis, INSERM U593 ISPED, Université Victor Segalen Bordeaux2, Bordeaux, France; for the Groupe d’Epidemiologie Clinique du SIDA en, Aquitaine (GECSA).

 

Background:

Hepatic steatosis is common in HCV-infected patients and independently associated with genotype 3 infection and high body mass index (BMI). The influence of HIV infection and highly active antiretroviral therapy (HAART) on the occurrence of steatosis in co-infected patients is poorly documented.

Aims: To study the prevalence and determine the factors that could be associated with hepatic steatosis in HCV-HIV co-infected patients, namely HCV genotype, BMI and HAART.

 

Methods:

148 HCV-HIV co-infected patients from the Aquitaine Cohort (95 males, median age : 39 yrs; median CD4 count: 499/µl) were included. All patients were eligible for HCV antiviral therapy and their alcohol intake was <50g/day. Data collected at the time of liver biopsy included : type of HAART (protease inhibitors, non nucleoside reverse transcriptase inhibitors: NNRTI, nucleoside reverse transcriptase inhibitors), CDC stage of HIV infection, HIV plasma viral load, BMI, glycemia, total cholesterol, triglycerides, transaminases and HCV genotype. Histological activity and fibrosis were graded according to the Metavir scoring system. Steatosis was classified as : none, minimal (≤ 10% hepatocytes), mild-to-moderate (11% - 30%), or severe (> 30%).

 

Results:

Overall, steatosis was present in 99 patients (67%) (minimal N=44, mild-to-moderate N=28, severe N=17) and was considered as microvesicular in 7%, macrovesicular in 40% and mixed in 53%.

Prevalence and severity of steatosis

None

34%

Minimal (≤ 10%)

36%

Mild to Moderate (11-30%)

19%