DDW 2007:  Monday Abstracts:


Topic:  Treatment – Disease Progression

361. Eradication of HCV Improves Hepatic Expression of Insulin Receptor Substrate 1/2 and Insulin Resistance. 

T. Kawaguchi; T. Ide; E. Taniguchi; E. Hirano; M. Itou; S. Sumie; Y. Nagao; C. Yanagimoto; S. Hanada; H. Koga; M. Sata



HCV infection is associated with increased insulin resistance. We have previously shown that HCV down-regulates hepatic expression of insulin receptor substrate (IRS) 1/2, central molecules for insulin signaling, through up-regulation of suppressor of cytokine signaling 3. Thus, HCV itself seems to play an important role for the development of insulin resistance. However, the effects of antiviral treatment on impaired glucose metabolism remain unclear. The aim of this study is to examine the effects of eradication of HCV on hepatic expression of IRS1/2 and insulin resistance.


Subjects and Methods:

We analyzed 80 biopsy-proven patients with chronic HCV infection. Patients were received interferon-α or interferon-α plus ribavirin for 6 months and were classified into three groups at 6 months after the conclusion of antiviral therapy according to their response to antiviral therapy: sustained responders (n = 26), relapsers (n = 11), and non-responders (n = 43). Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR). Hepatic expression of IRS1/2 was evaluated by immunoblotting and immunostaining in 14 sustained responders.



In non-responders, BMI significantly decreased to 21.5 ± 1.4 kg/m2 from 22.9 ± 3.1 kg/m2 (p < 0.05) at the end of follow-up. However, there were no significant changes in HOMA-IR values at the end of follow-up compared to those before antiviral therapy (HOMA-IR: 3.9 ± 1.5 vs. 3.7 ± 1.5, N.S.). In relapsers, no significant differences were seen in BMI (21.9 ± 1.5 kg/m2 vs. 22.0 ± 1.4 kg/m2, N.S.) and HOMA-IR values (3.5 ± 1.6 vs. 3.6 ± 1.1, N.S) at the end of follow-up compared to those before antiviral therapy. In sustained responders, there was no significant difference in BMI at the end of follow-up (22.3 ± 1.7 kg/m2 vs. 22.1 ± 1.8 kg/m2, N.S). On the other hand, HOMA-IR values significantly decreased to 2.3 ± 1.1 from 3.2 ± 0.9 (p < 0.01) by the end of follow-up. Immunoblotting showed a 3-fold increase in hepatic expression of IRS1/2 after eradication of HCV. Immunostaining revealed that increased IRS1/2 expression occurred in hepatocytes, but not non-parenchimal cells.



We demonstrated that eradication of HCV improves hepatic expression of IRS1/2 and insulin resistance.


Topic:  Treatment General

362. Restoration Of Innate Immunity And Inhibition of Essential Host Factor For Replication Achieve Better Clinical Effect In Patients With Chronic Hepatitis C 

K. Inoue; T. Watanabe; M. Yoshiba



Persistent infection is a distinguishing feature of hepatitis C virus. A crucial strategy against innate immunity is impairment of the IRF-3 pathway, which results in low response of IFN induction system. Recent improvement of infectious culture system revealed that cyclosporineA or other cyclophilin inhibitors can suppress HCV replication. Cyclophilins are essential host factor for HCV replication. We adopted divided administration of IFN-β to restore the immune response with cyclosporine A as a cyclophilin inhibitor in induction and intensified therapy based on recent advances in molecular virology. We report here a better clinical effect of our protocol.



Patients (n= 70; 45 men and 25 women; average age, 61) were enrolled into the present study to confirm the efficacy, safety and tolerability of the new treatment. Serum HCV RNA level was 1600 KIU/ml (420-15000 KIU/ml) and genotype 1b. The treatments consisted of an induction therapy, an intensified therapy and a maintenance therapy. The induction therapy comprised intravenous 1 MU IFNβ every 4 hours for the first 3 days, 1.5 MU IFNβ every 6 hours for the next 4 days and 2 MU IFNβ every 8 hours for the following 3 weeks, totaling 168 MU of IFNβ. The intensified therapy was induction therapy shortened to 2 weeks. The maintenance therapy comprised of pegylated IFNa2b and ribavirin. CsA was given 4 times daily for a total dose of 200 mg during the induction and the intensified therapies. Ribavirin was given twice daily for a total dose of 800 mg (body weight over 60 kg) or a total dose of 600 mg (body weight equal to or less than 60 kg) during the maintenance therapy. This protocol was approved by the institute review board.



The sustained virological response rate of the present study was 65.8% (47/70). The sustained biochemical response rate of the present study was 80.4% (55/70). Safety analysis showed that 22 patients had mild retinopathy, 5 had severe proteinuria and one had encephalopathy, which was probably related to CsA. Administration of CsA was discontinued in 4 cases. All adverse effects were completely reversible. The treatment protocol was well tolerable.



Recent advances in molecular virology related HCV revealed the mechanism of HCV persistence and HCV replication. Rational attempt based on recent progress in HCV basic research can overcome the persistence of HCV and achieve better clinical effect. Host factor targeted treatment will be a promising new HCV treatment.


Topic: Experimental Therapies (both HCV-976 and 503034)

364. Favorable Cross-Resistance Profile of HCV-796 and SCH-503034 and Enhanced Anti-Replicon Activity Mediated By Combination Treatment. 

R. Ralston; A. Y. Howe; R. Chase; A. Skelton; X. Tong; M. Flint; S. Mullen; C. Broom; E. Emini



Cell-culture replicon studies evaluated the combined antiviral effects of two novel inhibitors of hepatitis C virus (HCV): SCH-503034 (Schering-Plough), a NS3 protease inhibitor, and HCV-796 (Wyeth/ViroPharma), a non-nucleoside polymerase inhibitor. Each inhibitor demonstrated significant antiviral activity in early clinical studies. Replicon studies demonstrated that genetic variants exhibiting reduced susceptibility can be selected from each compound. Because SCH-503034 and HCV-796 target different viral enzymes, a potential exists for enhanced in vivo antiviral effect if the inhibitors are used in combination, as well as the potential for forestalling in vivo selection of clinically resistant HCV. The present replicon studies were performed to ascertain the likelihood of achieving these goals.



The combined antiviral effect of SCH-503034 and HCV-796 was evaluated using genotype 1b HCV replicon cells. Each compound was individually assessed for its ability to inhibit the activity of variant replicons exhibiting reduced susceptibility to the other inhibitor.



The combination of SCH-503034 and HCV-796 notably enhanced replicon inhibition in treated cells, in a dose-dependent manner, compared with the effect of each inhibitor used alone. The antiviral effect of the combination was at least additive. No cytotoxicity was observed. SCH-503034 exhibited equivalent inhibitory activity against the wild-type replicon and replicon variants expressing single polymerase amino acid substitutions that engender reduced susceptibility to HCV-796. The inhibitory effect of HCV-796 against replicon variants with protease amino acid substitutions mediating reduced susceptibility to the protease inhibitor was found to be identical to that observed against the wild-type replicon. The combination significantly reduced the frequency of emergence of resistant colonies compared to each inhibitor used alone.



·        The anti-replicon activity of the combination of SCH-503034 and HCV-796, as well as the activity of each compound against replicons with reduced susceptibility to the other compound, strongly support the combined use of these two inhibitors in clinical trials.

·        The cell-culture replicon data suggest that the in vivo antiviral effects of the combination will be notably improved over the effects seen to date with monotherapy.

·        Importantly, compared with monotherapy, the combination will likely impose a greater genetic barrier to the selection of clinically resistant viral variants.


Topic:  Disease Progression

366. TLR-stimulated non-parenchymal liver cells are potent suppressors of HCV replication. 

R. Broering; J. Wu; G. Gerken; J. F. Schlaak


Aims and Background:

Only little is known about the role of non-parenchymal liver cells (NPC) of the hepatic sinusoid (Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC)) in the antiviral defence against HCV. Therefore, the aim of this study was to further elucidate their role in the local innate immune response against HCV in the liver using a murine replicon system.


Materials and methods:

To study the effect of type I and II IFNs murine MH1 cells harbouring the HCV-Con1 replicon I377/NS3-3 were cultured in the presence or absence from various concentrations of IFN-α, IFN-β and IFN-γ. In addition, the cells were cultured with cell culture supernatants from KC and LSEC stimulated with TLR-ligands 1-9 for 20 h. Then, total RNA of the MH1 cells was isolated and the HCV replicon concentration was measured by quantitative real-time PCR.



The replicon RNA is increasing over a time course of 60 h with a fold change about four, independent from the passage number and confluence of the cells. Treatment of these cells with IFN-α, -β or -γ led to decreased HCV replication in a dose dependent manner with IC50s that were comparable to data from human HCV replicon systems (2-10 U/ml). All three IFNs led to a maximal suppression of HCV replication of about 80%. Only cultivation of MH1 cells with supernatants from TLR3- and 4-stimulated KC or LSEC stimulated with TLR3 led to a marked inhibition of HCV replication by NPC. While TLR3- and 4-stimulated KC could suppress HCV replication by about 80% in our system, supernatants of TLR 3-stimulated LSEC could suppress HCV replication by about 60%, respectively. The suppressive effect of TLR3- and -4 stimulated cells could be completely blocked by preincubation with antibodies against IFN-β.



In conclusion, these results show that the HCV-Con1 Replicon I377/NS3-3, when replicated in a murine system, is sensitive to IFN-α, -β and -γ. Furthermore, TLR3-stimulated NPC are potent suppressors of HCV replication which is possibly mediated through IFN-β. These novel findings are of particular relevance for the control of HCV replication by the innate immune system of the liver.


Topic:  Diagnostic tools – Biochemical/imaging

437. Point Of Care Non-Invasive 13C Methacetin Breath Testing Accurately Identifies Significant Liver Inflammation and Fibrosis: A Novel Method For Assessing Liver Damage. 

G. Lalazar; O. Pappo; B. Müllhaupt; O. Goetze; M. Margalit



Significant liver disease may be present in a seemingly healthy population with normal liver enzymes and minimal symptoms. The serum ALT level may not reflect the degree of liver damage, and liver biopsy has been the gold standard for assessment of fibrosis and inflammation. The point of care non-invasive BreathID® continuous online 13C methacetin breath test (MBT) reflects hepatic microsomal function (CYP1A2) and has been shown to correlate with hepatic fibrosis.



To assess the ability of the BreathID® 13C MBT to differentiate patients with significant liver inflammation and/or fibrosis from healthy controls.



184 patients with chronic HCV infection, who had undergone a liver biopsy within 9 months, and 81 healthy controls (no known liver disease, normal liver enzymes and ultrasound) matched for age and sex, underwent 13C MBT following ingestion of 75mg of methacetin. Forty three controls and 11 patients underwent the MBT at least twice to determine test reproducibility. MBT parameters included PDR peak (percentage dose recovered) and CPDR10, 20, 30, 60 (cumulative PDR10, 20, 30 and 60 minutes after ingestion of methacetin, respectively). Correlations between breath test parameters and HAI (Hepatic Activity Index) inflammation score or METAVIR fibrosis score were evaluated. We compared MBT parameters between controls and patients grouped by HAI and METAVIR scores.



In HCV patients, all MBT parameters correlated significantly with inflammation and fibrosis scores (p<0.0001). MBT accurately differentiated between controls and patients with significant periportal and bridging inflammation (HAIa > 2), any inflammation type (total HAI ≥ 4) (AUC 0.87 and 0.82, 95%CI 0.78-0.97 and 0.74-0.91; sensitivity 88% and 74%; specificity 78% and 77%; NPV 97% and 84%; and PPV 45% and 65%, respectively), or patients with significant fibrosis (METAVIR > 2) (AUC 0.96, 95%CI 0.92-1.00; sensitivity 96%, specificity 86%, NPV 97%, and PPV 81%). Inter-test variability was ≤ 13% (95%CI 0.11-0.15). Results were independent of BMI in patients and healthy controls.



The point of care BreathID® continuous online 13C MBT accurately differentiates patients with significant liver inflammation and/or fibrosis from healthy controls. This test may prove to be a powerful non-invasive tool for detecting occult liver dysfunction.


Topic:  Disease Progression

438a. A comparison of risk factors for intra- and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. 

T. M. Welzel; B. I. Graubard; H. B. El-Serag; Y. H. Shaib; A. W. Hsing; J. A. Davila; K. A. McGlynn



Cholangiocarcinomas can be anatomically classified as extrahepatic (ECC) or intrahepatic (ICC) tumors. Despite differences in their clinical and pathological presentation, ECCs and ICCs share some common risk factors such as PSC. In contrast, some recent evidence suggests that the etiopathogenesis of ECC and ICC may differ. For example, ICC and hepatocellular carcinoma (HCC) may arise from common progenitor cells. Also in support of this hypothesis are the divergent temporal trends in ECC and ICC incidence in the United States. While the incidence of extrahepatic cholangiocarcinoma (ECC) has remained constant, the incidence of intrahepatic cholangiocarcinoma (ICC) has increased, resembling HCC incidence trends. To provide clues to etiology, the association of ECC and ICC with pre-existing medical conditions was examined in this population-based case-control study.



Using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, all ICC and ECC patients diagnosed between 1993 and 1999 were identified. Controls were chosen at random from among individuals with no cancer diagnosis in the underlying populations of the SEER11 regions. Logistic regression analysis was used to calculate adjusted odds ratios.



549 ECC, 535 ICC cases and 102,782 controls met the inclusion criteria. In addition to established risk factors, such as choledochal cysts, cholangitis and inflammatory bowel disease, several other medical conditions were significantly associated with increased risk of ECC and ICC, including biliary cirrhosis (ECC, ICC: p=0.0001), cholelithiasis (ECC, ICC: p=<0.0001), alcoholic liver disease (ECC p<0.0001; ICC p=0.01), nonspecific cirrhosis (ECC, ICC: p<0.0001), diabetes (ECC, ICC: p=<0.0001), thyrotoxicosis (ECC p=0.006; ICC p=0.04) and chronic pancreatitis (ECC, ICC: p=<0.0001). Conditions only associated with ICC were obesity (ECC p=0.75; ICC p<0.01), chronic non-alcoholic liver disease (ECC p<0.08; ICC p=0.02), hepatitis C virus (HCV) infection (ECC p<0.67; ICC p=0.01) and smoking (ECC p=0.07, ICC p=0.04).



This study identified several novel conditions that were significantly associated with both ECC and ICC risk. In addition, the current study found that HCV infection, obesity, chronic non-alcoholic liver disease, and smoking are significantly associated with ICC, but not ECC risk. As several of these pre-existing conditions (HCV infection, obesity, chronic non-alcoholic liver disease) are increasing in the U.S. it is possible that these conditions contribute to the divergent incidence trends of ECC and ICC, and explain the similar incidence trends of ICC and HCC.

Topic:  Exprimental Therapies – HCV – 796

440. Pharmacodynamic Analysis of the Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Combination With Pegylated Interferon Alfa-2b in Treatment-Naïve Patients With Chronic HCV. 

E. S. Maller; D. Raible; P. Chandra; D. Harper; J. Speth; P. Shaw; G. Bichier; S. Villano



HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated antiviral activity across multiple HCV genotypes, both in vitro and in Phase 1 clinical studies.


In a randomized, double-blind study, adult patients with chronic HCV infection who were naïve to treatment were randomized to receive oral HCV-796 (100, 250, 500, or 1000 mg) or placebo every 12 hours for 14 days. All patients were to receive pegylated interferon alfa-2b (PEG, 1.5 μg/kg) on day -1 (one day before start of HCV-796/placebo) and day 7. Each cohort receiving HCV-796+PEG enrolled 9-12 patients. Virologic response was analyzed by individual pharmacokinetic (PK) parameters and various demographic/baseline characteristics. HCV RNA was assayed with a lower limit of detection of 50 IU/mL.


Overall, the mean baseline HCV RNA level was 6.4 log10, and 66% of patients were infected with HCV genotype 1. At day 14, the mean reduction in HCV RNA ranged from 3.3-3.5 log10 in the combination therapy groups vs. 1.6 log10 in the PEG group. Activity differed by HCV genotype. Mean reductions at day 14 for genotype 1 ranged from 2.6-3.2 log10 in the combination therapy groups vs. 1.2 log10 for PEG. For genotype non-1 the respective reductions were 3.5-4.8 log10 vs. 2.6 log10. Based on individual HCV RNA plots over time, there was somewhat greater variability in virologic response in the HCV-796 100 mg q12h combination group compared with higher dose groups. However, analyses of individual virologic responses in the combination therapy groups did not reveal correlations with individual HCV-796 PK parameters (Cmax, AUC, or Cmin) across the range of doses tested. At HCV-796 doses of 250 mg q12h or higher, combination with PEG resulted in 33-67% of genotype 1 patients with reductions from baseline >3 log10 on day 14 (13-17% below 50 IU/mL). For genotype non-1, 67-100% had reductions >3 log10 on day 14 (50-75% below 50 IU/mL). There were no apparent differences in virologic response in the combination therapy groups when analyzed by patient age, race, sex, or baseline HCV RNA level.


The combination of HCV-796 and PEG provides antiviral activity across multiple HCV genotypes that is greater than either agent used alone. Pharmacodynamic analyses suggest similar short-term antiviral activity at HCV-796 doses of 250 mg q12h or higher when combined with PEG. Clinical studies of more long-term administration of combination therapy are in progress to determine if these effects are durable.


Topic:  Current Therapy - Pegasys

441. Peginterferon Alfa-2a (40KD) Plus Ribavirin for 16 or 24 Wks in Pts With HCV Genotype 2/3 Infection and Advanced Fibrosis/Cirrhosis. 

M. L. Shiffman; F. Suter; B. R. Bacon; D. R. Nelson; H. Harley; R. Solá; S. D. Shafran; K. Barange; A. Lin; G. Hooper; S. Zeuzem



Chronic hepatitis C (CHC) pts with cirrhosis have a higher risk of developing severe complications and are in particular need of treatment. In the ACCELERATE trial of peginterferon alfa-2a plus ribavirin (RBV) in pts with HCV genotype 2 or 3 (G2/3) infection, cirrhosis was a significant negative prognostic factor of a sustained virologic response (SVR). We further analyzed the ACCELERATE database to compare the efficacy of treatment in pts with and without cirrhosis, and whether on-treatment virologic response would assist treatment optimization.



Pts (n=1469) received peginterferon alfa-2a (PEGASYS®) 180μg/wk plus RBV (COPEGUS®) 800mg/d for either 16 or 24wks. SVR (undetectable [<50IU/mL] HCV-RNA at 24wks post-treatment) was analyzed according the presence or absence of baseline cirrhosis in 1309 pts receiving treatment as defined by the protocol. Cirrhosis included advanced fibrosis/transition to cirrhosis (Knodell ≥3, Metavir ≥3, or Ishak modified HAI score of 4 [with nodules or >3 bridges] or ≥5). Additional analyses determined SVR rates in pts with and without rapid virologic response (RVR; undetectable HCV-RNA [<50IU/mL] at treatment wk 4).



Cirrhotic pts had lower SVR rates than non-cirrhotic pts; for both groups, SVR was higher with 24 vs. 16wks’ treatment (Table). RVR was achieved by 56% of pts with cirrhosis and 71% of non-cirrhotic pts. Non-cirrhotic pts with RVR had SVR rates of 85% with only 16wks’ treatment; extending treatment to 24wks resulted in an SVR rate of 91% (p=0.02; two-sided Fisher’s exact test). In cirrhotic pts with RVR, 24wks’ treatment resulted in higher SVR rates than with 16wks (87% vs. 71%; p=0.01). In pts without an RVR, both cirrhotic and non-cirrhotic, 24wks’ treatment produced higher SVR rates than 16wks (p=0.04 and p<0.0001, respectively).



·        Higher SVR rates with peginterferon alfa-2a plus RBV therapy are achieved in G2/3 pts without cirrhosis, supporting early treatment before progression to advanced liver disease.

·        In pts with RVR, 24wks’ treatment resulted in SVR rates >87% in both cirrhotic and non-cirrhotic pts. Cirrhotic pts without RVR have a chance of SVR of only 30% with the currently recommended 24-wk regimen; in these pts, longer treatment durations might be beneficial.

·        Assessing on-treatment virologic response at wk 4 thereby allows treatment optimization in both cirrhotic and non-cirrhotic pts with HCV G2/3 infection.















SVR in pts with RVR





SVR in pts without RVR






Topic:  Experimental Therapies – Celgosivir

442. Phase II Study of celgosivir in combination with Peginterferon alfa-2b and ribavirin in chronic hepatitis C genotype-1 non-responder patients 

K. D. Kaita; E. M. Yoshida; D. Kunimoto; F. Anderson; M. Sherman; P. Marotta; L. J. Scully; K. M. Peltekian; R. A. Enns; F. Diaz-Mitoma; S. S. Lee; L. Worobetz; J. Pankovich; A. Petersen



Celgosivir is a new class of antiviral medicine in clinical development for the treatment of chronic hepatitis C virus (HCV) infection. Researchers tested this new antiviral medicine and measured its potential to offer improved treatment outcomes when combined with other anti-HCV drugs.



The current study evaluated 57 chronic HCV genotype-1 patients, separated by prior treatment status into non-responders or partial responders and randomized to three treatment groups:


1.     celgosivir 400 mg once daily in combination with peginterferon alfa-2b and ribavirin (PRC);

2.     celgosivir 400 mg once daily in combination with peginterferon alfa-2b (PC); or

3.     placebo with peginterferon alfa-2b and ribavirin (PR, active control).


All patients were treated for 12 weeks. The non-responders cohort enrolled 36 patients (PRC: 15; PC: 11; PR: 10) and the partial responder cohort had 21 patients (PRC: 3; PC: 9; PR: 9).



For prior non-responder patients, an Early Viral Response (EVR) was achieved in 42 percent (5/12) of those in which celgosivir was added to the standard peginterferon alfa-2b and ribavirin therapy compared with only 10 percent (1/10) of patients receiving just peginterferon alfa-2b and ribavirin. Non-responder patient study results also demonstrate an improved mean decrease in HCV viral loads when celgosivir is added to peginterferon alfa-2b and ribavirin of 1.63 log10 IU/mL versus 0.92 log10 IU/mL in patients treated with peginterferon alfa-2b and ribavirin alone. Eleven of the 36 non-responder patients were classified as a very difficult-to-treat patient subgroup (null responders) as they were shown to have a prior HCV treatment response of =0.4log10 to optimized therapy. In the present study, the mean decrease in HCV viral loads in these null responder patients was 1.86 log10 IU/mL with celgosivir plus peginterferon alfa-2b and ribavirin while the two null responder patients treated with peginterferon alfa-2b and ribavirin was 0.32 log10 IU/mL. The observed difference in mean viral load between the PRC and PR treatment groups provides evidence that the combined effect of celgosivir with peginterferon alfa-2b and ribavirin provides a clinically significant treatment benefit for difficult-to-treat chronic HCV infected patients.



"This study is the first demonstration that celgosivir in combination with peginterferon alfa-2b and ribavirin results in a clinically significant decrease in HCV viral loads in patients highly resistant to current standard treatment," said Kelly D. Kaita, M.D., of the University of Manitoba in Canada, and lead author of this study. "Further clinical research on the best dosing regimen and combinations is warranted to optimize the potential of this innovative combination for chronic HCV patients."

Source;  DDW press release


Topic:  Experimental therapies – Telaprevir  VX 950

443. Predicting HCV Treatment Duration with an HCV Protease Inhibitor Co-administered with Peg-IFN/RBV by Modeling both Wild-type Virus and Low Level Resistant Variant Dynamics. 

A. Khunvichai; H. Chu; V. Garg; J. G. McHutchison; E. Lawitz; M. Rodriguez; T. Kieffer; J. Alam



HCV protease inhibitors, such as telaprevir, inhibit viral replication and have induced marked decline of plasma HCV RNA titers in genotype-1-infected (GT-1) patients. Viral dynamic (VD) modeling assuming homogenous wild-type (WT) viral population suggested that protease inhibitors may significantly shorten treatment duration required to eradicate the virus (Chu, 2005 AASLD #1260). The objective of this work was to extend the previous empirical model to account for the presence of both WT virus and low-level telaprevir-resistant variants and estimate the required treatment duration.



Plasma HCV RNA data from 12 treatment-naïve, GT-1-infected patients dosed for 4 weeks with telaprevir co-administered with peginterferon-alfa-2a (Peg-IFN) and ribavirin (RBV) (Lawitz, 2006 DDW #686F) were analyzed using a VD model (Neumann, Science 1998) incorporating the pharmacokinetics (PK) of telaprevir. Simulations were performed with model parameter values obtained from VD model (ε, δ, etc.) and PK parameters, for patients with predominately WT virus and low levels of resistant variants (assuming an initial variant level of 100-3000 IU/mL, a variant IC50 value ~7-to 20-fold increase from WT, and similar fitness between resistant variants and WT (Sarrazin, 2005 AASLD #LB06)). Because resistant variants were shown to be sensitive to IFN or RBV in vitro (Lin, 2006 AASLD #89) the effectiveness of Peg-IFN/RBV in blocking virion production was assumed to range 80%-95% against both WT and variant, consistent with clinical observations.



The results of the simulations (Figure 1) indicate that treatment duration with co-administration of telaprevir with Peg-IFN/RBV required to suppress WT and low-level resistant variants below 1 copy (total body burden) is less than 12 weeks.



These results indicate that even in the presence of resistant variants, co-administration of a potent protease inhibitor with Peg-IFN/RBV may result in rapid viral eradication, allowing a substantial reduction in treatment duration from the current 48 weeks. The model supports the study of telaprevir-based treatment with Peg-IFN/RBV for 12 weeks. This hypothesis is being tested in ongoing clinical trials.



Topic:  Current therapies – Pegasys

444. Sustained Virologic Response (SVR) Resulting From Treatment with Peginterferon Alfa-2a (40KD) (PEGASYS®) Alone or in Combination with Ribavirin (COPEGUS®) is Durable and Constitutes a Cure: an Ongoing 5-year Follow-up. 

M. G. Swain; M. Lai; M. L. Shiffman; W. E. Cooksley; A. Abergel; A. Lin; E. Connell; M. Diago



The current standard of care in chronic hepatitis C virus (HCV) infection is combination therapy with peginterferon and ribavirin. Sustained virologic response (SVR) rates of up to 66% have been reported in pts with HCV mono-infection. The durability of SVR is being investigated in a long-term follow-up study of pts treated for chronic HCV infection. Here we present the latest results of this ongoing study.



Pts who took part in one of nine randomized trials of peginterferon alfa-2a (40KD) (PEGASYS®) as monotherapy or in combination with ribavirin (COPEGUS®), and who were negative for serum HCV-RNA (<50IU/mL) at the final virologic assessment were eligible for inclusion in the long-term follow-up study. Serum HCV-RNA was determined annually for 5 years from the date of last treatment.



To date 997 pts are undergoing long-term follow-up, including 163 HCV mono-infected pts treated with peginterferon alfa-2a (40KD) monotherapy, 741 mono-infected pts treated with combination therapy, and 93 HIV-HCV co-infected pts treated with either monotherapy or combination therapy. The overwhelming majority of pts (989/997; >99%) remain HCV-RNA negative at a mean of 4.1 (range 0.4-7) years after treatment cessation (an outcome we consider to be consistent with a cure). Eight pts became HCV-RNA positive (>50IU/mL) between 1.1-2.9 (mean 2.0) years after completing treatment. There were no consistent patterns in terms of age, gender or HCV genotype among these 8 pts and none showed evidence of liver cirrhosis. Two pts had low baseline viral load (<400,000IU/mL) while the remaining 6 pts had a baseline viral load ranging from 700,000–12 millionIU/mL. The proportion of these incidents representing new infections or true ‘relapse’ is currently unknown.



·        These results show that an SVR following treatment with peginterferon alfa-2a alone or in combination with ribavirin is durable in almost all (99.2%) pts with chronic HCV infection, validating the use of the word ‘clincially cured’ for those achieving an SVR.

·        The author noted that of the 8 patients who became HCV positive during follow-up, that one was a clear case of reinfection because that patients tested positive for a different genotype than the genotype in the original study. 

·        The authors are not sure if the other 7 patients are from reinfection or because the virus returned after therapy.   Another physician stated that because there is a 1% false-positive result that there cold be a possibility that the viral load tests have been false positive.  Unfortunately, those patients have not lost to follow-up.   


Treatment (population)

Number of studies


Mean years after treatment

Pts with detectable HCV RNA (n)

Monotherapy (elevated ALT)a





Combination (elevated ALT)a





Combination (‘normal’ ALT)





Mono and combination (HIV-HCV co-infection)





a1 study contained monotherapy and combination therapy arms.


Topic:  Experimental therapies – general

Background and Aims:

HCV replication depends on membrane constituents for assembly and release of the polyprotein. HMG CoA reductase (HMGR) inhibition reduces cellular sterol proteins such as geranylgeraniol, and markedly suppresses in vitro HCV replication. Our aims were to prospectively evaluate HMGR inhibition changes in lipid profiles, and HCV RNA levels in prior CHC non-responders(NR).



For this open-label ascending dose cohort study, 11 CHC genotype-1 NR, received Rosuvastatin (Crestor) initially at 20mg qd for 4 wks, and 40 mg qd for a further 8 wks. HCV RNA (NGI SuperQuant), fasting lipid and biochemical profiles were obtained at baseline, at intervals during the 12 week dosing period, and at 4 wks after treatment. Associations between changes in lipid profiles and liver transaminases or HCV RNA were determined by nonparametric Spearman’s Rho pairwise correlation.



Our study cohort was mostly male (M/F=8/3) mean age 50.8 ± 4.1 yrs. Statin therapy was tolerated without a significant ALT flare (×3 baseline). Despite favorable reductions in LDL and cholesterol, no single patient achieved >1log HCV RNA decline during treatment, a trend towards inverse correlation between HDL and HCV RNA was apparent at baseline (Rho -0.516) and F/U (Rho -0.56; p=0.09), but not during study dosing. Inverse correlation between TG and ALT was observed at F/U (Rho -0.65, p=0.02), with similar trends at baseline (Rho -0.56), 20mg (Rho -0.53) and 40mg (Rho -0.51). At 20 mg there was a positive correlation between change (Δ) in TG and Δ HCV RNA (Rho 0.75, p=0.007), and a negative correlation between Δ ALT and Δ cholesterol (Rho -0.64, p=0.03) and ΔLDL (Rho -0.67, p=0.02). At 40 mg Δ TG maintained a positive correlation with Δ HCV RNA, Rho 0.65, p=0.03), but not for ALT and serum lipids. Similar correlates were not observed at F/U as serum lipids were close to reverting to baseline.



Short-term rosuvastatin therapy results an improved lipid profile that is not associated with significant changes in HCV RNA or serum ALT in CHC genotype-1 NR. This could relate in part to an inability to achieve adequate HMGR inhibition in vivo. Assessment of HCV RNA in specific lipid fractions is in progress. Associations between changes in TG, HDL and HCV RNA during statin therapy require further evaluation.







Log10 HCV RNA (copies/mL)

7.13 ± 0.61

7.07 ± 0.61

7.08 ± 0.57

168.91 ± 25.86

Total Cholesterol (mg/dL)

174 ± 26.63

121.54 ± 17.71

114.11 ± 20.64

168.91 ± 25.86



53.36 ± 12.23

48.73 ± 13.84

51.19 ± 12.08

52.54 ± 13.31



95.73 ± 26.26

54.23 ± 12.80

45.07 ± 17.05

92.91 ± 26.74

Triglycerides (mg/dL)

128.41 ± 64.1

107.00 ± 60.96

89.86 ± 41.38

118.91 ± 50.94



90.04 ± 53.69

87.50 ± 48.28

90.42 ± 54.11

81.82 ± 25.86



Topic:  Disease progression – metabolic disorders

513. Associate Factors Of Nonalcoholic Fatty Liver Disease : Results From A Population-Based Study.

A. Colecchia; A. Vestito; E. Paltrinieri; M. Bacchi-Reggiani; A. Di Biase; G. Mazzella; M. Montagnani; F. Lodato; A. Morselli-Labate; F. Pasqui; D. Festi



Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disease; however a few studies assessed its prevalence in general population and its association with abnormal liver enzymes is not still clear.



to evaluate the prevalence and associated factors of NAFLD in a general population and its relationship with abnormal liver enzymes.


Material and Methods:

We carried out a cross sectional study in a general population, aged 18-84 yrs, of a small town; 1534 out of 1646 ( 93%) subjects agreed to participate to the study. All subjects underwent abdominal ultrasound, physical examination, fasting blood specimen collection, seven day dietetic diary.



479 out of 1534 ( 31.2%) subjects were excluded (391 alcohol, 20 HBV, 63 HCV and 5 autoimmune); thus analyses were performed on 1055 subjects (68%). 382 out of 1055 subjects ( 36.1%)( males 57.8%, mean age: 52.1 ± 12.7) had NAFLD evaluated by US. 88 out of 1055 subjects ( 8.3%) had abnormal ALT ( 15.7% in NAFLD vs 4.2 % in normal subjects; p< 0.001); prevalence of NAFLD was higher in subjects with abnormal ALT than those with normal ALT [ 60 out of 88 (68.2%) vs 319 out of 967( 33%)( p< 0.001)]. Frequency of NAFLD was related to increased BMI,; however 80 out of 382 ( 20%) subjects had normal BMI. Associated factors were, at univariate analysis, male sex, aging , blood hypertension, diabetes, hypercholesterolemia, low HDL-cholesterol, Tg/Hdl ratio ≥ 3.5, hypertriglyceridemia, BMI, large waist circumference and abnormal ALT, AST and gGT; while, at multivariate analysis, they were sex male (OR:1.89), systolic hypertension (OR:1.9), hyperglicemia (OR:1.9), visceral obesity (OR:4.9), Tg/HDL ratio (OR:2.9), ALT (OR:2,5) and gGT (OR:1.8).



NAFLD is highly prevalent in general population; among the associated factors, obesity and Tg/HDL ratio (marker of insulin resistance) were the strongest ones. Furthermore, abnormal liver enzymes (namely ALT) are significantly associated with NAFLD; however, since they largely underestimate the disease prevalence, they cannot be used as markers of NAFLD.



Topic:  Epidemiology

M1001. Cost-Effectiveness of Testing for Hepatitis A Immunity Prior to Initiating Hepatitis A Vaccination in Patients with Chronic Hepatitis C. 

M. K. Chapko; H. S. Yee; A. Monto; J. A. Dominitz



Individuals with hepatitis C (HCV) are at risk for more fulminant courses of acute hepatitis A (HAV) should they acquire this infection. Thus, HAV vaccination is recommended for this population. The relative cost-effectiveness of universal vaccination versus first testing for prior immunity is unclear. Testing may reduce the proportion of patients acquiring immunity because some may not return for test results prior to immunization.



Decision analysis compared two strategies: (1) vaccinate all patients without testing for immunity and (2) test for hepatitis A antibodies followed by immunization in those who are susceptible. Parameters in the model included prevalence of prior HAV immunity and incidence of future HAV infection; vaccine effectiveness after each dose; proportion completing each dose; vaccine cost; HAV testing cost, plus cost and quality of life associated with future HAV.



Testing first costs less (mean cost per individual = $97.10) than vaccinating without testing for immunity ($119.37) when baseline values for parameters are used and when the prevalence of hepatitis A immunity is 30% prior to immunization. However, vaccinating without testing results in a larger proportion of individuals who achieve immunity (88.1% versus 76.5% when 30% are HAV antibody positive prior to immunization). The added cost of vaccinating without testing for immunity is $191.82 per additional individual protected from HAV. The incremental cost of vaccinating without testing for immunity is $91,319 and $182,453 per quality adjusted life year (QALY), when the prevalence of HAV immunity is 20% and 30%, respectively, prior to immunization. Sensitivity analyses indicate that the incremental cost per QALY of vaccinating without testing for immunity decreases dramatically as the future incidence of HAV increases. The incremental cost per QALY of vaccinating without testing for immunity increases dramatically as the prevalence of existing HAV immunity increases and as the severity of the patient’s cirrhosis increases.



HAV vaccination without testing for immunity is only cost-effective when the prevalence of HAV immunity in the group being vaccinated is 20% or less, when using a cost-effectiveness threshold of $100,000 per QALY.


Topic:  HIV/HCV Coinfection


M1002. Barriers to Vaccination against Hepatitis A among Patients Coinfected with HIV and Hepatitis C. 

S. Dhalla; C. T. Tenner; N. E. Shukla; A. Aytaman; G. Villanueva; G. Punla; C. Patterson; J. Comas; E. J. Bini



Hepatitis A virus (HAV) superinfection is associated with a high risk of mortality in patients with chronic liver disease. HAV vaccination is recommended for all patients with chronic hepatitis C virus (HCV) infection, as well as for those with HIV infection. Although patients with HIV-HCV have a dual indication for HAV vaccination, it is unknown how many of these individuals receive the vaccine in clinical practice. We hypothesized that HIV-HCV coinfected patients would be more likely to receive the HAV vaccine than those with HIV or HCV monoinfection.



Patients with known HIV and HCV status completed a detailed questionnaire at the time of their scheduled visit to the outpatient primary care or gastroenterology clinic at 3 study sites. Data collected included patient demographics, personal vaccination history, and barriers to vaccination.



Among the 2,038 patients, 715 were uninfected, 121 had HIV, 893 had HCV, and 309 had HIV-HCV. Overall, 360 of the 2,038 patients (17.7%) were told by their doctor that they had been exposed to HAV, including 4.2% of the uninfected patients, 15.7% of those with HIV, 23.2% of those with HCV, and 33.7% of the coinfected subjects (P <0.001). Among the 1,650 patients who were not previously exposed to HAV, only 412 (25.0%) reported that they received the vaccine, 900 (54.5%) were not vaccinated, and 338 (20.5%) did not know if they were vaccinated. The proportion of patients vaccinated against HAV differed significantly according to infection status (12.9% in uninfected vs. 28.0% in HIV vs. 37.3% in HCV vs. 22.8% in HIV-HCV patients; P <0.001). In the 900 subjects who were not vaccinated, there were significant differences in the types of barriers according to infectious status (see table).



1.     Although HIV-HCV coinfected patients were more likely to be vaccinated than uninfected patients, there were no more likely to receive the vaccine than those with either HIV or HCV monoinfection.

2.     There are marked differences in the types of barriers to HAV vaccination.

3.     Public health programs to increase awareness of HAV vaccination among uninfected, HIV-infected  and HIV/HCV coinfection.to overcome barriers to immunization are needed.








My doctor did not offer the vaccine to me






I am afraid of the vaccine






I am afraid of needles






I don’t like visiting the doctor






I don’t understand why I need the vaccine






I was feeling too sick






It takes me too long to get to my doctor






I did not know about a vaccine against HAV






I could not afford to pay for the vaccine







Topic:  Current therapies – general

M1005. Prevalence and clinical significance of hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy. 

H. Hofer; M. Schoeniger-Hekele; C. Mueller; C. Gurguta; P. Steindl-Munda; P. Ferenci


Background and Aim:

Hepatitis G virus (HGV) infection per se is not associated with liver disease. Coinfection with HGV in patients with chronic hepatitis C (CHC) may influence the clinical course and response rates of antiviral therapy with interferon/ribavirin. Aim of the study was to investigate prevalence of HGV coinfection and outcome of antiviral combination therapy in HGV/HCV coinfected patients.



Three hundred and four patients with chronic hepatitis C (m=93, age:42 [18-65] median were investigated.  These patients participants from previous randomized controlled trials.  HGV RNA detection was done by polymerase chain reaction prior to initiation of interferon/ribavirin combination therapy with standard (N=111) or peyglated interferon (N=193) and after six month follow up period.  A pre-treatment liver biopsy was done and stage of fibrosis was determined according to the metavir scoring system.



A HGV/HCV Co-infection could be identified in 37 (12.2%) out of 304 patients (available data).


The predominant HCV-genotype in HGV coinfected individuals was HCV-2a (51.4%) and the most common source of infection was intravenous drug abuse (N=21).  HGV coinfection was more common in patients with HCV-3 compared to HCV-1 or HCV-4 (19/52 (36.5%) vs. 14/187 (7.5%) vs. 4/61 (6.5%), p<0.01).


As compared to patients with HCV infection alone, patients with HGV/HCV confection were younger (35(18-56)) vs. 41 (19-65), years; median [range], p<0.01) and advanced fibrosis (F3-F4) was less frequent (21.6% vs. 33%, p<0.05. 


A sustained virological response (undetectable HCV-RNA) was achieved in 26/34 [76.5%) HCV-3a: 14/16 (87.5%); HCV-1: 9/14 (64.2%), HCV-4: 3/4 (75%) HGV/HCV co-infected patients as compared to 116/222 (52.3%) (HCV-3a: 22/26 (84.6%), HCV-1: 63/147 (42.8%), HCV-4: 31/47 (65.9%)) in monoinfected patients (p<0.01).


After antiviral treatment HGV RNA became undetectable in 23/32 (71.8%) patients.  In patients with still detectable HGV RNA (but a sustained virological response of HCV) (N=4), ALT levels remained within the normal range at the end of follow-up.



Intravenous drug abuse is a major risk factor for HGV coinfection in patients with chronic hepatitis C.  Coinfection with HGV does not aggravate clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy.  Due to the younger age, less fibrosis and the high frequency of HCV -3a HGV confected patients show a favourable response to antiviral combination therapy.  Interferon/ribavirin combination therapy also clears HCV infection in a high proportion of cases.


Topic:  Epi – Psychosocial

M1015. Rates and Predictors of Depression in an Out-patient Hepatology Practice 

G. S. Sayuk; S. El-Dirani; J. E. Elwing; P. Lustman; M. Lisker-Melman; J. S. Crippin; R. E. Clouse



Depression interferes with all aspects of daily living, adherence to medical recommendations, and treatment outcomes. Depression may be under-recognized in patients with chronic liver disease (CLD) because many of its symptoms overlap with symptoms attributable to liver dysfunction. The rate of depression symptoms across types of chronic liver disease is not known. We administered a commonly used depression assessment instrument, the Beck Depression Inventory (BDI), to out-patients attending a university-based practice to determine the rate of current depression symptoms and predictors of elevated scale scores.



345 pts with chronic liver disease [51.1 ±11.9 yr; 193 (55.9%) female; 104 (30.1%) cirrhotic] completed the 21-item Beck Depression Inventory during an office visit (max score 63).


Etiologies of liver disease were:

·        Hepatitis C (HCV) 115 (33.3%),

·        NASH/cryptogenic 78 (22.6%),

·        Primary sclerosing cholangitis (PSC) 18 (5.2%),

·        Primary biliary cirrhosis (PBC) 13 (3.8%),

·        Hepatitis B (HBV) 16 (4.6%),

·        Autoimmune hepatitis (AIH) 25 (7.2%) and,

·        Other chronic liver disease 52 (15.1%).


Prevalence rates of pts having total BDI ≥16, an accepted cut-off for suspecting major depressive disorder, and a score ≥10 on the cognitive symptom scale (cBDI, excludes overlapping somatic symptoms) were determined per chronic liver disease group.


Predictors of total Beck Depression Inventory score were determined from a linear regression model that included demographic (age, sex, BMI), clinical [type 2 diabetes (T2DM), prednisone use, interferon use, IV drug use (IVDU), current alcohol use], and liver disease variables (MELD score, encephalopathy, AST).



Beck Depression Inventory scores ≥16 were found in 37.4% of the total subject group, ranging from 25.0 – 42.6 % without significant difference across the represented disorders:

·        Hepatitis C - 42.6%,

·        NASH/cryptogenic - 34.6%,

·        Primary sclerosing cholangitis 38.9%,

·        Primary biliary cirrhosis 38.5%,

·        Hepatitis B (HBV) 25%,

·        Autoimmune hepatitis 40%  and,

·        Other chronic liver disease 29.6%
(χ2 = 3.96, p=0.78)

Beck Depression Inventory scores ≥10 were found in 24.6% of chronic liver CLD, ranging from 12.5 – 27.8% across disorders:

·        Hepatitis C – 27.8%,

·        NASH/cryptogenic – 26.9%,

·        Primary sclerosing cholangitis 27.8%,

·        Primary biliary cirrhosis 23/1%,

·        Hepatitis B 12.5%,

·        Autoimmune hepatitis 24.1%
(χ2=3.65, p=0.81).


In regression models of all CLD subjects, younger age, female sex, type 2 diabetes, and IVDU predicted higher total Beck Depression Inventory and higher cBDI scores (p<0.05 for each). Liver disease variables were not independent predictors of Beck Depression Inventory scores in either model.



·        High levels of current depression symptoms are present in a large proportion of out-patients with chronic liver disease.

·        This finding is not related solely to chronic liver disease symptoms that might mimic depression and is not conspicuously affected by type of chronic liver disease.

·        Depression symptoms are best predicted by clinical features associated with depression in non-chronic liver disease populations (female sex, type 2 diabetes, IVDU) rather than type of liver disease or measures of liver disease severity.


Topic:  Epi - General

M1024. Prevalence of Hepatitis C Among Arab & Chaldean Americans in Southeast Michigan. 

L. H. Jamil; M. C. Duffy; M. Fakhouri; E. Barkho; R. Khoury; H. Fakhouri; H. Jamil



The prevalence of Hepatitis C antibodies (anti-HCV) in the U.S. ranges is approximately 1.6%, with a higher prevalence among African Americans and Hispanics. Patients from Middle Eastern countries may have additional risk factors for Hepatitis C Virus (HCV) transmission, such as reusing needles for medical therapy, circumcision by informal health care providers, folk and traditional medical procedures, etc. There are no published studies on the prevalence of anti-HCV among the Arab/Chaldean (belonging to the Chaldean Catholic Church) American population in the U.S.



Retrospective review of data collected during an HCV public awareness and education program conducted by the Arab American and Chaldean Council (ACC), a non profit organization, in the Arab/Chaldean American population residing in Southeast Michigan. Inclusion criteria were anti-HCV positive subjects of Arabic/Chaldean descend, born in an Arab country but residing in Metropolitan Detroit who underwent HCV antibody testing (Home Access Hepatitis C Test). Subjects with an “Indeterminate result” were excluded from further analysis.



A total of 492 subjects’ data from 62 different zip codes in SE MI., were reviewed. Analysis was performed on 484 subjects. Excluded subjects were either born in the U.S (8), not of Arab/Chaldean descend (3), or tested indeterminate (2). Mean age was 43.2 years (range 18-77 years), males were 50.1%, and 30% did not speak English.  The mean number of years of residence in the U.S was 10.4 (range 0.5-52 years).


The overall prevalence of anti-HCV was 5.4% (20 subjects, 9 males, 11 females), with 30% (6 subjects) between ages 40-49. Prevalence among Chaldeans was 2.3%, and among Arab Americans 5.1%. Highest prevalence was among Jordanians 20% (2 out of 10), followed by Egyptians 7.6% (8 out of 105).


Five subjects (20%) reported having an episode of “hepatitis”, and 4 subjects (20%) reported jaundice. Risk factors included needle prick or shared needle (65%), shared personal hygiene (60%), tattoos and body piercing (40%), blood transfusion before 1992 (25%), medical therapy by non-sterile instruments (15%),



This is the first study to examine the prevalence of anti-HCV among the Arab and Chaldean Americans in the U.S.  These individuals have a much higher prevalence of HCV antibody (5.4%) than the general American population.  The 1990 U. S. census found 870,000 Americans who listed “Arab” as one of their top two ancestries.  This number is likely higher, given the overall growth of the U.S. and the fact that many may not list ancestries for various reasons.  It is estimated that there are 3 to 5 million Arab-Americans residing in the U.S.  today.  It is not known how many of those were born abroad or in the U.S.  Based on our prevalence of Anti-HCV of 5.4%, we estimate that between 156,000 to 260,00 Arab/ChaldeanAmericans are Anti HCV positive.  With an estimated persons ever being infected nationwide being 4,060,000, up to 6% or more of Anti-HCV positive in this relatively small ethnic community that has not been studies.  Today, Arab/Chaldean Americans, like many minority groups, are geographically concentrated.  Over 2/3 live in ten states: one-third in California, New York, and Michigan.  They are also more likely than other Americans to live in large metropolitan areas.  Thirty-six percent of Arab-Americans are found in ten cities --primarily Detroit, New York, or Los Angeles.  Minorities in general are less likely to receive preventive medicine and may therefore be less likely to be diagnosed with hepatitis C and receive treatment once identified.  In addition, primary care physicians may be less likely to test for HCV in these individuals because of a general lack of awareness of the increased prevalence of Anti-HCV in this population.  Further studies are needed to better address the communities the communities need s and further public health about HCV in needed in this population. 



·        Prevalence of Anti-HCV is 5.4% in the Arab/Chaldean American Community residing in SE Michigan, tripe the national average.

·        Among those testing positive, 46% were male, 615% were between 40-59 years of age, 69% had less than or equal to years of education, and 65% had to health insurance.

·        Risk factors:  IVDA 72%, 62% risky sexual behaviour, 52% shared personal hygiene products, 15% had received a blood transfusion prior to 1992, and 13% have received an injection by a non-sterile needle.


Topic:  Disease Progression - General

M1779. Hyperlipidemia is very infrequent but is undertreated in chronic HCV. 

C. A. Munroe; J. Chan ; H. Zheng; R. T. Chung



The prevalence of hyperlipidemia in the U.S. has been estimated at approximately 47% of the adult population. Current guidelines cite chronic liver disease as a contraindication to HMG CoA reductase inhibitor (“statin”) therapy. Recent studies have suggested that statins may be used safely in patients with chronic HCV. We sought to determine:

1.     The prevalence of hyperlipidemia in chronic HCV;

2.     The use and safety of statins in HCV; and

3.     The influence of concurrent statin use on SVR rates after treatment with PEG-IFN and ribavirin (RBV).



We retrospectively analyzed the records of patients with chronic HCV referred to our clinic between 2001 and 2006. Patients selected were either (1) currently on statins or (2) candidates for therapy by NCEP/ATPIII criteria but not on a statin. Of those receiving statins, discontinuation rates and serial LFT data were analyzed. Those hyperlipidemic patients who received at least 12 weeks of PEG-IFN and RBV therapy for HCV were also analyzed.



A total of 1,262 anti-HCV positive patients were seen between 2001 and 2006. Of these patients, 54 (4.3%) were on statins, and another 58 (4.6%) met criteria for initiation of statin therapy but were not started on treatment. In total, only 8.9% of patients with HCV were hyperlipidemic. In contrast, analysis of NHANES III showed that 47% of the US population was hyperlipidemic using similar criteria (p<0.001).


Statins used included atorvastatin (85%), simvastatin (11%) and pravastatin (4%). The mean ALT values before and during statin therapy was 42.6 +/- 26.8 U/L and 47.9 +/- 43.3 U/L, respectively (p=0.54).


The mean ALT of the patients in the non-statin group was 57.4 and 54.1 U/L. Only 2 (4%) patients had to discontinue statins because of adverse events, one of which was an LFT flare.


Seven patients already on statins (2 genotype 1, 5 genotype 2) were treated with pegIFN and RBV, and 5 (1 genotype 1, 4 gentoype 2) achieved SVR (71%). In contrast, 7 of 23 (30%) patients (17 genotype 1, 4 genotype 2, 1 genotype 4, 1 genotype not recorded (NR)) in the hyperlipidemic non-statin group experienced SVR (5 genotype 1, 1 genotype 2 and 1 genotype not recorded) (p=0.22).



1.     Hyperlipidemia warranting statin therapy was observed in only 9% of patients with HCV.

2.     Only half of hyperlipidemic patients in this cohort were treated for their dyslipidemia.

3.     Statins can safely be administered to patients with chronic HCV.

4.     Statins may enhance the antiviral effectiveness of PEG-IFN and RBV.

These findings suggest that hyperlipidemia in chronic HCV is very infrequent, but when present, is undertreated. Further study is warranted to determine whether statins augment the antiviral effect of pegIFN and RBV.


Topic:  Disease Progression - General

M1783. Statins Improve ALT values in Chronic Hepatitis C Patients with Abnormal Values. 

T. Bader; M. Madhoun; S. Rizvi; K. Seres; J. Fazili



There are no prospective reports of HCV pts taking statins. FDA inserts for statins list “active liver disease” as a contraindication, but the meaning of this is unclear. As part of an IRB and FDA approved 14 day study looking at the antiviral effect of fluvastatin (FLV) in vivo, we report the total bilirubin (TB) and ALT results and compare it to our retrospective hepatitis C registry data.



All 3 pts who started with abnormal ALTs made significant improvement (see table). 9 pts who started with normal ALTs stayed normal. There were no significant changes in TB (TB data not shown). These benign results occurred despite FLV doses that were up to 4X the highest FDA approved dose of 80 mg.


ALT improvement in those who started with abnormal values caused us to look at our HCV registry in a different way. Instead of noting changes in ALT between HCV pts who do or do not take a statin, we asked how many who had abnormal ALTs when they started the statin improved their subsequent value, and how many who were normal at initiation of a statin stayed normal.


13 of 60 pts started a statin with abnormal ALT values; of these 13, 12 improved their ALT and one pt stayed unchanged. Of the 47 beginning in the normal range, 45 stayed normal; the remaining 2 who developed a mildly abnormal ALT (<85 IU/ml) after beginning a statin had heavy alcohol use.



This is the first report of prospectively using a statin in HCV pts. 2 remarkable observations were that pts who start with abnormal ALTs improve their ALTs and those who start with normal ALTs stay within range. The look-back at our registry supports the prospective data findings. Retrospectively, others (Clin Gast Hepat 2006; 4:902-907; Hepatology 2006;(suppl 1)44:520A) [total of 340 HCV statin users in both studies] have also not noted any significant ALT changes among HCV pts who take statins versus those who do not. However, the latter studies did not report the distinctions we have made. The data reported here not only support the lack of harm in this situation, but also seem to suggest a possible salutary effect that needs further study.


ALT values (normal < 64 IU/ml)

FLV dose


Day 7
on drug

Day 14
on drug

Day 21
(off drug
(X 7d)



















drop out†

drop out†

*ALT values that are out-of-range before study. †pt had a flu-like reaction "possibly" related to drug for 5d; the 7d value was taken 2d after stopping FLV. Significant changes in ALT were defined as a 10% change from baseline and for total bilirubin it was +/- 1 mg/dl.


Topic:  Epi – General

M1786. Hepatitis C and Diabetes: An Update from the National Health and Nutrition Examination Survey. 

F. K. Friedenberg



Previous epidemiologic studies using the NHANES database have revealed a higher than expected prevalence of Diabetes in patients infected with HCV. It has been hypothesized that insulin resistance may be the etiologic link although a precise cause and effect relationship remains unclear.



This study's aim was to clarify the relationship between HCV and diabetes using the most recent iteration of the NHANES survey (2003-2004).



Demographic, physical examination, and laboratory data from the 2003-04 NHANES survey were combined into a single database using SPSS v.14.0. HCV status was determined using an ELISA, confirmed by RIBA.  Diabetes status was classified based on the subject's self-reported medical history. Cases coded as missing or indeterminate for either disorder were censored.



The final database included 7,283 persons; 87 (1.2%) had HCV and 486 (6.7%) were diagnosed with Diabets. Mean age was 35.7± 23.6 (29.4% age ≥ 50); 50.7% female, 42.5% Caucasian.


In univariate analysis, Diabetes and HCV status were closely linked (chi-sq = 7.2;p=0.007). In HCV positive patients 13.8% were diagnosed with Diabetes; in HCV negative patients the prevalence was 6.6%. Alternatively, 2.5% of patients with Diabetes were HCV positive, while only 1.1% diabetes negative patients were infected. However, there was no relationship between HCV status and levels of glycohemoglobin, C-peptide, insulin, and plasma glucose. Not surprisingly, Diabetes was strongly linked to family history of Diabetes, Body Mass Index, waist circumference, and age ≥ 50 (all p < 0.01). Diabetes status was not associated with race or gender. A logistic regression model (Diabetes status as dependent variable) demonstrated that age ≥ 50 (p<0.01), Family history of DM (p<0.01),and BMI (p<0.01), but not HCV status (p=0.17) were associated with Diabetes status. Waist circumference was not used in the model due to excessive co-linearity with Body Mass Index.



·        There appears to be a relationship between HCV status and prevalence of diabetes.

·        HCV status is not associated with markers of insulin resistance.

·        In regression analyses, after consideration of relevant confoundersm, HCV status is not associated with diabetes status.


Topic:  EPI - Veterans

M1787. The Validity of Viral Hepatitis and Chronic Liver Disease Diagnoses in VA Administrative Databases. 

J. R. Kramer; J. A. Davila; E. Miller; P. A. Richardson; T. P. Giordano; H. B. El-Serag



Veterans Affairs (VA) administrative databases can be useful tools for epidemiological and outcomes research by employing ICD-9 codes to identify individuals with specific clinical conditions. The validity of the codes for viral hepatitis and chronic liver disease is unknown.



We aimed to determine the positive predictive value (PPV), negative predictive value (NPV), % agreement and kappa for the ICD-9 codes for HCV, alcoholic liver disease (ALD), and cirrhosis.



We conducted a retrospective study comparing the VA administrative data to the gold standard chart-abstracted data in the Michael E. DeBakey VA Medical Center between 9/1998 and 7/2004. We identified 4537 patients in VA inpatient and outpatient databases with an ICD-9 code for HCV (070.41, 070.44, 070.51, 070.54 or V02.62) or ALD (571.0, 571.1 or 571.3).



We selected 300 patients from this group, oversampling for cirrhosis codes (571.2, 571.5 or 571.6). A trained clinician abstracted the medical record. The gold standard for HCV was defined as a positive HCV ELISA or PCR RNA test or presence of an HCV diagnosis in the progress notes of the medical chart. ALD was defined by a diagnosis of ALD in the progress notes. Cirrhosis was defined as either stage 4 on liver biopsy; any 2 of the following on imaging: cirrhosis, ascites, HCC, or portal hypertension; or the presence of at least 2 of the following conditions in the progress notes: cirrhosis, ascites or peritonitis, varices, HCC, hepatorenal syndrome, hepatic encephalopathy, or 2 of the following labs: albumin <3.0, total bilirubin >2.0, or INR >1.2. The PPV (probability that HCV in administrative data is present according to gold standard) for any HCV code was 92.8% and the NPV (probability that HCV absent in administrative data is absent according to gold standard) was 92.3%. This yielded 93% agreement and kappa=0.62. For ALD, the PPV and NPV was 65.4 and 92.3, with 90% agreement and kappa=0.57. Requiring at least 1 inpatient or 2 outpatient ALD codes improved the PPV to 81.3 with 91% agreement, while the NPV and kappa stayed the same. For cirrhosis, the PPV and NPV of the ICD-9 codes was 92.9 and 87.6 with 88% agreement and kappa=0.63. Among those with an ICD-9 code for HCV, the PPV and NPV for cirrhosis was 91.3 and 88.6, with 89% agreement and kappa=0.61; while among those with an ICD-9 code for ALD, the PPV and NPV was 96.9 and 77.3, with 84% agreement and kappa=0.69.



In conclusion, diagnostic codes for HCV, ALD and cirrhosis in VA data are highly predictive of the presence of these conditions in medical records, and therefore can be reliably used for research purposes. We offer algorithms to further improve the accuracy of these codes.


Topic:  Disease Progression

M1788. Liver disease in hepatitis C virus carriers found at the occasion of blood donation and outcomes with or without interferon treatment: A study on 1019 carriers followed for 5-10 years. 

J. Tanaka; K. Katayama; M. Mizui; H. Yoshizawa



Liver disease was diagnosed in 1019 individuals for whom ongoing infection with hepatitis C virus (HCV) was identified on blood donation, and they were followed for 5-10 years with or without interferon treatment.



At the baseline, chronic hepatitis was detected in 529 (51.9%) carriers at a frequency higher in men than women (62.6% [229/478] vs. 42.5% [230/541], p < 0.01); cirrhosis was diagnosed in 5 (0.5) and hepatocellular carcinoma (HCC) in 1 (0.1%) (Table.1). Of the carriers who were followed for 5 years or longer, the loss of HCV RNA from serum was achieved in 61 (31.0%) of the 197 with interferon (IFN) treatment and only 1 of the 211 (0.5%) without it (p < 0.0001). HCC developed in 8 (4.1%) with IFN, of whom 7 did not respond to it, and 6 (2.8%) without IFN (Table 2). Follow-ups of the 949 carriers identified older age (p < 0.002), male gender (p < 0.01) and cirrhosis (p < 0.0001) as factors accelerating the development of HCC. Relative risk for HCC, estimated by the Cox proportional hazard model, was 1471 fold for the initial diagnosis with cirrhosis, 188 fold for the age >60 years and 2.08 fold for the male gender(Table 3).



Based on the results obtained, identification of HCV carriers among the general population, followed by treatment with IFN on those indicated, would help decrease the development of HCC and lessen medical as well as economical burdens associated with it.


Topic:  HIV/HCV Coinfection

M1789. Prevalence and Impact of Alcohol Use Among Patients with HIV-HCV Coinfection: A Prospective National Multicenter Study. 

E. J. Bini; S. Currie; B. S. Anand; H. Shen; N. Brau; W. N. Schmidt; R. Cheung; T. R. Morgan; K. Chang; M. C. Pedrosa; A. Aytaman; T. L. Wright; V.



Alcohol use among patients with HIV is not only associated with decreased antiretroviral therapy (ART) adherence and decreased HIV suppression, but also increased risk of ART-induced hepatotoxicity and high-risk sexual behavior. Although patients with HIV-HCV coinfection are at increased risk of developing ART-associated hepatotoxicity as compared to those with HIV, little is known about alcohol use and its effects in coinfected subjects. The aims of this study were to determine the prevalence of alcohol use among patients with HIV-HCV vs. HCV monoinfection, and to evaluate the impact of alcohol use on the prevalence of advanced liver disease, elevations in ALT levels, and HCV treatment candidacy in coinfected subjects.



Data on alcohol use were prospectively collected from 280 HIV-HCV coinfected and 2,958 HCV monoinfected patients seen at 24 medical centers throughout the U.S. Alcohol use was categorized as follows: non-drinkers vs ever drinkers, maximum number of drinks consumed on a regular basis (<6 vs. ≥6 drinks/day), CAGE score <2 vs. ≥2, and recent alcohol use (past 12 months). Advanced liver disease was defined as a history of ascites, encephalopathy, or variceal bleeding. Treatment candidacy was assessed using 2 methods: standardized published criteria and the opinion of the treating clinician.



There were no significant differences in age or sex between the 2 groups, although coinfected patients were more likely to be non-white (75.9% vs. 42.1%, P <0.001). Coinfected patients were less likely to consume ≥6 drinks/day on a regular basis (52.3% vs. 62.6%, P = 0.002) and were less likely to have a CAGE score ≥2 (49.6% vs. 62.3%, P <0.001). However, the proportion who were ever drinkers (78.9% vs. 83.0%, P = 0.10) and recent alcohol use (35.4% vs. 36.7%, P = 0.66) was similar in coinfected and HCV monoinfected patients. Among the 280 coinfected patients, recent alcohol use was associated with total bilirubin levels ≥2.0 mg/dl (9.2% vs. 2.8%, P = 0.02) and evidence of advanced liver disease (7.3% vs. 1.1%, P = 0.006), but not with elevated ALT levels (72.9% vs. 76.8%, P = 0.47). Coinfected patients who reported recent alcohol use were less likely than non-drinkers to be a HCV treatment candidate using published criteria (16.2% vs. 29.8%, P = 0.01) and clinician opinion (23.7% vs. 40.1%, P = 0.006).



·        Recent alcohol use is common among coinfected patients, and is associated with advanced liver disease and a lower likelihood of being a HCV treatment candidate.

·        Screening for alcohol use and abuse should be routine part of clinical care for HIV/HCV coinfected patients.

·        HIV-HCV coinfected patients should receive counseling about the hazards of ongoing alcohol consumption.


Topic:  Epi

M1790. Molecular Epidemiology Of Hepatitis C Virus In Myanmar (Formerly Burma) With Identification Of New Genotype 6 Subtype. 

A. Lwin; T. Shinji; M. Khin; N. Win; M. Obika; S. Okada; N. Koide



This study aimed to describe the prevalence and distribution of Hepatitis C virus (HCV) genotypes in Myanmar (formerly known as Burma or the Union of Burma). A total of 154 anti-HCV antibody-positive serum samples were collected from four different border cities of Myanmar.



The overall prevalence of HCV infection in general was 11.6% (154/1333) and regionally, it was 13.5% (47/349), 12.8% (64/501), 4.2% (16/380) and 26.2% (27/103) in northeastern, northwestern, southern and western city, respectively.


HCV was genotyped in 145/154 (94.2%) samples by reverse transcriptase polymerase chain reaction, direct DNA sequencing and phylogenetic analysis on the partial core genome. Genotype 6 was the most prevalent genotype in this study [71/145 (49%)], followed by genotype 3 [57/145 (39.3%)], genotype 1 [16/145 (11%)], and genotype 2 [1/145 (0.7%)]. We successfully characterized multiple HCV genotypes/subtypes as 1a, 1b, 2a, 3a, 3b, 6m, 6n, and a new 6 subtype. Among them, subtype 6n was the most predominant subtype (38.6%), followed by subtype 3b (29.7%), 3a (9.6%), 6m (9%), 1b (6.9%), 1a (4.1%), new 6 subtype (1.4%) and 2a (0.7%). Subtype 6n was more widely distributed in the northern cities whereas subtype 3b in the western city.



This study revealed the regional differences of HCV genotype distribution in Myanmar and the distinct geographic variation with other Southeast Asian countries in terms of the existence of the new subtype of genotype 6.

Topic:  HIV/HCV Coinfection

M1791. The Prevalence and Risk Factors for Abnormal Liver Enzymes in HIV Positive Patients without Hepatitis B or C Coinfections. 

R. K. Sterling; S. Chui; K. Snider; P. G. Smith; D. Nixon



Abnormal liver enzymes (LFTs) are frequently seen in those with HIV. Because HCV and HBV overshadow other possible variables, little is known about the prevalence and predictive factors of abnormal LFTs in the absence of viral hepatitis.



We performed a retrospective analysis of HIV clinic patients to determine the prevalence and factors associated with abnormal LFTs, defined as > 1.25 ULN. Multiple logistic regression was used to identify independent predictors of elevated LFTs. Variables were determined at the onset of abnormal LFTs or by history and included diabetes mellitus (DM), hypertension (HTN), dyslipidemia, HCV and HBV status, HAART use (NRTI, NNRTI, and PI) and metabolic syndrome (MS), defined as 2 or more of the following features: DM, HTN, dyslipidemia, or BMI > 30.



Of over 1600 patients, charts on 1208 adults were available for review. The mean age was 42, 64% were male, 25% were Caucasian, 24% had HCV and 7% HBV, mean BMI 26.5, 22% had BMI > 30, DM in 7.6%, HTN in 27%, dyslipidemia in 25%, MS in 22%, 41% had HIV RNA < 400 copies/ml, mean CD4 was 445, and 24% had CD4 < 200. Those without HCV or HBV (n=679) were younger (40 vs. 46 yrs), Caucasian (26 vs. 13%) had a BMI > 30 (25 vs. 17%) and had dyslipidemia (28 vs. 18%) compared to those with coinfection (n=294). The prevalence of elevated LFTs in those without HCV or HBV were AST 20%, ALT 15%, and ALP 43% compared to 64%, 46%, and 63% in those with HCV or HBV (all p<.0001). The majority of elevated LFTs (98%) were mild-moderate (grade 1-2; 1.25-5 x ULN) and AST was highly correlated with ALT (r=.80; p<.0001); however, neither were associated with increased ALP. Of those without HCV or HBV, increased AST was associated with HTN (p=.014), lower HIV RNA (p=.0012), and absence of PI use (p<.0001); increased ALT was associated with HTN (p=.01), HIV RNA (p=.02), CD4 < 200 (p=.005), MS (p=.04), and absence of PI use (p=.0038); increased ALP was associated with age (p=.007), BMI (p=.02), CD4% (p=.0002), DM (p=.037), and NRTI use (p=.006).



These data are the first attempt to quantify the prevalence and factors associated with elevated LFTs in HIV patients without HCV or HBV coinfection. We observed that mild-moderate increased liver enzymes are common in those infected with HIV and, in the absence of HCV or HBV coinfections, increases in ALP were the most common abnormality seen in 43%. Absence of PI use was independently associated with elevations in both AST and ALT while features typical of hepatic steatosis (DM and BMI) were only associated with increased ALP. The clinical significance of these findings needs further study and histologic assessment.


Topic:  Disease Progression - Race

M1792. Clinical cirrhosis in chronic hepatitis c (CHC) varies by race-ethnicity. 

S. Iwata; M. Kohla; R. Taylor; R. Ea; S. Keyhan; M. Bonacini



Liver fibrosis progression in HCV, based on a single liver biopsy, appears to be in part determined by race-ethnicity. Cirrhosis was found to be more common in Asian patients in the U.K (Clin Gastroenterol Hepatol 2005;3:910-17).


Little is known of the frequency of clinical cirrhosis in Asian patients in the U.S.



To compare histological and clinical features of CHC in a multiethnic cohort of liver patients.



Retrospective query of an electronic medical record for CHC patients evaluated from 1999-2005. We excluded patients who had HIV, HBV, had died or received a liver transplant. Histologic cirrhosis was defined as either advanced fibrosis (Metavir) at biopsy. Clinical cirrhosis was defined as any of: varices, ascites or splenomegaly. Liver Cirrhosis (LC) was defined as histological or clinical cirrhosis. Chi-square, t-tests were performed with Statview.



714 patients were categorized into 5 groups: 21 American-Indian (AmInd), 288 Caucasian), 150 Hispanic (H), 122 African-American (AA), 133 Asian (As) patients, and). Median age of AA (54 years) and As (53) was higher than C (52), H (50) or AmInd (49) (p<0.05). Forty-one to 56% were male (NS). BMI was significantly lower in Asians. AmInd (62%) and H (37%) had a higher percentage of alcohol abuse than AA and C (32%) and As (8%) (p<0.0001). There was no statistical difference in HCV RNA levels, but favorable genotypes were less common in As and AA (table). LC was found in 25% of the cohort: 5% histologic, 14% clinical cirrhosis, and 6% both. Histologically, H had higher hepatic fibrosis score vs. As and C. H and C patients had the same likelihood of having LC, higher than AA or As (table).



In our cohort, severity of CHC is affected by race. Using only histology, cirrhosis is significantly underestimated. Asians in the U.S. have a lower chance of cirrhosis than Caucasians or Hispanics. Using clinical criteria for defining cirrhosis differences between C and H patients were not evident.



21 Am Ind

288 C

150 H

122 AA

133 As

Fibrosis mean



2.6±1.3 #




2 (10%)

36 (13%) ##

29 (19%) *

9 (7%)

8 (6%)

Clinical/histo cirrhosis (LC)

5 (26%)

90 (31%)*

47 (31%) *

17 (14%)

22 (17%)

HCC (%)

1 (5%)

3 (1%)

4 (3%)

5 (4%)

9 (6%)


# ANOVA; p=0.02 vs. As, p=0.002 vs. C ## p<0.05 vs. AA, As * p<0.01 vs. AA and As

Topic:  Epi


M1793. High Prevalence of Hepatitis C in Recently Released Prisoners and Missed Opportunities for Treatment and Care. 

S. Currie; D. P. Tracy; R. K. Fox; K. Page-Shafer



HCV prevalence in incarcerated populations is 30 – 50%, over 20 times higher than the general population. Upon release from correctional facilities, prisoners return to the community through parole programs, after a median duration of 23 months of incarceration. These parolees often face barriers to accessing health care due to a lack of health insurance and lack of access to overloaded public programs. Veteran parolees with health benefits do not have this difficulty. Little is known about the prevalence and management of HCV among parolees in the VA.



To determine HCV prevalence among veterans recently paroled from prison and, in those who are HCV positive, examine the number who had received HCV management and care, including HCV antiviral treatment and immunizations.



A convenience sample of 73 veterans who had been released from prison in the past 6 months participated in the study through self, correctional, community or medical referral. Data were collected at baseline for socioeconomic, behavioral and incarceration histories. Serum was also collected and tested for HCV antibody, RNA and HCV genotype (GT). Clinical data were abstracted from patient medical records; those with a positive anti-HCV and detectable HCV RNA were classified as having chronic HCV.



Of the 73 parolees, 37(50.7%) were Black, 26(35.6%) were Caucasian, 10 (13.7%) other. This group was poor (83% had an annual income less than $10,000), had low levels of education (47.9% had ≤12 years education); 76.7% reported a history of injection drug use (IDU), and 56% reported a history of mental health problems. Anti-HCV prevalence was 79%; 51(89.5%) of those had chronic HCV, the majority with Genotype 1 (82.4%). The majority of parolees had accessed a number of health services at the VA Medical Center: 67% had received medical care since their release either through regular and urgent care (56.9%) or urgent care alone (9.8%) and 71% had accessed a drug and alcohol program, 37.3% had obtained prescriptions, however, only 11(21.6%) of the 51 had reported that they had accessed HCV care and 29.4% had not yet been vaccinated for HBV.



·        HCV prevalence is extremely hight among veteran parolees.

·        Most veterans know their HCV positive status.

·        Although the majority of veterans were accessing the VHA for regular, urgent, alcohol and drug and prescription  health care services, very few had accessed services specifically for HCV.

·        More integrated HCV care should be considered with primary and other health services to reduce the number of missed opportunities in this highly prevalent population.


Topic:  Experimental therapies – General

M1794. PF-03491390, a pancaspase inhibitor, reduces aminotransferases levels and is well tolerated in patients with chronic hepatitis C (HCV). 

J. G. McHutchison; M. L. Shiffman; E. Schiff; P. Pockros; J. Spandon; G. Burgess



In patients with chronic HCV, elevated serum levels of AST and ALT, and increased rates of hepatocyte apoptosis and activated caspases, reflect hepatocellular damage. The pancaspase inhibitor, PF-03491390, reduced elevated AST and ALT levels in patients with chronic HCV infection, during a 12-week double-blind treatment phase of a multicenter, parallel-group, dose-ranging study.1



A total of 39 patients with documented chronic HCV and liver fibrosis, randomised to placebo for 12 weeks in the double-blind treatment phase of a previously reported study, received open-label PF-03491390.

Patient characteristics:

·        25 males; 14 females

·        Caucasians-28; Black-6, Hispanic-4, Asian-1

·        Age (years) – 51 (37-69)

·        Body mass index—29 (20-41)


35 of 39 patients completed the study; two patients were lost to follow-up; two patients prematurely discontinued from the study for other reasons (one relocated, one study side error).


Subjects received  oral PF-03491390 5 mg twice daily for the first week of active treatment, commencing at Week 13. If their aminotransferase levels remained above the normal range, the dose of PF-03491390 was incrementally escalated: 10 mg (Weeks 15–17); 25 mg (Weeks 18–20); 50 mg (Weeks 21–22), and 100 mg (Weeks 23–25), all administered twice daily. Serum aminotransferase levels and adverse events were monitored from Week 13 to Week 29.



Median AST and ALT levels decreased within one week of initiating PF-03491390 treatment and these reductions were maintained throughout the 12-week treatment period. (Table 1). Increasing the dose of PF-03491390 did not appear to intensify these effects. Dose escalation occurred in all patients, with 0, 3, 5, 8 and 21 patients, respectively, taking 5, 10, 25, 50 and 100 mg twice daily doses at Week 25. AST and ALT levels rapidly returned to near-baseline values when PF-03491390 was discontinued. The majority of adverse events were of mild or moderate severity and there were no discontinuations or dose reductions due to adverse events.



A total of 17 (44%) of patients reported a total of 34 adverse events during the study.  The majority of adverse events were of mild to moderate severity.  Only four adverse events were reported by more than one patients:  fatigue, arthralgia, headache and rash.  Neither of the adverse events were rated as severe were related to the study drug.



·        PF-03491390 effectively reduces AST and ALT levels in patients with chronic HCV infection; these effects occur early and are maintained for  12 weeks on treatment.

·        Results confirm those previously reported for the double-blind phase of the study.

·        PF-03491390 is generally well tolerated by patients with chronic HCV infection.

·        Initial observations suggest that doses of PF-03491390 in the range of 5-10 mg twice daily may be sufficient;  pharmacokinetic/ pharmcodynamic modeling for PF-03491390 is currently in progress.

·        Further studies are required to determine whether longer duration of treatment with PF-03491390 has continued effects on liver enzymes, which may influence liver histology in patients with chronic HCV infection and liver fibrosis.


Reference 1. Shiffman ML, et al. Hepatology 2006;44(suppl A):224A, Abst 95.


Topic:  Experimental therapies:  Valopicitabine

M1796. Final Results from a Phase IIA Pharmacokinetic Study of Valopicitabine (NM283) and Peg-IFNα-2b in Patients with Genotype 1 Chronic Hepatitis C. 

M. Rodriguez-Torres; N. H. Afdhal; E. J. Lawitz; E. Godofsky; B. Belanger; B. Fielman Constance; S. Knox; J. Leone; N. A. Brown



This Phase IIa study was designed to assess the potential for a pharmacokinetic (PK) drug interaction between NM283 and pegylated interferon alfa-2b (peg-IFNα-2b) in treatment naïve patients with HCV-1 infection. The safety, tolerability and comparative antiviral activity of NM283 alone and in combination with peg-IFNα-2b was also to be assessed, prior to longer-term studies.



Key eligibility criteria: HCV RNA >5 log10 IU/mL, ALT <5x ULN, compensated liver disease, and no previous antiviral therapy for hepatitis C. Thirty patients (pts) were to be randomized 2:3 to receive 800 mg NM283 (n=12) or 800 mg NM283/peg-IFNα-2b (n=18). NM283 was to be dosed orally once-daily for 28 days in both groups. Pts randomized to NM283/peg-IFNα combination treatment were to receive weekly doses of peg-IFNα-2b (1.0 μg/kg) starting on Day 8. Through serial amendments treatment up to 72 weeks was permitted according to virologic response and tolerance of study treatment. Serum HCV RNA levels were assessed at each visit by the TaqMan™ PCR assay (>10 IU/mL).



31 pts were enrolled and randomized to NM283 (n=12) or NM283/peg-IFNα-2b (n=19).  Two patients assigned to NM283/peg-IFNα-2b withdrew prior to the first dose of peg-IFN. Patients were predominantly male, with a mean age 45 yrs and mean baseline HCV RNA = 6.1 log10 IU/mL. Overall, 71% of pts were of Latino or African American descent who have historically have shown lower response rates than predominantly Caucasian populations. Study treatment was satisfactorily tolerated, with no serious adverse events or dose limiting toxicities.The most common adverse events were nausea, headache, vomiting, and occasional diarrhea. Nausea, vomiting, and diarrhea were more common with the combination regimen compared to NM283 alone, but were rarely treatment-limiting.


The PK results indicated that measures of NM283 systemic exposure (Cmax, 24-hr AUC) were unaltered by co-administration of peg-IFNα-2b. No pts receiving NM283 monotherapy met efficacy criteria to continue treatment beyond Week 24. Of the 17 pts who received NM283/peg-IFNα-2b, 9 completed at least 48 weeks of treatment, 8 of whom achieved PCR-nondetectable HCV RNA by week 48 (EOT). Final data will be presented at the meeting, including post-treatment SVR data.



With no PK interaction between NM283 and peg-IFNα, and no notable increase in treatment-limiting side effects, these Phase IIa results support the use of NM283 with peg-IFNα in longer-term treatment trials. Treatment with NM283 plus pegIFNα-2b, in the absence of ribavirin use, demonstrated a satisfactory safety and tolerability profile and consistent antiviral activity in this pilot study.


Topic:  Epi


M1797. Insulin Resistance In Viral Hepatitis B And C And Non Virus Related Chronic Hepatitis. 

F. Lodato; M. Montagnani; F. Azzaroli; M. Tame; A. Colecchia; P. Cecinato; R. Muratori; D. Festi; G. Mazzella



Insulin resistance (IR) is the background of many cryptogenetic liver diseases. In genotype 1 and 2 HCV chronic hepatitis (CH-C) the virus seems to induce insulin resistance (IR). In HBV chronic hepatitis (CH-B) the virus role in steatosis and IR is to be clarified. Aim of our study is to evaluate IR and the relationship with disease severity, in patients with CH-C, CH-B or with non-virus related hypertransaminasemia (NV-H).



Twenty-eight outpatients with NV-H and 50 outpatients in follow-up for Chronic hepatitis B (n=23) or Chronic hepatitis C (n=27) were consecutively enrolled between January and May 2006. Patients with alcohol consumption >10 gr/day were excluded. Abdominal circumference (AC), Body Mass Index (BMI), fasting blood glucose (FBG) insulinemia, OGTT, HOMA-r and liver ultrasonography were evaluated. ANOVA, Mann-Whitney test and chi square were used for statistical analysis. Data are expressed as mean ±SE.



Groups were comparable for age, BMI, AC and FBG; males were prevalent in Chonic hepatitis B (M:F 21:2 vs Chonric hepatitis C:17:10 and NV-H:12:16, p=0.001). Steatosis was present in 75, 52 and 82% respectively for NV-H, Chronic hepatitis B and Chronic hepatitis C (p=ns). Cirrhosis was present in 18% in NV-H, 48% in Chronic hepatitis B and 52% in Chronic hepatitis C (p=0.02). Insulin was higher in Chronic hepatitis C than NV-H (16.3±1.6 vs 10.8±1.2, p=0.016), and in cirrhosis vs non-cirrhosis [17.4±2.7, 16,4±1.2 and 18.7±2.7 ng/ml vs 9.4±1.1 (p<0.013), 10.3±1.3 (p<0.003) and 13.6±1.6 (ns) respectively for NV-H, Chronic hepatitis B & Chronic hepatitis C]. HOMA-r was 2.5±0.33, 2.9±0.32 and 4.2±0.41 respectively for NV-H, Chronic hepatitis B and Chronic hepatitis C (p=0.01). Cirrhosis had higher HOMA-r respect to non-cirrhosis in all groups [4.5±0.8, 3.9±0.47, and 4.9±0.7 2.1±0.3 (p<0.012), 1.95±0.21 (p<0.003) and 3.2±0.42 (p<0.05)]. Treatment with nucleos(t)ide analogues was related to significant reduction in HOMA-r in Chronic hepatitis B (2.5±0.4 vs 3.6±0.5, p=0.05).


At multivariate analysis HOMA-r was associated with age, Body Mass Index, AC and steatosis and independently related to AC in NV-H, to cirrhosis and antiviral treatment in CH-B, to AC and cirrhosis in CH-C.



Insulin resistance is associated with cirrhosis regardless of underlying disease when evaluated by HOMA-r. In CH-B, inhibition of viral replication by necleos(t)ide analogues seems to protect from IR, possibly through:


·        Reduction in liver inflammation secondary to inhibition of viral replication.


Topic:  Experimental therapies – Omega Interferon

M1798. Phase 2 Study of Omega Interferon Alone or in Combination with Ribavirin in Interferon-naïve Subjects with Genotype-1 Chronic Hepatitis C

V. Novozhenov; N. Zakharova; E. Vinogradova; I. Nikitin; V. Gorbakov; A. Yakovlev; S. Pak; V. Rafalski; P. Bogomolov; T. Alessi; D. Blanchett; J. McNally; B. R. Bacon



Omega interferon is a naturally occurring human type 1 interferon that is 60% homologous with alpha interferon and 30% homologous with beta interferon. Omega interferon monotherapy has demonstrated an antiviral effect in hepatitis C genotypes 1, 2 and 3 in prior clinical studies in the United States and Europe. This ongoing phase 2 study is designed to evaluate the safety, tolerability and antiviral effects of omega interferon administered alone compared with omega interferon in combination with ribavirin among treatment-naïve subjects with chronic Hepatitis C genotype-1.



102 subjects have been randomized; 35 to receive 25μg omega interferon s.c. (injected) daily and 67 to receive 25μg omega interferon s.c. daily in combination with ribavirin 1000-1200mg/day. All subjects are genotype-1, and 75% of subjects exhibited baseline HCV RNA levels >800,000 IU/mL (mean: 3,417,685 IU/mL; median: 2,086,000 IU/mL+). The maximum treatment duration is 48 weeks followed by 24 weeks post-treatment evaluation. In order to continue therapy after Week 12, subjects must demonstrate an early viral response, defined as a > 2 log reduction in HCV RNA level (lower limit of quantitation = 600 IU/ml) after 12 weeks of therapy.



Early virological response was observed in 21/35 (60.0%) subjects treated with omega interferon alone and 56/67 (83.6%) subjects treated with omega interferon plus ribavirin. 2/35 (6%) subjects treated with omega interferon alone and 24/67 (36%) subjects treated with omega interferon plus ribavirin had undetectable levels of HCV RNA at week 72 weeks (SVR – 24 weeks post treatment), (limit of detection = 50 IU/ml).


Overall, treatment was well tolerated. The most frequently reported adverse events (> 10% of subjects) were: influenza like illness, neutropenia, asthenia, pyrexia, leukopenia, fatigue, anemia, ALT increases, headache, hyperthermia, and serum bilirubin increases. Four serious adverse events (SAE) were reported. The most common causes for dose reduction were anemia and neutropenia. Study discontinuation due to adverse events occurred in two subjects, one with hyperbilirubinemia and one with allergic dermatitis.



·        Omega interferon and ribaviirn resulted in EVR and SVR rates similar to those reported with the combination of alpha interferon and ribavirin in interferon-naïve HCV genotype-1 patients.

·        EVR and SVR rates achieved with omega interferon plus ribavirin were superior to those achieved with omega interferon alone.

·        Omega interferon given alone or in combination with ribavirin was well tolerated with few patients requiring dose reductions or treatment discontinuation.

·        25 µg/day is an appropriate starting dose to evaluated continuous delivery Omega DUROS therapy in combination with ribavirin in future studies.


Topic:  Current HCV Treatment - General

M1800. Diabetes Mellitus is a Predictor of Treatment Failure in hepatitis C Patients Treated with Peg IFN and RBV 

H. M. Elgouhari; I. Hanouneh; C. O. Zein; A. E. Feldstein; N. N. Zein



Insulin resistance is a major feature of type II Diabetes mellitus (DM) and has recently been linked to treatment failure in HCV. However, there is paucity of data on treatment outcome in diabetic HCV patients.



1.     To determine the rate of SVR in HCV patients with Diabetes compared to those without DM;

2.     To assess the safety of combining insulin sensitizing agents (ISA) with Peg IFN/RBV in HCV patients.



Case-controlled retrospective assessment of prospectively collected data. All HCV plus diabetes patients (n=61) that were treated with standard doses of Peg IFN/RBV between 2002 and 2004 were identified.


A 1:1 control group of non-diabetes HCV patients (n=61) matched for genotype and ethnicity treated during the same time period at the same institution was identified. Descriptive statistics were performed to characterize both groups. Univariate analysis was performed to compare variables of interest. Logistic regression was performed to identify independent factors associated with treatment failure. Safety measures included the occurrence of any serious adverse events (SAE), early withdrawals or ALT flares during therapy.



Patients with Diabetes had higher Body Mass Index (BMI) than non-diabetes (32.4 + 6.0 vs 28.5 + 6.6, p=0.0009) and were more likely to have advanced fibrosis (56% vs 28%, p=0.003). SVR was observed in 14/61 (23%) of HCV plus diabetes patients compared to 31/61 (51%) of non-diabetes patients (p=0.001). By univariate analysis, Diabetes (p=0.001), genotype 1 (p=0.005), and African American ethnicity (p=0.03) were associated with lack of SVR. Multivariate logistic regression identified Diabetes [OR=3.9, 95% CI 1.7-9.3; p=0.001] and genotype 1 [OR=3.7, 95% CI 1.2-12.3; p=0.02] as independent predictors of treatment failure in patients with HCV. This association remained significant after adjusting for other relevant variables including presence of advanced fibrosis and ethnicity. Among patients with Diabetes, SVR was higher in patients who were on therapy with ISA (29%) compared to those who were not on ISA (20%). However, this difference in SVR did not reach statistical significance. The rates of serious adverse events, early discontinuation and ALT flares were similar between HCV plus diabetes patients receiving ISA (21 patients) and HCV plus diabetes not receiving ISA (40 patients).



1.     Diabetes is a predictor of treatment failure in HCV patients treated with Peg IFN/RBV.

2.     Based on this limited assessment, ISA appear to be safe when combined with Peg IFN/RBV in diabetic HCV patients and may be associated with higher SVR.

3.     Type II diabetes is associated with more advanced fibrosis stage in HCV patients compared to those without hepatitis C.


Topic:  Experimental therapies – R1626

M1801. Viral load and ALT reductions associated with R1626 monotherapy, a novel nucleoside analog, in chronic hepatitis C genotype 1 patients. 

S. Roberts; G. Cooksley; G. Dore; R. Robson; D. Shaw; H. Berns; M. Brandl; S. Fettner; G. Hill; D. Ipe; K. Klumpp; M. Mannino; E. O'Mara; I. Najera; Y. Tu; C. Washington


Background and Aims:

HCV polymerase is an essential enzyme for HCV replication. Inhibitors of the HCV polymerase enzyme are a promising class of compounds under development for the treatment of chronic HCV infection. R1626 is a pro-drug of the nucleoside analog R1479, developed to significantly increase bioavailability and HCV inhibition. We carried out a multiple ascending dose study to evaluate the safety and tolerability, pharmacokinetics and antiviral activity of R1479 in treatment-naïve patients chronically infected with HCV genotype 1.



A total of 47 patients were randomized to receive one of four dose levels of R1626 monotherapy or matching placebo for 14 days. Assessments included safety, pharmacokinetics, antiviral activity and resistance development. Regression analysis was conducted to evaluate the relationship between R1479 plasma concentration, ALT and viral load decreases.



The mean HCV RNA concentrations at baseline were ≥ 6.3 log10 IU/mL in all four treatment groups. Mean (median) HCV RNA reductions of 0.3 (0.2), 1.2 (0.8), 2.6 (2.7) and 3.7 (4.1) log10 were observed at doses of 500, 1500, 3000 and 4500 mg, bid, respectively. Sixteen of the 35 patients who received R1626 had HCV RNA reductions >2 log10 by Day 14. Regression analysis demonstrated a good correlation between R1479 Cmax, AUC and Cmin and viral load reduction. The mean Cmin values for the 1500, 3000 and 4500 mg bid dose groups were equal to or exceeded the IC90 as determined in the Replicon system. Individual patient response patterns at these doses showed consistent and time-dependent decrease in viral load. Although 6/9 patients in the 500 mg bid group showed no decrease or rebound in viral load due to sub-optimal drug exposure during treatment, none of these patients showed viral resistance. In addition, time- and treatment-dependent decreases in ALT levels were also observed, with 5/8 and 7/9 patients achieving normalized ALT levels in the 3000 and 4500 mg bid cohorts, respectively.



·        R1626 demonstrated linear pharmacokinetics up to 4500 mg bid

·        Tehre was a robust antiviral effect with mean viral load reductions of 1.2-27 log following 1500, 3000, and 4500 mg bid, respectively following 14 days of monotherapy.

·        Viral rebound during treatment was observed in three patients, all of whom received the lowest dose of 500 mg.  No viral resistance ws observed in these patients.

·        Tolerability was good following twice daily doses for 14 days up to 3000 mg bid.

·        Reversible mild to moderate haematological changes were treatment-and time-related.



Treatment with R1626, a novel and potent nucleoside analog targeting HCV polymerase, was well tolerated up to 3000 mg bid and significantly reduced HCV RNA in patients chronically infected with genotype 1 when used as monotherapy.  Does-, time-, and exposure-related decreases in viral load were observed following multiple doses of R1626, with decline observed as early as 4 hours following the first dose.  The maximum decrease in HCV RNA levels was noted on Day 14, the last day of dosing.  Importantly, no viral resistance was observed in those patients with no decrease or rebound of viral load during treatment.  A Phase 2 study of R1626 in combination with peginterferon alfa-2a with or without ribavirin in underway.


Topic:  Current HCV Treatment - General

M1802. Post-treatment intrahepatic gene expression profiles associated with long-term virologic responses following peginterferon and ribavirin treatment for HCV genotype 1. 

S. Wang; C. Huang; N. Ravendhran; W. M. Cassidy; H. Chen; C. D. Howell



A sustained virologic response (SVR) following HCV therapy results in durable improvements in liver histology and a decrease in hepatic decompensation and primary liver cancer. Whether treatment confers long-term benefit in the absence of a SVR is controversial.



To address this question, we compared gene expression in liver biopsies obtained at week (wk) 72 from 5 SVR (wk 48 & 72 serum HCV RNA negative (-), 4 HCV relapsers (REL) (HCV RNA- at wk 48 & positive (+) at wk 72), and 7 virologic nonresponders (NR) (HCV RNA+ at wk 24 & 48) after 48 wks of initial peginterferon alfa-2a (PEG-IFN) and ribavirin therapy. Control liver biopsies were from 12 untreated HCV genotype 1 patients. Liver cRNA was hybridized to the Affymetrix HG-U133 plus 2 gene chip (Affymetrix, Santa Clara, CA). Genes with a > 2-fold change in expression between groups were selected by Significance Analysis of Microarrays software and false discovery rate of < 0.05. Gene annotations and functional classifications were determined using DAVID 2006.



Compared to untreated HCV controls, 457 intrahepatic genes were down-regulated in SVR patients at wk 72. Of genes with known functions, immune response (66;14.2 %), response to virus (15; 3.2%), response to pest, pathogen or parasite (34; 7.3%), and protein localization and transport (34; 7.3%) were the most significant functional classes (p < 0.0001 for each category). Seventy-seven intrahepatic genes were down-regulated and 17 genes were up-regulated in REL patients. These genes were associated with biopolymer metabolism [21 (22.6%); p<0.005], response to virus [4 (4.3%); p<0.004), and protein/macromolecule metabolism [20 (21.5%); p = 0.07]. The 177 genes down-regulated in NR relative to controls were associated with alcohol metabolism [14 (4.7%); p < 0.001], protein localization and transport [18 (6.1%); p = 0.003), organic acid metabolism [16 (5.4%); p 0.004), and secretion [10 (3.4%); p = 0.007). Only 21 differentially expressed genes were shared between SVR and REL groups, and 13 genes between SVR and NR groups. In both instances, the mean fold change in gene expression was 1.5-2.0 times greater in the SVRs. Forty-five (10%) genes down-regulated in SVR relative to controls were associated with liver fibrosis, compared to 2 (2.1%) and 1 (< 1.0%) genes down-regulated in the REL and NR groups.



SVR patients exhibit more marked down-regulation of a greater number of intrahepatic genes families than NR and REL including genes associated with liver fibrosis. NR and REL patients show modest changes in a restricted set of gene families with no apparent relationship to liver fibrosis.


Topic:  Experimental therapies – Interferon-Beta

M1803. Feasibility of induction by twice-daily administration of interferon-beta prior to the standard combination therapy using pegylated interferon-alpha-2b plus ribavirin. 

T. Nakatani ; Y. Akashi; H. Matsuo; S. Takeyama; M. Uejima; Y. Yamane; K. Hashimoto; E. Kikuchi



It has been reported that longer treatment with combination therapy using pegylated interferon (IFN)-alpha-2b plus ribavirin (RIB) for patients infected with hepatitis C virus (HCV) leads to more effective viral eradication. However, in Japan where treatment period is limited, the achievement of early viral clearance should be necessary. We already confirmed the effectiveness of high dose IFN-alpha-2b induction in combination with RIB when the treatment period was limited to 24 weeks. In this study, it is evaluated whether IFN-beta induction is also effective in the 48-week combination therapy using pegylated IFN-alpha-2b plus RIB.



Forty patients chronically infected with genotype 1b HCV were divided into 2 groups. Thirty-two patients underwent standard 48-week combination therapy using 1.5 μ/kg of pegylated IFN-alpha-2b plus RIB (600-800 mg/day depending on body weight) (group 1). Eight patients received 3MU IFN-beta twice-daily for 2 weeks followed by the standard combination therapy described above (group 2). HCV quantity as well as its reduction profile such as HCV negativity and rate of 2-log decrease was assessed at the certain time point. Serum HCV-RNA was quantified using the Amplicor HCV monitor assay (SRL, Tokyo, Japan). Early virological response (EVR) defined as HCV-RNA negative at weeks 12 in the 48-week therapeutic period tends to be referred to as one of the predictable landmarks for the subsequent sustained virological response (SVR). We evaluated the effectiveness of IFN induction by assessing EVR.



HCV quantity of each patient was more than 100 KIU/ml, meaning the high baseline viral load. Gender, age, HCV viral load, platelet and ALT at baseline did not differ significantly between 2 groups. Serum HCV-RNA (KIU/ml) at baseline, weeks 2, 4, 8, 12 and 24 was 2419±1605/2406±1253, 222±210/36±103 (P<0.05), 165±209/6±18 (P<0.05), 103±183/4±7 (P<0.05), 75±155/3±8 (P<0.05) and 90±191/0±0 (P<0.05) in group1 and group2, respectively. HCV negativity at weeks 2, 4, 8, 12, 24 and 48 was 0%/0%, 0%/38%, 10%/56%, 29%/81%, 57%/100% and 79%/100% in group1 and group2, respectively. EVR in group2 was over 2.5 times higher than that in group1. The reduction rate of HCV-RNA by at least 2 logs at weeks 2, 4, 8, 12 and 24 was 25%/75%, 40%/100%, 63%/100%, 64%/100% and 83%/100% in group1 and group2, respectively. No more significant adverse effects were observed in group2 compared with group1 during the treatment period.



When the length of combination therapy using pegylated IFN-alpha-2b plus RIB is limited to 48 weeks, IFN-beta induction may be feasible in achieving SVR throughout early viral clearance.


Topic:  Experimental therapies – Valopicitabine

M1804. Valopicitabine (NM283) plus peg-interferon alfa-2a (peg-IFN) in treatment-naïve patients with HCV-1 infection: preliminary results at weeks 24 and 48. 

N. Gitlin; E. J. Lawitz; T. Nguyen; Z. Younes; J. Santoro; D. McEniry; R. Chasen; J. Goff; D. Dieterich; S. Knox; K. Kleber; J. Leone; B. Belanger; N. A. Brown; G. and the 006 Investigator



Current therapy (pegIFN/RBV) results in suboptimal virologic response rates particularly in patients with genotype 1 (HCV-1) infection. The antiviral activity profile of valopicitabine in combination with peg-IFN in treatment naïve patients with HCV-1 infection is being evaluated in this ongoing Phase IIb study.



Key eligibility criteria: no prior treatment, compensated disease, HCV RNA ≥5 log10 IU/mL, ALT <5 xULN. Patients were randomly assigned to one of five treatment groups:


PegIFN alone to W4, with valopicitabine 800mg/day added in W5; (B) valopicitabine 200mg/day + pegIFN; (C) valopicitabine ramped 400 to 800mg/day in 1st week + pegIFN; (D) valopicitabine 800 mg/day + pegIFN; and (E) valopicitabine 800 mg/day + pegIFN. PegIFN-α2a is dosed 180 μg QW starting Day 8 (Groups A-D) or Day 1 (Group E). Due to higher GI side effects with the 800mg/day valopicitabine dose, a protocol amendment was implemented to reduce the valopicitabine dose in Groups A, C, D and E to 200 or 400 mg/day. Most patients had received at least 12 weeks of treatment at the time of the dose reduction.



Up to W4 the rate of viral decline was valopicitabine dose-related. By W12, 85% of patients in Group B and 88% in Groups C-E achieved >2 log drop in HCV RNA. HCV RNA was below 600 IU/mL (Amplicor quantification limit) in most patients by W12. Results at W24 and W36 indicate continued antiviral efficacy in all arms, with HCV RNA non-detectable by TaqMan™ in most patients (Table). In Group B (valopicitabine 200mg/day + pegIFN), partial data through the end of treatment (W48) indicate maintained suppression of HCV RNA with good tolerance of study medication. Complete W48 data (end of treatment) will be presented.



Valopicitabine 200mg/day, plus pegIFN results in HCV RNA levels below the Amplicor PCR quantification limit in most pts by W12 and to date shows durable suppression of viremia with satisfactory tolerance in treatment-naïve HCV-1 patients.



Mean ↓ from Baseline
(log10 IU/mL)

Amplicor™ negative
< 600 IU/mL (%)

TaqMan™ negative
< 20 IU/mL (%)

Treatment Group


Week 24

Week 36

Week 24

Week 36

Week 24

Week 36










































Topic:  Experimental therapies - Taribavirin

M1805. Pre-Dosing Taribavirin Prior to Combination Therapy With Pegylated Interferon Alfa-2b Versus Standard Combination Dosing: 24-Week Interim Results Examining Safety and Viral Kinetics. 

M. Palmer; R. A. Rubin; V. K. Rustgi; D. Li; B. Murphy



Data from a phase 3 study revealed that dosing taribavirin (TBV), a pro-drug of ribavirin, with pegylated-interferon resulted in significantly lower rates of anemia compared to ribavirin and pegylated-interferon but did not meet the non-inferiority standard for efficacy. An examination of viral decay kinetics revealed the sharpest decline during TBV therapy occurred at weeks 4 through 6, when TBV had reached steady-state. This proof-of-concept study examined whether first-order viral kinetics could be influenced by pre-dosing TBV to steady-state prior to the introduction of pegylated interferon.



This US-based, multi-center, open-label, proof-of-concept study enrolled 23 patients in the TBV pre-dosing arm and 19 patients in the TBV standard dosing arm. Patients were randomized to receive TBV 600mg BID either as monotherapy for 4 weeks followed by combination therapy with pegylated interferon alfa-2b (pre-dose arm) or administered concurrently with pegylated interferon alfa-2b (standard dosing arm). All patients in the study were therapy-naïve, genotype 1, high viral load, with a mean weight of 77 kg in both arms. Log-transformed HCV-RNA change from baseline and the incidence of anemia (hemoglobin <10 g/dL) were assessed.



See table. Anemia was seen in 0% of the pre-dosed patients versus 5.3% in the standard dosing arm.



Patients receiving 4 weeks of TBV monotherapy prior to starting pegylated interferon had a steeper decline in HCV-RNA with no difference in the rate of anemia. The variance in the viral decline may be a function of both the impact of having TBV at steady state when pegylated interferon is introduced into therapy and/or increased conversion of TBV to ribavirin due to longer exposure. Based on this data, a larger study examining pre-dosing of both TBV and ribavirin is warranted to assess the impact of TBV steady-state on phase 1 viral decline.


Mean log-transformed HCV-RNA change from baseline


TBV pre-dosed (n=23)

TBV standard dosing (n=19)

CT-day 1



CT-day 2



CT-week 1



CT-week 4



CT-week 8



CT-week 12



CT-week 24




Topic:  Durrent HCV Therapies – Side Effects

M1806. Do growth factors improve EVR in chronic HCV-genotype 1 patients treated with Peg-Intron and Ribavirin? 

M. Kugelmas; O. Ryan; G. A. Spiegelman; M. Mah'Moud



Hematologic toxicity is one of the most common reasons for dose reduction or discontinuation when treating chronic hepatitis C. In turn, these dose reductions negatively affect the chance of achieving early virologic response (EVR) during therapy of patients with genotype 1 chronic hepatitis C (HCV-1).


Aims and Methods:

We are comparing standard of therapy (ST) with pegylated interferon alfa 2b (P-IFN) plus weight-based ribavirin (RBV) in patients with HCV-1 to an adjuvant therapy (AT) regimen where anemia is pre-emptively treated with darbepoetin alfa (3 mcg/kg SQ Q2W starting with hemoglobin <12 g/dL or <75% of baseline), neutropenia is pre-emptively treated with filgrastim (300 mcg SQ QW for ANC <900 mm3), and more lenient cut-off levels for thrombocytopenia are allowed in order to try to prevent dose reductions due to hematologic toxicity. The study is powered to show a 22% difference in SVR in favor of the adjuvant therapy arm.



To date 106 patients with HCV-1 have received at least 12 weeks of therapy, 54 in the ST arm and 52 in the AT arm. In the ST arm, 63% are male, 60% are heavier than 75 kg, 20% have advanced fibrosis (stage 3 or 4), 75% have high baseline viral load (> 600,000 IU) and 8 are AA. In the AT arm, 68% are male, 76% are heavier than 75 kg, 23% have advanced fibrosis, 69% have high baseline viral load and 10 are AA. In the ST arm, thirty-six of fifty-four patients achieved EVR, 9 with undetectable viremia. In the AT arm, thirty-seven of fifty-two patients achieved EVR, 15 with undetectable viremia. Twenty-six patients in the AT arm (50%) received growth factors (20 darbepoetin, 6 filgrastim). Fourteen patients in the ST arm had dose reductions, half reduced each drug. The hemoglobin nadir was noted around week 14-15 of therapy in both arms.



We have previously shown (DDW ’06) that the use of growth factors prevents dose reductions of P-IFN and RBV in patients receiving anti HCV-1 therapy and maintains more physiologic hemoglobin levels. This update shows non-statistically significant differences in EVR, but a mathematical edge in favor of the adjuvant therapy group, both for total patients achieving EVR (72.6% vs. 66.7%, AT vs. ST, respectively) and those who do so with undetectable viremia (40% vs. 25%, AT vs. ST, respectively). Ongoing results of the study will show whether use of growth factors will allow for higher sustained viral response (SVR). Study drugs and support were provided by Amgen Inc. (Darbepoetin and Filgrastim) and Schering Plough (Peg-Intron and Rebetol).


Topic:  Current HCV Therapies - General

M1808. Metabolic Syndrome Is A Strong Predictor Of Treatment Failure In Patients With Chronic Hepatitis C 

I. Hanouneh; A. E. Feldstein; R. Lopez; K. B. Cesario; A. A. Pillai; C. O. Zein; N. N. Zein



The metabolic syndrome (MS) is a unique pathophysiologic condition whose underlying mechanism is related to insulin resistance. In HCV patients undergoing therapy with Peg IFN/RBV, insulin resistance has been linked to treatment failure.



Our Aims were to estimate the prevalence of metabolic syndrome in HCV patients undergoing anti-viral therapy and to assess its predictive value in treatment outcome.



All HCV patients that were treated with Peg IFN/RBV between 2002 and 2004 and had clinical data to assess for MS were identified (n=251). MS was defined using the ATP III criteria. Descriptive statistics were computed for all factors. Univariate analysis was performed to compare variables of interest. A logistic regression analysis was performed to study multivariable associations. The final model contained gender, ethnicity, genotype, metabolic syndrome, fibrosis, and steatosis stage.



Metabolic syndrome was present in 71/252 (28%) patients. Metabolic syndrome was less common in Caucasian patients compared to non-Caucasian patients [49/193 (25%) vs 22/58 (38%), p=0.063].


Overall SVR was achieved in 121/252 (48%) patients. Genotype 1 (p<0.001), non-Caucasian ethnicity (p<0.001), male gender (p=0.04), higher fibrosis stage (p=0.03), higher BMI (p=0.013), and MS (p<0.001) were significantly associated with lack of SVR.


Adjusting for ethnicity, genotype, gender, fibrosis, and steatosis stage, subjects with Metabolic syndrome are more likely to fail treatment than those without Metabolic syndrome.



·        Metabolic syndrome is frequently seen in patients with hepatitis C and associated with steatosis and advanced fibrosis.

·        Consistent with previous studies, genotype 1 non-Caucasian ethnicity and advanced fibrosis are independent, predictors of poor response to pegylated interferon and ribavirin therapy.

·        Metablic syndrome appears to be an independent strong predictor of failure to achieve SVR.

·        If confirmed, metabolic syndrome could be easily incorporated into clinical practice to identify HCV patients who are less likely to benefit from antiviral therapy.


Topic:  Disease Progression - General

M1810. Serum Leptin Concentrations In Chronic Viral Hepatitis: A Clinical Approach. 

S. Manolakopoulos; S. Bethanis; C. Liapi; P. Sklavos; F. Stripeli; A. Margeli; A. Christidou; A. Katsanika; E. Vogiatzakis; D. Tzourmakliotis; S. Theocharis



The role of serum leptin and the relationship between leptin and insulin resistance in patients with chronic viral hepatitis (CVH) remain obscure. Our aim was to investigate the relationship between serum leptin concentrations and the severity of liver disease in a cohort of subjects with HbeAg-negative chronic hepatitis B (CHB) and hepatitis C(CHC)



We studied 50 (36 men) consecutive patients suffering from biopsy-proven chronic hepatitis C due to HBV(n=25) or HCV(n=25)infection. Thirty-two (17 men) healthy volunteers served as controls. Levels of serum leptin and insulin were determined at baseline and at the end of the treatment.



Patients with severe fibrosis (stages 4-6)presented higher serum leptin levels compared to those with lower fibrosis stage(7276 pg/ml vs 4395 pg/ml,p=0.01). In patients with chronic hepatitis B those with a virologic response to lamivudine monotherapy presented lower serum leptin levels (5334 vs 13111.5 pg/ml,p-value=0.003) than non-responders. In genotype 1 chronic hepatitis C patients, insulin resistance was associated with lower response rate to antiviral therapy(Graph 1).



Increased leptin concentrations are associated with more severe disease state in patients with chronic hepatitis C and represent a negative prognostic factor for response to lamivudine monotherapy in chronic heptitis B. In chronic hepatitis C insulin resistance influences negatively the response to antiviral treatment in patients infected with genotype 1.


Topic:  Experimental therapies - Taribavirin


M1811. Pharmacokinetic/Pharmacodynamic (PKPD) Modeling of Hemoglobin (Hgb) in a Phase 3 Study With Taribavirin and Ribavirin in Therapy-Naïve HCV Patients. 

R. Braeckman; D. Fisher; N. Holford; P. Pockros; B. Murphy



Patients receiving a fixed dose of taribavirin (TBV, 600 mg BID), an oral pro-drug of ribavirin (RBV), in two Phase 3 studies experienced lower rates of anemia compared to standard dose ribavirin (1-1.2 g/day), although SVR rate was lower with taribavirin.



To develop a PKPD model to describe the dose-exposure-effect relationship between taribavirin/ribavirin and Hgb to predict optimized taribavirin regimens and identify predictors of anemia.



A compartmental PK model and a mechanistic Hgb turnover PD model were constructed and fitted to observations from 752 (taribavirin, n=494; ribavirin, 258)  patients in the VISER1 study. The anemia model (Hgb) involves homeostasis and turnover of red blood cells (RBC). Circulating ribavirin increases Hgb elimination due to RBC hemolysis. A feedback mechanism driven by decreasing Hgb levels stimulates Hgb production. The model accounts for the relationship between doses of  taribavirin and ribavirin, their respective ribavirin concentrations and the decrease of the Hgb levels versus time. The data were fitted according to this model using the NONMEM® software (Globomax, Hanover, MD, USA). Logistic regression analyses of SVR and anemia rates versus ribavirin plasma AUCs were also performed.



The apparent elimination clearance (CL/F) of ribavirin was 2.3-fold larger following administration of taribavirin compared to ribavirin; therefore, ribavirin concentrations were 2.3-fold lower with taribavirin (~15 mg/kg). Both body weight and creatinine clearance influenced ribavirin exposure with taribavirin.


The anemia model satisfactorily fitted the Hgb data, yielding model parameter estimates. This relationship between circulating ribavirin and Hgb was the same in both taribavirin and ribavirin dosing groups. The ribavirin  concentration that yielded half-maximal effect of ribavirin on Hgb turnover (EC50) varied minimally with gender: 7.2-7.6 mcg/mL (males and females, respectively). The maximal hemolytic effect (Emax) was influenced by gender, HCV genotype, patient age and weight.


Pharmacometric modeling based on logistic regression of VISER1 patients with HCV genotypes non-2/3 indicates that an ribavirin target exposure of 50 mcg×hr/mL (24-hour AUC) would lead to a SVR of 59% and anemia rate of 12%. Analysis of actual response rates by taribavirin dose/kg in VISER1 showed an SVR rate of 52% and anemia rate of 6.5% in patients (n=138) receiving >18 mg/kg TBV.



1.     Higher taribavirin doses are predicted to increase ribavirin exposure and, in turn, SVR rate.

2.     Taribavirin 32 mg/kg predicts the same ribvavirin exposure as with standard ribavirin.  

3.     Taribavirin doses in the range of 20-28 mg/kg may achieve SVR comparable to rivavirin but less anemia compared to standard doses of ribavirin, 


Topic:  Experimental therapies - General

M1812. In Vivo Efficacy of a Fully Human Monoclonal anti-E2 Immunoglobulin in Passive Immunoprophylaxis of HCV Infection. 

A. Krishnan; K. Viker; B. Knudsen; P. Parren; F. Beurskens; M. R. Charlton



HCV infection is the most common indication for liver transplantation in Western Europe and North America. In contrast to HBV infection, pooled immunoglobulin-based immunoprophylaxis has not been effective in preventing posttransplant HCV infection to date. This may, in part, be due to the relatively low concentrations of HCV-specific antibodies present in pooled immunoglobulin preparations, a barrier that might be overcome by production of human monoclonal antibodies (hmAb) ex vivo.


Specific aim:

To determine whether a fully human, high concentration mAb to the E2 epitope of HCV that recognizes noncovalently linked E1E2 complexes and which has demonstrated neutralizing of binding activity in vitro (Virology 249, 32–41 (1998)) can prevent HCV infection in vivo.



Human hepatocytes, freshly harvested from resected liver wedges were transplanted into mice transgenic for five amino acid deletion isoform of human hepatocyte growth factor backcrossed with a SCID strain. Animals received retrorsine (to provide a replicative advantage to transplanted human hepatocytes) and multiple doses of CCL4 (to cause necrosis of murine hepatocytes). Engraftment of human hepatocytes was determined by semi-quantitative analysis of human albumin production by Western blotting. Following maximal engraftment, mice were randomly assigned to receive either E2-hmAb (Genmab, Utrecht, Netherlands)(100mg/kg)(n=6) or placebo (n=6) followed by inoculation with high HCV RNA titer human serum pooled from chronically infected patients with HCV genotypes 1a and 1b. Analysis of post-inoculation HCV RNA was carried out in a blinded fashion on post-inoculation days 1, 8, 15, 22 and 29 using a highly sensitive real-time nucleic acid amplification assay (Cobas Taqman, Roche Molecular Systems Inc., Branchburg, N.J).



One of six mice (17%) in the E2-hmAb group had HCV RNA detectable postinoculation (day 8 only, 4.3 log10 IU/ml). Five of six mice (83%) receiving placebo developed sustained levels of HCV RNA (days 8-29, range 3.5-5.7 log10 IU/ml).



These data indicate that a fully human E2-mAb can provide passive immunity against HCV infection of human hepatocytes in vivo. Further studies are needed to determine the minimally effective concentration (EC50) of the studied mAb prior to consideration of clinical studies.


Topic:  Current HCV Therapies – Side Effects

M1813. Genome-wide analysis for genes that mediate IFN-induced depression in HCV patients. 

M. Trippler; Y. Erim; S. Bein; G. Gerken; J. F. Schlaak


Aims and background:

Combination therapy with pegylated interferon (IFN)-alpha and ribavirin for chronic hepatitis C can induce depressive side effects in up to one third of patients. Therefore, this study assessed the primary transcriptional in vivo response to IFN-alpha in HCV patients to identify possible mechanisms that mediate IFN-induced depression.


Patients and methods:

A total of 50 Caucasian patients with histologically proven chronic hepatitis C were treated with standard combination therapy consisting of pegylated IFN-α2a (Pegasys, 180µg once weekly) with ribavirin (800-1200 mg daily) for 6 or 12 months. RNA was isolated (PAXgene, PreAnalytiX) from peripheral blood which was collected 12h before and 12h after the first injection of IFN-α. The transcriptional profile was analysed using human genomic microarrays (Affymetrix HG U133A) and quantitative real-time RT-PCR. Array data were normalized (RMA Express software) and fold change values were subjected to significance analysis (SAM software) and class prediction analysis (PAM software) to identify genes which are differentially regulated in patients with or without IFN-induced depression.



14/50 patients (28%) developed clinically relevant IFN-induced depression. Using class prediction analysis, the development of depression could be predicted by 24 genes with 95% accuracy. 10 of these genes were significantly higher expressed in patients with IFN-induced depression compared to patients without depression. Interestingly, 4 of these genes were previously described as being associated with recurrent major depression, whereas the remaining genes were identified as known classical ISGs. This data was verified by quantitative RT-PCR. Basal gene expression before IFN injection was not significantly different in both groups of patients. Expression of these genes is currently being assessed in patients hospitalised for severe major depression and normal healthy controls.



These data suggest a direct role of IFN response genes in generating depression as side effect of antiviral therapy. Finally, the functional analysis of the differentially regulated genes that were identified in this study could lead to the discovery of novel therapeutic approaches to improve the efficacy of and adherence to HCV therapy and, possibly, major depression.


Topic:  Experimental therapies - general

M1815. Rectal administration of low dose interferon alpha for patients with chronic hepatitis C led to elevation of platelet count and serum albumin level as well as suppression of viral replication. 

Y. Haruna; A. Inoue



It was suggested that rectally administered interferon (IFN) is transferred into the lymphatic system via rectal mucous membrane in animal study. We reported that administration of low dose IFN suppository could suppress hepatitis C virus (HCV) replication in patients with chronic hepatitis C. In this study, we focused on examining the long-term biological effects after the therapy.



Fourteen patients with chronic hepatitis C participated in the study. The IFN suppository, which was made in the Department of Pharmacy of Osaka Prefectural Medical Center, contained 1000 units of lymphoblastoid IFN alpha. The patients had administration of one IFN suppository daily for 24 weeks. Serum HCV viral loads, liver function and blood cell count were tested every 4 weeks during the treatment and until 72 weeks after the end of the treatment. The CD4/CD8 ratio and 2’-5’ oligoadenylate synthetase (2-5 AS) activity in peripheral blood were examined before and at week 8.



In 13 out of the 14 patients, viral load was decreased at week 4. The ratio of the viral load compared with before the treatment (mean ± S.E.) was 0.555 ± 0.102 (rang: 0.004 to 1.430) at week 4. The suppression of viral replication was sustained during the treatment (p<0.0001), whereas the viral load increased after the end of treatment. The 2-5 AS activity and CD4/CD8 ratio were significantly changed during the treatment. The 2-5 AS activity (pmol/dl, mean ± S.E.) was 87.9 ± 12.7 before and 120.8 ± 18.2 at week 8 (p=0.0076). The CD4/CD8 ratio (mean ± S.E.) was 2.67 ± 0.34 before and 2.06 ± 0.25 at week 8 (p=0.013). Platelet count (104/mm3) was increasing during the treatment, and the increased count was sustained until 72 weeks after the end of treatment (mean ± S.E., 16.1 ± 1.1 before and 18.8 ± 1.4 at 4 weeks after the end of treatment). Serum albumin (g/dl) also showed increase both during and after the treatment (4.10 ± 0.07 before and 4.27±0.09 at 4 weeks after the end of treatment). Statistical analysis using one way repeated measure ANOVA confirmed significant sustained increase of both platelet count and albumin level during and after the end of treatment (p=0.0057 and p=0.0217, respectively). No side effect was seen during and after the treatment.



·        The low dose IFN suppository treatment suppressed HCV replication with elevated 2-5 AS activity and decreased CD4/CD8 ratio. Also, both platelet count and serum albumin level were increased after the end of treatment as well as during it.

·        The low dose IFN suppository treatment could be indicated to patients with thrombocytopenia or poor hepatic functional reserve (e.g. cirrhotic patients).


Topic:  Experimental therapies – ITMN-191

M1816. Characterization of HCV NS3/4A Protease Inhibition by ITMN-191 Reveals Picomolar Potency and Slow Dissociation: Implications for the Use of ITMN-191 in Chronic HCV Treatment 

P. Rajagopalan; S. Misialek; L. M. Blatt; S. D. Seiwert; K. Kossen



Combination therapy for chronic hepatitis C with pegylated interferon alfa and ribavirin (SoC) results in a Sustained Virologic Response (SVR) rate of approximately 50%. Direct antiviral agents may improve the rate of SVR when used in combination with SoC or in novel regimens. ITMN-191 is a potent HCV NS3/4A protease inhibitor in clinical development. The current study examines ITMN-191 potency and binding kinetics in biochemical assays.



The activity of NS3/4A protease was observed using a continuous fluorescence resonance energy transfer (FRET)-based peptide cleavage assay under conditions that maximize sensitivity and protease stability. Dissociation of ITMN-191 was assessed by monitoring recovery of protease activity following rapid dilution of pre-formed NS3/4A-ITMN-191 complex.




·        ITMN-191 is an extremely potent inhibitor of HCV NS3/4A protease with a true biochemical potency of 36 pM against genotype 1b.

·        Binding follows a two step mechanism where initial complex formation is followed by isomerization to a more stable complex. 

·        Dissociation of ITMN-191 FROM ns3/4a is a very slow process with a t1/2 of 5 hours.

·        The slow dissociation of ITMN-191 from NS3/4A is evidenced by persistent inhibition in both biochemical assays and HCV replicon reduction in cell based assays.

·        These studies may have clinical significance as bulk drug levels following Cmax may under represent potential virologic responses. 


Topic:  Disease Progression – Metabolic disorders

M1819. The association of selected adipokines with hepatic steatosis in patients with chronic hepatitis C infection. 

S. Galhenage; K. Patel; H. M. Patton; T. Walker; W. Symonds; M. F. Abdelmalek; J. G. McHutchison



It is unclear whether the ability of adipokines to modify host lipid metabolism is associated with steatogenesis in patients with chronic hepatitis C (CHC) infection. We thus evaluated the relationship between adipokine levels and steatosis in patients with CHC infection.



Liver biopsies and matched serum samples from 241 untreated CHC patients were selected from Duke serum and tissue repository. Biopsies were blindly evaluated for degree of steatosis by 2 pathologists with high concordance (Kappa 0.84,p<0.005). Steatosis was recorded as % affected hepatocytes and graded: 0(0-2%),1(3-29%),2(30-59%)and 3(≥60%). HCV genotype, serum HCV RNA and body mass index(BMI) were measured. Serum leptin, adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and tumor necrosis factor (TNF-α) were measured using conventional assays. Comparisons between adipokines and steatosis % were made by pairwise correlation and multivariable stepwise linear regression weighted for BMI.



Patients were mostly males (174/241, 72%), mean age 44.2 ± 7.4 yrs, genotype-1 infection (149/241, 46.9%), with steatosis present in 113 (46.9%). No significant differences were noted in BMI between genotype 1(Genotype 1) and genotype non-1(G non-1) patients (27.8 vs.27.7 kg/m2).


Mean steatosis was significantly lower in Genotype 1 compared with Genotype  non-1 (8.46% vs. 15.47%, p=0.006). No correlation of steatosis was observed with log HCV RNA (p=0.62). For all patients, linear regression for steatosis percentage indicated weak positive correlation with IL-6 (R2=0.16, p=0.04) and PAI-1 (R2=0.033, p=0.003) and negative correlation with adiponectin (R2 =0.015, p=0.04).


Analysis of variance indicated differences in mean adiponectin (p=0.01) and PAI-1(p=0.04) by fat grade. Stepwise linear regression modeling for steatosis % weighted for BMI indicated independent negative correlation for adiponectin, and positive correlation for IL-6 and PAI-1 (R2 =0.154, p<0.0001) for G1 infection. There was no association observed between adipokine levels and steatosis % for G non-1 infection.



Steatosis in Genotype 1 chronic hepatitis C may be associated with adiponectin and PAI-1, indicative of the role of host metabolic factors in steatogenesis. These associations were not apparent in genotype non-1 infection, reflecting other pathogenetic mechanisms of steatosis e.g. virally mediated factors in genotype 3.




Standard Error

p value






-7.02 x 10-8

3.69 x 10-8







Multivariable stepwise linear regression for steatosis % weighted for BMI in genotype 1 infected patients.


Topic:  Disease Progression - General

M1820. Regulatory failure of serum prohepcidin levels in patients with hepatitis C. 

M. Nagashima; M. Kudo


Background / Aims

Elevated serum ferritin and hepatic iron concentrations are frequently observed in chronic hepatitis C (CHC), which may be related to hepcidin. Because the role of hepcidin in chronic hepatitis C patients remains unknown, We aimed in this study to generate some information about hepcidin in chronic hepatitis C. 



To determine whether serum hepcidin correlates with markers of iron status in patients with viral hepatitis, we measured serum prohepcidin levels in patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and in healthy controls.



Serum prohepcidin and ferritin levels were negatively correlated (r=-0.182, P=0.037) in HCV patients and positively correlated in HBV patients and in healthy controls. The total iron scores in liver specimens from HCV patients were also negatively correlated (r=-0.403, P=0.013). Serum prohepcidin levels in patients with liver cirrhosis (LC) were significantly lower than in patients with chronic hepatitis (CH). In both chronic hepatitis and liver cirrhosis, serum prohepcidin levels were significantly lower in HCV patients than in HBV patients.



Failure of homeostatic regulation of serum prohepcidin concentrations may be induced by HCV infection, resulting in elevation of serum ferritin levels, which leads to the progression of liver injury by iron overload in chronic hepatitis C patients.


Topic:  Disease progression – metabolic disorders

M1822. The association of adipokine levels with changes in steatosis following treatment in patients with chronic hepatitis C infection. 

S. Galhenage; K. Patel; H. M. Patton; T. Walker; W. Symonds; M. F. Abdelmalek; J. G. McHutchison



Steatosis in chronic hepatitis C (CHC) infection is associated with both host metabolic and viral factors. The role of adipokines in development of steatosis in chronic hepatitis C infection remains unclear. We evaluated the relationship between several adipokines and changes in steatosis following interferon (IFN)-based therapy for chronic hepatitis C. 



Paired pre- and post-treatment (Rx) liver biopsies and matched serum samples were selected from a repository. Biopsies were blindly evaluated for steatosis and recorded as percetnqage of  affected hepatocytes and graded according to:  0(0-2%),1 (3-29%), 2 (30-59%) or 3 (≥60%). Leptin, adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1)and tumor necrosis factor (TNF-α) levels were measured using conventional assays.


Treatment consisted of interferon monotherapy or combination therapy with ribavirin. Sustained virological response (SVR) and non-response (NR) were defined as absence at 6 months or persistence of HCV RNA post-treatment respectively. Comparisons were by paired t-test and contingency analysis.



The study cohort of 52 chronic hepatitis C patients (M/F 40/12), genotype 1 (29/52, 55%), had mean baseline steatosis 13.17 ± 2.33%.There was no mean difference in steatosis percentage between paired biopsies for genotype 1(-0.89%, p=0.32)and genotype non-1 patients(-7.4%,p=0,12).


There was an association with direction of change in steatosis grade and adipokines for TNF-α (p=0.05) and PAI-1(p=0.006). For genotype 1, change (Δ) in steatosis percentage correlated with Δ IL-6 only (R2 =0.16, p=0.03. For genotype non-1, there was trend toward positive correlation for Δ PAI-1 and Δ steatosis percentage (R2=0.16, p=0.06. Mean Δ TNF-α was greater in genotype 1 patients with SVR compared to NR with no other differences for adipokines by virologic response for genotype 1 or genotype non-1.


There were no significant differences in mean adipokine levels before and after Rx for genotype 3 (n=12) and non-3 (n=38) and no correlation for Δ adipokines and Δ steatosis %. Mean adipokine differences for G3 SVR (n=5) vs G3 NR (n=7) were not significant; for non-3 NR (n=28) vs. SVR (n=10) only TNF-α levels were significantly different(37.63 vs -157.6, p=0.007).



The adipokines TNF-α, IL-6 and PAI-1 may have limited utility in following changes in steatosis in chronic hepatitis C genotype 1 infection. Similar associations were not apparent for genotype genotype non-1 or genotype 3 related changes in steatosis or viral response.





p value

G non-1 SVR

G non-1 NR

p value

Δ IL-6














Δ Leptin







Δ Adiponectin

-2 x 106

6.4 x 106



2.2 x 106









Δ Steatosis %








Topic:  Disease Progression – Metabolic disorders

M1823. Chronic HCV Infection causes Insulin Resistance- A Meta-analysis. 

S. Jalil; R. R. Mummadi; G. K. Sood


Background and Aim:

Chronic Hepatitis C virus (HCV) infection is associated with increased risk of type 2 diabetes. It has been postulated that HCV infection promotes Insulin resistance (IR) and leads to development of diabetes. Recently, several studies have reported the link between chronic HCV infection and insulin resistance before the development of diabetes. These studies however are heterogeneous in their design and outcome measures. We performed a meta-analysis of available studies (1988 through November 2006).



Electronic databases Medline, CINAHL and Science Citation Index were searched. Studies with non-diabetic, non-cirrhotic chronic HCV infected patients with a healthy control group for comparison were included for analysis. Main outcome analysis was level of Insulin resistance as measured by homeostasis model assessment for insulin resistance (HOMA-IR). HOMA-IR data for HCV patients and controls were abstracted. Meta-analysis was performed using Comprehensive Meta Analysis Software Version 2.



A total of 342 journal articles and abstracts were reviewed. Eight studies which met the search criteria were selected. There were 951 chronic HCV patients with HOMA-IR results. The pooled data of HOMA-IR from six studies favors insulin resistance in patients with chronic hepatitis C infection (Std diff in means: 3.79, SE: 0.056, CI: 3.59-3.81; p= 0.001) as shown in table 1.



This meta-analysis suggests that chronic HCV infection is associated with insulin resistance when compared to healthy controls. The insulin resistance in chronic hepatitis C patients is independent of genotype.  There is increased incidence of steatosis in genotype 3 infection. 


Topic:  Disease Progression - General

M1826. Hepatitis C and End Stage Renal Disease: A Global Survey. 

J. A. Ortiz; J. M. Palma-Vargas; F. H. Wright; F. E. Membreno; S. Harrison; P. F. Foster



Hepatitis C virus (HCV) is an important cause of morbidity in patients with End Stage Renal Disease (ESRD). Treatment algorhytms for these complex patients have yet to be validated. To determine the degree of variability in treating this patient population, we sent a 22 question survey to over 1000 transplant professionals via the Internet. Specific topics involved in this survey were: Pre-transplant HCV diagnosis strategies, Pre-transplant HCV treatment modalities, Transplant strategies and post-transplant HCV therapies and immunosupression.



There were 137 respondents as follows: 32 hepatologists, 31 nephrologists, 28 multi-organ transplant surgeons, 22 liver transplant surgeons, 19 kidney transplant surgeons and 5 miscellaneous. Three surveys were eliminated due to incomplete answers leaving 134 surveys for the final analysis.


In addition to serologic viral studies, 61% of the respondents would perform a liver biopsy for the pre-transplant HCV work-up. Biopsy time intervals varied widely among answers and 38% of the respondents had no established protocol. The majority of the respondents (75%) stated that the hepatologist or gastroenterologist were involved in the decision -making process.


Regarding pre-transplant HCV therapy, 68% of the respondents would treat at least some of these patients with interferon. Thirty eight percent would use ribavirin. Dosage varied widely among the respondents.


Transplant strategies included the use of HCV positive donors for HCV positive recipients in 64% of respondents. Additionally, 4% would use HCV positive donor organs for HCV negative recipients. Combined liver/kidney transplantation was advocated by 50% in the asymptomatic biopsy proven cirrhotic patient on dialysis.


Regarding post-transplant HCV therapy, 17% of the respondents would treat kidney transplant recipients with interferon and 33% would treat dual liver/kidney transplant recipients with interferon.


Finally, immunosupression management after kidney transplant in this setting showed that the majority of respondents are inclined to adjust it, however the methods varied widely.



This global survey indicates that management of the HCV patient with ESRD pre and post-transplant varies greatly depending on the practitioner. A consensus conference is required to establish guidelines based on organized prospective multi-center trials.


Topic:  Acute –

M1827. Persistence of Hepatitis C Viraemia is not Related to Defective Interferon Alpha Production from Peripheral Blood Mononuclear Cells. 

D. Manning; M. O'Brien; C. O'Farrelly; J. E. Hegarty



Complex host and viral factors interact to determine the outcome of hepatitis C viral (HCV) infection. The main focus of research into the pathogenesis of HCV has been on the adaptive immune system. Interferon alpha, a protein with antiviral and immunomodulatory properties is a key component of the innate immune system and is the therapeutic strategy of choice for HCV infection.



The objective of this study was to evaluate the production of interferon alpha from total peripheral blood mononuclear cells (PBMCs) from patients who had been exposed to hepatitis C from contaminated anti-D immunoglobulin in 1977/ 8. Our hypothesis was that patients who failed to spontaneously clear HCV may have defective interferon alpha production.



PBMCs were isolated by density gradient centrifugation from 24 females (13 polymerase chain reaction positive) who had been exposed to hepatitis C from a single source in 1977/ 8. PBMCs were stimulated for 24 hours with polyinosinic acid: polycytidilic acid (poly I: C) which was transfected into the cytoplasm with Lipofectamine 2000. Poly I: C is a synthetic double stranded RNA which acts as a TLR3 ligand. Interferon alpha levels in the supernatants were measured using a commercially available enzyme linked immunosorbent assay kit (PBL Biolabs, Piscataway, New Jersey). Statistics were analysed using SPSS software.



Interferon alpha was detected in all samples following stimulation with poly I: C transfection. Interferon alpha was not detected in any sample stimulated with poly I: C or Lipofectamine 2000 alone. The interferon alpha concentrations as measured by ELISA were (results expressed as median [interquartile range] in pg/ ml): PCR positive patients 52.9 [44.94 – 66.48], PCR negative 49.94 [45.96 – 94.43]. There was no significant difference between these results (p = 0.77).



Interferon alpha production from PBMCs in-vitro is not defective in patients who fail to spontaneously clear HCV. A defect in the response to interferon alpha may be responsible for persistence of viraemia in these patients


Topic:  Diseaese progression – general

M1829. Proteinuria in chronic HCV infection: a link for chronic kidney disease (CKD)?  

S. K. Satapathy; C. Lingisetty; S. Chaudhari; S. Williams



The role of Chronic HCV infection in the etiology of chronic kidney disease (CKD) is still a matter of debate. Proteinuria by dipstick, a simple test in practice, is a useful and cardinal sign of underlying renal abnormalities.



To elucidate the impact of hepatitis C virus (HCV) infection on the occurrence of proteinuria amongst adults.



A retrospective chart review of the urinalysis with dipstick for proteinuria detection was done on 568(M:F::383:185) HCV positive patients, and were compared with 349 HCV negative (M:F::232:117) patients matched for age, race, and sex who were seen at the GI clinic. Urine analysis was available in 432 HCV positive patients and 284 controls. Proteinuria was categorized into nil, intermittent or persistent.



Persistent proteinuria was noted in a significantly higher number of patients with chronic HCV infection, [36(8.3 %) vs. 12 (4.2%), p=0.032], although intermittent proteinuria was comparable in both groups [73(17%) vs. 44(15.5%), p=0.619]. Proteinuria was significantly absent more commonly in the control group compared with HCV positive group [229(80.6%) vs. 319(73.8%), p=0.036].


The difference in persistent proteinuria was found even after excluding diabetics [22(6.6%) vs. 5(2.2%), p=0.017]. Multivariate logistic regression analyses showed that Serum Creatinine [P <0.0001, OR=1.774; 95% CI: 1.34-2.348] and diabetes mellitus [P=0.038, OR=0.303; 95% CI: 0.098- 0.937] were the significant factors associated with proteinuria, followed by body weight, HCV viral load, age, Genotype status, HIV status, hypertension, sex and race.



Proteinuria is significantly associated with chronic HCV infection.


Logistic regression analysis of various factors predicting proteinuria



Odds Ratio

95% C.I.






Serum Creatinine





Diabetes Mellitus




















Genotype 1




















Race(Being Black)





Race(Being Hispanic)





Intravenous Drug Abuse






Topic:  Disease Progression – Metabolic disorders

M1831. Metabolic predictors of steatosis and fibrosis in chronic hepatitis C(HCV).  

P. K. Pandya; J. S. Nachnani; P. Callahan; D. Reker; S. Mathur



Histologic evidence of steatosis in liver biopsies of HCV patients is well documented. Recent evidence suggests that HCV is directly responsible for steatosis in genotype 3 infection whereas steatosis in genotype 1 is a consequence of metabolic derangement specifically insulin resistance (IR). The relative contribution of associated cytokine and adipokine abnormalities on steatosis and fibrosis remains unclear.



To systematically characterize the metabolic abnormalities and correlate these findings with concomitant histologic evidence of steatosis and fibrosis.



Demographic, anthropometric, serologic, and metabolic parameters were studied in a cross-sectional study of treatment naïve veterans with chronic hepatitis C. Insulin resistance was defined as a HOMA (fasting insulin (mU/L) x fasting glucose (mmol/L)/22.5) greater than 2.5. Serum levels of TNF-α, IL-6, adiponectin and leptin were measured using ELISA. Chronic HCV inflammatory activity and fibrosis were determined according to the modified hepatic activity index (HAI). Univariate analysis and multivariate analysis were performed.



The average age, BMI, viral load, ALT and HOMA were 52.6±7.2, 28.8±5.8, 3.4x106,64.5±62.6 and 4.71±5.9 respectively. All but two of the patients were male. Caucasians and African Americans comprised 68.8% and 22.5% of the cohort.


The predominate genotype in the cohort was genotype 1(78.5%). 55% of the cohort was insulin resistant. Univariate analysis using fibrosis as a dependant variable showed Waist Hip ratio > 1 (p=0.04), Race (p=0.01), perisinusoidal fibrosis(p=0.0038), HOMA (p=0.0001), TNF(p<0.0001), Steatosis(p=0.0086), IL-6(p< 0.0001), and BMI (0.003) to be significant.


For steatosis, Race (p=0.02), perisinusoidal fibrosis(p=0.0015), HOMA(p < 0.0001), IL -6 (p=0.0006), Adiponectin (p=0.01), Leptin (p=0.03) and BMI (p=0.02) were found to be significant. Multivariate analysis using regression with steatosis as the dependent variable identified HOMA (p=0.0007) but not leptin, adiponectin, TNF a, IL-6, age, or BMI (p=ns) as an independent variable. For fibrosis HOMA (p=0.03), adiponectin(p=0.048), TNF a(p=0.2), and IL-6 (p=0.009) were independently associated while age, BMI, and leptin were not.



·        Insulin resistance is common in chronic HCV.

·        HOMA but not BMI independently predicts both steatosis and fibrosis.

·        Adiponectin, IL-6 and TNF-α were independent predictors of fibrosis while adipokines or cytokines were not predictive of steatosis.

·        Insulin resistance is an independent predictor of steatosis and fibrosis.

·        Hence therapeutic modulation of insulin sensitivity in insulin resistant HCV patients should be further evaluated.


Topic:  Disease Progression—Metabolic disorders

M1832. Lack of association between hepatitis C and diabetes mellitus: a case-control study. 

S. K. Satapathy; C. Lingisetty; S. Chaudhari; S. Williams



Although a higher prevalence of type II diabetes mellitus (diabetes) has been reported in patients with hepatitis C virus (HCV) infection, the results are conflicting and even negative association has been reported.



The aim of this study was to determine relationship of diabetes with chronic HCV infection in a large population of HCV patients, by comparing with an age, race, and sex matched control population. The presence of diabetes was ascertained by using American Diabetes Association guidelines based on fasting glucose measurement and medication history. Presence of HCV infection was assessed by serum testing for anti-HCV antibodies.



A total of 568(Male:Female::383:185) anti-HCV positive patients were compared with 349 anti-HCV negative (Male:Female::232:117) patients matched for age, sex and race who were seen in GI clinic.



The prevalence of type II diabetes in the anti-HCV positive group was comparable to that of the control group [105 (18.5%) vs. 56(16%), P=0.346]. These differences did not change on sub-group analysis of the Black patients [27(17%) vs. 17(17.3%), p=0.940], although there was a trend for higher number of diabetics among Hispanic patients [75(21.2%) vs. 34(15.3), p= 0.078].


Multivariate logistic regression analysis revealed higher age [p< 0.017 OR=1.037, 95% CI= 1.007– 1.069], and presence of hypertension [p<0.0001, OR=0.214, 95% CI= 0.115–0.401] were the only significant predictors for the presence of DM in patients with chronic HCV infection. Gender, race, body weight, serum creatinine, HCV-genotype at baseline, IVDU, and HIV status were not predictors.



·        In our study no significant differences were notes in regards to the prevalence of diabetes in patients with chronic HCV and controls without chronic HCV infection (18.5% vs. 16%, p=0.346. 

·        Higher age and presence of hypertension were the only significant predictors for the presence of diabetes in patients with chronic HCV infection.


Logistic regression analysis of various factors predicting Diabetes Mellitus:




Odd's Ratio

95% C.I.
















Race (Being Hispanic)















Genotype 1










Race(Being Black)










Intravenous drug abuse





Serum Creatinine






Topic:  Diagnostic tools – non-invasive markers

M1833. Investigating the Cause of High Ast/Alt Ratio in HCV-Induced Liver Cirrhosis. 

J. Loubert; V. Raymond; S. Selliah; M. Bilodeau



For more than 50 years, the enzymatic activities of serum transaminases (aspartate-AST and alanine-ALT) have been used to evaluate liver diseases. Mostly synthesized by hepatocytes, these enzymes are released in the serum when the liver undergoes injury and cell death. There is good clinical evidence that a higher ratio of AST over ALT (AS/LTr) is indicative of the presence of underlying cirrhosis especially in HCV-infected patients: the explanation of this feeding is unknown. In order to define the respective role of fibrosis and HCV proteins in this observation, experiments were performed to measure the respective activities of theses enzymes in tissue samples or hepatocytes obtained from different experimental models.


Material and Methods:

AST and ALT activities were measured in:

1.     Tissue homogenates from normal (N), HCV-infected cirrhotic (F4-HCV) and non-HCV-infected cirrhotic (F4) human livers;

2.     Cell homogenates from purified hepatocytes isolated from N and F4-HCV livers; and

3.     Cell homogenates from hepatoma-derived parental (Huh7), sub-genomic HCV replicon-transfected (9-13) and interferon-cured replicon (TX) cell lines.



AST levels were 140±16 IU/mg liver in homogenates from normal livers in comparison to 106±12 IU/mg liver in F4-HCV and 115±7 IU/mg liver in F4 livers. ALT levels were 65±10 IU/mg liver in normal livers, 32±4 IU/mg liver in F4-HCV livers and 34±5 IU/mg liver in F4 livers. AS/LTr were significantly higher in both F4-HCV and F4 livers in comparison to controls (3.4±0.4 and 4.0±0.4 vs 2.3±0.1; p<0.02). When AST and ALT were measured in purified preparations of hepatocytes, AST levels were higher in cells obtained from F4-HCV livers in comparison to normal livers (167±31 vs 100±8 IU/mg prot) whereas ALT levels were lower (34±6 vs 49±3 IU/mg prot). This led to higher AS/LTr in hepatocytes from F4-HCV livers (6.2±1.5 vs 2.1±0.2, p=0.01). On the other hand, AST and ALT levels were lower in 9-13 cell line homogenates compared to the parental Huh7 (100%±3 vs 61%±7, p=0,04). Levels were corrected in the TX cell line.


Our data demonstrate that the tissue concentrations of AST and ALT are affected by the presence of fibrosis, this observation being independent of the presence of HCV infection. In hepatocytes isolated from cirrhotic livers, AST activity is higher than in normal hepatocytes: this is the reverse for ALT. On the other hand, HCV proteins might negatively affect the activity of these enzymes irrespective of the presence of fibrosis.



The intracellular activity of these routinely used enzymes are significantly affected by the presence of liver fibrosis and possibly too by HCV infection.


Topic: Disease progression – general

M1836. Prevalence of Gallstones Among Persons With Hepatitis C Virus Infection In Pakistan 

S. Memon; N. K. Khatri; U. Soomro; W. Jafri; R. Ghori



Although cirrhosis is a risk factor of gallstones, a recently published data also suggested that Chronic Hepatitis C (CHC) infection is associated with gallstones in men in USA. We determined the association between Hepatitis C Virus infection (HCV) infection and Gallstones (GS) in a representative sample of adults in Pakistan.



We included all the consecutive adults with HCV antibody positive (patients) and HCV antibody negative (Controls) who visited our hepatology clinic from June 2006 to October 2006. We noted the stage of disease, weight, BMI, associated Diabetes Mellitus (DM), ethnicity and number of children in case of women. After taking verbal consent, their HCV status checked and Ultrasound abdomen was also done. Patients who had cholecystectomy in past before the declaration of their HCV status were excluded.



A total of 762 participants with 467 HCV antibody positive and 295 as control were included. There were 420 (55%) men (270 HCV antibody positive and 150 control) and 342 (45%) women (197 HCV positive and 145 control). The prevalence of gallstones was significantly higher (p value =0.048) in HCV antibody positive men (9.4%) than controls (4.0%). There was no such difference noted in case of women (p value = 0.4). The prevalence of gallstones was increased significantly with severity of liver disease, increasing age, marital status, and residence in village.



Chronic HCV infection was strongly associated with gallstones among men but not in women in our study in Pakistan.  In addition, gallstones were more common in adults with increasing age and severity of liver disease.


Topic:  Disease progression – general

M1837. Co-infection with Cytomegalovirus in Chronic Hepatitis C Infection. 

D. Majumdar; S. D. Ryder; P. McClure ; W. Irving



CMV infection is a common worldwide infection with an adult prevalence rate of 40-95%. Although in the immune-competent host it usually causes an asymptomatic infection, it is an important cause of graft dysfunction following OLT (including when the underlying cause of liver damage is HCV infection). In the non-transplant setting, progression of HCV infection is seen with co-infection with HIV and HBV. This study examines the role of CMV co-infection in chronic HCV infection in immune-competent hosts.



Data were obtained from the Trent HCV database. Patients were excluded if they had coexisting HIV or hepatitis B infection. They were categorised as HCV RNA negative (anti HCV positive), HCV RNA positive with mild (Ishak stage 0 and 1) and severe (Ishak stage 4, 5, 6) liver fibrosis. We compared the CMV status among HCV RNA positive versus the negative group, and among those with mild and severe fibrosis. We also compared CMV seropositivity rates in responders and non-responders to PEG interferon and ribavirin combination therapy. Serum samples were tested for CMV serostatus using Vironostika anti-CMV III EIA kits.



153 patients were HCV RNA negative (54.2% CMV seropositive), 54 were HCV RNA positive with mild fibrosis (66.7% CMV seropositive) and 116 (67.2% CMV seropositive) had severe fibrosis. 114/165 (69%) HCV RNA positive patients achieved SVR following combination therapy. On univariate analysis there was no relationship between CMV seropositivity and development of severe fibrosis or achievement of SVR. HCV RNA positive patients however had a higher rate of CMV seropositivity (67.1%) versus HCV RNA negative patients (54.2%), odds ratio (OR)1.72 (95% CI: 1.09 to 2.7, p=0.019, n=323). On multivariate analysis taking into consideration confounders (age at testing, sex, risk factors for infection, alcohol intake), age at sample testing was found to be the only variable associated with both CMV (mean±SD, 45.4±10.2, n=197 and 42.1±10.9, n=126 for CMV positive and negative respectively, p=0.005) and HCV RNA positivity (mean±SD, 49.6±6.9, n=170 and 38.0±10.7, n=153 for HCV RNA positive and negative respectively, p<0.001). On adjusting the OR for age, there was no significant difference between the groups.



CMV serostatus in the immune-competent patient with chronic HCV infection does not have any effect on spontaneous viral clearance rates, liver fibrosis development, or the achievement of SVR with treatment.


Topic:  Disease Progession – Extrahepatic Man.

M1838. Clinical Spectrum of Chronic Hepatitis C Virus-related Cryoglobulinemia in the US. 

G. Lake-Bakaar; I. M. Jacobson; M. Al Sibae



Several studies have described the clinical spectrum of liver disease in patients with chronic Hepatitis C Virus HCV-related mixed cryoglobulinemia, HCV-C. However, the majority of these reports have been from outside the US. Geographic factors can significantly influence observed associations in patient with HCV-C.


We have analyzed clinical data from 43 patients with HCV-related cryoglobulinemia, presenting to a large academic referral center in NY. The diagnosis of symptomatic HCV-related cryoglobulinemia (HCV-C) was based on the presence of HCV RNA in plasma associated with typical lower limb purpuric rash; inflammatory polyarthralgias; and sensory or motor peripheral nerve disturbance.



The majority of the patients were female, aged over 50 years. Most were genotype 1 (87%) with evidence of significant fibrosis. Reduced levels of serum complement, C3, C4 or CH50 typified the group. Rheumatoid factor RF, abnormal ALT and overt renal disease were present in a minority of the patients. There was clinical evidence of autoimmune disease in approximately 25% of patients.



The association between HCV-C and advanced fibrosis or cirrhosis of the liver is confirmed. The genotype distribution reflects that which is predominant in our patient population. Most of our patients have reduced levels of serum complement. This may be a better discriminate for HCV-C than RF. The high incidence of overt autoimmune disease might reflect increased production of cross-reacting antibodies.


Patient Characteristics


Proportion (95% CI)


Proportion (95% CI)

Sex: Female

58% (42-72)

Abnormal GGT

51% (43-68)

Age >50

74% (58 – 86)

Rheum factor pos

46% (28-65)

Autoimm disease

25% (13 – 41)

C3/ C4/ CH50 Abn

71 (55-84)

Renal disease

4% (0.5 – 16)

Stage F2-4

73% (57 – 85)

Abnormal ALT

37% (22 - 53)

Genotype 1

87% (73 – 95)


Topic: Disease progression – general

M.1839 Early Occult Portal Hypertension in Chronic Hepatitis C  

David S. Zimmon, Forrest Manheimer Dept of Medicine; Fred B. Smith, Sergei Aksenof, Dept of Pathology, St. Vincent’s Hospital, New York, N.Y.



We examined 23 patients with chronic hepatitis C  (HCV) for esophageal varices (EV) by upper gastrointestinal endoscopy, for portal hypertension (PH) by wedged hepatic vein catheterization for measurement of portal pressure (PP) and for histopathologic grade and stage (Scheuer) by liver biopsy retrospectively by two blinded pathologists. Initially only patients requiring transjugular liver biopsy for contraindications to percutaneous biopsy including bleeding diathesis, morbid obesity or thrombocytopenia were examined. Recognition of severe PH as evidence of global progressive liver disease in the absence of EV prompted PP measurement in subsequent chronic HCV patients. Patients with edema or ascites were excluded.



In two HCV patients right atrial pressures were 12 and 13mmHg implying systemic hypervolemia.


In 16 patients without EV 16/23 (69%) PP was greater than 10mmHg (range 12-28, mean 19 mmHg).


In 8/23 (31%) with suspected or small (+1) EV easily missed during endoscopy, PP ranged from 10-20 (mean14) mmHg. Small EV, easily overlooked at endoscopy, may indicate severe PH and should be considered an indication for hemodynamic evaluation. Endoscopy and PP measurement seek PH in the basal fasting state when PP is at its nadir. Two of 23 liver biopsies were inadequate for interpretation. Stage 4 (cirrhosis) was seen in 7/21 (33%). Stage 1 (19%) or Stage 2 (28%) was present in 48% with 4/21 (19%) stage 3. Over all PH was found in 67% before cirrhosis was apparent on liver biopsy or EV were obvious at endoscopy.


In this small number of referral (to hepatologists) biased patients neither biopsy stage nor absence of esophageal varices excluded PH and associated hemodynamic abnormalities including hypervolemia and high IVC pressure. PH was recently identified in HCV as an early rejection signal after hepatic transplantation in HCV. Conversely frank cirrhosis may be present without EV.



Our findings suggest that PH develops early in chronic HVC and is often not detected by endoscopy or transjugular liver biopsy. This implies a need for early hemodynamic screening to identify global progressive disease.


Topic:  Experimental therapies - general

M1840. Trial of oral n-acetylcysteine (NAC) to treat insulin resistance in chronic hepatitis C(HCV). 

P. K. Pandya; S. Mathur; P. Callahan; D. Reker



The prevalence of insulin resistance and type 2 DM (diabetes) is significantly higher in HCV patients compared to controls. Furthermore in patients with HCV, insulin resistance is associated with advanced liver fibrosis and reduced outcomes to antiviral therapy. NAC has been shown to improve insulin resistance in recent studies, but its effect in HCV patients is not known. Additionally, a recent study has revealed that NAC inhibited TNF-alpha-mediated activation of NF-kappaB and improved the adverse changes in the levels of IL-6, PAI-1 and adiponectin in adipocytes.



To study the effect of NAC on insulin sensitivity and adipocytokine derangements in insulin resistant patients HCV patients.



33 consecutive treatment naïve patients with chronic HCV and insulin resistance as defined by HOMA > 2.5 were randomized to receive 2400 mg of NAC or no medication for 30 days. Detailed anthropometric and metabolic parameters were studied before and after therapy. Demographic, histologic, and metabolic parameters between patients and controls were compared with two tailed t-test or X2 analysis. Pre and post treatment values were similarly compared. Repeated measures analysis to test the effects between subjects and within subjects were evaluated with repeated measure analysis using ANOVA for the primary endpoint variable of HOMA.



15 treatment and 14 control patients completed therapy. The demographic, metabolic, viral, and histologic parameter of control and treatment groups were similar (p=ns). Similarly comparing pretreatment to post treatment values in controls and NAC treated groups revealed no statistically significant changes (Table 1). The effect of therapy on HOMA with repeated measure analysis revealed no differences between subjects (p=0.14) or within subject differences (p=0.96)



Short term therapy with the hepatoprotective antioxidant NAC failed to improve insulin sensitivity in insulin resistant patients with chronic HCV. Additionally the proinflammatory cytokines and adipokines were unchanged after therapy.


Table 1




NAC Treated



Pre Tx

Post Tx

Pre Tx

Post Tx

BMI (kg/M2)





AST (IU/ml)





ALT (IU/ml)










Adiponectin (mg/l)





Leptin (ng/ml)





TNF α(pg/mL)





IL 6 (pg/mL)





Viral load (IU/ml)







Topic:  Diagnostic Tools – non-invasive

M1842. Transient elastography in chronic hepatitis B and C predicts severe fibrosis similarly. 

C. Verveer; H. R. van Buuren; P. E. Zondervan; B. E. Hansen; H. Janssen; R. J. de Knegt



Assessment of liver fibrosis is important in chronic liver diseases. In chronic hepatitis B and C it helps to determine prognosis and indication for therapy. Transient elastography is a novel method for measurement of liver fibrosis. In contrast with the liver biopsy it is comfortable and without any risk.

The Fibroscan® has been validated in large cohorts of hepatitis C patients, but its use in hepatitis B patients is still undetermined. We investigated whether reliability of the Fibroscan® in viral hepatitis B and C are comparable.



All consecutive patients undergoing a liver biopsy had an additional Fibroscan®-measurement. Correlation between liver histology (Metavir) and the outcome of liver elasticity (Fibroscan®, kPa) was determined. In this cohort we studied the outcomes between both groups of elasticity measurements and liver fibrosis stages in order to investigate comparability.



Among 68 hepatitis B patients 7 had Metavir F0, 25 F1, 21 F2, 9 F3 and 6 F4; corresponding elasticity was (mean:) F0 5.36 kPa, F1 7.69 kPa, F2 9.15 kPa, F3 13.41 kPa and F4 17.05 kPa.


Among 73 hepatitis C patients 3 had Metavir F0, 31 F1, 23 F2, 13 F3 and 3 F4; corresponding elasticity was (mean): F0 3.40 kPa, F1 6.48 kPa, F2 7.82 kPa, F3 12.86 kPa and F4 13.73 kPa.


To determine the predictive value of the elasticity corresponding to severe fibrosis logistic regression was performed. Graphs for HBV and HCV were not significant different indicating comparable elasticity measurements for predicting fibrosis in HBV or HCV.



The Fibroscan® is applicable in both chronic hepatitis B and C with a similar predictive value for liver fibrosis.


Topic:  Disease Progression – Extrahepatic Man.

M1843. Associations among Susceptibility Factors for Human Porphyria Cutanea Tarda. 

S. Jalil; J. J. Grady; K. E. Anderson



Porphyria cutanea tarda (PCT) is the most common form of porphyria and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Both familial and sporadic forms become manifest in the presence of multiple susceptibility factors that lead to excess iron or oxidative stress in hepatocytes. Most previous studies have addressed one or a few such factors individually. We examined associations among multiple factors in a large cohort of patients seen at a single medical center.



Susceptibility factors as well as demographic and clinical features, including smoking and diabetes, were tabulated by a retrospective chart review for all 143 PCT patients seen at the gastroenterology clinic or General Clinical Research Center from 1987 through 2006. All presented with blistering skin lesions on sun exposed skin. PCT was confirmed by elevated plasma and/or urine porphyrin levels, with a predominance of uroporphyrinogen and heptacarboxylporphyrin. Associations among multiple known or suspected susceptibility factors were examined by contingency tables and logistic regression.



Patients were all adults (range 33-86, mean 52.2 yrs), and predominantly male (66%) and Caucasian (88%). The mean age of onset of PCT was 41 ± 8.8 yrs. The most common susceptibility factors were ethanol use (in 87%), smoking (81%), chronic hepatitis C virus (HCV) infection (69%) and HFE mutations (51%, with 6% C282Y/C282Y and 8% C282Y/H63D). Less common were estrogen use (24%, but in 63% of women), diabetes (8%), HIV (13%) and inherited UROD deficiency (17 % with low erythrocyte UROD activity). More than 70% had 3 or more susceptibility factors. A significant association was found between HCV and ethanol use (OR: 6.3) and smoking (OR: 11.9). HCV was also associated with HIV (OR: 4.9). Estrogen use was somewhat more common among Caucasians, and diabetes more common with inherited UROD deficiency. Significant associations among other factors were not found.



1.     Multiple susceptibility factors are found in the great majority of individuals patients.

2.     Susceptibility factors that related to life style and behavior, namely ethanol (alcohol) use, smoking, HCV and HIV showed statistically significant associations within the cohort.

3.     A significant proportion (48%) of patients had BMI >25 kg/m2  and were at risk for steatosis, which may be another susceptibility factor.

4.     Combination of particular susceptibility of PCT.

5.     Studies of these associations in PCT in other geographic areas would be of interest.   


Topic:  Diagnostic tools – non-invasive

M1844. Point of Care Non-Invasive 13C Methacetin Breath Testing Accurately Identifies Significant Liver Inflammation and Fibrosis: A Novel Method For Assessing Liver Damage. 

G. Lalazar; O. Pappo; B. Müllhaupt; O. Goetze; M. Margalit



Significant liver disease may be present in a seemingly healthy population with normal liver enzymes and minimal symptoms. The serum ALT level may not reflect the degree of liver damage, and liver biopsy has been the gold standard for assessment of fibrosis and inflammation. The point of care non-invasive BreathID® continuous online 13C methacetin breath test (MBT) reflects hepatic microsomal function (CYP1A2) and has been shown to correlate with hepatic fibrosis.



To assess the ability of the BreathID® 13C MBT to differentiate patients with significant liver inflammation and/or fibrosis from healthy controls.



184 patients with chronic HCV infection (59 females, 125 males, mean age 45.8, BMI 24.9), who had undergone a liver biopsy within 9 months, and 81( 38 females, male 43, mean age 39.8, BMI 24) healthy controls (no known liver disease, normal liver enzymes and ultrasound) matched for age and sex, underwent 13C MBT following ingestion of 75mg of methacetin. Forty three controls and 11 patients underwent the MBT at least twice to determine test reproducibility. MBT parameters included PDR peak (percentage dose recovered) and CPDR10, 20, 30, 60 (cumulative PDR10, 20, 30 and 60 minutes after ingestion of methacetin, respectively). Correlations between breath test parameters and HAI (Hepatic Activity Index) inflammation score or METAVIR fibrosis score were evaluated. We compared MBT parameters between controls and patients grouped by HAI and METAVIR scores.



In HCV patients, all MBT parameters correlated significantly with inflammation and fibrosis scores (p<0.0001). MBT accurately differentiated between controls and patients with significant periportal and bridging inflammation (HAIa > 2), any inflammation type (total HAI ≥ 4) (AUC 0.87 and 0.82, 95%CI 0.78-0.97 and 0.74-0.91; sensitivity 88% and 78%; specificity 78% and 77%; NPV 97% and 84%; and PPV 45% and 65%, respectively), or patients with significant fibrosis (METAVIR > 2) (AUC 0.96, 95%CI 0.92-1.00; sensitivity 96%, specificity 86%, NPV 97%, and PPV 81%). Inter-test variability was ≤ 13% (95%CI 0.11-0.15). Results were independent of BMI in patients and healthy controls.



The point of care BreathID® continuous online 13C MBT accurately differentiates patients with significant liver inflammation and/or fibrosis from healthy controls. This test may prove to be a powerful non-invasive tool for detecting occult liver dysfunction.


Topic:  Current Treatment - General

M1845. Retrospective Analysis of the Effect of Taking a Statin Along with Peginterferon and Ribavirin (PI+R) on SVR. 

T. Bader; M. Madhoun; S. Rizvi



104 patients taking PI+R were compared to 30 patients who by chance took triple therapy [(PI+R) plus a statin]. A modified intent to treat approach was taken whereby if any patient had a least one data point after starting therapy, he or she was included in the denominator.


Virtually all patients taking a statin were on simvastatin (n=25); 2 were on lovastatin, 2 on atorvastatin and 1 on fluvastatin.


The pooled SVR rate* for the 104 patients on standard treatment was 37%. This is the highest SVR ever reported in the medical literature for a VA based population.


The pooled SVR rate for the triple therapy group was 63%. In terms of HCV subgroups, the effect was statistically strongest for genotype one, the most difficult subgroup to treat.



Statins appear to be associated with a higher SVR rate of standard PI+R therapy. This observation principally occurs on the basis of a medium powered statin (simvastatin) in terms of the Ikeda experiment (Hepatology 2006;44:117-125). The only patient to take fluvastatin during the study was cured. Statins need to be studied prospectively for their effect on hepatitis C and the outcome of treatment.


SVR Rate


No Statin

p value


Genotype 1


















*Pooled analysis makes the population proportion 70% genotype 1 and 30% non-genotype 1 in order to mimic the proportion of genotypes in the USA. This is the standard method of reporting SVRs.


Topic:  Current HCV Teatment - Pegasys

M1846. Cost-effectiveness of Early Treatment of Chronic Hepatitis C With Peginterferon Alfa-2a (40KD) Plus Ribavirin Before Progression to Advanced Liver Disease. 

J. Hornberger; P. Pockros; T. Chu; K. K. Patel; M. L. Shiffman



Current guidelines recommend a pegylated interferon plus ribavirin (RBV) as treatment of choice for chronic hepatitis C (CHC). The rate of sustained virologic response (SVR) achieved with such therapy is >80% in pts with HCV genotypes 2 or 3 and approximately 50% in pts with genotype 1 infection. However, data from clinical studies indicate that pts with more advanced liver disease are less likely to achieve an SVR, suggesting that treatment should be initiated at an earlier stage of disease to optimize the chance of cure.



To determine the cost-effectiveness of treating mild CHC compared with delaying treatment until liver disease progresses to a moderate or cirrhotic stage.



Using pooled data from two randomized trials of peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®), we constructed a state-transition probability model to evaluate the cost-effectiveness of early treatment before progression to advanced liver disease. In the model (US societal perspective), treatment-naive genotype 1 pts (mean age 41y) with mild CHC were either treated early or underwent regular monitoring (annual blood tests, liver biopsy every 3-5y). Fibrosis progression rates were summarized from published longitudinal studies. Quality of life (QoL) and direct medical costs (in 2006 US$) were based on literature estimates (discounted at an annual rate of 3% over the 30-y lifetime of the model).



The model showed that early treatment with peginterferon alfa-2a plus RBV in genotype 1 pts with mild CHC reduced the 30-y risk of cirrhosis by 13.5% (23.7% early vs 37.2% delayed), increased mean overall survival by 0.48 y and increased mean survival adjusted for QoL by 0.75 y. Although the additional drug cost of early treatment with peginterferon alfa-2a + RBV was $9,911 vs delayed treatment, this was offset by cost savings from reduced monitoring and treatment. Delayed treatment was predicted to require an average of 4.0 biopsies (costing $9,178) and additional treatment of progressive liver disease and complications of cirrhosis (costing $6,347). Compared with delayed treatment, early treatment with peginterferon alfa-2a plus RBV was therefore associated with cost savings of $5,443 over the lifetime of each pt. One-way sensitivity analysis showed that age and social discount rate were the most influential parameters in the model.



Early treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®) in pts with HCV genotype 1 infection is projected to reduce the risk of cirrhosis, increase life expectancy, and cost less than monitoring and subsequent delayed treatment of more advanced disease.


Topic:  Current Treatment - Pegasys

M1849. Herbal and Milk Thistle Use in the HALT-C Trial of Advanced Chronic Hepatitis C. 

L. B. Seeff; T. M. Curto; G. Szabo; G. T. Everson; H. L. Bonkovsky


Background & Aims:

The HALT-C (Hepatitis C Antiviral Long-Term Treatment against Cirrhosis) Trial involves persons with chronic hepatitis C (CHC) and biopsy evidence of marked fibrosis or cirrhosis who had failed previous antiviral therapy. Enrollees initially received lead-in treatment with peginterferon alfa-2a and ribavirin. Non-responders were then randomized to 3.5 years reduced dose peginterferon or no treatment.


Herbals, used for centuries in China and other Far East countries, have more recently gained popularity in western countries.  They are used commonly for treating a variety of chronic diseases including chronic viral hepatitis.  One of the most popular herbals is Silymarin (milk thistle), which is often taken together with anti-virals (complementary medicine) or may be used on its own (alternative medicine).  Surveys in liver clinics indicate that 20% to 40% of persons chronic liver disease herbals, predominately Silymarin. 


Our aim was to determine whether these patients, treated with standard therapies at least once in the past and willing to be re-treated again long-term, nevertheless used herbal supplements, primarily milk thistle (MT), and whether MT affected symptoms, quality of life (QOL) and biochemical and virological features of HCV infection.



Baseline evaluation prior to the 24-week lead-in included history, physical examination, biochemical and virologic assessment, and liver biopsy. Patients also completed baseline questionnaires on prior and current use of over-the-counter supplements and herbal preparations.



Among 1145 enrollees, 641 (56%) never used herbals, 235 (21%) used them in the past only, and 269 (23%) were using them at enrolment.  0f the 64 herbs used Silymarin was taken by 195 person (72%).  772 (67%) never used Silymarin.  178 (16%) used it in the past, and 195 (17%) using it at baseline.  The baseline use of all herbals and of Silymarin varied widely among the 10 different centers.  Baseline data from the 10 participating centers revealed variable Silymarin use, being most frequent in Denver (33%) and Ann Arbor (22%) and least frequent in Boston (9%) and Bethesda (8%). More men than women used MT (18% vs 14%), and its use was more frequent among whites (19%) than Hispanics (10%) and blacks (9%).


Although univariate analyses identified that Silymarin users had significantly fewer symptoms and better quality of life indices than non-users, most of these differences became non-significant after adjusting the analyses using relevant covariates.  There were no association between the use of Silymarin and lowered levels of HCV RNA. 



·        Approximately 15% of persons with chronic hepatitis C, previous non-responders to orthodox antiviral therapy and now willing to enrol in a long-term treatment trial with peginterferon, nevertheless used Silymarin at study entry—men more frequently than women, and Non-Hispanic Whites more frequently than African Americans and Hispanics.

·        In this survey of self-motivated users of herbal Silymarin was not associated with lower levels of ALT or HCV RNA.

·        Only a prospective, randomized, controlled study using standardized formulation of Silymarin will determine this product has any value for hepatitis C.  Such a study is currently in progress. 

Topic:  Pegasys

M1850. Differences between genotype 1 patients with SVR or relapse after treatment for chronic hepatitis C (CHC) with peginterferon alfa-2a (40kd) (PEG) and ribavirin (RBV). 

E. Zehnter; S. Mauss; K. Boeker; L. Thomas; S. Racky; W. Schmidt; R. Ullrich; I. Sbrijer; R. Heyne; A. Schober; C. John; K. Hey; B. Bokemeyer; B. Kallinowski; B. Moeller; S. Pape; U. Alshuth; D. Hueppe



Although treatment with pegylated interferon and ribavirin have increased the SVR substantially there is still a relapse rate after end-of-treatment response about 20-30%. It is unknown whether there are defined parameters at baseline or in the course of treatment, which are deciding for relapse.



The Association of German independent Gastroenterologists (bng) together with Roche is conducting a nationwide observational study to determine the quality of treatment for CHC in routine clinical practice. Until May 2006 data of 4377 patients in different phases of treatment with PEG and RBV were recorded. From 648 pts with Genotype 1 compete data with regard to EOT and SVR were available.



517/648 pts (75.6%) with EOT achieved an SVR, so 24.4% had a relapse.


Demographic data for 167 relapsers (REL) vs 517 pts with SVR (SVR) were: mean age REL 46.8 y, SVR 41.81y, whereas female relapsers were 51.9 yrs old, 58.7%/56.3% male, BMI 25.8/24.7 kg/m2, mean duration of infection: 14.5y/11.0 y, source of infection (>1 answer possible): transfusion 24.0%/20.7%, iv drug abuse 27.0%/38.1%, medical action 11.4%/12.6%, unknown 30.5%/24.8%, concomitant diseases 56.3%/50.9%. 39.9% of REL pts had low viral load at baseline (cut-off of 400,000 IU/ml) in contrast to 55.2% of SVR pts. No differences between REL and SVR was seen in the calculated cumulative dose of PEG (95.9%/96.3%) or in treatment duration (47.7 weeks), but 28.0% REL got less than 80% of the cumulative RBV-dose compared to 20.8% pts with SVR. AE rate was 57.5% in REL and 51.3% in SVR. One third of pts was checked for HCV-RNA in week 4: only 10.8% of REL achieved RVR against 25.8% of SVR pts. The difference in EVR (>=2-log10 drop in HCV RNA or HCV RNA undetectable at week 12) was smaller: 91.6% vs 96.6%



1.     Concerning baseline predictive values besides age and duration of infection there were no differences in host related parameters.

2.     Differences were given in the cumulative dose of ribavirin and virus determined factors like viral load and decay in viral load over treatment time.

3.     The latter leads to assumption, that a decline in relapse rate is achievable through optimization of treatment duration.


Topic:  Pegasys

M1851. Analysis of early viral kinetics in chronic hepatitis c genotype 2 or 3 patients treated with peginterferon alpha-2a and ribavirin. 

T. Scherzer; K. Staufer; P. Steindl-Munda; H. Holzmann; P. Ferenci



In genotype 1/4 chronic hepatitis C patients previous studies have demonstrated that the rapidity of viral response allows individualisation of therapy (24 weeks to 72 weeks). We evaluated the rapid virological response at week 2 and 4 in patients with genotype 2/3 to predict the response to combination therapy.



In 84 treatment-naive genotype 2/3 chronic hepatitis C patients (15 genotype 2, 69 genotype 3a, f: 34, m:55; mean age: 37.8a) treated in our centre in a multicenter prospective, randomized, controlled trial evaluating 180µg peginterferon alfa-2a (PEGASYS®, Roche, Basel, CH) combined with ribavirin (COPEGUS®,Roche, Basel, CH) 400 or 800mg/d for 24 weeks (Ferenci et al, EASL 2006), viral response was evaluated by qualitative and quantitative PCR (COBAS® AMPLICOR, Roche-Diagnostics, Pleasanton, USA, detection limit <50IU/ml) after 2 and 4 weeks of therapy.



Of the 84 patients 78 completed treatment and follow-up. In 28 patients (36%) HCV-RNA became undetectable at week 2 and in further 39 patients (50%) at week 4. Thus 67 patients had undetectable HCV after 4 weeks, 8 patients cleared HCV between week 4 and 24. The rapidity of viral response was independent of the mean (±SD) baseline viral load (HCV-RNA-negative at week 2: 3.1±4.0 MIU/ml; at week 4: 3.3±4.5; HCV-RNA-positive at week 4: 2.9±4.0).


Seventy five had an end-of-treatment (EOT) response, 60 achieved a sustained virologic response (SVR) and 15 relapsed. Relapse rates were similar among week 2 and 4 virological responders (14.3% vs. 13,4%), but were higher in patients with detectable virus at week 4 (47%). SVR rates were identical among the HCV-RNA-negative patients at week 2 (86%; PPV 0.857, NPV 0.28) and those becoming negative at week 4 (77%; PPV 0.853, NPV 0.533).


The overall predictive performance of an HCV-RNA test with a detection limit of 50IU/ml was more accurate at week 4 (PPV 0.855, NPV 0.85, sensitivity 0.883). There was no difference between week 2 and 4 virological response rates, EOT and SVR for the different doses of ribavirin.



HCV-RNA should be tested after 4 weeks of therapy. 86% of virologic responders at week 4 achieved an SVR. Measuring viral load at earlier time points adds no further information. SVR in patients treated with 400 or 800mg of ribavirin were identical. Reduction of treatment durations in rapid virologic responders should be prospectively studied.


Topic: Current HCV therapies – general

M1852. Role Of Hmg-Coa Reductase Therapy In Hepatitis C (HCV) Treatment Outcomes. 

V. Singh; E. J. Carey; M. Rudraraju; M. J. Rosati; C. A. Grumeretz; V. Balan; H. E. Vargas



Approximately 3 million people have ongoing HCV infection in the US. Treatment with pegylated interferon and ribavirin is the current standard for treatment, but sustained virological response (SVR) is only 55-60%. Recent pre-clinical studies have described a potential benefit of HMG Co-A reductases (statins) therapy in improving treatment outcomes.



To determine the difference in HCV treatment outcomes and potential toxicity (heralded by Liver Injury Tests (LIT) elevations) in patients on concomitant statin therapy at the initiation of therapy for HCV.


Methods and Patients:  

We performed a case control study based on 298 patients who underwent treatment with PEG-IFN and ribavirin combination from January 2000 until September 2006. Of these, 17 (5.7%) were on a statin at the initiation of HCV treatment, predominantly for management of dyslipidemia.


Two groups of patients were identified:


·        Group 1 included all patients treated with PEG-INF and ribavirin therapy and treated with a statin for any duration of time after the initiation of antiviral therapy (N = 17) and

·        Group 2 consisted of HCV patients undergoing PEG-INF and ribavirin therapy who never received a statin, matched for age, sex and genotype (N = 34).


The two groups were compared in terms of virological response to treatment, with attention to Early Virological Response (EVR), End of Treatment Response (ETR) and Sustained Virological Response (SVR) and LITs before and after treatment.



Group 1 had improved ETR rates (100% versus 78.2%, p= 0.05) and SVR rates (82.3% versus 53.1%, p=0.05) compared to Group 2. SVR was defined as persistence of undetectable HCV RNA at 24 weeks after completion of treatment. The difference in EVR among both groups was not statistically significant (82.3 % versus 58.8%, p=0.10). The LIT in both groups improved with treatment without any evidence of hepatotoxicity. Mean AST, ALT and Alkaline Phosphatase decreased significantly from initiation to end of treatment as expected. The mean LIT of both groups did not differ from each other significantly both before and after treatment.



1.     Patients undergoing antiviral therapy for HCV treatment who receive concomitant statin therapy have improved ETR and SVR.

2.     Statins may play a role in improving treatment outcomes of hepatitis C and this influence should be studied prospectively.

3.     Statins do not appear to be harmful in this setting and should not be viewed as absolutely contraindicated in patients undergoing hepatitis C treatment.


Topic:  Disease Progression – Extrahepatic Man.

M1853. Outcomes of pegylated interferon and ribavirin therapy for HCV patients with cryoglobulinemia as compared to patients without cryoglobulinemia. 

S. Ali; R. R. Meidinger; Z. Kayali; K. E. Brown; M. D. Voigt; D. R. LaBrecque; W. N. Schmidt



Mixed cryoglobulinemia occurs in 40-50% of patients with chronic HCV infection. Cryoglobulins (CGs) have been associated with increased risk of cirrhosis and extrahepatic complications of chronic HCV infection. Although earlier studies reported the efficacy of interferon monotherapy for patients with CGs no large study has compared viral response rates prospectively in patients with and without CGs after treatment with peginterferon and ribavirin. The aim of our study was to determine whether the response of patients with CGs to peginterferon and ribavarin differs from that of patients without CG. We also wished to determine whether CGs affected other variables known to be important for treatment outcome.



167 HCV treatment-naïve patients were recruited prior to initiation of standard dosages of peginterferon-α and ribavirin. Serum CGs were measured prior to therapy.  Patients were treated for 24 (genotypes 2, 3) or 48 weeks (genotype 1). At 6 month follow-up, patients were classified as sustained virological responders (SVR), non-responders (NR) or responders/relapsers (RR) according to established criteria.



51 patients (31%) were CG positive, and 116 patients (69%) were CG negative. There were no differences in age, sex, or genotype distributions between the two groups.

·        There was no difference in the percentages of SVR, NR or RR in either group.

·        There was a significant increased percentage of CG+ who discontinued anti therapy early.

·        There were no differences in response between the groups when stratified according to age, sex, or pathological findings.

·        A higher percentage of CG positive patients with high viral loads achieved SVR than CG negative patients. 

·        A higher percentage of CG negative genotype 1 patients achieved SVR than CG positive patients.

For multivariate analysis, a logit model for viral response was used with the independent variable CG positive and each covariate fitted individually.  Initial testing showed that being CG positive or CG negative did not alter the covariate model main effect.  The only significant covariate effect on viral response was genotype.


Covariables tested in the model were gender, viral load, activity , steatosis, age, RF and ALT.



·        The presence of CG did not affect the overall percentages of SVR, RR and NR profiles in HCV positive patients.

·        A higher percentage of patients with CG who achieved SVR had high viral load than patients without CG who achieved SVR.

·        Patients with CG were statistically more likely to discontinue therapy early or be lost to follow-up.

·        Multivariate analysis showed no difference in the effect of covariates on the responses to CG positive and CG negative patients. 

Topic:  Current Treatment - Pegasys

M1854. Treatment Duration and Histological Response to Peginterferon Alfa-2a/Ribavirin. 

P. Pockros; P. Martin; F. M. Hamzeh; E. Lentz; A. Lok



Current treatment practice in HCV, aimed at achieving SVR, is to discontinue treatment in patients with detectable serum HCV RNA at 24 weeks. Although histologic improvement is associated with SVR, patients treated with peginterferon alfa-2a/ribavirin have shown improvement in inflammation without SVR. Longer treatment duration may enhance histologic improvement regardless of SVR. We have compared histologic responses in HCV genotype 1 patients treated for 24 or 48 weeks.



All HCV genotype 1-infected patients (n= 211) with paired biopsies prior to and 24 weeks after the end of treatment from two registration trials of peginterferon alfa-2a/ribavirin were included. Metavir score was used to stage fibrosis (0-4) and to grade activity (0-3). Improvement was defined as decrease of ≥1 stage or ≥1 grade and worsening as increase of ≥1 stage or ≥1 grade. Statistical evaluations were performed using the Cochran-Mantel-Haenszel Test stratified by ribavirin dose (800 or 1000/1200 mg/d).



Improvement in activity and/or fibrosis score was observed in 93 (86%) of 108 patients who achieved SVR, and in 45 (44%) of 103 patients who did not (p<.001). Among the latter, a higher percentage of those treated for 48 weeks had improvement in activity or fibrosis than those treated for 24 weeks (p=0.049). A similar trend, favoring longer treatment for patients without SVR, was observed when analyzing patients with histologic worsening. Among patients who achieved SVR, there was no difference in histologic improvement between those treated for 24 and 48 weeks.



·        Among patients chronically infected with HCV genotype 1, those who achieved SVR after treatment with peginterferon alfa-2a plus ribavirin were more likely to have histologic improvement than those who did not.

·        Among patients who achieved SVR, the proportion with histologic improvement was similar in groups treated for 24 or 48 weeks, regardless of ribavirin dose.

·        Among patients who did not achieve SVR, 9 of 72 (13%) treated for 48 weeks but none of 31 treated for 24 weeks (O=.054) had improvement in fibrosis stage.  The percentage of patients with either inflammation or fibrosis  improvement was significantly (P=.044) better for those who were treated for 48 than for 24 weeks, after controlling for ribavirin dose.

·        These findings suggest that longer treatment duration may be necessary for fibrosis improvement in patients without SVR.

·        Fifty of 72 (69%) and 18 of 31 (58%) patients without SVR were relapsers in the 48- and 24-week treatment arms, respectively. Although the numbers were small, the trend favoring 48 weeks in histologic outcome was similar in relapsers and nonresponders.

·        The numbers in this retrospective analysis were small.  The hypothesis generated from this study, that a longer duration of treatment may be beneficial for histologic outcome should be tested in a larger clinical trial.

Histologic improvement in relation to SVR and treatment duration


Treatment Duration (wk)


≥1 grade

≥1 stage

≥1 grade or ≥1 stage improved

x (%)


x (%)


x (%)





14 (93%)


1 (7%)


14 (93%)




76 (82%)

14 (15%)

79 (85%)




9 (29%)




9 (29%)




30 (42%

9 (13%)

36 (50%)










Topic:  Current HCV Therapies - General

M1855. Predictive Value of a 12 Week Follow-up HCV RNA on SVR in Chronic HCV Patients Treated with Peg/RBV. 

D. Friedman; S. Rashdan; C. D. Levine; J. Weinstein; R. H. Ghalib



The primary goal of HCV treatment is an SVR determined by a negative HCV RNA at 24 weeks after discontinuation of therapy. One report on early relapse rate in patients treated with standard IFN or Peg IFN monotherapy noted only 2% of patients became HCV RNA positive between 12 and 24 weeks after discontinuation of therapy. No data has been reported on early relapse rates following response to Peg IFN plus ribavirin therapy. Therefore this study was designed to assess the predictive value of the 12 week follow-up viral load in determining SVR.



This was a cohort study of HCV patients treated from 2003 to present. All patients who were HCV RNA undetected (<29 IU/mL) at the end of treatment with viral counts done at follow-up week 12 and 24 were included.



154 patients qualified for inclusion (89 men, 65 women). Age range was 18-79 (mean 48.7 ± 8.8). Race distribution was White 119 (77%), Black 12 (8%), Hispanic 16 (10%), and other 7 (5%). Fibrosis was stage 0-1 in 23, stage 2 in 38, stage 3 in 35, and stage 4 in 44 patients. Genotype distribution was 87 (56%) with 1, 43 (28%) with 2, 18 (12%) with 3, 4 (3%) with other. Duration of treatment in genotype 1 was 44-72 weeks (mean 49.1 ± 4.9) and genotype 2/3 was 12-60 weeks (mean 27.1 ± 11.6). This was the first treatment in 114 (74%) patients, 16 (10%) were relapser and 22 (14%) were nonresponders. Treatment was with Peg IFN alfa-2a in 58 (38%), Peg IFN alfa-2b in 70 (45%), and CIFN in 26 (17%). In predicting SVR (Table 1), the follow-up week 12 viral count had a sensitivity of 99%, specificity of 94%, PPV of 97%, and NPV of 98%. Follow-up 12 week viral count did not predict the SVR status in 4 patients all of whom had cirrhosis and were in their first treatment course. One patient positive at follow-up week 12 (HCV RNA 9000 IU/mL) later achieved an SVR. The accuracy of prediction in cirrhotics was sensitivity 95%, specificity 88%, PPV 86%, and NPV 95%.



A follow-up week 12 viral count is useful in predicting attainment of SVR and is 100% accurate in patients without cirrhosis. In this sample, 9% of patients with cirrhosis were misclassified by the follow-up week 12 viral count. Use of an earlier viral count in patients without cirrhosis would allow earlier retreatment for those with relapse and allow earlier confirmation of successful treatment.


Table 1: Post Treatment HCV Viral Counts in Patients with EOT Response







12 Week Follow-up HCV RNA














Topic:  Current Treatment - Pegasys

M1856. Treatment of chronic hepatitis C (CHC) with peginterferon alfa-2a (40kd) (PEG) and ribavirin (RBV) in patients older than 60 years 

U. Meyer; E. Zehnter; S. Mauss; K. Boeker; T. Lutz; S. Racky; W. Schmidt; R. Ullrich; I. Sbrijer; R. Heyne; A. Schober; C. John; K. Hey; B. Bokemeyer; B. Kallinowski; B. Moeller; S. Pape; U. Alshuth; D. Hueppe



In the US, Japan and Western Europe infection with hepatitis C becomes more and more an issue for patients older than 60 yrs. However the feasibility of treating these patients is still under discussion.



The Association of German independent Gastroenterologists (bng) in cooperation with Roche, Germany, is conducting a nationwide observational study to determine the quality of treatment for CHC in routine clinical practice. This ongoing study includes screening and treatment phases. Between March 2003 and May 2006 data from 11700 patients have been documented at > 500 centers. A cross sectional analysis for all pts > 60 yrs was done, who have started a treatment with PEG and RBV. Results of efficacy, tolerability and compliance were recorded.



1529 pts (13.1%) of the cohort were > 60 yrs. Of them 382 (25.0%) received treatment with PEG plus RBV. Demographic data of treated pts were: mean age 65.2 y, 43.5% male, BMI 26.1 kg/m2, severe fibrosis or cirrhosis (F3/F4, Desmet-Scheuer) 30.9%, GFR <90 ml/min/1.73m2 26.5%, concomitant diseases 65.7%, most frequently heart disease (52.6%), diabetes (16.7%) and diseases of the joints (10.8%), Caucasian 96.2%, mean duration of infection: 18.1y, source of infection (>1 answer possible): transfusion 35.6%, iv drug abuse 0.8%, medical action 16.5%, unknown 42.7%. Genotypes: 1(85.6%), 2(8.9%), 3(3.1%), 4/5/6(2.4%). As of May 2006 229/279 (82%) patients reached an Early Virological Response at week 12 (>=2-log10 drop in HCV RNA or HCV RNA undetectable). To date, 52.3% GT-1 (N=139/266) achieved EoT-Responses. Complete treatment data are available for 188 patients, who were treated according to consensus recommendations. Sustained Virological Response (SVR) was achieved by 68/188 pts (36.2%). 106/382 pts (27.8%) patients discontinued therapy: 49.1%, due to virological nonresponse, 46.2% for poor tolerability, 2.8% were lost to follow-up, 4.7% for personal reasons and 2.8% for lack of compliance. 37% of pts (especially with G1) got less than 80% of the cumulative PEG-dose for 48 weeks, this is the case for 46% of pts regarding RBV as well.



·        Comparing data of patients > 60 yrs with other usually studied populations reveal that due to poorer conditions at the beginning of treatment therapy has to be discontinued very often especially for poor tolerability.

·        In this group of patients another more careful action is necessary to prevent the escalation of adverse events leading to discontinuation.


Topic:  HIV/HCV Coinfection

M1857. Outcomes in a Multidisciplinary HIV/Hepatitis C Co-Infection Program: Validation of a Model of Care and Comparison with Major Clinical Trials. 

B. S. Zingman; H. Morales; F. Rodriguez; K. Freeman; T. Portzline; R. Cruz; L. Aliaga; R. Yanes; J. Shuter



A multidisciplinary HIV/Hepatitis C (HCV) Co-Infection Program was established in 2003 at the MMC AIDS Center’s Center for Positive Living/ID Clinic, an inner city clinic serving a largely poor and minority HIV+ population with 38% HCV co-infection.  The staff include a medical director, NP, patient educators, psychiatrist, substance use counselor, nutritionist, social worker, and statistician. Validation of this treatment model is needed, including demonstration of outcomes in comparison to major clinical trials of HCV treatment in co-infection.



This is a prospective evaluation. Standard treatment durations and dosing of pegylated interferon/ribavirin by HCV genotype (geno) were used. All treated patients are included including those retreated for failure. EVR=>1 log drop in HCV RNA at 12 wks; ETR=undetectable HCV RNA at completion of planned treatment; SVR=undetectable HCV RNA >6 months after ETR.


All analyses are ITT with censoring of: those on treatment <12 weeks could not be designated as EVR; EVRs who moved are unevaluable for ETR; ETRs who moved or are <6 months after ETR (“pending”) are unevaluable for SVR. Overall SVR Rates = %ETR x %SVR.



As of 9/30/06, 116 HCV treatment courses were initiated in 114 patients (74% male, 74% Hispanic, 75% HCV geno 1), with 38 in progress (13 under <12 wks treatment). See Table for treatment outcomes.


The Overall SVR Rates of the Program compare favorably to a 27% SVR rate (14% geno 1, 73% other genos) in Chung NEJM 2004; a 40% SVR rate (29% geno 1, 62% genos 2/3) in Torriani [APRICOT] NEJM 2004; and a 27% SVR rate (17% genos 1/4, 44% genos 2/3/5) in Carrat [RIBAVIC] JAMA 2004.



·        The Montefiore HIV/HCV Co-Infection Program’s multidisciplinary approach demonstrates outcomes comparable to major U.S. and international studies of HCV treatment in co-infected patients.

·        The Program’s results are especially notable given its inner-city population and inclusion of some with previous treatment failure.

·        The data suggest that this model, if widely replicated, could improve HCV treatment outcomes among co-infected patients.



All Evaluable

Evaluable Geno 1

Evaluable Geno 2/3/4


71/102 (70%)


25/25 (100%)


36/75 (48%)

19/57 (33%)

17/18 (94%)


20/31 (65%)

8/18 (44%)

12/13 (92%)

Overall SVR Rate

31% (95% CI 23-41%)

15% (95% CI 8-25%)

87% (95% CI 69-97%)




Topic:  Current HCV treatment – General

M1858. Cardiac stress test may not be indicated in patients with cardiac risk factors prior to antiviral therapy for chronic HCV. 

C. D. Abrasley; K. Lavu; G. K. Sood; W. D. Johnson; M. Azzouz



Antiviral therapy for chronic hepatitis C (HCV) is associated with ischemic cardiac morbidity including interferon associated toxicity and hypoperfusion related to anemia. Cardiac screening using stress testing is a routine practice prior to therapy in patients with risk factors considering that cardiac ischemia is a treatment exclusion criterion. Limited data exists on the validity of such practice and impact on treatment outcome and cost effectiveness.



A retrospective review of patients with HCV enrolled through our VA liver clinic 2002-2005 was performed. Data on 103 patients was analyzed including demographics, cardiac risk factors, and results of stress testing when applicable.  Patients with cardiac risk factors (age, hypertension, diabetes, family history, hyperlipidemia, tobacco use, abnormal EKG) underwent stress testing (exercise or nuclear) unless a recent heart catherization was done. Patients with abnormal stress test underwent further cardiac evaluation. Cardiac events including angina pectoris or myocardial infarction that occurred during or after therapy were analyzed.



A total of 103 patients, 52 blacks and 51 whites were included in this review with mean age of 50.3 ± 0.56. The mean BMI was 32.4 ± 3.84 with 52% having hypertension, 16% diabetes, 33% a family history of coronary artery disease (CAD), 27% hyperlipidemia, 64% tobacco use, and 19% having abnormal EKG. Three patients had stable documented CAD and received antiviral therapy without cardiac events. A total of 66 patients had pretreatment stress testing (exercise or nuclear) with 14 (21%) abnormal results. Cardiology evaluated all 14 patients and performed cardiac catherization on 11, and recommended medical therapy on 3. Only 1 of 11 catherizations was found to be abnormal with non-critical CAD. All patients received antiviral therapy and no cardiac events occurred during treatment.


Three patients had Acute Coronary Syndrome (ACS) 8 weeks to 2 years following therapy. All three patients were in the group with normal cardiac stress tests and none in the group with abnormal or no stress test. Thus, 3/52 negative stress test patients had ACS compared to 0/14 positive stress test patients.



Although the potential for adverse cardiac events exist for patients with HCV receiving antiviral therapy; the routine practice of pretreatment cardiac stress test in patients with cardiac risk factors may not be warranted as it did not impact cardiac outcome and added to the cost of therapy in our sample. A larger sample with prospective analysis is needed to support our conclusion


Topic:  Current HCV Treatment- general

M1859. Does RVR Predict SVR in Patients with Chronic HCV Genotype 2/3 Treated with Peginterferon and Ribavirin? 

S. Rashdan; D. Friedman; C. D. Levine; J. Weinstein; R. H. Ghalib



Response to current treatment for HCV has been defined by viral decrease at set times of 12 and 24 weeks of treatment. Previous studies have shown that genotype 1 patients with undetectable virus at week 4 of therapy (RVR) are more likely to achieve an SVR. The primary aim of this study was to determine the predictive value of the RVR for SVR in HCV genotype 2/3 patients treated with Peg/RBV.



This retrospective cohort study evaluated HCV genotype 2/3 patients treated between 2003 and 2006 at the Liver Institute at Methodist Dallas who had week 4 viral counts available. Nine patients were excluded for ESRD, coinfection with HIV, liver transplantation, and unavailable follow-up data.



The sample included 56 patients [39 genotype 2 (70%) and 17 genotype 3 (30%)]. There were 30 females (54%) and 26 males (46%) with a mean age of 47.8 ± 10.1 years.


The sample was predominately Caucasian (44, 79%) with 3 African Americans (5%), 7 Hispanics (13%) and 2 Asians (4%).


Mean BMI was 27.9 ± 5.4 with 22 (39%) having stage 3-4 on biopsy. Ten patients had received prior treatment. Patients were treated with Peg alfa-2a (26, 46%), Peg alfa-2b (24, 43%) and CIFN (6, 11%) and 38 (68%) received weight based ribavirin dosing. Viral responses by time points were: 77% RVR (n=43; 33/39 genotype 2 and 10/17 genotype 3); 98% EVR (n=55; 38/39 genotype 2 and 17/17 genotype 3); 70% SVR (n=39; 29/39 genotype 2 and 10/17 genotype 3). In patients who were EOT negative, the relapse rate was higher in the genotype 3 patients (38%) vs. genotype 2 (22%). Of the 43 patients with RVR, 34 (79%) achieved SVR compared to 5 (38%) of the 13 patients without RVR (p<.009; total sample PPV=79% and NPV=62%; genotype 2 PPV=79% and NPV 50%; genotype 3 PPV=80% and NPV=71%).


The association of other factors for SVR was tested in a logistic regression that identified fibrosis (S0-2 vs. S3-4), prior treatment, and ribavirin dose reduction (any reduction vs. none) as significant variables (-2 log likelihood 35.8; model Chi-square 18.9, df=3, p<.0001)



Analysis of HCV response in these genotype 2/3 patients revealed that those with an RVR were significantly more likely to achieve SVR. Other factors that were significantly associated with SVR were the stage of fibrosis, failing prior therapy, and any ribavirin dose reduction during treatment. No significant relationship was found for IFN drug, weight based ribavirin dosing, gender, BMI, genotype 2 vs. 3, or interferon dose reduction. Further investigation is indicated to determine treatment variations that may improve SVR in patients who do not achieve RVR.


Topic:  Current HCV Therapies – general

M1860. Peripheral Blood Leukocyte Ifnar-2 Expression in Aging Patients with Chronic Hepatitis C and an Effect of Ifn Therapy  

K. Ishii; K. Higami; K. Matsumaru; N. Takamura; H. Nagai; Y. Sumino; K. Miki



Age is well known to have influence on the efficacy of IFN therapy. We previously reported that the type 1 IFN receptor 2 (IFNAR-2) expression by leukocyte subsets, including lymphocytes (Ly), monocytes (Mo), and granulocytes (Gr), showed changes during IFN therapy in chronic hepatitis C (CHC) patients. The present study was performed to investigate IFNAR-2 expression by leukocyte subsets in aging patients with CHC during IFN therapy.


Patients and Methods:  

Thirty-five adults with biopsy-proven CHC (M/F: 22/13, an age between 21 and 71 years, a baseline serum HCV-RNA level quantified by RT-PCR between 0.5 and 730 KIU, and infection with HCV genotype 2a or 2b) were studied. Seven patients were treated with IFN-alpha alone (5-6MU), 15 patients with consensus IFN (12-18MU) alone, or 13 with IFN-alpha 2b (6MU) plus ribavirin (400-800 mg/day). All IFNs were administered daily for 2 weeks, followed by the same dose thrice weekly for 22 weeks. Patients were divided into 2 groups according their ages; a young group: 21 patients aged < 56 years (median age: 45; range: 28-56 years), and an old group: 14 patients aged > 57 years (median age: 64; range: 59-71 years). Blood samples were collected on days 0, 3, 7, and 14 of treatment. IFNAR-2 expression was determined by calculating the mean fluorescence intensity (MFI) after staining with an anti-IFNAR-2 antibody. Qualitative RT-PCR was tested at multiple times during and after treatment. When qualitative RT-PCR was negative at 24 weeks after the end of therapy, patient was defined as a sustained viral response (SVR). When that was positive, patient was defined as a non-SVR.



The baseline MFI of Ly, Mo, and Gr showed no significant differences between the 2 groups. The MFI of Mo increased to reach a peak on day 3 and thereafter decreased gradually in both groups. The MFI of Mo at days 3, 7, and 14 was significantly higher than at baseline in the young group, but that was significantly higher only at day 3 than at baseline in the old group. The MFI of Gr was decreased gradually in both groups, but only showing significant change in the young group. Negativity for serum qualitative HCV-RNA was seen in 17 (81%) patients from the young group and in 11 (79%) patients from the old group at week 2, and in 20 (95%) and in 12 (85%) patients at week 4, respectively. Finally, the SVR was obtained in 19 (90%) patients from the young group and in 12 (85%) patients from the old group.



Aging may blunt IFNAR-2 expression by Mo during an early phase of treatment, which  may be related to response to IFN and an early HCV clearance. However, aging did not affect SVR rate in CHC patients infected with genotype 2a or 2b.  So those patients should be considered for treatment regardless of their age.


Topic:  Current HCV Therapies – Pegasys

M1861. Efficacy and Safety of Peginterferon Alfa-2a/Ribavirin in Methadone Maintenance Patients: Randomized Comparison of Direct Observed Therapy and Self Administration 

H. L. Bonkovsky; A. Tice; R. G. Yapp; H. C. Bodenheimer; A. Monto; S. Rossi; M. S. Sulkowski



Treatment compliance is a challenge in treating patients with chronic hepatitis C (CHC) on methadone maintenance. To determine if direct observed therapy (DOT) enhances compliance relative to self administration (SA), a prospective, open label, multicenter, randomized pilot study of the safety, feasibility and tolerability of peginterferon alfa-2a/ribavirin treatment was performed in patients in methadone maintenance programs not previously treated for CHC.



Patients were randomized 1:1 to directly observed therapy or self administration. Directly observed therapy patients were seen every week for 48 weeks at methadone clinics, whereas self administration patients were seen per assessment schedule and only at the investigative sites. Patients infected with HCV genotype 1 were treated for 48 wks with peginterferon alfa-2a (180 μg/wk) plus ribavirin (1000/1200 mg/d), whereas patients infected with HCV genotypes 2 and 3 were treated for 24 wks with peginterferon alfa-2a (180 μg/wk) plus ribavirin (800 mg/d).



Patients randomized to the two groups were well matched for sex, age, race/ethnicity, baseline serum [HCV RNA], body mass index (BMI), and HCV genotypes.


The Table shows SVR rates by group and HCV genotype.  Stepwise logistic regression analysis, using as factors treatment (SA vs DOT), gender, age (≤40 vs >40 yrs),  genotype (1 vs 2,3), race (Caucasian vs other), baseline [HCV RNA] (≤800,000 vs >800,000 IU/mL), and ALT (≤90 vs >90 U/L), showed that DOT treatment was the only significant predictor of SVR (OR 4.3, 95% CI 1.06-17.3, P=.042) and Caucasian race (OR 10.8, 95% CI 1.13-104, P=.039).   Based on defined efficacy stopping rules, 77% (37/48) completed the prescribed length of therapy. Two directly observed therapy and 3 self administered patients were withdrawn for adverse events, while 6 and 9, respectively, were withdrawn for non-safety reasons. The most common adverse events in both groups were fatigue, nausea, depression, and headache.



·        Patients in methadone maintenance programs can be treated safely and successfully with peginterferon alfa-2a plus ribavirin for chronic hepatitis C while continuing methadone treatment.

·        Overall SVR rates and rates of patient dropout, discontinuance, and dose adjustments similar to other studies in methadone maintenance patients.

·        The DOT group had a higher SVR rate than the SA group.

·        The DOT group also had lower postbaseline BDI-II scores than the SA group

o       Occurrence of higher SVR and lower postbaseline BDI-II score in the DOT group (may or may not indicate correlation).

o       Need to condu7ct trials in larger number of patients.

o       Treatment with peginterfeorn alfa-2a once weekly, at the methadone maintenance clinic, is an efficient way to administer both medications at the same time.


These findings suggest that peginterferon alfa-2a/ribavirin can be used safely and successfully to treat CHC patients on methadone maintenance. Moreover, there may be a benefit of directly observed therapy in this challenging population. Further studies are warranted.


% SVR (n/N)

HCV Genotype

All Patients (N=48)

DOT Group (n=24)

SA Group (n=24)


44% (21/48)

54% (13/24)

33% (8/24)


31% (9/29)

23% (3/13)

38% (6/16)


63% (12/19)

91% (10/11)

25% (2/8)









Topic:  Current HCV Treatment – Side Effects

M1862. Improvement in Adherence to Therapy, Adverse Events (AEs) and Quality of Life (QOL) in Patients with Chronic Hepatitis C Treated with Pegylated Interferon Plus RibaPak™ Compared with Pegylated Interferon Plus Ribavirin. 

M. Palmer



Adherence to pegylated interferon (PIFN) plus ribavirin (RBV) has been shown to be a crucial factor in achieving early virologic response (EVR) and subsequently sustained virologic response (SVR) in patients with hepatitis C (HCV). Studies have shown that adherence to RBV, especially in the first 12 wks of therapy, may be more important than adherence to PIFN. In the HIV patient population, fewer pills required/day results in better adherence, improved results, and improved QOL. RibaPak (RBP) is a 400 mg and/or 600 mg RBV tablet that requires up to 66% fewer tablets than RBV (200mg).


This study was undertaken to determine if simplifying the dosing regimen of RBV has an impact on adherence, AEs and QOL in HCV patients on combination therapy.



From May - Nov 2006, 107 patients were identified who were on treatment with RBP and PIFN. 92 patients met the following requirements: RBP for ≥12 wks and complete data for comparison. Pts. were divided into 3 groups:

·        Group A (n= 22): Treatment experienced (n=8 relapsed, n= 5 nonresponder, n=9 early termination due to AEs or noncompliance) with PIFN plus RBV,

·        Group B (n= 49): Treatment naïve -pts switched to RBP after ≥12 wks RBV, and

·        Group C (n=21): Treatment naïve pts on RBP for ≥12 wks. Groups A and B were evaluated q4 wks X ≥ 12 wks for: AEs, adherence, drug preference and QOL. Group C was evaluated for adherence.

·        Group D (n=21): Control group – consecutive matched Naive patients on  weeks on PINFN plus RBV.



·        Group A: 7 pts reported less AEs (nausea, dyspepsia, loss of appetite (LOA) and/or weight loss) on RBP. 27 missed RBV vs 3 missed RBP in the 1st 12 weeks of respective therapies. 15 pts preferred RBP due to simplification of regimen or diminished AEs. 7 pts found no difference in treatment regimens. 14 pts reported improved QOL on RBP.

·        Group B: 17 pts reported less AEs. 11 missed RBV vs 0 RBP. 40 preferred RBP/9 no difference. 37 improved QOL.

·        Group C: 1 missed RBP; 5 missed ribavirin.



·        In all 3 groups there is a trend toward:

o       Diminished AE’s mostly GI, in patients taking BRP

o       Improved QOL in patients taking RBP

o       Improved adherence in patients, taking RBP

o       Less concomitant medication use

o       Patient preference for RBP


Topic:   Current HCV Therapies – side effects

M1863. Prevalence and Risk Factors of Thyroid Disease in Patients Treated For Hepatitis C Virus. 

H. Wiesinger; J. Amar; H. Chaun; R. A. Enns; L. Halparin; B. McDougall; S. Whittaker; A. S. Ramji



An increased incidence of thyroid disease in patients with hepatitis C treated with interferon-α monotherapy or combination with ribavarin for has been described. However predictive factors for developing thyroid complications in this population is not well described, particularly when using pegylated interferon in combination with ribavirin.



To determine the prevalence and predictive factors of thyroid disease in patients with hepatitis C treated with combination pegylated interferon/ribavirin compared to those treated with an interferon-α/ribavarin combination.



A retrospective analysis of all hepatitis C patients treated with combination pegylated interferon-α2b and ribavirin or interferon-α/ribavarin from 1995 to 2005 at a tertiary care centre was conducted. Patients were separated into two groups: (a) those with no thyroid abnormalities during therapy; and (b) patients with a change from normal to abnormal TSH levels, or those requiring treatment for either hyper- or hypothyroidism. The two groups were compared for predictive factors including: demographics, HCV genotype, stage of disease, and therapy type.



Of 137 patients, 26 (19%) developed abnormal TSH during their treatment. Eight of these patients required treatment for either hyper- or hypothyroidism. Twenty two of 26 patients (85%) developed thyroid abnormalities within the first 24 weeks of treatment, with 38% occurring in the first 12 weeks. Females were affected more than males (31.6% vs 14.1%, respectively, p=0.02). Thyroid dysfunction occurred more frequently in patients treated with pegylated interferon than those treated with a non-pegylated formulation (27.1% vs 12.8%, respectively, p=0.035). Genotype, biopsy stage and response to treatment were not predictive of thyroid abnormalities.



Thyroid function abnormalities are more common in patients treated with pegylated interferon/ribavirin than in those with interferon/ribavirin, and more prevalent early in treatment course.  This may be due to the sustained serum concentration of pegylated interferon.  Thyroid function testing should be done at baseline and frequently throughout treatment.  TSH abnormalities should be investigated and treated accordingly. 


Topic:  Current HCV Therapies – General

M1864. Predictors of Treatment Among Patients With Chronic Hepatitis C Virus Infection. 

F. Kanwal; T. Hoang; B. M. Spiegel; S. Eisen; A. Gifford; S. M. Asch



Chronic infection with hepatitis C virus (HCV) is a prevalent and expensive condition affecting 1.3% of the US population. Of these, approximately one-third are eligible for anti-viral therapy based on standard inclusion and exclusion criteria for treatment. It is unclear how many of these eligible patients receive anti-viral treatment, and whether the receipt of anti-viral treatment is associated with patient characteristics, provider experience, and facility factors. We performed a retrospective analysis in the Veterans Administration (VA) system to identify predictors of treatment receipt in a large cohort of patients with chronic HCV.



Using administrative and clinical data from 5 VA Medical Centers in Southern California, we conducted a retrospective cohort study of 14,275 HCV patients who were seen between 01/2000-12/2005. We defined patients as being eligible for HCV treatment if they had ≥1 positive HCV RNA test, had ≥2 visits/year to the treating facility, and did not have absolute or relative contra-indications to HCV treatment as specified in the AASLD guidelines (e.g., decompensated liver disease, solid organ transplantation, severe medical illness or depression etc.). Using logistic regression analysis, we identified patient, provider, and facility-level predictors of treatment receipt.



6,686 (46.8%) of 14,275 HCV patients met our a-priori criteria for treament “eligibility.” Of these, 3,226 (48%) were seen by a specialists, of whom 697 (10.5%) received treatment. Treatment rates varied from 3% to 15% across the 5 facilities. Significant predictors of treatment receipt included lower patient age (β=-0.03, p<0.0001), presence of cirrhosis (β=1.15, p<0.0001), lower ALT (β=-0.152, p<0.0001), higher hemoglobin (β=0.26, p<0.0001), and lower platelet count (β=-0.002, p=.01). In addition, treatment rates were 3 times higher among providers who treated >20 patients per year versus providers with lower annual treatment numbers. Patients seen at the facilities with the lower treatment rate were 18% less likely to receive treatment compared to those seen at the facilities with a higher treatment rate.



HCV patients who are younger, have cirrhosis, and are seen by more experienced providers at facilities with high treatment rates appear more likely to receive treatment. These data suggest that although patient characteristics are important predictors of treatment in HCV, most of the variation in treatment rates is explained by system-level factors. These potentially modifiable system-level factors are high-yield targets for future quality improvement initiatives in HCV.


Topic:  Current HCV Treatment – General

M1866. Antiviral Completion Rates and Sustained Viral Response in Hepatitis C Patients with- versus without- Pre-existing Major Depressive Disorder. 

P. Hauser



To determine and compare antiviral completion and sustained virologic response (SVR) rates between hepatitis C (HCV) patients with- versus those without pre-existing major depressive disorder (MDD). As HCV patients with MDD are often excluded from antiviral therapy because of the presumed risk of worsening depressive symptoms secondary to interferon our objective was to examine the validity of this assumption.



We conducted a retrospective chart review of all patients treated for HCV at the Portland VA Medical Center who signed informed consent allowing collection and analysis of clinical data from electronic medical records. We collected data on genotype, pre-treatment psychiatric diagnosis and antidepressant use, antiviral therapy, side effects, emergency room (ER) visits and in-patient hospitalizations during treatment, as well as completion and SVR. Patients were divided into two groups- MDD (patients who had a pre- antiviral treatment diagnosis of MDD and were taking antidepressant medication at least 3 months prior to starting antiviral treatment), and controls (no MDD- patients who did not have a pre-antiviral treatment diagnosis of MDD and had been antidepressant free for at least 3 months prior to starting antiviral treatment).



Relative to the control group, the MDD group had a similar percent of patients that were genotype 1. There was no significant difference between groups in the percent of patients who had ER visits (MDD- 9/30 or 30% versus controls- 4/25 or 16%) or required in-patient hospitalization (MDD- 2/30 or 7% versus controls- 2/25 or 8%). Only one MDD patient had an ER visit for psychiatric reasons and no MDD patients attempted suicide. Side effects and reasons for discontinuation of antiviral treatment were not different between groups. Also there were no differences between groups in antiviral treatment completion rates (MDD- 18/30 or 60% versus controls - 17/25 or 68%) or SVR (MDD- 15/30 or 50% versus controls - 13/25 or 52%).



The results of our retrospective chart review suggest that patients with pre-antiviral treatment MDD on antidepressants are no more likely than patients without MDD to have side effects or adverse events during antiviral treatment. Furthermore, patients with MDD have similar completion and SVR rates. Our results suggest that patients with MDD can be safely and effectively treated with antiviral therapy using an integrated care model involving mental health care providers.


Topic:  Current HCV Therapies – Disease Progression

M1867. Change of Serum Cholesterol Fractions In Patients With Chronic Hepatitis C After Sustained Viral Response To Ifn Therapy 

K. Ishii; N. Takamura; K. Higami; K. Matsumaru; T. Ikehara; H. NAGAI; M. Watanabe; Y. Sumino; K. Miki



Chronic hepatitis C virus infection (HCV) is suggested to have relationship with host lipid metabolism. Several IFN regimens are active against chronic hepatitis hepatitis C (CHC). The goal of this study was to clarify change of host lipid metabolism in patients with sustained viral response (SVR) by several IFN therapy regimens.


Patients and Methods:  

Thirty-six adult patients with biopsy-proven CHC were studied. The