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The Liver Meeting |
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October 29 - November 2 |
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 |
Quartile 2 |
Quartile 3 |
Quartile 4 |
Fisher |
Logistic |
|
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
- Dose reducing peg IFN α 2a up to 60% of the full dose had a minimal effect on SVR during initial 20 weeks
- Dose reducing RBV during the initial 20 weeks up to 60% had an effect on SVR only when the dose of Peg IFN α 2a was concomitantly decreased to less than 80% of target dose
- Discontinuing the dose of RBV during the initial 20 weeks of treatment had a dramatic effect on SVR with no patient receiving an SVR
- Dose reduction of RBV and/or PEG to 60% of the target dose between week 20 and 48 did not effect SVR
- Dose reduction of Peg and/or RBV to <60% of target dose or d/c of RBV between week 20 and 48 was associated with a 10% or greater reduction in SVR
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:
- In a large cohort of non-diabetic patients with CHC and advanced fibrosis who failed to respond to prior IFN +/- RBV therapy were 95% HCV genotype non-3. 95% had HOMA IR > mean of US patients controls.
- Although the population had a high degree of IR, IR was primarily associated with the same factors found in population not selected for liver disease including race, obesity and hypertriglyceridemia
- IR was strongly associated with steatosis and degree of fibrosis on biopsy
- On univariate analysis IR was associated with a lower rate of week 20 VR and SVR
- On multivariate analysis, IR was associated with lower week 20 VR but not SVR, while hepatic steatosis was associated with a lower rate of week 20 VR as well as SVR after controlling for genotype, race and fibrosis score.
*
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
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
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
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
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
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 |
p value |
|
Recent and/or Past Alcohol Use: |
|
|
|
|
Alcohol use vs Non-alcohol use |
|
|
|
|
|
|
|
|
|
|
|
|
Amount of alcohol consumed: |
|
|
|
|
721 |
199 (28) |
0.04 |
|
213 (24) |
213 (24) |
|
|
563 (23) |
563 (23) |
|
|
Cage score |
|
|
|
|
1,681 |
452 (27) |
0.0003 |
|
2,380 |
523 (22) |
|
|
Recent Alcohol Use: |
|
|
|
|
2,575 |
685 (27) |
0.0001 |
|
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 |
|
Recent and/or Past Alcohol Use: |
|
|
|
|
|
Drinker vs. Non-Drinker |
|
|
|
|
|
142 |
45 (32) |
29 (20) |
38 (27) |
|
584 |
173 (30) |
104 (18) |
177 (30) |
|
Amount of alcohol consumed: |
|
|
|
|
|
Non drinker |
142 |
45 (32) |
29 (20) |
38 (27) |
|
178 |
49 (27) |
27 (15) |
58 (33) |
|
406 |
124 (31) |
77 (19) |
119 (29) |
|
Cage score |
|
|
|
|
|
339 |
97 (29) |
57 (17) |
96 (28) |
|
387 |
121 (31) |
76 (20) |
119 (31) |
|
Recent Alcohol Use: |
|
|
|
|
|
532 |
164 (31) |
105 (20) |
137 (26) |
|
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:
- Alcohol use reduced patient eligibility for HCV antiviral treatment.
- Once treatment was initiated, recent alcohol use was the only variable associated with early treatment discontinuation and sustained virologic response rate.
- Patients who use alcohol and complete the full course of treatment have a comparable response to HCV treatment as non-drinkers.
- Patients with history of past and recent alcohol use should not be excluded from anti-HCV therapy.
- Recent alcohol users may require additional screening and support to ensure their ability to complete treatment.
Topic: Interferon Based Therapy
Presentation
Time: 10/30/2004 5:30:00 PM Program#/Poster#:
356
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
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
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
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
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
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
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
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:
- 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.
- Medication discontinuations were equal between the two groups.
Topic: Interferon Based Therapies
Presentation
Time: 10/30/2004 5:30:00 PM Program#/Poster#: 368
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
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
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
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
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
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:
- to check whether there is cognitive impairment in patients with chronic HCV hepatitis.
- 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:
- 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.
- However some of these function tend to show significant improvement after 3-6 months of treatment.
- 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
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
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
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
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
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
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
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
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 |
93% ± 1 |
98% ± 1 |
96% ± 1 |
92% ± 2 |
|
Actual RBV dose before Wk 12 |
76% ± 2 |
99% ± .3 |
97% ± 1 |
93% ± 2 |
|
Actual PEGASYS dose (mean % ± SE) |
75% ± 3 |
88% ± 2 |
86% ± 1 |
77% ± 4 |
|
Actual RBV dose |
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
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
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
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