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