Posters – Tuesday May 23, 2006  8:00AM  Hepatitis C

 

HCV Treatment Issues and Early Drug Development

 

Abstract T1793 – Preclinical Characteristics of ITMN 191, an Orally Active Inhibitor of the HCV NS3/4A Protease Nominated for Preclinical Development

S. Seiwert; S. W. Andrews; H. Yang; H. Tan; B. Marafino; R. Rieger; R. B. Franklin; J. Pheneger; P. A. Lee; Y. Jiang; A. L. Kennedy; S. M. Wenglowsky; M. R. Madduru; G. A. Doherty; K. R. Condroski; C. Lemieux; L. Pieti Opie; F. Sullivan; N. Neitzel; G. P. Hingorani; J. Otten; B. Brandhuber; G. Vigers; J. A. Josey; L. M. Blatt

 

Current treatment options for chronic HCV infections provide sustained virologic response rates of ~50%, indicating novel therapeutic approaches are needed. We therefore embarked on a rational drug design campaign to produce inhibitors of the HCV NS3/4A protease. ITMN 191 emerged from this discovery effort and was nominated as a preclinical candidate. Here we describe the preclinical characterization of ITMN 191.

 

In biochemical assays using HCV NS3/4A protease domains derived from genotypes 1b, 1a, 2, or 3, the EC50 value of ITMN 191 is <300 pM, 400 pM, 400 pM, and 12.4 nM, respectively. Its EC50 value against full-length genotype-1b protease is 900 pM. ITMN 191 retains subnanomolar to low-nanomolar potency against the NS3/4A variants at positions A156 and D168 that confer resistance to other experimental NS3/4A inhibitors. In a genotype-1b replicon system EC50 = 2.1 nM and EC90 = 5.6 nM. ITMN 191 is 97.9% bound by human serum protein, and its replicon potency is shifted modestly by human serum. ITMN 191 does not inhibit a panel of selected serine proteases, a broader ligand panel, or hERG ion channel. Its CC50 value is >50 μM. ITMN 191 does not inhibit CYP isoforms 1A2, 2C19, 2C9, or 2D6 at 10 μM; it inhibits roughly 33% of the activity of the 3A4 isoform at this concentration. Use of CYP inhibitors show ITMN 191 to be metabolized by multiple CYP isoforms. After 120 min incubation with rat, dog, human, or monkey hepatocytes, 81%, 73%, 35%, or 19% of input compound remained intact, respectively. After a regimen in which a human equivalent dose of 290 mg BID PO was administered for 7 days, compound trough liver levels in rats and cynomolgus monkeys were 390-fold and 52-fold the EC90 value, respectively, after the last dose in the study. Plasma exposure was linear with dose in both species to at least 300 mg/kg.

 

In conclusion, ITMN 191 is a highly potent, orally absorbed inhibitor of the NS3/4A protease found in the liver of rats and cynomolgus monkeys at levels predictive of human efficacy. Based on these data, ITMN 191 has been nominated for preclinical development and is currently undergoing IND-enabling toxicologic assessment.


Abstract T1794 – Structure-Based Design of Novel Isoindolene Inhibitors of HCV NS3/4A Protease and Binding Mode Analysis of ITMN 191 by X-ray Crystallography

K. R. Condroski; H. Zhang; S. Seiwert; J. A. Ballard; B. A. Bernat; B. Brandhuber; H. Colwell; D. Smith; G. Vigers; S. W. Andrews; A. L. Kennedy; Y. Jiang; S. M. Wenglowsky; J. A. Josey; L. M. Blatt

 

A need exists for novel treatments of chronic hepatitis C since the current standard of care, PEG IFN-α-2 + ribavirin, results in a sustained virologic response in 50% of patients. Recent advances in the field have identified the HCV serine protease NS3/4A as a promising target for drug discovery. Developing potent inhibitors of NS3/4A has been challenging from a medicinal chemistry standpoint due to its relatively flat and largely featureless binding site. Additionally, rapid error-prone replication leading to multiple active genotypes and quasi-species has slowed the drug discovery process for HCV NS3/4A inhibitors. In our effort to design potent inhibitors of HCV NS3/4A protease we used an iterative structure-based design approach powered by protein crystallography that guided the rational design of analogs leading to the effective optimization of the P2 moiety, the linker, the P1’ moiety and contacts to the NS3/4A catalytic triad. By gaining potency from optimized contacts in each region of the target, it was possible to achieve exceptionally potent NS3/4A inhibitors that maintain potency across genotypes and mutant strains. These efforts resulted in identification of ITMN 191, a potent, selective HCV NS3/4A protease inhibitor. Analysis of a crystal structure of an ITMN 191–NS3/4A protease complex led to an understanding of the structural factors responsible for the subnanomolar potency of ITMN 191 in NS3/4A of genotype 1 and its significant potency against NS3/4A derived from HCV genotypes 2 and 3. In addition, these studies inform the differences in activity observed for prototypical peptide-based protease inhibitors such as VX-950 and SCH 503034. In conclusion, these studies rationalize the potency characteristics of the preclinical candidate ITMN 191.

 


Abstract T1795 – Pharmacokinetic Analysis and Liver Concentrations of a Series of Macrocyclic Peptidomimetic Inhibitors of HCV NS3/4A Protease: Identification of ITMN 191, a Potent NS3/4A Protease Inhibitor with High Liver Exposure Across Multiple Species

R. Rieger; P. A. Lee; S. Seiwert; S. W. Andrews; G. P. Hingorani; T. K. Pope; J. Pheneger; N. Neitzel; R. B. Franklin; J. A. Josey; L. M. Blatt

 

Inhibition of the HCV serine protease, NS3/4A, represents a promising new strategy for control of chronic HCV infection. Given that viral replication of HCV is reported to occur primarily in hepatocytes, achieving high drug concentrations in liver is believed to be critical to the clinical success of protease inhibitors. In addition, clinical trials with peptide-based NS3/4A protease inhibitors have demonstrated a positive correlation between the magnitude of antiviral effect and the trough concentration of drug in plasma, which is thought to be a surrogate for trough concentrations of drug in liver. With the goal of identifying potent NS3/4A protease inhibitors providing high liver concentrations, particularly at trough, we analyzed a series of macrocyclic peptidomimetic inhibitors for plasma pharmacokinetic (PK) parameters and tissue concentrations (liver and heart) following a single oral dose of 30 mg/kg in Sprague-Dawley rats. These data demonstrated that modest structural changes resulted in radically different compound ratios between liver, plasma, and heart. ITMN 191 provided an average liver Cmax of 3,098-fold the replicon EC90 value and much lower exposures in plasma (10-fold less) and heart (50-fold less). ITMN 191 concentrations in plasma and liver were further examined in multidose PK studies in rats, dogs, and monkeys. Following a 7-day PO BID dosing regimen of 30 mg/kg in rats, average concentrations of compound in liver at apparent Cmax and trough were 1,646-fold and 152-fold the EC90 value, respectively, after the last dose on Day 7. A liver-to-plasma ratio of 2.4:1 was observed at apparent Cmax. Following a 7-day PO BID dosing regimen of 15 mg/kg dose in beagle dogs, average concentrations of compound in liver at apparent Cmax and trough were 3,048-fold and 58-fold the EC90 value, respectively, after the last dose on Day 7. A liver-to-plasma ratio of 51:1 was observed at apparent Cmax. Lastly, following a 7-day PO BID dosing regimen of 15 mg/kg dose in cynomolgus monkeys, average concentrations of compound in liver at apparent Cmax and trough were 238-fold and 52-fold the EC90 value, respectively, after the last dose on Day 7. A liver-to-plasma ratio of 70:1 was observed at apparent Cmax. In conclusion, the high Cmax and trough liver concentrations of ITMN 191 across three preclinical species contributed to the decision to nominate it for further development.


Abstract T1796 – The novel Lambda-interferons IL-28A and IL-29 inhibit HCV replication in vitro and hepatic IL-28 mRNA expression is increased in HCV and CMV infection in vivo

S. Brand; J. Dambacher; F. Beigel; M. Storr; T. Olszak; K. Zitzmann; B. Goeke; C. J. Auernhammer; A. Kaul; R. Bartenschlager; H. Diepolder

 

Background:

IL-28A and IL-29 belong to a novel group of interferons named IFN-lambdas. Recently, we demonstrated antiviral properties for these cytokines in intestinal epithelial cells (Am J Physiol Gastrointest Liver Physiol 2005; 289:G960-8).

 

Aims:

The aim of this study was to analyze receptor expression, signal transduction and antiviral functions, particularly against hepatitis C virus (HCV) infection, mediated by IL-28A and IL-29 in hepatic cells.

 

Methods:

The mRNA expression of IL-10R2 and IL-28R1, the receptor subunits required for IL-28A and IL-29 signaling, was determined by RT-PCR in hepatic cell lines. Lambda-interferon induced signal transduction was analyzed by Western blotting using phospho-specific antibodies against STAT proteins. The activation of the antiviral proteins was analyzed by luciferase assays and Northern Blot analysis. The effect of IL-28A and IL-29 on replication of HCV was analyzed in Huh-7 cells stably expressing HCV replicons and firefly genes using luciferase assays. The IL-28A mRNA expression in HCV infected human liver biopsy samples (n=10) and control liver biopsy samples (n=19) was measured by quantitative PCR. To analyze regulation of IL-28 mRNA expression in viral infection in vivo, C57/BL6 mice were infected i.v. with one million pfu murine cytomegaly virus (MCMV) of the Smith strain for 45 hours. Murine IL-28 mRNA expression in liver tissue was measured by RT-PCR.

 

Results:

Both receptor subunits necessary for IFN-lambda signaling (IL-10R2 and IL-28R1) are expressed in the hepatic cell lines HepG2, Hep3B and Huh-7. The IL-28R receptor complex is functional resulting in increased phosphorylation of STAT-1 and STAT-3 proteins following IL-28A and IL-29 stimulation. Moreover, both cytokines activate the transcription of the antiviral proteins MxA and 2’,5’-OAS. 100 ng/ml of IL-28A and IL-29 decreased HCV replication in Huh-7 cells to 1.76 ± 0.08% and 1.38 ± 0.20%, respectively (control 100%, IFN-alpha 10 U: 0.31 ± 0.14%). IL-28A mRNA expression was significantly higher in liver biopsy samples of HCV patients than in samples of patients with non-viral hepatitis (36.7-fold increase; p<0.05). Similarly, murine IL-28 mRNA expression was increased 3-fold in liver tissue from MCMV infected mice compared to uninfected control mice (p=0.003).

 

Conclusion:

Hepatic IL-28 mRNA expression is elevated in human HCV and murine CMV infection and IFN-lambda mediated signaling inhibits HCV replication in vitro. These results suggest that IFN-lambda could play a role in the antiviral immune defense against HCV and may have a therapeutic potential.


Abstract T1797 – Celgosivir and castanospermine are highly synergistic against bovine viral diarrhea virus when combined with interferon alpha 2b or with interferon alpha 2b and ribavirin

D. Dugourd; R. W. Siu; J. R. Fenn

 

Celgosivir is an alpha glucosidase inhibitor that is being developed for the treatment of Hepatitis C virus (HCV) infections in humans. The purpose of this study was to evaluate the in vitro antiviral activity of celgosivir and its major metabolite, castanospermine, when combined with current approved therapies (ribavirin, interferon α2b, or both) in a surrogate model of HCV (Bovine Viral Diarrhea Virus (BVDV)). Compounds alone or in combination were tested against BVDV in infected Madin-Darby Bovine Kidney (MDBK) cells. Synergies were analyzed using isobolograms and volume of synergy measurements (MacSynergy II™ software). The celgosivir-interferon α2b combination was significantly more synergistic than the celgosivir-ribavirin combination (~3-fold), or the ribavirin-interferon α2b combination (~2-fold). Similarly, the castanospermine-interferon α2b double combination was more synergistic than the castanospermine-ribavirin combination (~5-fold), or the ribavirin-interferon α2b combination (~3.3-fold). The combinations of celgosivir-interferon α2b or castanospermine-interferon α2b led to significant decreases in the EC50s of celgosivir (up to >20-fold) and castanospermine (up to >50 fold). The effective EC50s of celgosivir or castanospermine were further reduced by the addition of ribavirin. The cytotoxicity of the double and triple combinations was additive or less than additive, indicating that combinations of celgosivir or castanospermine with ribavirin and/or interferon α2b were generally less toxic than expected. These results indicate that the combination of celgosivir with interferon α2b or with interferon α2b and ribavirin may be effective in the treatment of HCV.


Abstract T1798 – Activation of T lymphocytes correlates with the efficacy of IFN in genotype 2 patients with chronic hepatitis C

S. Abe; R. Narita; T. Oto; A. Tabaru; M. Otsuki

 

Background and Aims:

It is well-known that the patients with HCV genotype 2a/2b have higher sustained virological response than those with genotype 1b after interferon (IFN) treatment in chronic hepatitis C (CHC). However, it is not clarified whether there is a difference in activation of T lymphocytes among HCV genotypes after IFN treatment. We evaluated the relationship between HCV genotypes and the host immune response by examining the levels of serum soluble interleukin-2 receptor (sIL-2R) that reflects activation of T lymphocytes.

 

Methods:

One hundred and eleven CHC patients were included. Forty patients received IFN monotherapy (group A): 6-10 million units (MU) of IFN-α2b daily for 14 days followed by 3 times per week (tiw) for a total of 24 weeks, whereas 71 patients received the combination therapy with IFN and ribavirin (RBV) (group B): 6-10 MU of IFN-α2b daily for 14 days followed by tiw for a total of 24 weeks and 600 or 800 mg RBV per day. We measured serum sIL-2R levels in those patients before (T0) and 2 weeks (T2) after the treatment.

 

Results:

The sustained response rates in genotype 2a/2b patients were significantly higher than those in genotype 1b patients both in group A (77.8% vs 38.5%, P = 0.0146) and B (88.9% vs 25.0%, P < 0.0001). In IFN-sustained responders, sIL-2R levels at T2 were significantly higher than those at T0 both in group A and B (P = 0.0049 and P = 0.0002, respectively). In IFN-nonresponders, sIL-2R levels at T2 were not different from those at T0 (P = 0.0555) in group A, but were significantly higher than those at T0 (P = 0.0143) in group B. In genotype 1b patients, sIL-2R levels at T2 were not different from those at T0 (P = 0.1520) in group A, but were significantly higher than those at T0 (P = 0.0274) in group B. In genotype 2a/2b patients, sIL-2R levels at T2 were significantly higher than those at T0 both in group A and B (P = 0.0025 and P < 0.0001, respectively).

 

Conclusion:

These findings suggest that the activation of T lymphocytes after IFN treatment contributes to high sustained response rates, especially in patients with HCV genotype 2a/2b.


Abstract T1799 – Pharmacokinetics of celgosivir, a novel antiviral agent, following oral administration in rats: determination of the gastrointestinal first-pass effect

E. Rubinchik; D. J. Erfle; J. J. Clement; C. J. Pasetka

 

Celgosivir is a novel antiviral agent currently in clinical development for the treatment of chronic hepatitis C virus (HCV) infection. Non-clinical and clinical studies indicate that, following oral administration, celgosivir (6-O-butanoyl castanospermine) is readily converted to its primary metabolite castanospermine. Both celgosivir and castanospermine inhibit alpha-glucosidase-I, an enzyme that is involved in the processing of viral glycoproteins. In peripheral blood, celgosivir is detected only sporadically for a short period after dosing while castanospermine is present at significantly higher levels for a much longer period. However, the extent of liver exposure to celgosivir has not been conclusively established as the low peripheral blood levels may be the result of first-pass metabolism. The objective of this study was to determine celgosivir and castanospermine levels in the portal and caudal venous blood during the first hour following oral celgosivir dosing.

 

Five male Sprague-Dawley rats with portal vein catheters were administered celgosivir orally at 400 mg/kg. Blood samples were collected from the portal and caudal veins at pre-determined time-points. The heparinised blood was immediately extracted with an acetone/methanol mixture. Celgosivir and castanospermine concentrations were determined using high performance liquid chromatography coupled with mass spectrometric detection.

 

Following oral dosing, celgosivir was detected in both portal and caudal venous blood. Celgosivir concentrations in the portal vein were on average 4.4-13.2 times higher than those in peripheral circulation. The average maximum concentration (Cmax) of celgosivir in the portal vein was 1,887 ng/mL with an area under the curve (AUC0-60 min) of 1,003 ng.hr/mL. Comparatively, the portal vein Cmax of castanospermine was 105,630 ng/mL with an AUC0-60 min equivalent to 63,876 ng.hr/mL. The average celgosivir concentration in portal blood was up to 3.4% of the total amount of both analytes.

 

Based on the results described, it was concluded that following oral celgosivir dosing the liver was exposed to both celgosivir and castanospermine, with the majority of drug being converted to castanospermine prior to liver exposure. This conversion most likely occurred in the gastrointestinal tract.

 


Abstract T1800 – Peginterferon Alfa-2a (40KD) plus Ribavirin (RBV) in Pegylated Interferon Alfa-2b (12KD)/Ribavirin Non-Responders: Week 12 Efficacy and Safety Outcomes of the REPEAT Study

D. Jensen; A. Di Bisceglie; N. Gitlin; B. Freilich; K. Reddy; V. Feinman; S. Arora; P. Marcellin

 

The REPEAT study is currently investigating the efficacy/safety of Peg-IFNα-2a (40KD) plus RBV in previous non-responders to Peg-IFNα-2b (12KD)/ribavirin. Here, we report results of a protocol-planned interim efficacy/safety analysis after 12 weeks of re-treatment.

 

Methods:

Non-responders to ≥12 weeks of approved doses of Peg-IFNα-2b (12KD)/ribavirin who remained HCV RNA positive throughout treatment were eligible. 950 patients were randomized to 1 of 4 groups: Peg-IFNα-2a (40KD) 360 μg/week for 12 weeks then 180 μg/week for a further 60 or 36 weeks (Arms A and B, respectively); Peg-IFNα-2a (40KD) 180 μg/week for 72 or 48 weeks (Arms C and D, respectively). All 942 treated patients received RBV 1000/1200 mg/d. HCV RNA was measured by quantitative (≥600 IU/mL) or qualitative (≥50 IU/mL) PCR assay. Data from Arms A+B (Peg-IFNα-2a [40KD] fixed-dose induction), and Arms C+D (Peg-IFNα-2a [40KD] standard dose) were combined.

 

Results (Table):

Baseline characteristics were similar in the 2 groups. At week 12, a significantly greater proportion of patients treated with fixed-dose induction Peg-IFNα-2a (40KD) had an early virological response (EVR; HCV undetectable, HCV non-quantifiable, or ≥2-log10 drop in HCV RNA), compared with standard-dose Peg-IFNα-2a (40KD). No substantial increase was seen in the incidences of adverse events (AEs) and serious AEs in patients treated with fixed-dose induction vs standard-dose Peg-IFNα-2a (40KD).

 

Conclusion:

Over the first 12 weeks of retreatment, standard doses (180 μg/week) of Peg-IFNα-2a (40KD) plus RBV are associated with an EVR rate of 45% in previous non-responders to Peg-IFNα-2b (12KD)/ribavirin. A fixed induction dose (360 μg/week) of Peg-IFNα-2a (40KD) plus RBV was found to be even more effective than standard doses at inducing an EVR (62%); moreover, the safety profile of Peg-IFNα-2a (40KD) plus RBV did not appear to be compromised in patients receiving fixed induction doses.

N (%)†

Peg-IFNα-2a (40KD) dose during weeks 1−12

(+RBV 1000/1200mg/d)

 

 

180 µg/week (n=469)

360 µg/week (n=473)

Male

319 (68)

297 (63)

Mean age ± SD, yrs

48.8 ± 8.8

48.3 ± 9.1

Caucasian/Black

413 (88)/42 (9)

418 (88)/39 (8)

Genotype 1 / 2 or 3

425 (91) / 16 (3)

429 (91) / 17 (4)

Mean HCV RNA ± SD, x106 IU/mL

4.9 ± 5.7

5.4 ± 6.6

Cirrhosis/advanced fibrosis

133 (28)

119 (25)

Median duration of previous treatment, weeks

28

28

EVR‡ at week 12

210 (45)

291 (62)*

Peg-IFNα-2a (40KD) dose modified or discontinued

63 (13)

88 (19)

≥1 AE/serious AE

430 (92)/19 (4)

441 (93)/10 (2)

 


Abstract T1801 – Impact of Therapy of Chronic Hepatitis C (CHC) on Quality of Marital Relationships.

M. O'Brien; L. S. Rosenthal; E. Lebovics

 

BACKGROUND:

Impairment of quality of life by therapy of CHC has been documented in studies utilizing validated social science questionnaires. Specific impact on close valued relationships such as marital or significant others has not been examined.

 

METHODS:

Questionnaires were sent to 445 consecutive patients treated with either interferon-alpha 2b or pegylated interferon plus ribavirin. Questions addressed communication within the relationship, sexual intimacy, ability to share household responsibilities, quality of shared leisure time, arguing, and overall quality of the marriage prior to treatment initiation, during treatment, and after treatment completion. Responses were scored on a scale of 1 to 5, with 5 being the highest functioning. Also, patients were asked whether they separated or divorced during or shortly after their treatment and if this was attributable to therapy.

 

RESULTS:

Of 114 respondents, 15 patients (13.1%) were either separated (n=10; 8.8%), or divorced (n=5; 4.4%) during or shortly after treatment. Six of the 10 who separated and 2 of the 5 who divorced stated this was in part secondary to CHC therapy. Mean scores for all parameters assessing aspects of the marital relationship significantly decreased from baseline to during therapy (p<0.001 for each) and returned to baseline after therapy. 35% of patients had no impairment in communication, 49% had a drop of 1-2 points, and 12% a drop of 3-4 points. 30% reported no change in sexual intimacy, 50% had a drop of 1-2 points, and 19% a drop of 3-4 points. 27% reported no change in sharing household responsibilities, 48% had a drop of 1-2 points, and 23% a drop of 3-4 points. 29% reported no change in quality leisure time spent with spouse, 32% had a drop of 1-2 points, and 16% a drop of 3-4 points. 49% reported no change in frequency of tense arguments with significant other, 37% had a drop of 1-2 points, and 7% a drop of 3-4 points. 53% reported no impairment in overall quality of marriage, 37% had a drop of 1-2 points, and 7% a drop of 3-4 points.

 

CONCLUSIONS:

·       CHC therapy impairs marital relations and may contribute to separation and divorce.

·       Patients should be counseled prior to initiation of therapy of these potentially life altering effects, and appropriate care taken to prevent such outcomes.

·       Future studies should address whether these results differ from a population matched for psychosocial conditions.

 


Abstract T1802 – Prior HCV Treatment Experience and its Relationship To Sustained Virologic Response (SVR): An Analysis of the WIN-R Study Database, A US Academic Community Based Trial

P. Kwo; I. Jacobson; R. Brown; B. Freilich; B. Afdhal; J. Santoro; S. Becker; A. Wakil; D. Pound; E. Godofsky; R. Strauss; D. Bernstein; S. Flamm; N. Bala; V. Arraya; M. Davis; H. Monsour; J. Vierling; F. Regenstein; V. Balan; M. Dragutsky; M. Epstein; R. Herring; L. H. Griffel; C. Brass

 

Background:

Registration trials using PEG IFN and ribavirin, conducted by investigators experienced in the treatment of CHC have demonstrated SVR rates of 54-56%. Whether these SVR rates can be replicated in clinical practice in the community remains unclear. Aim: To determine investigator factors that affect SVR rates in patients receiving PEG IFN alfa-2b 1.5 ug/kg/week with ribavirin for HCV treatment.

 

Methods:

Patients in academic or community settings with CHC were randomized to PEG IFN alfa-2b 1.5 ug/kg once weekly plus RBV 800 mg/day or RBV based on weight. Treatment was 48 weeks for patients with HCV G1, patients with G2 or 3 were randomized to 24 or 48 weeks. Follow-up for all patients was 24 weeks. HCV RNA was determined by PCR. 25 academic and community investigators, all having participated in CHC registration trials or having extensive experience in HCV therapy served as regional PIs . High enrollment sites (≥ 25 patients enrolled) had selected data verified by study monitor. Analyses performed by logistic regression analysis. Results: 225 sites enrolled 4913 patients with overall SVR of 43.6%., 923/4913 (18.8%) were treated at regional PI sites, 3990/4913 were at non-regional PI sites(81.2%). 3114/4913 patients were treated at monitored sites (63.4%). 1800/4913 patients (36.6%) dropped out (DO).

 

Conclusions:

1. Patients within regional PI sites are more like to achieve SVR and less likely to drop out than patients within non-regional PI sites

2. Within non-monitored sites (<25 patients enrolled), patients within regional PI sites are more like to achieve SVR and less likely to drop out than patients within non-regional PI sites

3. No differences were seen in SVR or DO for monitored and non-monitored sites.

 

Research Support: Schering Plough

 

SVR all patients

SVR regional PI patients

SVR non-regional PI patients

OR

p-value

2140/4913(43.56%)

445/923 (48.21%)

1695/3990 (42.48%)

1.261

0.0016

SVR all patients

SVR monitored sites

SVR non-monitored sites

 

 

2140/4913 (43.56%)

1372/3114 (44.06%)

768/1799 (42.69%)

1.057

0.3518

SVR all monitored patients

monitored regional SVR

monitored non-regional SVR

 

 

1372/3144 (43.64%))

351/763 (45.88%)

1021/2351 (43.43%)

1.11

0.2121

SVR all non-monitored patients

SVR regional non-monitored patients

SVR non-regional non-monitored patients

 

 

768/1799 (42.69%)

94/160 (58.75%)

674/1639 (41.12%)

2.039

<0.0001

DO all patients

DO regional PI patients

DO non-regional PI patients

 

 

1800/4884(36.86%)

312/921 (33.88%)

1488/3963(37.55%)

0.852

0.0376

DO all patients

DO monitored sites

DO non-monitored sites

 

 

1800/4884 (36.86%)

1124/3104 (36.21%)

676/1780 (37.98%)

0.927

0.2182

DO all monitored patients

monitoredregional DO

monitored non-regional DO

 

 

1124/3104 (36.21%)

268/762 (35.17%)

856/2342 (36.55%)

0.942

0.4932

DO all non-monitored patients

DO regional non-monitored patients

DO non-regional non-monitored patients

 

 

676/1780 (37.98%)

44/159 (27.67%)

632/1621 (38.99%))

0.599

0.0054

 


Abstract T1803 – Employment Status and Work Performance during Therapy of Chronic Hepatitis C (CHC)

M. L. O'Brien; L. S. Rosenthal; E. Lebovics

 

BACKGROUND

Impairment of quality of life by therapy of CHC has been documented in studies utilizing validated social science questionnaires. Impact on work performance is ill-defined.

 

METHODS

Questionnaires were sent to 445 consecutive patients who underwent treatment with either interferon alpha 2b or pegylated interferon plus ribavirin. Six questions addressed ability to concentrate at work and cope with job stress, work stamina, perception of evaluation by superiors, absenteeism, and overall quality of work performed. Responses were scored 1 to 5 (very poor/poor/fair/good/excellent) for before, during, and after treatment. Also, patients were asked whether they discontinued work (fired/quit/disability leave) and whether CHC therapy contributed to any change in employment status.

 

RESULTS

116 patients responded. Among this group, 30 (26%) were either fired (n=6, 5%), quit (n=2, 2%) or took disability leave (n=22, 19%) from their jobs during CHC treatment. All patients who were fired or quit and 86% of those who took leave attributed their change in employment status to adverse effects of CHC therapy. Mean baseline scores (prior to CHC therapy) for each of the 6 work performance questions was between 4 and 5. During therapy, mean scores for each question dropped to between 2 and 3 (p<.001). Scores returned to baseline levels after therapy. Of note, 59% of patients reported that CHC therapy caused a decline in their overall work performance.

 

CONCLUSIONS

·       In this series CHC therapy was associated with a 26% rate of discontinuation of employment due to either termination or temporary disability leave.

·       59% of patients reported a significant impairment of overall work performance.

·        On the whole, there was no perception of work performance impairment at baseline and after therapy was completed. Patients should be counseled accordingly prior to initiation of therapy.

 


Abstract T1804 – The Treatment of Chronic Hepatitis C in HIV Infected Patients: A Meta-Analysis

A. I. Kim; R. Bouajram; A. Dorn; S. Saab

 

Background:

Hepatitis C (HCV) disease appears accelerated in patients coinfected with human immunodeficiency virus (HIV). The objective of our study was to further understand incremental improvement and safety concerns with combinations of peginterferon, interferon and ribavirin based on data obtained from prospective randomized contolled trials (RCTs).

 

Methods:

A search of MEDLINE and the Cochrane database, and a hand search of abstracts from national meetings was performed. We extracted data on baseline characteristics, types of treatment, efficacy, and adverse events.

 

Results:

In 6 RCTs, 1756 patients were randomized. Sustained virologic response (SVR) was greater for patients treated with peginterferon plus ribavirin compared to patients treated with interferon plus ribavirin (odds ratio [OR], 3.00; 95% confidence interval [CI], 2.27-3.96; P=<0.0001)(Figure 1). This increased SVR with peginterferon and ribavirin was also true for patients with HCV genotypes 1 or 4 (OR, 4.40; CI 2.75-7.03; P=<0.0001) and genotypes 2 or 3 (OR, 2.56; CI 1.71-3.85; P=<0.0001). SVR rates were also higher with peginterferon and ribavirin as compared to peginterferon monotherapy (OR, 2.60; CI, 1.84-3.67; P=<0.0001). Severe adverse effects (OR, 1.09,CI, 0.74 – 1.4, P=<0.59) and withdrawal rates (OR, 0.97,CI, 0.75 – 1.25, P=<0.79) were similar between patients treated with peginterferon and ribavirin compared to patients treated with interferon and ribavirin.

 

Conclusion:

·       Patients with chronic HCV with HIV coinfection have a greater likelihood of achieving SVR with treatment of peginterferon plus ribavirin.

·       The likelihood of serious adverse effects and study withdrawal were similar.

 


Abstract T1805 – Cost-Effectiveness of First-Line Peginterferon Alfa-2a (40KD) (PEGASYS®) plus Ribavirin (COPEGUS®) in Patients with Mild Chronic Hepatitis C (CHC) in the US

H. B. El-Serag; K. K. Patel; N. Wintfeld; J. Green; S. D. Sullivan

 

Introduction

Patients with mild CHC treated with peginterferon alfa-2a (40KD) plus ribavirin attain higher sustained virological response (SVR) rates than patients with incomplete septa or cirrhosis [1]. This report utilizes these findings to assess the cost-effectiveness of treating patients with mild CHC with peginterferon alfa-2a (40KD) plus ribavirin.

 

Methods:

Data for HCV genotype 1 patients with mild CHC [1] were obtained from two phase III multinational, randomized, controlled trials [2,3]. Mild CHC was defined as a fibrosis score of F0, F1, or F2 using the METAVIR scale. Treatment of patients with mild CHC with peginterferon alfa-2a (40KD) (180 µg/week) plus ribavirin (1000/1200 mg/day) resulted in an SVR of 56% (95% CI 50-63%) [1]. The life-time disease progression to cirrhosis, hepatocellular carcinoma, and liver transplant in patients who failed to achieve an SVR was based on published data [4]. The impact of EVR at week 12 (85%; 95% CI 80-89%) on the cost of treatment was included in the model. Quality of life weights and resource costs were based on published literature. Costs related to the treatment of adverse events were not included in the analysis.

·       Costs (in US$ 2004) and benefits were discounted at 3%.

·       Sensitivity analyses were performed to evaluate uncertainty in model parameters. 

·       The model was run until 100% of the cohort had died.

·       The incremental cost-effectiveness ratio (ICER) was computed as the incremental total medical cost divided by the incremental gain in quality-adjusted life-years (QALYs)

 

Results:

Cost-effectiveness

Compared with no treatment, peginterferon alfa-2a (40KD) plus ribavirin was associated with an increase in 1.46 QALYs in HCV genotype 1 patients with mild chronic hepatitis C, yielding an incremental cost per QALY gained of $3396. 

 

Sensitivity analyses

·       Despite wide variations in model parameters, including an SVR rate as low as 50%, an EVR rate as low as 80%, and a time horizon as short as 20 years, the ICER did not exceed $27,000 per QALY gained. 

·       The ICER did not fall below the commonly cited threshold in the USA of $50,000 per QALY gained until the SVR rate was decreased to as low as 13%.  This provides further evidence of the robustness of the model results.

·       The most influential parameters in this analysis were the time horizon and the discount rate. 

 

Conclusion:

·       Compared with no treatment, for adults with mild CHC, peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) is a cost-effective treatment strategy in the US setting.

·       The cost-effectiveness of peginterferon alfa-2a (40KD) plus ribavirin compared with no treatment in these patients is most likely a result of a reduction of the incidence of future complications, including cirrhosis, hepatocellular carcinoma and liver transplantation, and an increase in life expectancy and QOL.

·       The practice of determining the need for antiviral therapy based on histology may need reassessment in view of these findings.

 

1Shiffman et al. Gastroenterology 2005;128(Suppl) Abstr S1568

2Zeuzem et al. Gastroenterology 2004;127:1724

3Fried et al. NEJM 2002;347:975

4Hui et al. J Hepatol 2003;38:511

 


Abstract T1806 – Stratification of High Viral Load: Impact on Sustained Virologic Response in the WIN-R Trial

I. M. Jacobson; R. S. Brown; B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; F. Ahmed; L. H. Griffel; C. A. Brass; G. WIN-R Study

 

Background:

Pretreatment Hepatitis C (HCV) viral levels have been associated with the likelihood of achieving a sustained virologic response (SVR) during the course of antiviral therapy with pegylated interferon and ribavirin (RBV).

 

Aim:

To assess the relationship of pretreatment HCV viral load with SVR rates in patients with genotype 1 using data from the WIN-R Trial, the largest HCV therapeutic trial to date.

 

Methods:

Patients in a community setting with chronic hepatitis C were randomized to Peg IFN alfa-2b 1.5 µg/kg once weekly plus RBV 800 mg/day or RBV based on weight: <65 kg- 800 mg/day, 65 to <85 kg- 1000 mg/day, 85 to < 105 kg- 1200 mg/day, and 105-125 kg- 1400 mg/day. Treatment was 48 weeks for patients with HCV genotype 1. Follow-up for all patients was 24 weeks. HCV RNA was determined by PCR (Taqman/SPRI) at weeks 24, 48 and 72. SVR rates were analyzed according to baseline HCV viral loads in patients with genotype 1. Low viral load was defined as < 2 million cop/ml; high viral load was defined as ≥ 2 million cop/ml.

 

Results:

225 sites enrolled 4913 patients (2444 FD and 2469 WBD) who received at least one dose of drug. Intention-to-treat analysis showed a significant improvement (p=0.02) in SVR with WBD (44%) compared to FD (41%). 3018 patients had genotype 1 with an overall SVR rate of 33% (984/3018). In patients with genotype 1, SVR rates were significantly higher (p = 0.006) in patients with a low HCV viral load (35%, 452/1279) than in those with a high viral load (31%, 532/1739). SVR rates in patients with viral load < 2 million cop/ml were compared with patients with viral loads ≥ 2 million cop/ml as shown in the Table. Reductions in SVR were noted in more patient groups with baseline HCV RNA levels of 2-15 million cop/ml than in patients with > 15 million cop/ml.

 

Conclusion:

Within the genotype 1 patient population with high viral load as defined traditionally (≥2 million cop/ml), those with very high viral loads do not have impaired rates of SVR.

 

HCV viral load (cop/ml)

SVR (n)

p value*

< 2 million

35% (452/1279)

-

2-5 million

30% (167/550)

0.039

5-10 million

30% (153/504)

0.456

10-15 million

25% (70/279)

0.001

15-20 million

39% (53/136)

0.401

20-30 million

35% (61/174)

0.942

30+ million

29% (28/96)

0.222

 


Abstract T1807 – SVR can be achieved with less than 48 weeks of peginterferon-α2a combination therapy in a significant proportion of HCV-G1 patients

K. Tang; E. Herrmann; E. Paulon; I. Pachiadakis; N. Tatman; R. Williams; S. Zeuzem; N. Naoumov

 

Background and aims:

48 weeks of peginterferon combination therapy is the current consensus recommendation for the treatment of chronic hepatitis C genotype 1 (CHC-G1) patients. The likelihood of a SVR is increased considerably among patients showing an early on-treatment viral response (EVR). We aimed to establish whether shorter durations of this treatment could be given without a compromise in therapeutic efficacy.

 

Methods:

Forty-five treatment-naďve, non-cirrhotic CHC-G1 patients were treated with peginterferon-α2a plus ribavirin (P2aR). Patients with undetectable HCV RNA within 12 weeks of treatment were randomised to continue a further 12, 24, or 36 weeks of treatment from the time of viral clearance. The remaining patients all received 48 weeks of the same treatment unless EVR was not attained. Plasma HCV RNA was quantitated in all patients by real-time RT-PCR (TaqMan™) at days: 0, 1, 2, 3 and weeks 1, 2, 4, 8, 12, and monthly thereafter. Early viral kinetic patterns, during treatment, were determined by mathematical modelling. Hepatocyte HCV RNA was measured to examine relationships with treatment duration and outcome.

 

Results:

·       32/45 (71%) patients had undetectable HCV RNA by 12 weeks of treatment (TW12).

·       11 patients were randomised to receive a further 12 weeks of treatment (G12), 10 received 24 weeks (G24), and 11 had a further 36 weeks of therapy (G36).

·       Of the remaining 13 patients (G48), 10 had an EVR, and had a full 48 weeks of treatment.

·       ITT analyses showed EVR in 42/45 patients (93%), ETR 89%, and SVR 56%. Among patients with undetectable HCV RNA by TW12, 21/32 (66%) had a SVR.

·       G12 patients underwent a mean treatment duration of 18.9±3.6 weeks, with SVR in 5/11 patients (46%),

·       G24 patients were treated for 31.6±3 weeks, SVR 8/10 patients (80%), and G36 patients were treated for 43±10.4 weeks, SVR in 8/11 patients (73%).

·       Duration of treatment and viral load at TW12 were found to be significant predictors of SVR by multivariate analyses.

·       Viral kinetic parameters from mathematical modelling did not differ significantly between G12, G24, and G36.

·       The mean antiviral efficacy (ε) was lower in G48 (49.5% vs 86.3%, p=0.025), as was the treatment-induced infected cell loss (Mδ) (0.17 vs 0.58/day, p=0.019), compared to the randomised groups combined.

 

Conclusions:

·       In HCV-G1 patients, a minimum of 24 weeks of viremia-free time on P2aR is required for achieving a high rate of SVR.

·       32 weeks of total treatment duration appears sufficient to obtain SVR in a substantial subset of patients showing rapid viral clearance.

·       Prolonged therapy above 48 weeks may be necessary for slow responders to achieve a good outcome.

 


Abstract T1808 – Peginterferon Alfa-2a (40KD) (PEGASYS®) Plus Ribavirin (RBV) (COPEGUS®) in Pegylated Interferon Alfa-2b (12KD)/Ribavirin Non-Responders with Cirrhosis/Advanced Fibrosis: Interim Analysis of the REPEAT Study

N. Gitlin; A. Di Bisceglie; P. Marcellin; H. Bonkovsky; R. Rai; M. Rizzetto; G. Teuber; D. Jensen

 

REPEAT will assess the efficacy/safety of Peg-IFNα-2a (40KD) + RBV in prior non-responders to Peg-IFNα-2b (12KD)/ribavirin. We report outcomes in patients (pts) with cirrhosis/advanced fibrosis according to geographic region from a protocol-planned interim efficacy/safety analysis after 12wks of retreatment in REPEAT.

 

Methods:

Prior non-responders to ≥12wks of Peg-IFNα-2b (12KD)/ribavirin who were HCV RNA positive throughout treatment were eligible. 950 pts were randomized to 1 of 4 groups: Peg-IFNα-2a (40KD) 360μg/wk for 12wks then 180μg/wk for 60 or 36 wks (Arms A or B); Peg-IFNα-2a (40KD) 180μg/wk for 72 or 48 wks (C or D). All 942 pts treated received RBV 1000/1200mg/d. HCV RNA was measured by quantitative (≥600 IU/mL) or qualitative (≥50 IU/mL) PCR at baseline and after 12 wks' retreatment. Data from Arms A+B (Peg-IFNα-2a [40KD] induction dose), and C+D (Peg-IFNα-2a [40KD] standard dose) were combined. Outcomes were assessed in pts with a local baseline histological diagnosis of cirrhosis/advanced fibrosis.

 

Results (Table):

Cirrhosis/advanced fibrosis was present in 133/469 pts (28.4%) receiving Peg-IFNα-2a (40KD) 180μg/wk and 119/473 pts (25.2%) receiving Peg-IFNα-2a (40KD) 360μg/wk. Baseline characteristics were generally similar in the 2 groups. At wk 12, more pts with cirrhosis/advanced fibrosis receiving induction-dose Peg-IFNα-2a (40KD) achieved an early virological response (EVR; HCV RNA undetectable, unquantifiable or ≥2-log10 drop), vs standard-dose Peg-IFNα-2a (40KD). Virological response rates in pts with cirrhosis/advanced fibrosis were similar in US/Canadian and European/Brazilian pts across both treatment groups.

 

Conclusion:

Induction-dose (360μg/wk) Peg-IFNα-2a (40KD) (PEGASYS®) + RBV (COPEGUS®) is more effective than standard-dose (180μg/wk) Peg-IFNα-2a (40KD) + RBV over the first 12 wks of retreatment in pts with cirrhosis/advanced fibrosis who have previously failed to respond to Peg-IFNα-2b (12KD)/ribavirin. Outcomes in these pts do not appear to differ according to geographic region.

 

 

Peg-IFNα-2a (40KD) dose during wks 1−12 (+RBV 1000/1200mg/d)

 

 

180µg/wk (C+D; n=133)

360µg/wk (A+B; n=119)

 

Baseline characteristics

No. of patients (%)

 

Male

102 (77)

80 (67)

Mean age±SD, yrs

51.1±8.0

51.7±9.1

Caucasian

119 (89)

110 (92)

Genotype 1

121 (91)

108 (91)

Mean HCV RNA±SD, x106 IU/mL

5.2±5.6

4.5±5.5

 

EVR‡ at wk 12

 

All patients

50 (38)

60 (50)

USA/Canada

21/55 (38)

21/45 (47)

Europe/Brazil

29/78 (47)

39/74 (53)

 

 


Abstract T1809 – Population Pharmacokinetics of Single- or Multiple-Dose Ribavirin (COPEGUS®) Administered With or Without Peginterferon alfa-2a (40KD) (PEGASYS®) in Chronic Hepatitis C (CHC) Patients

J. Wade; E. Snoeck; M. Lamb; F. Duff; K. Wang; J. Grippo; K. Jorga

 

Addition of ribavirin to interferon-based therapy reduces relapse rates during follow-up in a dose-dependent manner in patients with CHC. However, higher sustained virological response rates, with higher doses of ribavirin, must be balanced against potential increases in dose-dependent anemia. As such, a thorough understanding of the pharmacokinetics of ribavirin will help achieve optimal treatment outcomes. We analyzed the population pharmacokinetics of ribavirin (COPEGUS®) in CHC patients, including those receiving concurrent peginterferon alfa-2a (40KD) (PEGASYS®).

 

Methods:

7025 plasma concentration measurements from 380 subjects recruited to 5 clinical studies were analyzed; 3 studies were phase I crossover studies where subjects received ribavirin as a single 600mg dose, and 2 were randomized, multinational, phase III studies in which the dose of ribavirin was 800, 1000 or 1200 mg/day, where samples were collected at steady state (weeks 8–48). The population pharmacokinetic model developed to describe ribavirin pharmacokinetics was a 3-compartment model with a sequential zero order followed by a first-order absorption process. Inter-occasion variability and food effects were included.

 

Results (Table):

The only covariate with a clinically significant influence on ribavirin pharmacokinetics was lean bodyweight (LBW, range 41–91kg), influencing both clearance (15.3-23.9L/h over the LBW range) and the volume of the larger peripheral compartment (V2; the volume of distribution of the first peripheral compartment) (3506-6206L over the LBW range). Ribavirin clearance varied by <20% across the renal function range and between ethnic groups. Residual variability was very low for the final model (17%).

 

Conclusion:

The model provided a good description of ribavirin pharmacokinetics in CHC patients, as confirmed by the accurate estimates of the parameter values and the low residual variability. LBW was the only covariate that influenced clearance or volume of distribution, supporting the current recommendation that ribavirin dose should be adjusted according to bodyweight to ensure adequate exposure in patients with difficult-to-treat genotype 1 infection.

 

Parameter

Estimation

Std error (%)

Interindividual variability (%)

Std error (%)

Clearance

19.8 L/h*

1.8

16

29

LBW on CL

0.00869

20

-

-

Bioavailability (F1)

(high fat meal)

1.46

4.8

22

14

Central Volume (V1)

472 L

8.2

42

25

1st Peripheral Volume (V2)

4910 L*

5.6

37

31

LBW on V2

0.011

32

-

-

2nd Peripheral Volume (V3)

871 L

4.9

18

43

Residual error

17.0 %

5.5

-

-

 


Abstract T1810 – Growth Factors Versus Dose Reduction for Pegylated Interferon Alfa-2b and Ribavirin Associated Neutropenia and Anemia in HIV/HCV Co-Infected Patients

J. S. Kadam; K. Jones; R. Peterson; L. Dove; D. Pearce; T. Hassanein; L. Doonquah; M. Glesby; L. Heller; D. Aboulafia; J. Rodriguez; H. Bonilla; J. Galpin; J. Aberg; B. Johnston; R. Liu; I. M. Jacobson; A. H. Talal

 

Background:

HIV/HCV co-infection is a major cause of liver-related morbidity and mortality. Pegylated interferon (PEG-IFN) and ribavirin (RBV) are frequently associated with neutropenia and anemia. We conducted a prospective, randomized trial in HIV/HCV co-infected patients to compare two management strategies, dose-reduction vs. growth factor supplementation, for treatment of anemia and neutropenia secondary to RBV and PEG-IFN, respectively.

 

Methods:

103 HIV/HCV co-infected, therapy-naďve subjects with baseline hemoglobin (hgb) levels of ≥11 gm/dl and absolute neutrophil counts (ANC)≥1,200/mm3 received PEG-IFN α-2b 1.5ug/kg/wk and RBV 13 ± 2 mg/kg/day for up to 48 weeks. Hgb and ANC were measured at baseline and weeks 1,2,4 and monthly thereafter. Subjects were randomized pretreatment; those who had ≥3 gm/dL decline in hgb or hgb ≤10 gm/dL received either recombinant human erythropoietin (epoetin alfa) 40,000 U/wk (group A, n= 44) or RBV dose reduction to 10 mg/kg/d (group B, n= 46). Subjects whose ANC was ≤750 cells/mm3 received either granulocyte-colony stimulating factor 5 mg/kg twice weekly (group A, n=44) or PEG-IFN dose reduction to 1.0 ug/kg/wk (group B, n=46). We calculated the maximum hgb and ANC decline by subtracting the nadir hgb or ANC from the baseline measurement. Similarly we calculated the maximum hgb or ANC increase by subtracting the highest hgb or ANC from the nadir value.

 

Results:

Seventy-two percent of the patients were male, 43% African American, 84% genotype 1, 60% stage 1-2, and 58% acquired HCV via injection drug use. The baseline mean hgb was 14.53 ± 2.7 gm/dL and mean ANC was 2396 ± 1046 cells/mm3. At week 4,44 patients(24-group A, 20-group B) were anemic. Maximal mean hgb decline (week 4) did not differ between the two groups(group A: 3.17 ± 1.5, group B: 3.51 ± 1.43 gm/dL,p=NS). Maximal mean hgb increase also did not differ between the groups(group A: 2.53 ± 1.83, group B: 1.7 ± 1.05 gm/dL, p=NS). Thirty patients had an ANC ≤ 750 cells/mm3(13-group A,17-group B). At week 2, maximal mean ANC decline did not differ between the groups (group A: 937.75 ± 642.1, group B: 1146.5 ± 377 cells/mm3, p=NS). Maximal mean ANC increase also did not differ between the groups (group A: 738.38 ± 1180.65, group B: 219 ± 1031.29 cells/mm3, p=NS). Fatigue (73%) was the most common adverse event. Seven patients discontinued secondary to severe adverse events, 5 of which were likely related to PEG-IFN/RBV therapy.

 

Conclusion:

Growth factor supplementation and dose reduction appear to be equally effective for the management of neutropenia and anemia in HIV/HCV co-infected individuals treated with PEG-IFN and RBV.

 


Abstract T1811 – High Response Rates with Peginterferon Alfa-2a (40KD) (PEGASYS®) plus Ribavirin (COPEGUS®) in Treatment-Naive Japanese Chronic Hepatitis C Patients: A Randomized, Double-Blind, Multicenter, Phase III Trial

T. Sakai; S. Iino; T. Okuno; M. Omata; K. Kiyosawa; H. Kumada; G. Yamada; N. Hayashi

 

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) produced sustained virological response (SVR) rates of up to 52% [Ann Intern Med 2004;140:346] in genotype 1 patients in large, randomized, multinational, phase III trials. As these trials did not include Japanese patients, we compared the efficacy and safety of peginterferon alfa-2a (40KD) alone or in combination with ribavirin in Japanese patients with HCV genotype 1b infection.

 

Methods:

Treatment-naďve adults with genotype 1b infection, quantifiable HCV-RNA, elevated ALT activity and a liver biopsy consistent with a diagnosis of chronic hepatitis C were randomized equally in a double-blind manner to peginterferon alfa-2a (40KD) 180 µg/week plus either ribavirin 600-1000 mg/day or placebo for 48 weeks. The primary efficacy endpoint was SVR (HCV RNA <50 IU/mL after 24 weeks’ untreated follow-up). Patients were stratified according to HCV-RNA level (<800,000 vs ≥800,000 IU/mL). ITT analysis was used.

 

Results (Table):

200 patients were randomized to treatment. The SVR rate in the combination therapy group was significantly higher than that in the monotherapy group, regardless of baseline HCV-RNA level (odds ratio [OR] 4.55; 95% CI 2.48–8.37; p<0.001). Multiple logistic regression analysis showed that no included variables significantly and independently influenced the odds of achieving an SVR. In patients receiving monotherapy, a lower baseline HCV-RNA level (OR 0.997; 95% CI 0.995–0.999; p=0.002) and younger age (OR 0.939; 95% CI 0.900–0.979; p=0.001) significantly increased the likelihood of achieving an SVR. Adverse events were generally mild and typical of those associated with interferon-based therapy.

 

Conclusion:

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) is effective and well tolerated in treatment-naďve Japanese patients infected with HCV genotype 1b. The 61% SVR rate in genotype 1b patients exceeds those reported previously in international trials.

 

Treatment

Baseline characteristics

SVR rate, n (%)

Age (years)

Male, n (%)

Weight (kg)

Overall

Baseline HCV-RNA (IU/mL)

<800,000

≥800,000

Peginterferon alfa-2a (40KD) + ribavirin

52

62 (63)

63

60/99 (61)*

32/49 (65)*

28/50 (56)

Peginterferon alfa-2a (40KD) + placebo

51

62 (61)

62

26/101 (26)

19/53 (36)

7/48 (15)

 


Abstract T1812 – Antiviral Outcomes of Patients with Chronic Hepatitis C and Depression Treated with Pegylated Interferon Alfa-Based Therapy: A Multicenter Experience

A. Knott; E. Dieperink; M. Wingert; P. Thuras; P. Hauser; J. Davison; S. Currie; S. B. Ho

 

Background:

Depression is often considered a contraindication for interferon (IFN) alfa-based antiviral treatment. Currently there are few data indicating whether patients with depression can safely receive antiviral treatments.

 

Aim:

Determine safety and efficacy of IFN-based therapies for chronic hepatitis C patients with active depressive illness.

 

Methods:

Retrospective chart review of 91 HCV patients at 4 urban VA Medical Centers who screened positive for depressive symptoms and underwent Peg-IFN alfa-based therapy combined with weight-based ribavirin. Primary outcome: antiviral treatment outcome.

 

Results:

The sample was predominantly male (95.6%), Caucasian (86.8%), genotype 1 (63.7%). Almost half had fibrosis stage 3 or 4. Average entry Beck Depression Inventory (BDI) was 18.0 (SD ±8.3), with 33% of patients having a BDI ≥20. Almost 75% (68/91) of patients had a current diagnosis of depression, 47% (43/91) had anxiety disorders and 16% (15/91) had other psychiatric diagnoses. Alcohol and other substance use disorders (SUD-marijuana, cocaine, methamphetamine) were diagnosed in 22% (20/91) and 16% (15/91) respectively, and 26% (24/91) used recreational drugs in the last year. 65 (71.4%) patients were on antidepressants prior to antiviral treatment, 9 (9.9%) patients started antidepressants during treatment. Significant differences in patient characteristics existed between the 4 sites (number of current/lifetime MH diagnoses, current MH diagnoses). Approximately one-quarter (24/91) of patients terminated treatment early (1% [1/91] psychiatric and 3% [3/91] SUD related non-compliance, 12% [11/91] unable to tolerate side effects, 2% [2/91] adverse event, 1% [1/91] medical reasons, 4% [4/91] multiple reasons). Entry BDI ≥20 (OR=4.09, 95% CI 1.34-12.49) and having used drugs in the 12 months prior to treatment start (OR=3.99, 95% CI 1.14-13.99) were associated with early termination of antiviral treatment, while liver biopsy stage ≥2 (OR=.25, 95% CI .07-.88) reduced the likelihood of early termination. Of the 72 evaluable patients, 27 (37%) achieved SVR and 17/72 (25%) were non-responders at 24 weeks.

 

Conclusions:

·       The data indicate that HCV patients with depressive symptoms who start antiviral treatment evaluation with BDI scores ≥20 and recent recreational drug use are at higher risk for early termination of antiviral treatment. These patients warrant closer medical and psychiatric follow up prior to and during antiviral treatment.

·       Conversely, these results also suggest that patients with stable depressive disorders and baseline BDI <20 may be effectively treated with interferon-based therapy.

·       Alothough most of the same were psychiatrically ill, few patients terminated interferon therapy due to psychiatric or SID related non-compliance.


Abstract T1813 – Predictive Factors in Treatment of Chronic Hepatitis C (cHC) Patients with Peginterferon alfa-2a (40KD) and Ribavirin

E. Zehnter; S. Mauss; C. John; R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U. Alshuth; D. Hueppe

 

Aim:

Predictive factors that have been identified up to date in treatment of cHC patients shall be analyzed through a German wide observational study, developed by the “Association of German Independent Gastroenterologists” (bng, Berufsverband Niedergelassener Gastroenterologen Deutschlands e.V.) and Hoffmann-La Roche AG.

 

Patients and methods:

From March 2003 – March 2005, 9414 patients in various phases of cHC treatment were assessed in an observational quality assurance trial. 4001 of these patients received treatment with peginterferon alpha-2a, mostly in combination with Ribavirin. For 1175 patients treated according to consensus guidelines, treatment has been completed. For these patients descriptive, univariate and multivariate analyses (logistic regression model (LR), with 95% confidence intervals for the odds ratio (OR)) were performed to determine factors associated with SVR (sustained virologic response: defined as result of HCV-PCR qualitatively negative or quantitatively below detection limit, meaning ≤650 IU/ml 24 weeks after end of treatment).

 

Results:

Over all SVR was attained in 838 of 1175 patients (71%). In univariate analyses, SVR was significantly associated with GT-2/3 (p=0.000), age < 40 y (p=0.000), body weight < 85 kg (p=.001), BMI < 25 kg/m2 (p=0.012), GGT male ≥ 66, female ≥ 39 U/l (p=0.000), platelets ≥ 150000 /µl (p=0.000), serum ferritin < 200 µg/l (p=0.000) and EVR (defined as ≥ 2-log10 drop in HCV RNA or HCV RNA undetectable (p=0.000). No predictions could be established for gender, GPT and viral load.

 

In a multivariate analysis, EVR was the strongest independent significant predictive factor OR=0.40 (0.16-0.102) controlled for the effect of platelets (OR=7.690 (2.146-27.553) and serum ferritin (OR=2.326 (1.296-4.177).

 

Conclusion:

The best predictors of curative chances for antiviral therapy of HCV-patients under non-clinical conditions are EVR, normal serum ferritin and normal platelets. Other established biological markers as GT, age, body weight, BMI and GGT were confirmed to predict curative chances under non-clinical conditions.

 


Abstract T1814 – A randomized trial comparing Short Course versus Standard Treatment with non-pegylated interferon α and ribavirin in patients with Chronic Hepatitis C Genotype 3 Virus Infection.

S. S. Hamid; W. Jafri; Z. abbas; F. Ismail; Z. Abbas; K. Mumtaz; S. Abid

 

Hepatitis C virus (HCV) genotype 3 responds well to combination interferon and ribavirin therapy and may require a shorter treatment than the recommended 24 weeks. Some reports are available of short course therapy using pegylated interferons, but none using standard (non-pegylated) interferon α.

 

AIMS:

This on-going randomized study was designed to compare the efficacy of interferon α and ribavarin therapy given for 16 weeks vs 24 weeks, in achieving sustained virological response in patients with favorable predictive factors who are infected with HCV genotype 3.

 

METHODS:

Adult patients (between 16-45 yrs of age) with fully compensated liver disease and no clinical, radiological or biopsy evidence of cirrhosis, were started on interferon alpha 2b 3 miu three times per week along with weight based ribavirin 800-1200 mg/day. Patients who became HCV PCR negative, with normal ALT, after 4 weeks of therapy, were randomized to receive either a further 12 (trial arm) or 20 weeks of therapy (standard arm). Sustained virological response (SVR) was assessed at 24 weeks after the end of therapy in both the groups by checking ALT and HCV RNA by PCR.

 

RESULTS:

A total of 75 patients have been enrolled in the short course trial arm and 64 in the standard therapy arm so far. Pre-treatment characteristics including age, serum ALT levels and other lab values were similar in both groups. End of treatment response has occurred in 63/75 (84%) in the short course arm and 58/64 (90%) in the standard arm, while SVR has occurred in 85% patients (51/60) who have completed the study in the short course and in 83% patients (40/48) in the standard treatment arm (p=0.1). Men were more likely to relapse in both treatment arms (8/9 in the short course and 5/8 in the standard arm). Side effects, including cytopenias, were similar in the two treatment arms (mean hemoglobin drop of 2.3 gms/dl, mean WBC drop of 1.9 mm3 and platelet drop of 17,000/hpf).

 

CONCLUSIONS:

·       This study demonstrates that, in carefully selected patients with HCV genotype 3 infection, 16 weeks of therapy with standard interferon α in combination with ribavirin is as effective as 24 weeks therapy in achieving a high rate of SVR.

·       This promises to be the most cost effective therapy reported as yet for the treatment of HCV type 3 infection. Further studies using even shorter courses of combination therapy seem warranted in HCV genotype 3 infection.


Abstract T1815 – Treatment of chronic hepatitis C with peginterferon alfa-2a (40kd) and ribavirin in patients with or without drug use

E. Zehnter; S. Mauss; C. John; R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U. Alshuth; D. Hueppe

 

Injection drug use is the most common mode of acquisition of new HCV infections in the western world. However the feasibility of treating patients on opioid maintenance therapy is still under discussion.

 

Methods:

The Association of German independent Gastroenterologists (bng) in cooperation with Hoffmann-La Roche, Germany, is conducting a nationwide observational study. Between March 2003 and September 2005 data from >10000 patients have been documented at > 500 centers. Cross sectional analyses for patients with drug use (DU) or without (NDU), who have started a treatment with peginterferon alfa-2a (40KD) and ribavirin were done. Data of treatment, compliance and side effects were recorded.

 

Results:

In 2217/9414 pts concomitant disease is drug and/or alcohol abuse. Treatment rate for alcohol abusers is 19.8% (142/717) and for drug users 29.3% (551/1883). Demographic data are available for 635 treated DU vs 3366 NDU: mean age DU 36.1 y, NDU 42.8 y, 75.8%/59.2% male, naive/relapser/unknown DU 89.6/6.5/3.9%, NDU 84.1/11.3/4.6%, BMI 24.5/25.0 kg/m2, mean duration of infection: 8.4y/12.0 y, distribution of GT-1 in DU/NDU 49.6%/ 61.5%, GT-2/3 47.1%/35.1% and GT-4,5,6 3.3%/3.4%.

As of September 2005 338/394 DU (85.8%) and 704/874 NDU (83.3%) reached an Early Virological Response at week 12 (≥2-log10 drop in HCV RNA or HCV RNA undetectable).

 

To date, 95.1% DU (N=212/223) and 93.1% NDU (N=1042/1119) have achieved EoT-Responses. Complete treatment data are available for 208 DU and 967 NDU patients, who were treated according to consensus recommendations. Sustained Virological Response (SVR) was achieved by 153/208 DU (73.6%) and 645/967 NDU-patients (66.7%).

 

A total of 87/446 DU and 407/2315 NDU (18.7%/17.6%) patients have discontinued therapy: 28.7%/40.8% due to virological nonresponse, 19.5%/26.5% for poor tolerability, 19.5%/12.3% were lost to follow-up, 13.8%/8.1% for personal reasons and 23.0%/9.6% for lack of compliance.

 

Conclusion:

Pegylated interferon alfa-2a and Ribavirin seems reasonably safe and sufficiently effective in patients with drug abuse, mainly patients on methadone substitution. In spite of comparable efficacy results, treatment outcome varies due to inhomogeneity of patient groups i.e. age, sex, duration of infection and genotype.

 


Abstract T1816 – Sustained virological response in the antiviral therapy of chronic hepatitis C – is there a predictive value of interferon-induced depression?

A. Schaefer; M. Scheurlen; B. Weissbrich; K. Schoettker; M. R. Kraus

 

Background and aims:

The goal of our study was to determine a putative contribution of cytokine-induced depression to a predictive model of sustained virological response (SVR) in chronic hepatitis C. The analysis comprised a control for known predictors of SVR (e.g. virus genotype and gender).

 

Methods:

In a longitudinal study, we included a sample of 101 therapy-naďve HCV outpatients who were enrolled frm July 2000 to March 2004. They received a combination treatment with pegylated interferon alfa-2b and ribavirin. Neuropsychiatric side-effects were monitored prospectively (Hospital Anxiety and Depression Scale, DSM-IV criteria for major depression).

The primary end point with respect to SVR was failure to detect HCV by PCR 24 weeks after the antiviral therapy.

 

Results:

Overall SVR rate was 72.3 %. Classification data (DSM-IV criteria; HADS cutoff) and the extent of interferon-induced depressive symptoms were not significantly linked to virus eradication. Consideration of other potentially confounding variables did not increase the predictive value of depression for therapy outcome.

Virus genotype (P = 0.045) and gender (P = 0.016) contributed significantly to a predictive logistic regression model. However, mean (P = 0.811) and maximum (P = 0.744) increases in HADS depression were no significant predictors of SVR.

 

Conclusion:

·       There is no evidence for a significant direct association between depression and the efficacy of antiviral treatment in chronic hepatitis C.

·       Patients experiencing no or minor neuropsychiatric side effects do not have to worry about a “lower chance” of successful therapy.

·       Therefore, interferon-induced depressive symptoms are still important to be monitored and treated if necessary – however, they cannot be used to predict the individual’s therapy success.

 


Abstract T1817 – Registry of Liver Diseases: Phase I

S. E. Steinberg

 

Introduction:

The establishment of registries of patients with various diseases has been identified as a critical element in the developing infrastructure of clinical and translational research. Among the capabilities of clinical registries are the ability to monitor the natural history of disease; to identify areas of investigation; to evaluate the feasibility of testing a hypothesis; to identify subjects for basic science evaluations; and to expedite the implementation of clinical studies. LRI has initiated a registry of diseases of the liver with the aim of beginning to address these goals.

 

Methods:

Five academic centers were identified. A scientific advisory board was convened to determine the liver diseases to be included. These are: Alcoholic, alpha 1 anti-trypsin deficiency, autoimmune, congenital hepatic fibrosis, hemochromatosis, hepatitis C, hepatitis B, hepatocellular carcinoma, NASH, non-A non-B non-C hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and Wilson’s. A technology task force was convened to design an application that would facilitate the enrollment of patients in a centralized registry, while functioning as a “local” research database for the general use of each center. The registry application was developed utilizing SQL server which provided each site with a full copy of its own data and the ability to modify locally to support specific projects (e.g. tracking of stored serum and tissue samples). De-identified data from each site is uploaded to the master database nightly. Data was acquired electronically when available and supplemented by hand entry. HIPAA guidelines are observed and IRB approval was obtained for each participating institution.

 

Results:

·       The challenge of building a registry includes the huge burden of data collection. The technology solution has worked well and facilitated data collection.

·       Application designed and implemented

·       Firewall/security interfaces implemented

·       Automated lab data importation implemented

·       Automated de-indentified data uploads

·       Web enabled

 

Analysis of the initial phase of data accumulation has yielded 44,655 records including 18,545 HCV; 4,486 HBV; 2,652 NASH; 1,8972 Other liver diseases. It is recognized that the disease distribution, while generally reflecting the incidence in the general population, is also affected by the academic interests of the individual sites. The local functionality afforded the individual sites provides them with powerful tools to maintain and analyze their own data, while contributing to the central repository.

 

Conclusions:

·       The “feasibility” phase of the implementation of a registry of liver disease has been successfully completed.

·       Preliminary analyses of subsets of data has begun to yield useful information.

·       A large data based (>44,000) records of patients with liver disease is now available for chart review and prospective studies

·       The ongoing challenge will be to continue to expand the number of records and the data set and to add additional sites.

 


Abstract T1818 – Treatment of Hepatitis C Related Cryoglobulinemia with Rituxan.

A.Goldenberg, M.D., L.Teperman, M.D., P. Kelley, R.N., L.Hong, RPA-C, H.Tobias, M.D., Ph.D A. Goldenberg; L. Teperman; L. Hong; P. Kelley; H. Tobias

 

Introduction:

Cryoglobulinemia associated with chronic hepatitis C virus (HCV) infection produced neuropathy, rash, and vasculitis in two patients despite interferon and ribavirin treatment of HCV viremia.

 

Methods:

Two non-cirrhotic patients with active HCV increasing cryoglobulinemia and clinical deterioration were treated with Rituxan. Patient 1 (Pt-1)was 55 year old female, with HCV PCR RNA 5.47LogIU and patient 2 (Pt-2) a 51 year old male with HCV PCR RNA 4.9LogIU. Both presented with fatique lower extremity parathesisas and skin rash with biopsy proven vasculitis while receiving Pegasys (pt1) and Peg Intron (pt2), respectively. Each demonstrated a faint serum IgM kappa monoclonal paraprotein and elevated cryoglobulins (pt1 = 5% and pt2 =13%). Pt1’s bone marrow demonstrated less than 1% kappa restricted CD38/CD138 plasma cells and pt2’s bone marrow showed polyclonal B cells. Rituxan was administered at 375 mg per meter squared every week for 8 weeks.

 

Results:

Pt-1's lower extremity skin lesions resolved, and the parathesias were markedly reduced. Cryoglobulin was <1%. IgM kappa paraprotein remained detectable. IgG level normalized to 749. Rheumatoid factor level of 1907 IU/ml decreased to 626 IU/ml. Pt-2's Raynaud's complaints resolved. The IgM kappa paraprotein remained detectable and the IgG level normalized to 707. The cryoglobulins decreased to 4%.

 

Conclusions:

1. Rituxan can decrease serum cryoglobulin levels in patient's with HCV infection receiving interferon.

2. Rituxan's effect on suppressing HCV related cryoglobulinemia may be modulated by interferon treatment.

 


Abstracts T1819 – Pegylated Interferon Alfa-2b Plus Ribavirin for the Treatment of Chronic Hepatitis C Genotype 4 in Adolescents: A Pilot Study

F. Hasan; K. Alsarraf; W. Qabandi

 

Background:

Hepatitis C is endemic in the Middle East where genotype 4 accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype 4 are limited.

 

Aim:

The aim of this study is to evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype 4.

 

Patients and Methods:

In an open-labeled, uncontrolled pilot study, 12 adolescents (range 14-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mcg/kg body weight once per week plus oral ribavirin (15 mg/kg / day) for 48 weeks. Patients were followed up for 24 weeks. All patients had biopsy proven hepatitis without cirrhosis.

 

Results:

One patient withdrew from the study due to developing insulin dependent diabetes mellitus 4 months into treatment. The remaining patients took at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75 %). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required therapy with a growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism.

 

Conclusion

·       Adolescents chronically infected with HCV genotype 4 appear to have a favorable response to therapy with peginterferon alfa-2b plus ribavirin

·       Relatively mild histologic abnormalities (ie, the absence of severe fibrosis and cirrhosis) may explain the high SVR rate observed in this study

·       Therapy was well tolerated

·       Larger trials are needed to determine the optimal dose and duration of therapy in this patient population

 

 


Abstract T1820 – Peginterferon Alfa-2a (40KD) (PEGASYS®) Plus Ribavirin (COPEGUS®) for HCV Genotype 1 Patients: Predicting Sustained Virological Response (SVR) Rates and Anemia

E. Snoeck; J. Wade; M. Lamb; F. Duff; J. Grippo; K. Jorga

 

Introduction

Generalized additive models (GAM) were used to describe the likelihood of an SVR and risk of anemia in patients with chronic hepatitis C (CHC) receiving peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®).

 

Methods:

Data from 1732 CHC patients with elevated ALT levels treated with peginterferon alfa 2a (40KD) plus ribavirin in two randomized, multinational studies were pooled. Probabilities of SVR (HCV <50 IU/mL at end of follow-up; n=1036 genotype 1 patients) and anemia (hemoglobin <10 g/dL at any time during treatment; n=1732 patients of all genotypes) were modelled using GAM analyses, with numerous clinical variables considered for entry into the models. Baseline hemoglobin was only considered in the analysis for anemia.

 

Results:

In HCV genotype 1 patients, the probability of an SVR increased with increasing ribavirin dose/kg (Fig a), and with baseline ALT. Older age, a higher ribavirin apparent oral clearance and cirrhosis had a negative impact on achieving an SVR. The probability of anemia increased as a function of the ribavirin dose/kg (Fig b). Female gender and increasing ribavirin dose/kg were the most important prognostic factors for anemia, followed by low baseline hemoglobin, older age, low baseline ALT quotient and cirrhosis.

 

Conclusion:

The current GAM analysis shows that there is a substantial dose-dependent effect on SVR in HCV genotype 1-infected patients with ribavirin (Copegus) doses >10 mg/kg/day in combination with peginterferon-alfa-2a (40 KD) (PEGASYS).

The analysis also shows that ribavirin doses at or below 15 mg/kg/day are associated with little difference in the incidence of anemia.

These results trigger hypotheses worth of prospective evaluation:

o      The first is that, for heavier patients, ribavirin doses >1200 mg/day are likely to be associated with an additional efficacy benefit and a manageable anemia risk, provided that the dose does not greatly exceed 15 mg/kg/day (1200 mg dose for a 100 kg patient = 12 mg/kg/day).

o      The second is that HCV genotype 1-infected patients are likely to benefit from maintaining a cumulative ribavirin dose closer to 15 mg/kg/day during the treatment course.  This can be safely achieved through more gradual dose modification than the currently approved single-step reduction to 600 mg/day.

o      Both hypotheses are currently being evaluated in on-going clinical trials.

 


Abstract T1821 – Nitazoxanide in Treating Chronic Hepatitis C: In vitro Activity and a Clinical Case Report

J. F. Rossignol; B. E. Korba; S. M. Kabil

 

Introduction.

Nitazoxanide is an anti-infective drug from a new class called the thiazolides. It is marketed in the United States for treating gastroenteritis caused by Cryptosporidium parvum and Giardia lamblia and is in late stages of development for treating Clostridium difficile-associated disease. Based on earlier screening suggesting antiviral properties of the thiazolides, we tested nitazoxanide and its active circulating metabolite, tizoxanide, against hepatitis C virus in cell cultures. We also report the results of a patient with chronic hepatitis C treated with nitazoxanide after previously failing a 48-week course of peginterferon plus ribavirin.

 

Methods.

Nitazoxanide, tizoxanide, -interferon, and ribavirin were evaluated for activity against hepatitis C virus in AVA5 cell cultures. A 53 year-old Egyptian male with chronic hepatitis C, genotype 4, who had failed to achieve a sustained response to a 48-week course of peginterferon plus ribavirin was treated with nitazoxanide. Before treatment, the patient had normal ALT with a viral load of 3,650,400 IU. Nitazoxanide was administered by oral route, 500 mg twice daily with food for 32 weeks, and the patient was evaluated every 4 weeks during treatment. Evaluations included physical examination, laboratory safety tests and RT PCR for quantitation of HCV RNA.

 

Results.

The activity of nitazoxanide, tizoxanide, -interferon and ribavirin against hepatitis C virus replication in AVA5 cell cultures is presented below:

 

 

Compound

CC50 (µM)

EC50 (µM)

EC90 (µM)

Selectivity Index

- Interferon

>10,000*

2.2 ± 0.2*

8.5 ± 0.6*

>4,545

Ribavirin

61 ± 2.9

94 ± 10

>100

0.6

Nitazoxanide

38 ± 1.9

0.045 ± 0.003

0.539 ± 0.044

844

Tizoxanide

5.2 ± 0.4

0.034 ± 0.004

0.419 ± 0.051

152

 

The patient treated with nitazoxanide showed a 1 log10 reduction of serum HCV RNA at week 4 (3,650,000 declined to 331,000 IU) . The reduction was maintained through week 20. At week 24, the viral load declined to 5,000 IU, and at weeks 28 and 32, virus was undetectable. ALT remained normal throughout treatment. No significant adverse events were reported. The patient is continuing treatment to week 48 at which time treatment will be discontinued and sustained response will be evaluated.

 

Conclusions.

Our results suggest that nitazoxanide is effective in treating chronic hepatitis C. Double-blind placebo-controlled studies are being conducted in the United States and internationally.

 


Abstract T1822 – Quality Assurance in Clinical Everyday Life: Results of a German Post-marketing Surveillance on the Treatment of Chronic Hepatitis C with Peginterferon alfa-2B plus Ribavirin

D. Hueppe; E. Zehnter; M. P. Manns; S. Mauss; M. Zankel

 

BACKGROUND:

Pegylated interferon (PEG-IFN alfa) and Ribavirin (RBV) are the standard of care for hepatitis C virus (HCV) treatment. The efficacy and safety of PEG-IFN alfa-2b and RBV was observed in Germany in a post marketing surveillance study under daily life conditions. The patients were treated in hospitals, in medical practices and in medical practices that are members of the German association of gastroenterologists in private practice (bng).

 

METHODS:

·       Between September 2003 and November 2005, 219 active sites have treated 2318 naive or relapsed HCV patients with PEG-IFN alfa-2b and RBV and documented their cases.

·       Number of evaluable patients that reached end of therapy – 1259

·       Number of evaluable patients that reached end of follow-up - 545

·       Genotype distribution:

o      Genotype 1 - 53.5%

o       Genotype 2 - 8.0%

o      Genotype 3 -  33.7%

o      Genotypes 4 thru 6 - 2.8%

o      Missing genotype information 1.8%

·       Patient characteristics

o      Age - 40.4 (median 39.0)

o      Weight -78.4 (median 74)

o      Height -173.1 (median -173)

o      Male – 61.4%

o      Female – 37.1%

o      Cirrhosis – 5%

o      On substitution Tx.

o      Caucasian – 82.9%

·       Patient treatment characteristics prior to treatment:

o      Treatment naďve – 90.1%

o      Relapsers – 9.9%

 

If HCV-RNA was negative at 12 weeks of treatment or if there had been more than 2 log drop in HCV-RNA after 12 weeks of treatment, therapy was continued. 1259 evaluable patients reached the end of the therapy yet.

 

RESULTS:

·       HCV RNA negativity at end of therapy – 74.1% (naďve); 47.5% (relapsers)

·       SVR by BMI – 65.7% (all patients): 63.6% (<18.5 BMI); 70.5% (18.5-25.0 BMI); 58.3% (25.0-30.0 BMI); 56.9% ( ≥30.0 BMI);

 

No data from the poster on adverse events was available. 

 

CONCLUSION:

·       The response rates show that in Germany, the quality and safety of the treatment of chronic hepatitis C under real life conditions is on a high level.

·       A normal BMI (>=18.5–<25.0) favours the efficacy of the therapy.

·       Patients with abnormal transaminase values had a higher chance to be HCV-RNA negative at the end of the therapy.

 


Abstract T1823 – Efficacy and safety of peginterferon alfa-2a (40kd) and ribavirin in GT-2/3patients with chronic hepatitis C in a real world setting

E. Zehnter; S. Mauss; C. John; R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U. Alshuth; D. Hueppe

 

Introduction:

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

 

Methods:

Between March 2003 and September 2005 data from >10000 patients has been documented at > 500 centres. Cross sectional analyses for all GT-2 and GT-3 patients were done, who have started a treatment with peginterferon alfa-2a (40KD) and ribavirin. Data of treatment, compliance and side effects were recorded.

 

Results:

·       Demographic data are available for 1481 treated GT-2 (N=290) and GT-, 3 (N=1191) GT-3):

o      mean age GT-2 44,2y, GT-3 36.6 y,

o      57.9%/66.7% male,

o      Naďve / relapser/ unknown GT-2 91.0/4.8/4.2%, GT-3 88.6/7.0/4.4%,

o      BMI 25.1/24.3 kg/m2, mean duration of infection: 11.2y/9.6 y,

o      Source of infection (>1 answer possible):

§       IV drug abuse 39.7%, in GT-2 and 64.2% in GT-3,

§       Transfusion 19.7%/9.2%,

§       Medical measures 10.7%/5.4%,

§       Unknown 25.9%/14.6%;

§       95.8%/97.3% of patients were treated with a combination therapy.

·       As of September 2005, 168/182 patients with GT-2 (92.3%) and 661/702 with GT-3 (94.2%) reached an Early Virological Response at week 12 (≥2-log10 drop in HCV RNA or HCV RNA undetectable).

·       To date, 97.5% GT-2 (N=158/162) and 95.4% GT-3 (N=636/667) have achieved EoT-Responses.

·       Complete treatment data are available for 522 patients, who were treated according to consensus recommendations.

o      Sustained Virological Response (SVR) was achieved by 85/106 GT-2 (80.2%) and 346/416 GT2/3-patients (83.2%).

o      A total of 21/85 (7.2%/7.1%) patients have discontinued therapy:

§       9.5%/9.4% due to virological nonresponse,

§       42.9%/25.9% for poor tolerability,

§       9.5%/24.7% were lost to follow-up,

§       9.5%/11.8% for personal reasons and

§       19.1%/25.3% for lack of compliance.

 

Conclusion:

·       The results of this observational trial show that peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well tolerated in GT-2/3 patients with chronic hepatitis C in clinical practice.

·       The individual analysis of GT 2 and-3 shows clearly that baseline data like age and source of infection differ considerably. Therefore larger cohorts should be analysed separately to genotype 2 and 3 with respect to efficacy and tolerability, too.

 


Abstract T1824 – High Response Rates With Peginterferon Alfa-2a (40KD) (PEGASYS®) plus Ribavirin (COPEGUS®) in Japanese Non-Responders or Relapsers to Conventional Interferon

N. Izumi; S. Iino; T. Okuno; M. Omata; K. Kiyosawa; H. Kumada; N. Hayashi; G. Yamada; T. Sakai

 

Introduction:

Despite major improvements in the treatment of chronic hepatitis C, some patients do not respond to, or relapse following, interferon-based treatment. We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in Japanese patients who had not responded to conventional interferon monotherapy. This is the first trial investigating peginterferon alfa-2a (40KD) plus ribavirin in previously-treated Japanese patients.

 

Methods:

Previously-treated adults with detectable HCV-RNA, elevated ALT and a liver biopsy consistent with a diagnosis of chronic hepatitis C were treated with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 600–1000 mg/day for 48 weeks. Patients were classified either as non-responders (no HCV-RNA suppression below detection limits) or relapsers (reversion to HCV-RNA positive status after suppression) to previous interferon monotherapy. The primary efficacy endpoint was sustained virological response (SVR; undetectable [<50 IU/mL] HCV-RNA after 24 weeks’ untreated follow-up). ITT analysis was used.

 

Results (Table):

100 patients received treatment, and 54% achieved an SVR. SVR rates were similar in previous non-responders and relapsers, and in patients with high and low baseline HCV-RNA levels. Logistic regression analysis indicated that younger age significantly and independently increased the likelihood of achieving an SVR (odds ratio 0.92; 95% CI 0.88–0.97; p=0.001). Baseline HCV-RNA, fibrosis grade, age or bodyweight had no influence on SVR. Adverse events were generally mild in severity and were typical of those associated with interferon-based therapies. Overall, 16% of patients withdrew because of adverse events or laboratory abnormalities.

 

Conclusion:

Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) is associated with a relatively high response rate in Japanese chronic hepatitis C patients who failed to respond to or relapsed after conventional interferon monotherapy.

 

Baseline characteristics

Mean age, years

52

Males, n (%)

74 (74)

Mean bodyweight, kg

67

SVR rate, n (%)

 

All patients

Non-responders

Relapsers

All

54/100 (54)

19/40 (48)

35/60 (58)

Genotype 1b

43/84 (51)

18/36 (50)

25/48 (52)

Genotype non-1b

11/16 (69)

1/4 (25)

10/12 (83)

 


Abstract T1825 – Predictors of SVR in patients with treatment-naďve chronic HCV treated with PEG-IFN alfa-2b vs. PEG-IFN alfa-2a + ribavirin: A hierarchical linear regression analysis of retrospective data from 6 clinic sites

W. HCV Meta-Analysis; P. L. Almasio; L. Cavalleto; L. Chemello; D. Hueppe; S. Mauss; F. Poordad; N. N. Zein; S. Herrine; C. Trepo; D. Frame; K. Fahrbach; S. D. Ross

 

Objective:

To explore predictors of sustained viral response (SVR) in treatment-naďve chronic HCV patients treated with weight-based PEG-IFN alfa-2b (alfa-2b) or fixed dose PEG-IFN alfa-2a (alfa-2a) + ribavirin (RBV) in observational settings outside of clinical trials.

 

Methods:

Clinical investigators identified primarily through independent congress abstracts were recruited to contribute de-identified data for analysis. Eligible patients were treatment-naďve adults with chronic HCV (G1, G2, or G3), receiving PEG-IFN+RBV. Patients in clinical trials, those treated prior to 2001, with HIV or HBV co-infection, or with decompensated liver disease were excluded. Within each genotype the primary efficacy measure of SVR was analyzed using a hierarchical generalized linear model (HGLM) to control for patient- and site-level variation, and an adjusted odds ratio (OR) was calculated for the difference between PEG-IFNs. Patient selection criteria and analytic methods were determined prospectively by an expert panel. Prognostic impact of treatment regimen, weight, site, baseline ALT quotient, age, gender, and race were assessed.

 

Results:

Six sites (2 US, 2 German, 2 Italian) contributed data, totaling 824 patients (506 G1, 147 G2, 171 G3). Mean baseline weight for G1 patients was 78.4 kg for alfa-2a and 75.5 kg for alfa-2b (BMI 26.7 vs. 26.6, respectively). SVR in G1 patients was significantly higher for alfa-2b vs. alfa-2a (49% vs. 36%; HGLM analysis OR = 1.62, 95% CI 1.10-2.39, p=0.017). For G1 patients, higher baseline weight was a significant negative predictor of SVR (p=0.012). There was also a marginally significant (p=0.073) treatment x weight interaction, indicating a larger difference in SVR rates between the two PEG-IFNs (higher SVR observed with alfa-2b) as patient weight increases. Baseline ALT, race, age, and gender were not statistically significant predictors of SVR. Insufficient data were available to include fibrosis score, viral load, baseline platelet count, alcohol use, or concomitant medications in the model. Differences in SVR between PEG-IFNs for G2 and G3 patients were not significant, nor did any of the covariates used in the model reach statistical significance.

 

Conclusions:

Treatment with PEG-IFN alfa-2b has an advantage relative to PEG-IFN alfa-2a in achieving SVR in treatment-naďve, HCV+, G1 adults. Higher baseline weight was a significant negative prognostic factor for SVR. In G2 and G3, for which fewer patients were available for analysis, no statistically significant effects of treatment or patient covariates were observed. Cumulative analyses are planned to incorporate data from additional sites.


Abstract T1826 – Hepatocellular Carcinoma In Sustained Virologic Responders To Previous Interferon Therapy Is Associated With Excellent Prognosis

M. Akamatsu; H. Yoshida; S. Shiina; T. Teratani; H. Yoshida; J. Imamura; Y. Kondo; T. Ooki; R. Tateishi; N. Yamashiki; T. Kawabe; M. Omata

 

Background

Interferon (IFN) therapy improves life-expectancy among chronic hepatitis C patients (Yoshida, Gastroenterology 2002;123:483) and HCC patients after tumor ablation (Shiratori, Ann Intern Med 2003;138:299). We conducted this retrospective study to evaluate the prognosis of HCC in patients who had achieved sustained virologic response (SVR) to previous IFN therapy.

 

Methods

We compared overall and recurrence-free survival rates between 18 HCC patients who received IFN therapy and achieved SVR before HCC development (SVR group) and 468 HCC patients with Child-Pugh class A liver function who had not received interferon (controls).

 

Results

The overall survival rates were 77.2%, 45.9%, and 23.3% in the controls and 94.1%, 85.6%, and 85.6% in the SVR group at 3, 6, and 9 years, respectively. Cox proportional hazard regression revealed that the risk of death was significantly reduced in the SVR group (Risk Ratio: 0.225, 95% CI: 0.056 - 0.910, P = 0.0363). Recurrence-free survival, analyzed exclusively among those who received curative ablation or surgery, did not differ significantly.

 

Conclusion

Patients with HCC who had achieved SVR by previous IFN therapy showed excellent survival. Cumulative recurrence rates did not differ and the improved survival seemed to be attributable mainly to sustained liver function.

 


Abstract T1827 – Efficacy and tolerability of peginterferon alfa-2a (40kd) and ribavirin in GT-1 patients with chronic hepatitis C in Germany – a contribution to health care research

E. Zehnter; S. Mauss; C. John; R. Heyne; B. Moeller; T. Lutz; B. Bokemeyer; R. Kihn; G. Moog; H. Vornkahl; U. Alshuth; D. Hueppe

 

Introduction

The Association of German independent Gastroenterologists (bng) in cooperation with Hoffmann-La Roche, Germany, is conducting a nationwide observational study to determine the quality of treatment for chronic hepatitis C in routine clinical practice. This ongoing study includes screening and treatment phases and has as a goal, the establishment of optimal care for these patients.

 

Methods:

Between March 2003 and September 2005 data from >10000 patients have been documented at > 500 centres. A cross sectional analyse for all GT-1 patients was done, who have started a treatment with peginterferon alfa-2a (40KD) and ribavirin. Results of efficacy, tolerability and compliance were recorded.

 

Results:

Demographic data are available for 2384 treated GT-1 patients:

·       mean age 44,0 y,

·       59.2% male,

·       naive/relapser/unknown 82.5/12.9/4.6%,

·       BMI 25.2 kg/m2,

·       mean duration of infection: 12.4y,

·       source of infection (>1 answer possible):

o       iv drug abuse 34.8%,

o      transfusion 23.7%,

o      medical action 11.0%,

o      unknown 25.3%.

o      97% of patients were treated with a combination therapy.

o      As of September 2005 1220/1560 (78%) patients reached an Early Virological Response at week 12 (≥2-log10 drop in HCV RNA or HCV RNA undetectable).

 

To date, 77.6% GT-1 (N=782/1008) have achieved EoT-Responses. Complete treatment data are available for 618 patients, who were treated according to consensus recommendations. Sustained Virological Response (SVR) was achieved by 363/618 GT-1 (58.7%).

 

A total of 361 (15.1%) GT-1 patients have discontinued therapy:

·       46.3%, due to virological nonresponse,

·       24.7% for poor tolerability,

·       11.9% were lost to follow-up,

·       8.0% for personal reasons and

·       8.0% for lack of compliance.

 

While less than 10% of the patients got less than 80% of the cumulative dose regarding peginterferon alfa 2 for 48 weeks, it was more than a quarter of the patients regarding ribavirin for 48 weeks.

 

Conclusion:

·       The results of this observational trial show that peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well tolerated in GT-1 patients with chronic hepatitis C in daily clinical practice.

·       When treated according to current guidelines, patients achieved results similar to those achieved in controlled clinical trials.

·       This observational study contributes importantly to health care research of patients with chronic hepatitis C. 


Abstract T1828 – G-CSF is safe and improves adherence and SVR in HCV patients with genotype 1 who develop Peg-IFNa-2b related severe neutropenia.

J. Koskinas; G. Zacharakis; J. Sidiropoulos; J. Elefsiniotis; S. Savvas; D. Kountouras; M. Schina; P. Kostopoulos; A. Archimandritis

 

Background:

Peg-IFN treatment in patients with chronic HCV infection induces neutropenia with subsequent dose reductions that may reduce the SVR. Granulocyte colony-stimulating factor (G-CSF) has been used by some physicians instead of the standard dose reduction practice. However, additional studies are required before these agents can be recommended for routine use.

 

Aim:

To evaluate the safety and benefits of G-CSF compared to standard practice of dose reduction in patients with peg-IFN induced neutropenia.

 

Methods:

Open-label study of 39 treated-naďve patients of 249 (16%) with chronic hepatitis C genotype-1 infection who were on treatment with PEG-INFa-2b 1.5mcg/kg/week and RBV 800-1400mg/day weight based and developed significant neutropenia (ANC<1000/L). They received either a flexible scheme of 150-300ug G-CSF SC twice a week (one day after and two days before Peg-IFN injection), (Group A, 20 pts) or had escalating dose reduction of Peg-IFN for 2wks or discontinuation for 1-2 wks in unresolved cases (Group B, 19 pts). HCV-RNA was measured by Cobas Amplicor (Roche). Results: Both groups had no significant differences before treatment regarding age (53±9 years vs 47±7), sex (55% males vs 50%), HCV-RNA levels (2.76±1.9 million IU/ml vs 2.23±2.1), Hb levels (13.5±2.3 mg/dl vs 14±1.7) and WBC (6000/mm3 vs 5800), respectively. The mean decline of the neutrophils was 1760±1030/mm3 at 11±8.6 wks and 1630±890 at 12.3±6.1 in group A and B respectively. Patients who received G-CSF maintained neutrophil count between 1420-2720/mm3 and remained on G-CSF support for 29 wks (2-40). In this group, 12/20(60%) had EVR and 6/20 (30%) SVR.  In group B, Peg-IFN was temporarily withdrawn in 3/19 and reduced to 0.5mcg/kg/wk in 4/19 patients. The neutrophil count ranged between 1320-3400/mm3. In this group, 9/19 (47%) had EVR and 4/19 (21%) SVR (significant lower compared to group A, p<0.001). All patients completed 48wks of treatment with no major side effects or infection. No related to G-CSF side effects were encountered.

 

Conclusions:

The use of G-CSF 1) is safe and allows adherence to treatment schedule in patients with chronic HCV-1 infection who develop neutropenia during treatment, and, 2) relates to higher EVR and SVR and therefore it should be considered in clinical practice

 


Abstract T1829 – Treatment comparison of chronic hepatitis C patients with normal and elevated transaminses: viral load is predictive of ETR - preliminary results of a prospective trial

W. Vogel; H. Brunner; M. Rosenbeiger; I. W. Graziadei; A. Maieron; K. Jilek; R. Stauber 

 

About 30% of chronic hepatitis C (CHC) patients have persistently normal ALT (PNALT). This group of patients has been excluded from pivotal treatment trials. There is evidence that these pts respond similarly to those with elevated ALT to treatment with interferon and ribavirin, however, further studies are warranted. In this prospective, multicenter, open-labeled trial 240 de novo pts with biopsy-proven CHC with normal or elevated ALT levels received PegIntron 1,5 µg/kg/wk & Rebetol 0,8-1,2g/d for 48 weeks (genotype 1/4) or 24 weeks (genotype 2/3).

 

Study design:

Pts were stratified according to elevated or normal (>3 measurements over 3 months) ALT, high or low viral titer (cut-off 800.000 IU/ml, bDNA HCV RNA 3.0 assay; Bayer Diagnostics) and genotypes (GT) 1/4 or 2/3. Baseline data are available from 225 pts: 107 pts with PNALT (83 pts with GT 1/4, median ALT was 29 U/l, 24 pts with GT 2/3, median ALT was 25 U/l) and 118 pts with elevated ALT (88 patients with GT 1/4, median ALT was 79 U/l, 30 pts with GT 2/3, median ALT was 135).

 

Results:

There was no statistical significant difference in pretreatment characteristics between the two groups. 65,1% of pts with PNALT had a viral load lower or equal 800.000 IU/ml vs 66,4% of pts with elevated ALT. From 114/225 pts viral load was determined after week 4: 51,8% had undetectable RNA (49,2% PNALT and 54,9% high ALT; 37% of GT 1/4 pts and 93% of GT 2/3 pts). After week 12 167/225 pts were evaluated: 71,3 % had undetectable RNA (76,3% PNALT and 67% high ALT; 66% of GT 1/4 and 90% of GT 2/3).

 

195 pts have so far completed the study. 14,4% of these pts withdraw because of AEs; 4,1% had a breakthrough on therapy, and 14,9% did not show a 2log drop at week 12. Of these 195 pts 71,3% had undetectable RNA at end of treatment (74,1% normal ALT and 69,1% high ALT; 64% GT 1/4 and 89% GT 2/3). The differences in responses between the normal and high ALT group are not significant.

 

In an univariate analysis there is a significant difference in median virus load between pts with ETR response vs nonresponders (324000 IU/ml vs 754000 IU/ml; p < 0,001). Adjusted for GT and ALT level this difference remains statistically significant (p < 0,001).

 

There is trend to a higher ETR response in patients with a baseline viral load lower or equal 800000 IU/ml, and this trend is even significant in pts with GT 1/4 and elevated ALT (72,5% vs 43,5%).

 

Conclusions:

These findings suggest that pts with PNALT stratified for GT and viral load show the same ETR receiving as do patients with elevated ALT.

 


Abstract T1830 – Interferon-α Therapy for Patients with Comorbid Hepatitis C and Psychiatric Diagnoses

J. Nelligan; J. M. Loftis; M. Fireman; S. Ruimy; B. Zucker; A. Linke; D. Indest; P. Hauser

 

Introduction

The prevalence of chronic hepatitis C viral (HCV) infection among veterans who access Veterans Affairs (VA) medical facilities is approximately three times higher than that of the general U.S. population, 5.4% vs. 1.8%. Veterans with HCV also commonly have comorbid psychiatric diagnoses. This is particularly concerning because interferon-α (IFN) therapy is associated with psychiatric side effects (e.g., depression, irritability) and patients with psychiatric diagnoses are often excluded from IFN therapy.

Aim

The purpose of this study was to assess the effects of prior psychiatric diagnoses on IFN therapy completion and response rates.

Results

 Eighty two veterans [male (96%), mean age 51±5.3 years] who underwent IFN therapy between 2002 and 2005 at the Portland VA Medical Center consented to have their medical records reviewed. Data revealed that 54 (66%) veterans were diagnosed with a psychiatric or substance use disorder more than 1 year prior to starting IFN therapy, 8 (10%) were diagnosed in the year preceding the start of IFN therapy, and 20 (24%) had no psychiatric or substance use disorder. The most common psychiatric disorder was major depression (35 patients -56%), followed by posttraumatic stress (25 patients-40%) and anxiety disorders (8 patients-13%). The most common substance use disorder was alcohol abuse 24 patients-39%) followed by dependence on alcohol (23 patients - 37%), cocaine (6 patients - 10%), opiates (4 patients-6%), and other drugs (12 patients-19%). Of the 20 patients with no psychiatric history, 6 were started on a psychotropic medication during IFN therapy. Similarly, of 22 veterans with a psychiatric history and no record of psychiatric medication use prior to initiating IFN therapy, 6 started a psychotropic medication during IFN therapy. Treatment outcomes showed that of the patients who had completed IFN therapy, sustained viral response rates (SVR) were similar among all groups (see Table below).

Conclusion

·       Although 39% of patients terminated treatment early, only 1 patient terminated for psychiatric reasons despite the high prevalence of psychiatric comorbidity (n=62, 76%).

·       Taken together, these findings suggest that with routine mental health screening and coordinated care involving mental health, chemical dependency and medical professionals, patients with comorbid psychiatric diagnoses can successfully complete IFN therapy and achieve response rates comparable to those patients without psychiatric disorders.

 

Treatment Variables

Previous psychiatric diagnosis

(n=54)

Diagnosed w/psychiatric illness 1 year prior to IFN

(n=8)

No previous or current psychiatric diagnosis

(n=20)

IFN therapy completion (%)

34(62)

4(50)

12(60)

SVR (%)

24(44)

3(38)

9(45)

 


Abstract T1831 – Factors affecting SVR in Chronic Hepatitis C patients treated in the Central New York Region

N. Mehta; U. K. Murthy; V. Kaul; P. Mehta; L. Bank; B. Buniak; A. Goel; B. Kane; R. Levine; D. Reedy; A. Strapko

 

Background

We found a low SVR in HCV patients treated between Jul 2001 to Jul 2004 in the Central New York region.

 

Aims

1. To compare patient cohorts between different practice sites. 2. To identify variables affecting overall SVR in the region and at individual practice sites.

 

Methods

A retrospective review of 373 treatment naďve patients treated with peg-interferon alfa 2a/2b and ribavirin at University Hospital (Univ), Veterans’ Affairs medical center (VA), a University affiliated practice (UA) and 5 community practices (CP) was performed. Demographic, clinical, histologic, laboratory and HCV treatment-related data were collected. Patients who failed to complete intended duration of therapy (early d/c) and patients lost to follow-up were considered treatment-failures. Chi-square analysis was used to compare variables between sites.

 

Results

Overall SVR in 373 patients was 33.2%.

 

Patient characteristics at individual sites were significantly different (Table 1).

 

Ribavirin dose, dose reduction and use of growth factors was significantly different among various sites (Table 2).

 

Conclusions

1) Although there was a striking difference in HCV patient characteristics there was no difference in SVR among sites.

 

2) Even though community practices had a higher percentage of females, Caucasians, non-genotype 1, and less advanced fibrosis, SVR was low.

 

3) Further studies are required to investigate this lower than expected SVR.

 

Site (n)

Univ (75)

VA (70)

UA (114)

CP (114)

p value

SVR %

26.7

32.9

37.7

33.3

0.48

Age (mean in yrs)

45.9

49.7*

46.2

46.9

<0.01

Male %

62.7

92.9*

67.5

63.2

<0.001

Caucasian %

63.2*

82.1

84.5

76.9

<0.01

African American %

30.9*

16.4

8.2

13.8

<0.01

Genotype 1 %

79.4*

82.6*

61.5

69.4

<0.01

High Viral load %

43.2*

63.8

50.5

61.1

<0.03

Advanced Fibrosis/ Cirrhosis %

46.5*

33.3

31.9

23.5*

<0.02

Psychiatric diagnosis %

37.3

64.3*

57

30.7

<0.001

Diabetes mellitus %

17.3*

11.4

8.8

5.3

0.05

Site (n)

Univ (75)

VA (70)

UA (114)

CP (114)

p value

SVR %

26.7

32.9

37.7

33.3

0.48

Early dc %

37

21

21

29

0.06

Mean ribavirin mg/kg (sd)

11.3 (3.8)*

13.1 (2.8)

12.9 (2.7)

12.4 (2.4)

<0.01

Ribavirin dose>10.6mg/kg %

62.2*

88.2

84

79.4

<0.01

Dose reduction %

26.7

31.4

10.5*

24.6

<0.01

Epo/ G-CSF use %

7/0

46/23*

18/10

10/6

<0.001

 


Abstract T1832 – The Effect of Pegylated Interferon and Ribavirin on Posttraumatic Stress Disorder Symptoms in Veterans

E. Dieperink; J. Leskela; M. Dieperink; B. Evans; J. Durfee; K. McCarthy; P. Thuras; S. B. Ho

 

Background:

Nearly one third of veterans with chronic hepatitis C(HCV)infection are diagnosed with Posttraumatic Stress Disorder(PTSD).HCV patients with PTSD are frequently excluded from antiviral therapy but no studies exist regarding the effect of antiviral treatment on PTSD.

 

Purpose:

To better characterize PTSD symptoms in patients with HCV treated with pegylated interferon-alfa and ribavirin.

 

Methods:

Patients with PTSD diagnoses seen in a Hepatitis Clinic were prospectively followed at baseline, 4,8,12, and 24 weeks with two measures of PTSD symptoms(the Mississippi Scale for combat Related PTSD(Mississippi) and the PTSD Checklist-Military Version(PCL-M)), a measure of hostility/irritability (the Buss-Durkee questionnaire), and the Beck Depression Inventory(BDI).A comparison group of patients with PTSD and HCV who were not treated with antiviral therapy were followed using the same time-points and questionnaires. Five subjects with HCV and PTSD treated with antiviral therapy and 11 comparison subjects have completed the study. All subjects were treated as needed by their current mental health providers.

 

Results:

Mean age was 54 years, only one subject was genotype 2 and the rest genotype 1.Most subjects 4/5 treated with antiviral therapy had stage 3 fibrosis vs. only 2/8 of those not treated with antiviral therapy. All patients had significant PTSD and depressive symptoms characterized by mean baseline scores: Mississippi = 113.8(SD 16.7); PCL-M = 59.4(SD 10.7); and BDI = 21.5(SD 11.7).Although total PCL-M and Mississippi scores did increase over time [F(4,52)=3.13,p=.022 and F(4,49)=2.59, p=.048, respectively] there were no significant differences between antiviral and no antiviral treatment over time. Subjects treated with antiviral therapy did show a significant increase on the resentment Buss-Durkee factor when compared to those who were not administered antiviral therapy[F(4,52)=5.47, p=.0009].However, no significant differences were observed in the other Buss-Durkee factors including: suspicion, assault, indirect hostility, irritability and verbal hostility. As expected, BDI scores increased significantly over time in those subjects treated with antiviral therapy and were significantly different from the comparison group over time [F(4,52)=6.72,p=.0002].All PTSD patients completed a course of pegylated interferon and ribavirin.To date 2/5 subjects are sustained virologic responders and 3/5 are non-responders.

 

Conclusions:

Depressive symptoms but not PTSD or hostility worsen during antiviral therapy in patients with PTSD.PTSD by itself does not appear to be a contraindication to HCV antiviral treatment when administered with psychiatric collaboration.

 


Abstract T1833 – EVR is a poor predictor of SVR is African Americans with genotype 1 Hepatitis C infection: a community clinic experience

X. Zhao; J. Izanec; R. Rivera; M. Ramaswamy; X. Ma

 

Background/Aim:

African Americans with chronic hepatitis C (CHC) genotype 1 infection have a reported sustained virological response (SVR) rate of 23-32% to peginterferon/ribavirin therapy; it is suggested the early virological response (EVR) may predict SVR. Most data are from university-based studies and few are available from community practice. Our study is to assess the virological response to PEG-INF/ribavirin therapy in a community population of black patients with genotype 1 CHC.

 

Method:

Over 3years, 59 black patients with genotype 1 CHC started treatment with PEG-INF/ribavirin in our community hepatology clinic. Liver biopsy was performed in 56 (95%) patients. HCV RNA levels were measured at baseline and week 12, 24, 48, and 72 after initiation of treatment. Treatment failure was defined when patients did not achieve an EVR and/or had active viremia at 72 weeks.

 

Result:

The 59 black patients (54% male) had mean age of 49.8 ± 7.0 years, weight of 203.8 ± 40.0 lbs and baseline HCV RNA of 6.07 ± 0.61 log IU/mL. The EVR rate was 56% (33/59); 21 patients did not have an EVR, 3 were lost to follow-up and two were non-compliant. The SVR rate was 6% (3/50); 12 patients did not respond to therapy after having an EVR, 6 were lost to follow-up after their EVR, 3 withdrew had adverse reactions (2 with anemia, 1 with depression) and 9 patients are still undergoing treatment. Patients with undetectable HCV RNA at 12 weeks had a lower baseline HCV RNA (5.67 ± 0.69 log IU/mL vs 6.19 ± 0.44 log IU/mL, p<.01) or a inflammation score on liver biopsy than those without an EVR (inflammation score 4.07 ± 1.07 vs 5.55 ± 1.61, p<0.01). When EVR was used to predict SVR, the PPV was 11% (3/33).

 

Conclusion:

Black patients from a community population may have a EVR rate comparable with published data and yet a much lower SVR rate. EVR is not a good predictor for SVR in this patient population. Low baseline HCV RNA and minimal hepatocyte inflammation may be associated with better treatment response.

 

Outcome

Number of patients/total

EVR

33/59

No EVR

21/59

lost to follow-up

3/59

non-compliant with therapy

2/59

 

Outcome

Number of patients/total

SVR

3/50

no response

33/50

lost to follow up

9/50

withdrawn/non-compliant

5/50

 


Abstract T1834 – Early predictors of hemoglobin reduction during first four weeks of Peginterferon alpha-2a/ Ribavirin therapy in chronic hepatitis C

C. Spangler; S. Han; M. Morrissey Kwasny; S. Cohen; N. Reau; D. Jensen

 

BACKGROUND:

The standard of therapy in chronic hep C utilizes peginterferon alpha-2a and ribavirin (RBV). It has been shown that higher doses of RBV without dose reduction correlate with increased efficacy in genotype 1 patients. It has also been shown that higher doses of RBV are associated with hemolytic anemia in some patients which may lead to RBV dose reduction or use of recombinant epoetin. As this subgroup of patients is difficult to predict, the purpose of this study was to evaluate clinical and laboratory predictors of significant anemia (hemoglobin [Hgb] decline of 2.5 gm from baseline to week 4 of treatment)in patients undergoing therapy.

 

PATIENTS AND METHODS:

58 pts with genotype 1 chronic hep C receiving initial therapy with 180 mcg peginterferon alpha-2a/week and ribavirin 1,000-1,200 mg/day comprised the study population. Patients with coexisting HIV, HBV, decompensated cirrhosis, HCC, liver transplant, or prior therapy were excluded. Blood samples were obtained from each patient prior to treatment, and at weeks 1, 2, and 4, then monthly. From these samples, laboratory quantification of serum Hgb, platelets, creatinine, iron, ferritin, HCV RNA, along with body weight, and creatinine clearance (Cockroft) were recorded. Patients were grouped by decreases in hemoglobin levels of <2.5 grams and ≥2.5 grams after 4 wks of therapy. Demographics were compared between the two groups using a Chi-squared test of association, independent t-test, or Mann-Whitney test depending on the distribution of the data.

 

CONCLUSIONS:

·       We found no baseline predictors of eventual ribavirin-associated anemia in our study population.

·       However, significantly more pts with an eventual Hgb drop of ≥2.5 gms at wk 4 had a hgb drop of ≥1.5 gms by wk 2.

·       Therefore, patients on treatment who demonstrate a ≥1.5 gm drop in Hgb by wk 2 may be considered for earlier epoetin treatment, or RBV dose reduction.

 

 

Patients With Week 4 Hgb Drop

 

 

≥ 2.5 gms

< 2.5 gms

p-value

n=

26

32

 

Male/Female

16/10

19/13

0.94

Age

54.7 ± 9.6

51.9 ± 8.4

0.29

RBV dose/kg

12.9 ± 3.3

12.5 ± 2.5

0.54

HCV RNA Baseline Log10

5.9 ± 0.65

5.9 ± 0.66

0.9

Baseline Platelets (x1000/uL)

178.8 ± 66.3

195.9 ± 60

0.4

Baseline MCV (fL)

92.6 ± 4.8

92 ± 5.7

0.6

Fe (ug/dL)

135.6 ± 51.4

128.5 ± 50.1

0.84

Ferritin (ng/mL)

258.7 ± 284.8

381.4 ± 329.5

0.11

Cr (mg/dL

1.0 ± 0.2

0.9 ± 0.2

0.13

CrCl

102.1 ± 39.1

106.3 ± 36.8

0.35

Hgb Baseline (g/dL)

15 ± 1

14.8 ± 1.4

0.44

Pts with ≥1.5 gm Hgb drop at 2 wks from baseline

21/26

5/28

<0.001


Abstract T1835 – Tolerance of Patients with HIV Co-infection to Hepatitis C Treatment in a South Bronx Community Hospital

K. Kumbum; D. Widjaja; P. Remy; R. B. Cindrich

 

Background

Hepatitis C virus (HCV) treatment with pegylated interferon and ribavirin decreases morbidity and mortality from liver disease among HIV patients. HCV treatment in co-infected patients is limited by premature discontinuation and decreased likelihood of sustained virologic response (SVR). Older age, higher body weight and African American (AA) race have been associated with lower SVR. Since our institution serves these populations, we reviewed retrospectively success of treatment of HCV/HIV co-infected patients.

 

Method

We reviewed records of patients with HCV/HIV co-infection treated with pegylated interferon with or without ribavirin at clinics affiliated with Bronx Lebanon Hospital Center between 1/1/2002 and 12/31/2004.

 

Results

Forty co-infected patients with mean age of 47 years (range 30-60) and mean body weight of 167 lbs (range 114-243) received pegylated interferon. Of these, 27 were male, 23 were Hispanic, 16 were AA and 1 was White. Two were active injection drug users and one was active alcohol user. Thirty three had HCV genotype 1, two had genotype 2, four had genotype 3 and one had genotype 4. Fourteen (35%) patients had pre-treatment psychiatric problems, commonly depression and anxiety. Mean baseline laboratory tests: ALT 68 IU/L; hemoglobin 13.3 g/dL; absolute neutrophil count 1987/uL; platelets 178,000/uL; CD4 count 477/uL; CD4 T cell percent 24; CD4/CD8 ratio 0.64; HCV viral load 1,848,175 IU/mL. Of 40 patients, 16 experienced intolerable side effects. Of 24 without side effects, 14 (58%) did not achieve virologic response, 5 (21%) were non-compliant, 3 (13%) achieved SVR, 1 (4%) developed thyroid nodule and 1 (4%) lost to follow up.

Of the three patients with SVR one had infection with genotype 1a, another genotype 3a and the third had genotype 4. Common side effects reported were: fatigue, nausea, vomiting, and headache (31%), persistent anemia (19%), worsening psychiatric problems (19%), new onset psychiatric problems (19%) and decompensated cirrhosis (12%).

 

Summary

·       In our population comprised of AA and Hispanics only 13% achieved SVR. Compared to other studies this is substantially lower even considering decreased response amongst AA.

·       Investigation of factors contributing to decreased response in this population is warranted.

·       Detailed observation of compliance, nature of preexisting psychiatric conditions, education and co-morbidities is needed. Better treatment of psychiatric problems may improve response to treatment.

 

 


Abstract T1836 – Serum Lipoprotein Levels During Treatment Of Chronic Hepatitis C With PEG-Interferon-Alfa-2a & Ribavirin – A Differential Effect On Genotype 3 Patients

Y. Rotman; Z. Levi; H. Rachel; M. Cohen; O. Cohen-Ezra; V. Manhaim; M. Braun; Z. Ben-Ari; R. Tur-Kaspa

 

Background & aims:

Interferon treatment for hepatitis C was previously shown to be associated with changes in serum lipoproteins, secondary to direct inhibition of lipoprotein lipase. Infection with genotype 3 is associated with liver steatosis which is amenable to successful eradication of the virus. In this work we sought to determine the changes in lipoprotein levels among different genotypes during treatment with PEG-interferon alfa-2a (PEG-IFN) & ribavirin.

 

Methods:

Participants were part of a prospective, non-controlled, multi-center study on the safety and tolerability of PEG-IFN and ribavirin; our single-center data are reported. Patients were treated according to current guidelines. Lipoprotein levels, not measured as part of the protocol, were retrospectively retrieved.

 

Results:

The study group included 157 patients of mean age 47 years, mean weight 75kg and mean body-mass index (BMI) 26.8; 37% had advanced fibrosis on biopsy and 77% were infected with genotype 1. Baseline cholesterol & triglyceride levels were 169mg/dl & 110mg/dl, respectively. Pre- & on-treatment levels were available for 76 patients. The mean duration of follow-up was 75 weeks (range 12-135). Treatment with PEG-IFN reduced total cholesterol levels by a mean of 19.9mg/dl (p<0.001) and increased triglyceride levels by 41 mg/dl (p=0.001). Following treatment, the levels returned to their baseline. The change in lipoprotein levels was evident by week 6 of treatment. The magnitude of change in cholesterol & triglyceride levels was not dependant on sex, age, weight, BMI or histological stage. Mean cholesterol levels decreased during treatment for patients with non-3 genotypes. For genotype 3 patients (n=6), however, cholesterol levels increased during treatment (mean increase 26.7mg/dl, p<0.001 for comparison with non genotype 3). The increase in cholesterol levels for genotype 3 patients was due mostly to increased LDL cholesterol. Triglyceride level changes were similar across genotypes. Of 68 patients with normal baseline triglyceride levels, 9 patients (12%) developed on-treatment levels above 200mg/dl. Excessive increases above 400mg/dl occurred in 2 patients (3%), both infected with genotype 1. Adverse events related to triglyceride levels were not observed.

 

Conclusions:

Changes in serum lipoproteins during PEG-IFN treatment include a reversible increase in triglyceride and decrease in cholesterol levels. Rarely, the increase in triglycerides is excessive. Genotype 3 patients show a strikingly different pattern with cholesterol levels increasing during treatment. As this genotype is considered steatogenic, part of the effect may be directly related to viral suppression.

 


Abstract T1837 – Intervention of sex and age for antiviral effect in interferon and ribavirin combination therapy for hepatitis C

Y. Karino; J. Toyoa; N. Akutsu; M. Nakanowatari; T. Arakawa; Y. Kuwata; J. Akaike; K. Yamazaki; T. Ohmura; T. Sato; S. Iino

 

Aim:

To make clear the relation of sexuality and age in interferon (IFN) and ribavirin (RBV) combination therapy.

 

Methods

One hundred and seventy-five patients with chronic hepatitis C (genotype 1b and high viral load (>100KIU/ml), male 89 cases, female 86 cases, average age 53.8 years old) who took combination therapy of IFN and RBV were used for analysis. We administered IFN alpha 2b (6MU) to first 89 cases, and PEG IFN alpha 2b (60 to 150μg/week depending on body weight) to next 86 cases. We administered RBV in the basis of body weight dosage to 104 cases, and in the basis of the total body clearance (CL/F) dosage to next 71 cases.

 

Stratifying an object in sexuality and age (<50 years old, 50-59 years old, >60 years old), we analyzed an antiviral effect, i.e. HCV dynamics (1st phase and 2nd phase), disappearance of serum HCV RNA by the 12th week of therapy (early viral response: EVR) and by the 24th week of therapy (late viral response: LVR).

 

Results

In the male cases, EVR and LVR were each 61.8% and 75.8% (<50 years old), 42.9% and 75% (50-59 years old) and 41.7% and 60.9% (> 60 years old).

In the female cases, EVR and LVR were each 57.9% and 83.3% (<50 years old), 37.9% and 64.3% (50-59 years old) and 38.9% and 59.4% (> 60 years old).

In both male and female, EVR rate fell along with the progression of age, but the degradation of LVR was relatively mild. Both EVR and LVR were high in the male cases in each age group (not significant).

 

In PEG IFN alpha 2b administration cases, HCV dynamics of the 1st phase (log/ day), the second phase (log/ week), and the 3rd phase (log/week) were each 1.20, 0.64 and 0.34 (<50 years old), 0.95, 0.57 and 0.36 (50-59 years 0ld), 0.91, 0.49 and 0.31 (>60 years old) in the male caesm and 1.04, 0.66 and 0.27 (<50 years old), 0.97, 0.41 and 0.31 (50-59 years old), 1.03, 0.35 and 0.29 (>60 years old) in the female cases.

 

As for 1st and 3rd phase, there were not particular tendency among gender or age.  With the progression of age, attenuation of the second phase tends to deteriorate in both male and female cases, and it was remarkable in the female older than 50 years old in particular (not significant).

 

The serum ribavirin levels at the 4th week of therapy increased along with again.  There were no significant difference of serum ribavirin levels between the patients who achieved EVR and the patients who didn’t.  In 71 cases that administered ribavirin by a CL/F base (male 39, female 32), average serum ribavirin level of the fourth week of treatment was 2046ng/ml in the males cases and 2380ng/ml in the female cases (P<0.01).  However, as for EVR rate, the males cases (53.8%) was higher than the female cases (40.5%) (not significant).

 

Conclusion

With aging, the second phase of HCV dynamics deteriorated and EVR rate fell. This phenomenon was remarkable in the female cases older than 50 years old. From relatively high serum RBV concentration in the female cases, sensitivity of IFN was suggested to relate to attenuation of antiviral effect in the old female cases. The possibility that a long-term treatment improved an effect of an old patient was suggested.

 


Abstract T1838 – Patient age and impaired renal function as risk factors for hemolytic anemia in patients with chronic hepatitis C treated with combination therapy of interferon and ribavirin

Y. Iwasaki; H. Ikeda; K. Takaguchi; H. Kobashi; Y. Araki; T. Osawa; M. Tomita; N. Hashimoto; K. Yabushita; T. Shimoe; Y. Makino; K. Manabe; K. Sakaguchi; Y. Shiratori

 

Background and Aims:

Combination therapy of interferon and ribavirin is a standard of treatment for patients with chronic hepatitis C. However, dose reduction of ribavirin that is necessitated by hemolytic anemia is common. Since little information is available about host, viral, and treatment factors that may influence ribavirin-induced anemia, particularly in old patients, we have examined the influence of several variables on this side effect in a large cohort of chronic hepatitis C patients.

 

Methods:

We consecutively enrolled 269 patients with chronic hepatitis C; 174 men and 95 women, age (mean ± SD): 55 ± 9.5 years old, 189 with genotype 1 and 80 with genotype 2. They were scheduled to receive interferon alpha-2b daily for two weeks followed by three times per week for 22 weeks with daily administration of ribavirin (600 or 800 mg). Patients were assessed for safety and tolerance by monitoring adverse events including laboratory abnormalities every 2-4 weeks. Dose modification and premature discontinuation of the combination therapy due to anemia or decrease of a hemoglobin level less than 10 g/dL were the endpoints.

 

Results:

Of 269 patients, dose reduction and discontinuation of ribavirin were required in 134 of 269 (50%) patients. Univariate regression analysis revealed that patient age (older), gender (female), weight (≥60 kg), hemoglobin level at baseline (<14 g/dL), creatinine clearance (<100 mg/day), and dosage of ribavirin (800 mg) were significantly associated with dose reduction and discontinuation of ribavirin due to anemia. With multivariate logistic regression, a tendency toward a higher risk for anemia was seen in the older patients, with lower hemoglobin level, and with lower creatinine clearance. Similar results were obtained, when decrease of a hemoglobin level below 10 g/dL was used as an endpoint.

 

Conclusions:

·       These results demonstrated that patient age and impaired renal function, as well as low hemoglobin levels, are important risk factors for anemia in patients treated with combination therapy.

  • Thus, aged patients with impaired renal function as well as low haemoglobin levels at baseline, were important risk factors for anemia.

 


Abstract T1839 – 24 Week Response to Consensus Interferon plus Ribavirin Therapy in Patients who are Nonresponders or Relapsers to Prior PEG IFN plus Ribavirin Therapy

R. Ghalib; C. Levine; M. Mouti; J. Weinstein; A. Schwartz; A. Mejia; S. Cheng

 

Purpose:

To describe the 24 week viral response to consensus interferon (CIFN) plus ribavirin combination therapy in patients who were nonresponders or relapsers to prior therapy with PEG IFN plus ribavirin therapy for chronic hepatitis C (HCV).

 

Methods:

This is an interim analysis of the first 24 weeks of retreatment in patients who failed prior therapy. Patients were started on CIFN 15 mcg daily plus weight based ribavirin therapy. HCV RNA was monitored at week 4, and every 3 months. Growth factors were allowed.

 

Results:

Sample included 49 patients with 30 (61%) prior nonresponders and 19 (39%) prior relapsers. Nonresponders had an age range of 35-59 years (mean 50.1 ± 4.5); 19 (63%) males and 11 (37%) females; genotype 1 in 90% and 2 in 10%; race with 16 (53%) White, Black 11 (37%), and 3 (10%) other; biopsy stage 1-2 in 11 (37%) and 3-4 in 19 (63%). Relapsers had an age range of 40-60 years (mean 49.9 ± 5.8); genotype 1 in 13 (68%), 2/3 in 4 (21%) and 4 in 2 (11%); race with 15 (79%) White, Black 1 (5%), and 3 (16%) other; biopsy stage 1-2 in 4 (21%) and 3-4 in 15 (79%). Patients currently at ≥24 weeks of treatment in 18 (60%) of nonresponders and 17 (89%) of relapsers. Discontinuations before week 24 for adverse events occurred in 6 (20%) nonresponders and 1 (5%) relapsers. HCV RNA response at 24 weeks in nonresponders vs. relapsers was undetectable virus (< 5 IU/mL) in 9 (30%) vs. 15 (79%); ≥ 2 log decrease in 18 (60%) vs. 17 (89%); treatment was discontinued for viral rebound or < 2 log viral decrease in 12 (40%) vs. 2 (11%), respectively. Logistic regression for undetectable HCV RNA at week 24 identified BMI and African American as significant variables (-2 log likelihood 45.59; model Chi-square 12.14, df=2, p< .002).

 

Conclusions:

In nonresponders and relapsers to prior PEG IFN plus ribavirin therapy, the virologic response rates at week 24 with CIFN 15 mcg daily plus weight based ribavirin therapy are 30% and 79% for undetectable virus and 60% and 89% for > 2 log decrease, respectively. CIFN plus ribavirin therapy was tolerated in this population with 14% discontinuation rate for adverse events. Further investigation of predictive factors of sustained viral response is needed in the nonresponder and relapser population to guide selection of appropriate treatment candidates and therapies.