Saturday Poster Sessions, October 28, 2006

HCV: Pathogenesis

#271. Immunization with Hepatitis C Virus-Like Particles Induces Partial Protection against Hepatitis C Virus Infection in Chimpanzees.

G. A. Elmowalid; M. Qiao ; S. Jeong ; B. Borg; T. Baumert; R. Sapp; K. Murthy; Z. Hu; J. Liang.

 

Introduction:

Recombinant hepatitis C virus-like particles (HCV-LP) containing HCV structural proteins (core, E1, and E2) produced in insect cells resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice and baboons.

Aim:

Here we present evidence on the immunogenicity and induction of protective immunity by HCV-LP in chimpanzees.

 

Methods:

Two groups of two chimpanzees each were immunized with HCV-LP or HCV-LP + adjuvant ASO1B (a lipid-based adjuvant from GSK).

 

Results:

After four immunizations over an eight-month period, all animals developed strong HCV-specific cellular immune response including IFN-γ+CD4+ and IFN-γ+CD8+ T-cell and proliferative lymphocyte responses against core, E1 and E2. The immunogenicity of HCV-LP was not enhanced by the adjuvant. The chimpanzees in both groups were challenged with 100 CID 50 of HCV CG1B inoculum. Upon challenge with HCV, one chimpanzee developed transient viremia with low HCV RNA titers (~104 copies/ml) in the third and fourth weeks post-challenge. The three other chimpanzees became infected with higher levels of viremia (up to 10 5 copies/ml) but their viral levels became unquantifiable ( 600 copies/ml) ten to twelve weeks post-challenge. After HCV challenge, all four chimpanzees demonstrated a significant increase in both peripheral IFN-γ+ and IL-2+ T-cell and proliferative responses as well as the presence of intrahepatic T-cell response against the HCV structural proteins. The T-cell responses against various nonstructural proteins also became detectable within 3 weeks after infection. These T-cell responses coincided with the fall in HCV RNA level. Previously, three other naďve chimpanzees have been challenged with the same HCV inoculum at lower CID50 (3-10). One cleared the infection and two developed persistent infection with viremia in the range of 105-6 copies/ml.

 

Conclusion:

Our results suggest that HCV-LP immunization induces strong HCV-specific cellular immune responses and confers partial protection against HCV challenge in the chimpanzee model.

 


#277. Mouse Model for HCV Pathogenesis.

R. Witek; J. R. Bess; J. Dong; J. S. Elyar; C. Liu.

 

Introduction:

Hepatitis C virus (HCV) infection is a major health threat in the world. An estimated 170 million people are infected with the virus. Although it has been postulated that the host immune system plays a role in pathogenesis, the interaction of the virus and the host immune system remains obscure. One major obstacle to HCV investigations is the lack of a robust small animal model. Considering the vast amount of knowledge on mouse immune system, availability of a reliable murine model for HCV undoubtedly has a great advantage.

 

Aim:

The current research tests the feasibility of developing an animal model to study HCV immunopathogenesis.

 

Methods:

The experimental design utilized repopulation of mouse (Balb/cJ) livers with an HCV positive CG1b cell line (hepatocytes derived from Balb/cJ mouse) following partial hepatectomy (PHx) and monocrotaline (MCT) pre-treatment. MCT blocks endogenous hepatocyte proliferation, thus providing a proliferative advantage to the transplanted cells. Since the mice used in the experiment are immune competent, the effects of the immune system on HCV positive hepatocytes and their effects on liver pathology was systemically investigated by performing histological stainings and molecular analysis by RT-PCR.

 

Results:

In the first part of the experiment, HCV positive CG1b cell line was established by stably transfecting immortalized male BNL murine hepatocyte cell line with HCV-ribozyme based expression plasmid pEHr/Neo containing full-length HCV RNA genome. The RT-PCR analysis of the BNL-CG1b cell line reveals high expression of HCV RNA, and Western Blot shows expression of NS5a proteins. In the second part of the experiment, transplantation of BNL-CG1b cells led to liver repopulation in BALB/cJ mice verified by SRY analysis at 30 days post transplantation. H&E examination of liver tissue revealed increasing levels of inflammation and fibrosis progressing with time post transplantation (30, 60, and 90 days). However, SRY was not detected at 60 and 90 days.

 

Conclusion:

The results presented in the current study support the feasibility of creating a small animal model for HCV pathogenicity utilizing BNL-CG1b cell transplantation to MCT/PHx treated animals. The inflammation, lymphocytic infiltration and liver fibrosis observed in the experimental mice conform to liver pathology observed in patients with chronic HCV. It is possible that transplanted BNL-CG1b cells are invoking CD8+ CTL response (day 30) that led to the initial clearance of HCV producing cells (day 60).

 

The presented animal model offers an innovative approach to investigate HCV immunology and will be used for future studies to elucidate mechanisms of HCV liver immunopathogenesis.

 


#282. Persistence of hepatitis C virus (HCV) in chimpanzees is associated with a loss of intrahepatic T cell function during the late acute phase.

H. Watanabe; M. E. Major.

 

Background:

Infection with HCV frequently leads to chronic hepatitis and cirrhosis and is associated with hepatocellular carcinoma. The liver is the primary site of viral replication therefore we undertook a detailed intrahepatic study of the dynamics of T-cells, apoptosis, and gene expression during the acute phase of HCV infection in chimpanzees.

 

Methods:

We examined sequential liver biopsies from chimpanzees that developed persistent infection or spontaneously cleared the virus and correlated this data with viral kinetics and clinical signs of hepatitis. Studies used formalin-fixed biopsies and RNA extracted from frozen liver tissue. T cell infiltration was assessed in liver sections using antibodies specific for CD4 or CD8 and H&E staining. Apoptosis was assessed using a TUNEL assay and M30 antigen staining. Real-time PCR was used to assess mRNA levels for specific response genes.

 

Results:

Several features were common to all animals regardless of disease outcome. Using histological analyses we observed increased intrahepatic T-cell infiltration (5-10-fold above baseline) in both groups of animals with CD8+ T-cells representing the major population throughout infection. In some cases the onset of T-cell infiltration was early (2 weeks post infection) but in all animals the appearance of immune T cells was associated with liver apoptosis and mild ALT elevations. In all animals apoptosis (5-20% of liver cells) occurred prior to the ALT peak with no direct correlation between maximal apoptosis and peak ALT. Major differences associated with outcome were observed during the late acute phase. Liver biopsies from cleared animals showed an increased frequency of apoptosis, relative to persistently infected animals, which correlated with increased intrahepatic CD8+ T cell frequency (8-10-fold above baseline) in this group. Up to 20% of the infiltrating T cells observed during the late acute phase in the cleared animals stained positive for perforin expression whereas only 1-2% of liver infiltrating T cells in the persistently infected groups at this same time point were perforin positive.

 

Conclusions:

These data support the hypothesis that although both groups of animals mount immune responses during the acute phase these are not maintained in frequency or efficacy in animals that develop persistent infections. There is ongoing intrahepatic immune control of replication in the animals that clear virus but there is a reduction in both the numbers of T cells infiltrating the liver during the late acute phase in animals that develop persistent infections and significantly fewer of these cells are functional in clearing the virus by inducing apoptosis.


#292. Altered Hepatic Metabolic Function in Patients with Chronic Hepatitis C is Associated with Obesity, Insulin Resistance, or Hepatic Steatosis, Independent of Cirrhosis: Results from the HALT-C Trial.

G. T. Everson; C. C. Kulig; M. L. Shiffman; R. K. Sterling; T. R. Morgan; J. C. Hoefs; T. M. Curto; J. E. Everhart; D. Wagner.

 

Introduction:

 

Hepatic dysfunction in patients with chronic hepatitis C (CHC) could be related to metabolic effects of obesity, insulin resistance (IR), or hepatic steatosis, or underlying cirrhosis. In our study, we used multiple quantitative tests (QLFTs) and controlled for cirrhosis, to define associations of obesity, IR, and hepatic steatosis with altered hepatic function.

 

Patients and Methods:

All patients (N=285) were enrolled in the Hepatitis C Antiviral Long-Term Treatment to Prevent Cirrhosis (HALT-C) Trial. Patients had either bridging fibrosis (Ishak fibrosis score 3 or 4) or compensated cirrhosis (Ishak fibrosis score 5 or 6, 40%), 92% were infected with genotype 1, and all had failed prior treatment with interferon or interferon/ribavirin. Test compounds were given intravenously (lidocaine, 0.5mg/kg, galactose, 30g, [24-13C]cholate, 20mg, technetium sulfur colloid, 5mCi) and orally (antipyrine, 500mg, caffeine 300mg, [1-13C]methionine, 200 mg, [2,2,4,4-2H]cholate, 40mg). Caffeine elimination (Cf kelim), antipyrine elimination (AP kelim) and clearance (AP Cl), and MEGX formation quantified microsomal function. Methionine breath test (MBT) quantified mitochondrial function. Galactose elimination capacity (GEC) assessed cytosolic metabolism and blood flow. Clearance of orally administered cholate (CA Cloral), cholate shunt (CA Shunt), and perfused hepatic mass (PHM) measured by SPECT liver-spleen scan assessed portal inflow and shunt. Body mass index (BMI), insulin resistance (homeostasis model assessment (HOMA) = {[Glucose, mmol/L] x [Insulin, µU/ml]} / 22.5), and hepatic steatosis (graded 0, 1, 2, 3 by panel of HALT-C pathologists) were the independent variables.

 

Results:

Relationships between QLFTs and quartiles of BMI or HOMA, or grades of steatosis, were analyzed by ANOVA with a test for trend. BMI quartiles were associated inversely with MBT (P=0.03) and GEC (P<0.0001). HOMA quartiles were associated inversely with AP kelim (P<0.0001), AP Cl (P=0.03), MBT (P=0.0007), GEC (P=0.0001), PHM (P=0.0002), CA Cloral (P=0.002), and directly with CA Shunt (P=0.006). Hepatic steatosis was associated inversely with both AP Cl (P=0.05) and MBT (P=0.0006). After controlling for cirrhosis, the remaining significant relationships were BMI with GEC (P<0.0001), HOMA with GEC (P=0.04) and AP kelim (P=0.0004), and hepatic steatosis with AP Cl (P=0.02) and MBT (P=0.02).

 

Conclusion:

Altered hepatic metabolic function in patients with CHC is associated with obesity and insulin resistance, independent of cirrhosis. Hepatic steatosis, but not obesity or insulin resistance, is associated with impaired hepatic mitochondrial function.

 


#295. The Role of Hepatitis C Genotype 3 Core Protein Domain 3 in Intrahepatic Steatosis.

R. Jhaveri; J. G. McHutchison; K. Patel; A. Diehl.

 

Background:

Steatosis is a common histological finding and a poor prognostic indicator in patients with Hepatitis C virus (HCV) infection. The etiology of steatosis is multifactorial, but appears to be closely correlated with unknown viral factors in HCV genotype 3 infected patients. We previously identified novel amino acid polymorphisms at residues 182/186 within domain 3 of HCV Core protein that correlate with intrahepatic steatosis in a well characterized group of HCV genotype 3a infected patients. The combination of leucine-isoleucine (LI) and phenylalanine-valine (FV) at these positions correlated with steatosis while phenylalanine-isoleucine (FI) correlated with the absence of steatosis. In this project, we expressed these patient derived clones and corresponding mutants to examine if lipid accumulation occurred in cultured liver cell lines.

 

Methods:

We transfected human and rat liver cell lines with steatosis and non-steatosis associated HCV genotype 3a Core clones. Transfected cells were then stained using a combined immunofluorescence and oil red o protocol. Cells were analyzed using MetaMorph software that quantified the amount of oil red o in cells expressing HCV Core protein.

 

Results:

Expression of all the HCV Core isolates led to increased intracellular lipid compared to controls in 5H cells at transfection efficiency of 5%. Expression of a steatosis-associated clone (FV) led to significantly more intracellular lipid in transfected cells when compared with a non-steatosis clone (FI) (11.4%±6.7% vs. 7.8%±3.3%; p=0.02). Expression of a mutant designed to reverse the steatosis phenotype (FV to FI) resulted in a 27% decrease in the amount of intracellular lipid compared to the parent clone (11.4%±6.7% vs. 8.3%±4.8%; p=0.03). Mutation of another steatosis-associated clone (LI to FI) resulted in a 37% decrease in intracellular lipid compared to its parent clone (p=0.01).

 

Conclusions:

We have verified the importance of specific amino acids within domain 3 of HCV Core protein genotype 3a in altering host lipid metabolism and/or trafficking. Future work will attempt to identify the mechanisms involved.

 

 

Sample image of HCV Core expression and Oil Red staining.

 


#308. The Hepatitis C Virus Core Protein of Genotypes 1B and 3A Down-Regulate Insulin Receptor Substrate 1 via Genotype-Specific Mechanisms.

V. Pazienza; S. Clément; P. Pugnale; S. Conzelmann; M. Foti; A. Mangia; F. Negro.

 

Background/Aims:

Both molecular and clinical evidence support a link between the hepatitis C virus (HCV) infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 1b and 3a with the insulin signalling pathway.

 

Methods:

We measured the levels of insulin receptor substrate 1 (IRS-1), IRS-2 and other factors involved in the insulin signal transduction in human hepatoma cells (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by different molecular biology and immunofluorescence techniques.

 

Results:

IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotype 3a (P= 0.0067) and 1b (P= 0.04) as compared to cells transfected with the empty pIRES2-EGFP vector. IRS-1 degradation was associated with an increased phosphorylation at Ser636/639. However, whereas the core protein of genotype 3a promoted IRS-1 degradation by upregulating the suppressor of cytokine signal 7 (SOCS-7) and the downregulation of peroxisome proliferator-activated receptor γ (PPARγ), the downregulation of IRS-1 by the core protein of genotype 1b proceeded through the activation of the mammalian target of rapamycin (mTOR). These findings were confirmed by using specific inhibitors (siRNAs for SOCS-7, rapamycin for mTOR) or agonists (rosiglitazone for PPARγ).

 

Conclusions:

Despite the little sequence divergence of the HCV core proteins of genotypes 3a and 1b, the two proteins seem to interfere with the in vitro insulin signaling using genotype-specific mechanisms. This, coupled with mounting clinical evidence, suggests an evolutionary advantage for HCV to maintain an insulin resistant state.

 


#310. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C.

J. M. Pestka; M. B. Zeisel; P. Schürmann; B. Bartosch; F. Cosset; A. H. Patel; H. Meisel; J. Baumert; S. Viazov; K. Rispeter; H. E. Blum; M. Roggendorf; T. F. Baumert.

 

Background and aim:

In contrast to a detailed understanding of antiviral cellular immune responses, the impact of neutralizing antibodies for resolution of acute hepatitis C is poorly defined. The analysis of neutralizing responses has been hampered by the fact that patient cohorts as well as HCV strains are usually heterogeneous and that clinical data from acute-phase and long-term follow-up after infection are not easily available.

 

Methods:

Using an infectious retroviral HCV pseudo-particle model system, we studied a cohort of women accidentally exposed to the same HCV strain of known sequence.

 

Results:

In this single-source outbreak of hepatitis C virus infection in East Germany 1978-1979, viral clearance was associated with a rapid induction of neutralizing antibodies in the early phase of infection. Neutralizing antibodies decreased or disappeared following recovery from HCV infection. In contrast, chronic HCV infection was characterized by absent or low-titer neutralizing antibodies in the early phase of infection and persistence of infection despite the induction of cross-neutralizing antibodies in the late phase of infection.

 

Conclusions:

These data indicate that rapid induction of neutralizing antibodies during the early phase of infection may play an important role for control of viral infection and contribute to HCV clearance. This finding may have important implications for understanding of the pathogenesis of HCV infection and the development of novel preventive and therapeutic antiviral strategies.

 


#313. Insulin Resistance and Liver Fibrosis in Virus C Chronic Hepatitis and in Nonalcoholic Fatty Liver Disease.

G. Svegliati-Baroni; E. Bugianesi; E. Peruzzi; F. Ridolfi; F. Tarsetti; F. Ancarani; E. Petrelli; E. Brunelli; M. Lo Cascio; M. Rizzetto; G. Marchesini; A. Benedetti.

 

Background:

Insulin resistance, the hallmark of nonalcoholic fatty liver disease (NAFLD), is also frequently found in patients with chronic HCV hepatitis (CHC), and has been associated with histological liver damage (steatosis and fibrosis).

 

Aims:

To examine the relationship between histological findings and biochemical parameters of insulin resistance in CHC and NAFLD patients.

 

Methods:

We assessed the degree of basal insulin resistance (by the homeostasis model assessment, HOMA-R) and post-load insulin sensitivity (by the oral glucose insulin sensitivity index, OGIS) in 90 patients with CHC (23 genotype 3) and in 90 pair-matched patients with NAFLD. Basal and post-load insulin resistance were defined as HOMA-R ≥ 2.7 and OGIS ≤ 9.8 ml/kg*min, respectively corresponding to the upper and lower quartile of a control population. Steatosis was scored according to Brunt in both groups, fibrosis according to Brunt in NAFLD and to Ishak in CHC.

 

Results:

Severe steatosis (grade 3) was associated with HOMA-R (OR 4.42; CI 1.16-16.85; P=0.029) in NAFLD and with HOMA-R (OR 14.87; CI 1.17-89.70; P=0.038) and OGIS (OR 7.43; CI 1.25-44.07; P0.027) in genotype non-3 CHC, but not in genotype 3. After adjustment for age, gender and BMI, in NAFLD severe fibrosis ( stage 3-4) was predicted by elevated aminotransferases, fasting hyperglycemia, basal and post-load insulin resistance and steatosis at univariate analysis, but only by OGIS ≤ 9.8 (0.56; 0.35 – 0.91; P = 0.019) at multivariate analysis. In CHC, OGIS ≤ 9.8 (OR 9.43; CI 1.43-62.13; P=0.020) was the sole independent predictor of severe (stage 4-6) fibrosis. When split according to genotype, post-load insulin resistance was associated with severe fibrosis only in genotype non-3 patients.

 

Conclusions:

Post-load insulin resistance (OGIS ≤ 9.8 ml/kg*min) is an independent predictor of severe fibrosis in NAFLD and genotype non-3 CHC and represents a useful tool to select patients who may benefit of insulin-sensitizing therapy.

 


#317. Inhibition of Hepatitis C viral (HCV) replication by in-vivo dimerization of STAT1.

X. Li; H. Zhu; M. Butera; D. R. Nelson; C. Liu.

 

Background:  

It is known that type I interferons (IFN) induce intracellular antiviral state via the JAK-STAT signaling pathway. Dimerization of STAT1, STAT2, and STAT3 are key steps in this pathway. However, the precise role for each individual STAT in antiviral defense is not completely defined.

 

Aim:  

The goal of this study is to determine the role of STAT1 homodimers in the establishment of intracellular antiviral activity.

 

Methods:  

To create an inducible STAT1 dimerization system, STAT 1 open reading frame is fused with estrogen receptor (ER) domain, resulting in STAT1-ER fusion expression construct. The fusion protein dimerization is inducible by estrogen analog (4-HT). The construct was then transfected into HCV replicon cell line, FL-Neo. Various doses of 4-HT were incubated with the cells and the STAT1-ER dimerization was monitored by Western blot analysis using an anti-STAT1 antibody. The target genes of the STAT1 dimers were examined by cDNA microarray analysis and real-time RT-PCR assay. The effect of STAT1 homodimers on HCV replication was determined by HCV-specific real-time RT-PCR assay.

 

Results:  

The STAT1-ER fusion protein formed homodimers with 4-HT stimulation. The amount of dimers is positively correlated with the doses of 4-HT. By transfection assay, the formation of STAT1 homodimers substantially inhibited HCV full-length RNA in correlation with the formation of homodimers indicating the establishment of antiviral activity in the replicon cells. The dimmers also induced many interferon-stimulated genes (ISGs) in human hepatoma cells.

 

Conclusions:  

We have established an inducible and cytokine-independent STAT1 activation system. This system would provide a valuable tool to understand the molecular events triggering the intracellular anti-HCV activity in liver cells. The system would also allow us to identify STAT1-specific target genes.

 


#318. Hepatitis C virus is present in CD4+ T cells of chronically infected patients impairing their IFN-g production.

A. Perrella; A. D'Antonio; C. Esposito; D. Vergani; S. Grattacaso; C. Sbreglia; L. Atripladi; A. Di Spirito; D. Guarnaccia; O. Perrella.

 

Background/Aim:

HCV, a hepatotropic RNA virus responsible for frequent evolution to chronic hepatitis, impairs IFN- gamma production by T helper 1 lymphocytes (Tsai T et al. Hepatology 1999). HCV has been recently shown to infect B cells, monocytes and dendritic cells. We aimed to investigate whether HCV also infects CD4+ T lymphocytes, replicates in them, and influences IFN-gamma production.

 

Methods:

We enrolled 20 patients with histologically proven (Grade 10, Stage 2) chronic hepatitis C (CHC) (Group A) and 10 healthy blood donors as controls (Group B). We measured HCV-RNA by real-time PCR (Amplicore Roche 2.5 qualitative and quantitative system; cut off 50 IU/mL and 600 IU/mL respectively) in PBMC and CD4+ T cells (Dynal CD4+ separation kit; purity ≥90%) before, after 6-day stimulation with HCV (Core and NS3) and Influenza A (InfMp) peptides (2mcg/mL each), and after a further 2-days stimulation with PMA and ionomicin. IFN-gamma production by CD4+ T cells was assessed by an ELISpot assay (PMA and Ionomicin stimulation).

 

Results:

PBMC and CD4+ T cells from CHC patients were positive for HCV-RNA by qualitative assay before stimulation with HCV peptides, while healthy donors were negative. After 6-day stimulation, HCV-RNA was detectable by both qualitative and quantitative assay (752 +/- 46 IU/mL) in CD4+ T cells exposed to HCV peptides but not in those exposed to InfMp peptides. HCV-RNA levels in CD4 cells increased to 1856 +/- 125 IU/mL after further stimulation with PMA ionomicin, these cells showing a reduced IFN-gamma production compared to CD4+ T cells stimulated with InfMp viral peptide (188 +/- 82 vs 322 +/- 128 SFC - U Mann Whitney p < 0.01)

 

Conclusion:

These preliminary results show that in patients with CHC, the virus is present and replicates in CD4+ T cells impairing their IFN-gamma production. This impairment may promote chronic evolution of the infection.

 


#330. Treatment of Cirrhotic Patients with HCV Referred for Liver Transplantation Using an Escalating Dose Regimen of Pegylated Interferon Alpha-2a and Ribavirin.

H. Massoumi; H. Elsiesy; B. Peterson; V. Khaitova; E. Norkus; P. Grewal; L. Liu; P. Martin; P. Lopez; N. Bach; T. Schiano.

 

Introduction:

The rapid progression to cirrhosis and poor tolerability of interferon post liver transplant (LT) have necessitated the consideration of treating HCV with PEG-IFN and ribavirin in cirrhotic pts. At the Mount Sinai Medical Center, we have initiated a protocol using PEG in pts seen in the transplant office. The aim of our study was to assess the safety and efficacy of this treatment.

 

Method:

90 cirrhotic pts were prospectively treated from 2/03 to 4/06. Exclusion criteria included co-infection with HBV or HIV or renal insufficiency. We used an escalating dose regimen starting with 90 mcg of PEG-IFN alpha-2a and 400 mg of ribavirin and advanced to 180 mcg and 800-1200 mg respectively over a period of 8 weeks. Hematopoietic growth factors were started if hemoglobin was <12 or ANC was <750. Treatment was stopped if platelet count was <20,000. Pt demographics, comorbidities, BMIs, lab values, MELD and Child’s scores, CT liver volumes, complications and outcomes were recorded.

 

Results:

Mean age was 55.3 ± 6.9 years, 69% males, and 53% whites 23% Hispanics, 16% African Americans. 34% had a history of prior treatment with IFN. 76% had genotype 1 or 4. Mean Child’s score was 6.7 ± 2 and mean MELD 11.2 ± 3.7. 18% of pts needed dose reduction, 30% stopped treatment due to adverse effects, 11% had hepatic decompensation, 7% died and 14% underwent LT. Epoetin or darbepoetin was used in 58% and filgrastim in 31% of pts. End of treatment response (ETR) was seen in 65% of pts. During a mean follow up period of 9.6 months, 40% of responders had virological relapse; 4/32 pts followed for > 6months after therapy had SVR.

 

Pts who stopped PEG had significantly smaller liver volumes (1366 ± 279 vs 1738 ± 561) (p=0.005). Child’s score (p=0.002) and MELD (p=0.03) were strongly predictive for discontinuation of PEG; Child’s score appearing to be a stronger predictive factor than MELD. Rate of serious complications was 22% in Child’s class A, 53% in class B and 100% in class C(p<0.0005); Child’s C pts had a 15 fold increase risk for hepatic decompensation or death. Every 1 g/dl lower baseline serum albumin below 4.8 predicted a 96% higher risk of hepatic decompensation or death. No pt had significant bleeding related to low platelet count (mean platelet count 74 ± 52×1000; range of 18-346×1000).

 

Conclusion:

Using an escalating dose regimen of PEG-IFN alpha-2a and ribavirin and aggressive use of hematopoietic growth factors, we achieved a 65% ETR in cirrhotic pts. These results were tempered by 14% risk of hepatic decompensation or death and significant relapse rate. Serum albumin and Child’s score were predictive of hepatic decompensation or death.

 


#331. Identification of candidate genes that mediate depressive side effects of pegylated IFN-αlpha 2a in patients with chronic hepatitis C.

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

 

Aims and background:

Combination therapy with pegylated interferon (IFN)-alpha plus ribavirin has been shown to be the most effective treatment for chronic hepatitis C (HCV). One of the most common side effects is IFN-induced severe depression, which can impair quality of life, reduce treatment adherence and even lead to suicide. This study assessed the primary transcriptional response to IFN-alpha-2a plus ribavirin in HCV patients to identify possible candidate genes that mediate the depressive side effects of IFN-α.

 

Patients and methods:

A total of 18 Caucasian patients with histologically proven chronic hepatitis C were treated with standard combination therapy consisting of pegylated IFN-α2a (Pegasys, 180µg once weekly) for 12 months (HCV genotype 1, n=14) or 6 months (HCV genotype 2/3, n=1/3) in combination with ribavirin (800-1200 mg daily). 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 changes were calculated from before and after IFN injection. Fold change values were subjected to significance analysis (SAM software) and class prediction analysis (PAM software). The patients were investigated using the Mini-DIPS, a semi-structured interview, which facilitates relevant diagnostic criteria according to the four axis of the DSM-IV. Furthermore depression scores were evaluated with psychometric instruments, Beck`s Depression Inventory and Hospital Anxiety and Depression Scale.

 

Results:

8 patients were non-responders (NR) to therapy while 10 patients had a sustained virological response (SVR). 8/18 patients suffered from IFN-induced depression. Using class prediction analysis, the development of an IFN-induced depression could be predicted by 24 genes with 95% accuracy. 9 genes were significantly higher expressed in patients with IFN-induced depression compared to patients without depression. 6 of these genes were identified as typical interferon response genes. Interestingly, 3 of these 9 genes were previously described as being associated with recurrent major depression.

 

Conclusions:

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 drug targets to improve the efficacy of and adherence to HCV therapy.

 


#332. The Nonstructural 5A (NS5A) Protein of Hepatitis C Virus Genotype 1b Does Not Contain an “Interferon Sensitivity Determining Region”.

R. Brillet; F. Penin; C. Hezode; P. Chouteau; D. Dhumeaux; J. Pawlotsky.

 

Introduction:

Various explanations have been forwarded for differences in IFN-alpha-based treatment outcomes. Together with a number of host parameters and disease characteristics, virus-related factors play an important role in the likelihood of permanent viral clearance after therapy. The nonstructural protein 5A (NS5A) of HCV has been suggested to contain an “interferon sensitivity determining region“ (ISDR). If NS5A indeed contains an ISDR, the latter would be expected to impact mainly on the initial viral decline, meaning that the degree of viral decline on day 1 should be associated with qualitative or quantitative differences in NS5A functions and, thus, in the amino acid sequences that subtend these functions.

 

Aim:

This hypothesis was tested by studying patients receiving their first injection of standard IFN alpha, the IFN molecule with the most rapid initial antiviral effect.

 

Results:  

We studied whether the degree of viral decline on day 1 is associated with differences in amino acid sequences that subtend NS5A protein functions in 16 patients receiving their first IFN injection (11 responders, 5 nonresponders). Phylogenetic analyses of the full-length protein and of particular functional domains showed no relationship between the baseline protein sequence and the antiviral response. We analyzed nonstructural protein 5A quasispecies sequences amino acid by amino acid, and studied the physicochemical properties of the proteins. The sequences showed no differences in the number of mutations in the putative ISDR relative to the prototype HCV-J sequence between responders and nonresponders, or according to IFN antiviral efficacy. No relationship was found between antiviral efficacy at 24 hours and the baseline sequence of any region of the protein. Amino acid changes were observed in a few cases at 24 hours in both responders and nonresponders, but no consistent pattern of amino acid shifts was observed, ruling out the possibility that IFN administration selected “IFN-resistant“ variants.

 

Conclusion:  

Our findings show that there is no “interferon sensitivity determining region” in the NS5A protein of HCV genotype 1, and that the NS5A sequence does not influence the capacity of IFN to block viral replication. They do not rule out a role of NS5A in subsequent viral clearance, through effects unrelated to IFN resistance.


#335. Improved sustained virological response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (RBV)(COPEGUS®) in patients with “difficult-to-cure” characteristics.

M. Fried; D. Jensen; M. Rodriguez-Torres; L. Nyberg; A. Biscegli; T. Morgan; P. Pockros; A. Lin; L. Cupelli; D. Nelson.

 

Introduction:

Patients with HCV genotype 1 (G1) and high viral load (HVL) have historically been considered “difficult-to-cure” with response rates <50%. High bodyweight also negatively impacts SVR for all interferon-based therapies, although to a lesser degree. Thus, G1 pts with HVL and above average bodyweight represent a subgroup (≈20% of total population) for which improved treatment strategies are needed.

 

Aim:

The aim of this study was to determine if intensification of treatment using higher, fixed doses of PegIFNα-2a and RBV in patients with these treatment-resistant characteristics provide increased benefit with manageable risk.

 

Methods:

In this prospective, controlled pilot study, treatment-naďve HCV G1 adults with HCVRNA >800,000IU/mL and bodyweight >85kg were randomized to 48wks of either PegIFNα-2a 180 or 270µg/wk + either 1200 or 1600mg/d RBV. SVR=undetectable (<50IU/mL) HCVRNA at 24wks post-therapy.

 

Results (Table):

188 pts, from the United States, were randomized and treated—follow-up is available for 143 (76%); ≈18% of pts in each arm had bridging fibrosis/cirrhosis. Similar end-of-treatment response rates were seen in the 3 test arms; however the SVR rate was highest (47% vs 28%) with the most intensive regimen: PegIFNα-2a 270µg/wk + RBV 1600mg/d, compared to standard dosing. Improved SVR was driven by a lower relapse rate (40% vs 19%). Compared to standard dosing, this regimen was associated with an increased incidence of some hematological laboratory abnormalities, dose modifications for labs and AEs and premature withdrawals for AEs.

 

Conclusions:

In pts with treatment-resistant characteristics (G1, HVL and bodyweight >85kg), higher fixed doses of both PegIFNα-2a (40KD) (270µg/wk) and RBV (1600 mg/d) led to a substantial increase in SVR rate (19% more than standard dosing) but with some negative safety trends. The benefit of an increased SVR rate with higher fixed doses of PegIFNα-2a (40KD) and RBV should outweigh the increased potential for adverse events/lab abnormalities. These results provide the rationale for future studies attempting to optimize treatment response using higher doses of PegIFNα-2a and RBV and suggest opportunities to further improve benefit/risk in patients with unfavorable treatment characteristics.

 

 

PegIFNα-2a (40KD) 180 µg/wk +

PegIFNα-2a (40KD) 270 µg/wk +

RBV 1200 mg/d
(n=46)

RBV 1600 mg/d
(n=47)

RBV 1200 mg/d
(n=47)

RBV 1600 mg/d
(n=47)

Mean age, yrs
Mean HCV RNA, x106 IU/mL
Mean weight, kg

47
4.9
98

50
6.2
100

47
5.5
101

49
5.2
97

Virological response, % (ITT)
Undetectable HCV RNA at week 12
Undetectable HCV RNA at end of treatment (week 48)
SVR (week 72)

 

 

48

46
28

 

 

38

57
32

 

 

53

55
36

 

 

51

55
47

Relapse (%)

40

42

46

19

Serious adverse events (%)

9

13

13

11

Lab abnormalities (n, %)
Neutrophils <0.75 x109/L
Hemoglobin <8.5 g/dL

 

7(15)
2(4)

 

7(15)
3(6)

 

4(9)
1(2)

 

11(23)
8(17)

Dose modifications for adverse events or lab abnormalities (%)
Peginterferon alfa-2a (40KD)
Ribavirin

 

 

 

20
24

 

 

 

26
45

 

 

 

17
45

 

 

 

28
60

Withdrawals due to safety reasons (%)

13

6

17

23

 


#337. Clinical, biochemical, virologic and histologic outcomes of chronic hepatitis C following sustained virologic response (SVR) to HCV therapy: a prospective 5 year cohort study.

A. M. Di Bisceglie; S. L. George; K. L. Mihindukulasuriya; J. Hoffmann; B. R. Bacon.

 

Background:

Little is known about long-term outcomes in chronic hepatitis C following SVR. We determined the 5 year clinical, biochemical, virologic, and histologic outcome in 150 adults with chronic hepatitis C achieving SVR following antiviral therapy.

 

Methods:

Patients with SVR were enrolled 6 to 12 mos after completion of therapy. Subjects were seen initially and then annually to monitor clinical outcome, serum aminotransferases and HCV RNA. Those with initial stage >2 fibrosis were re-biopsied in year 4 or 5; data on other follow-up liver biopsies was also collected. Serum HCV RNA was assessed by PCR at every visit and by Transcription-Mediated Amplification (TMA, Bayer) on the latest available sample. The grade and stage of hepatitis C were assessed using the Scheuer scoring system.

 

Results:

76 patients (50%) were female, 148 were Caucasian (98%) and their mean age at entry was 49 years. Initial HCV genotypes were 1 (44%), 2 (28.6%), 3 (20.4%), 4 (1.3%) and unknown (16.6%). 86% received standard interferon alfa-2b with ribavirin, 4% pegylated interferon and ribavirin while treatment for the remainder was not recorded. 115 patients (77%) have been followed for at least 4 years. During this time, 2 developed HCC requiring OLT (both were cirrhotic) and another died of unknown causes. No other liver-related clinical outcomes were noted. Only 1 patient had transiently detectable HCV RNA by PCR, not accompanied by a rise in ALT. Serum from 8 of 146 patients (5.4%) was repeatedly reactive for HCV RNA by TMA a mean of 4 years after completion of treatment; serum ALT was normal in all 8 (mean 22, range 11-28). Among 40 subjects with pre-treatment liver biopsies available for review who underwent repeat liver biopsy, both the mean stage (2.3 vs 1.2, p<0.001) and mean grade (2.6 vs 1.5, p<0.001) of hepatitis improved significantly. The stage of fibrosis among 34 patients with stage 2 or greater improved in 27 (79%), remained unchanged in 7 (21%) and worsened in none (see table). Paired biopsies were available from 2 of the 8 TMA-positive patients. The grade and stage improved substantially in one (from G 3, S 4 initially to G 1, S 1) while in the other it was unchanged (G 2, S 1).

 

Conclusions:

Individuals with chronic hepatitis C who achieve SVR are at very low risk for virologic relapse, have continued improvement of liver histology over 5 years but may remain at risk of HCC if cirrhosis persists.

 

Stage Pre

No.

Stage of Fibrosis Post

Stage 4

Stage 3

Stage 2

Stage 1

4

7

2

2

1

2

3

14

0

1

3

10

2

13

0

0

4

9

1

6

0

0

1

5

 


#338. Pegylated interferon alfa 2 b + ribavirin are equally efficacious and well tolerated in patients >65 years old in comparison to other age groups: Subanalysis of a randomized, controlled study (WIN-R Trial).

S. L. Flamm; I. M. Jacobson; R. Brown; B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; J. Harvey; L. H. Griffel; C. A. Brass.

 

Background:

Peg interferon α (IFN) + ribavirin are the standard of care for chronic HCV. There is reluctance to administer anti-viral medications to older populations due to a fear of side effects and possible decreased efficacy. Limited data is available on pts. age >65 due to ineligibility for clinical trials. The role of age in determining response to IFN-based anti-viral therapy for chronic HCV has not been clearly defined.

 

Aim:

To determine if age is an independent predictor of sustained virological response (SVR) or medication tolerability within a randomized, controlled clinical trial of treatment-naďve pts. with HCV. Patient age grps studied: 18-25 yrs., n=69; 26-35 yrs., n=350; 36-45 yrs., n=1866; 46-55 yrs., n=2200; 56-65 yrs., n=368; and >65 yrs., n=55.

 

Methods:

A retrospective review of the multi-center WIN-R trial database was undertaken. Pts. were randomized to receive PEG IFNα 2b (1.5μg/kg/wk) + either ribavirin 800 mg/d or ribavirin 800mg-1400mg/d based on body wt. Pts. with HCV GT1/4 received 48 wks of therapy while pts with HCV GT 2/3 were randomized to 24 or 48 wks of therapy. 4913 pts. received at least 1 dose of medication and are included in this analysis. Although pts. age >65 yrs. were ineligible, 55 such pts. were enrolled as protocol exceptions. Logistic regression analyses of SVR comparing two age categories were performed. The potential influence of demographic variables on SVR was evaluated using the chi square test (two-way frequency table).

 

Results:

The overall SVR was 44%. SVR rates for the groups were: 18-25 yrs. = 57%, 26-35 yrs. = 41%, 36-45 yrs. = 45%, 46-55 yrs. = 432%, 56-65 yrs. = 41% and for >65 yrs. SVR = 46%. There was no difference in SVR in any other patient. age groups including patients. age >65 yrs. There were no differences in serious adverse events between all age groups. Patinets age 26-35 yrs., 36-45 yrs. and 46-55 yrs. had fewer adverse events than those in the 56-65 yrs. and the >65 yrs. age groups. Treatment discontinuations were significantly higher among the 26-35 yrs. group when compared to two groups but there was no difference in the treatment discontinuations in the >65 yrs. group compared with any other.

Conclusions:

 

Patients 18 to 25 years of age had the highest SVR rate (57%) among the 6 age groups.

• The SVR rate in patients older than 65 years (46%) was similar to the SVR rates observed in younger age groups (41%-57%).

• Although elderly patients tended to experience more AEs, the rate of SAEs was similar in all groups, and the incidence

of treatment discontinuation in elderly patients was similar to or less than that of younger patients.

• Data from this subanalysis of the WIN-R trial strongly suggest that patients should not be denied antiviral therapy based on age alone.

 


#339. A prospective, multicenter, observational study on compliance with viral hepatitis C treatments (CHEOBS study).

P. Cacoub; D. Ouzan; P. Melin; J. Lang; M. Rotily; T. Fontanges; P. Marcellin; M. Chousterman.

Objective:

The CHEOBS study is a French multicenter, prospective, observational study designed to analyse the factors related to compliance with the combination treatment with Peginterferon α-2b (PegIFN) and Ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Main results in patients (pts) with a genotype 2 or 3 infection are presented.

 

Patients and methods:

From Jan 2003 to Dec 2004, 702 out of 2,000 pts included were infected with a genotype 2 or 3 virus among which 641 pts had sufficient data to be analyzed: 356 pts (group 1) received an educational program to optimize the tolerance and the efficacy of HCV treatment whereas 285 pts (group 2) had no specific formation. Baseline characteristics, impact of the educational program on compliance and sustained virological response (SVR=6 months after stopping therapy) were assessed.

 

Results:

The mean age was 45±11 years, 59% were male, 17% were unemployed and 8% had poor socio-economic conditions. Pts were excessive alcohol consumers (>50g/d; 167, 26%), smokers (336, 53%), drug abusers (current [28, 4%], past [312, 49%]), had past depression (169, 26%) and/or current psychiatric disorders (150, 24%). HCV viral load was >800,000 IU for 163 pts (38%) and genotype was 2 (189, 30%) or 3 (452, 70%). A high stage of fibrosis was frequent; Metavir F2–F3 (201, 43%), cirrhosis (65, 14%). Co-morbidities included HIV co-infection (27, 4%), HBV co-infection (8, 1%), or other chronic diseases (147, 23%). HCV treatment naďve pts were 81% (520), 19% had pre-treatment once (93) or several times (27). Pts of group 1 had more frequently a past depression (30% vs 22%), current psychiatric disorders (27% vs 20%) and a current drug use (6% vs 2%)(p<0.05). The compliance at month 6 of treatment and the SVR in two groups are shown in the Table.

 

Conclusion:

·        This is the first prospective study that evaluated “real-life” treatment adherence in patients with genotype 2 and 3 chronic hepatitis C.

·        In this real-life, community-based setting, patients with genotype 2 and 3 chronic hepatitis C who received therapeutic education had:

o       Significantly greater adherence to peg-IFN alfa-2b plus ribavirin combination therapy because of increased adherence to ribavirin therapy

o       Significantly higher SVR rates and a decreased rate of relapse.

 

 

Group 1

Group 2

p

Duration of treatment, weeks

29.7 ± 14.0

28.3 ± 12.7

NS

Early withdrawal (<20 weeks), %

11.8

14.4

NS

PegIFN, µg/kg/w*

1.4 ± 0.3

1.3 ± 0.3

.015

28 RBV pills, %**

69.0

52.2

.001

Compliance with PegIFN + RBV, %

59.6

44.8

.006

Sustained responders, %

89.4

80.6

.017

Non responders, %

4.8

4.9

NS

Relapsers, %

5.8

14.6

NS

 

*during the last 4 weeks; **during the last 7 days

 


#340. Utility of virological response at weeks 4 and 12 in the prediction of SVR rates in genotype 2/3 patients treated with peginterferon alfa-2a (40KD) plus ribavirin: findings from ACCELERATE.

M. Shiffman; S. Pappas; B. Bacon; E. Godofsky; D. Nelson; H. Harley; M. Diago; A. Lin; G. Hooper; S. Zeuzem.

 

Introduction:

ACCELERATE, a prospective, randomized trial in 1469 GT2 or 3 pts shows that, overall, 24wks of PegIFNα-2a plus RBV is superior to 16wks (Table), confirming the recommended treatment duration. Utilizing this dataset, we determined on-treatment predictability of a wk4 and 12 response, to assess their clinical utility in the management of GT2 and 3 pts.

 

Methods

Methods In ACCELERATE, naďve GT2/3 pts received PegIFNα-2a 180µg/wk + RBV 800mg/d for 16 or 24wks. Predictability of a response at wk4 (RVR; undetectable HCVRNA [<50IU/mL]) and at wk12 (EVR; undetectable or unquantifiable HCVRNA or ≥2log10 drop) to forecast an SVR (undetectable HCVRNA after 24wks follow-up) was determined in the standard population (pts without any major protocol deviations).

 

Results

·        Demographic and disease characteristics for the intent-to-treat patient population (n=1463).  Overall, patients who received 16 and 24 weeks’ treatment were well matched with regard to demographic and clinical characteristics and the distribution of HCV genotype 2 and 3 infection.

Virologic response at week 4 (RVR) and 12 (EVR)

·        An RVR was achieved by 68% and 65% of patients in the 16- and 24-week arms, respectively.

·        An EVR as achieved by 99% and 97% of patients in the 16- and 24-week arms respectively

o       Of those patients who achieved an EVR, 95% and 94% respectively, had undetectable HCV RNA at week 12

o       The absence of an EVR was highly predictive of not achieveing an SVR (94%).  However, very few patients (1.9%) did not achieve an EVR.

Predictive value of RVR

·        The achievement of an RVR was strongly predictive of achieving an SVR after both 16 and 24 weeks of treatment.

o       Patients with an RVR who received 16 weeks of treatment had a high rate of SVR (82%).

o       Patients with an RVR who received 24 weeks of treatment achieved a rate of SVR that was 8% higher than that in patients who received 16 weeks (90%;  p=0.0001).

·        In patients who achieved an RVR, those with a low viral load (≤ 400,000 IU/mL) had a higher probability of achieving an SVR (≥90%), irrespective of treatment duration.

·        In patients without an RVR, 24 weeks of treatment was superior to 16 weeks overall (p<0.001) and for each genotype and baseline HCV RNA level.

 

Conclusion:

As almost every GT2/3 pt treated with PegIFNα-2a + RBV had undetectable HCVRNA by wk12, the clinical utility of a 12wk response was minimal. In contrast, a wk-4 RVR was important. GT2 and 3 pts with an RVR had a similarly high chance of achieving SVR with 24wks. However, GT2/3 pts without an RVR had low response rates – these pts should not be considered ‘easy-to-cure’ and would likely benefit from more intensive therapy. Detectable vs. undetectable HCV RNA at wk4 should be utilized to guide treatment decisions in GT2/3 pts.

 


#341. Evaluation of fibrosis regression using non-invasive methods in very long-term follow-up of HCV responder patients.

V. de Ledinghen; J. Foucher; L. Castera; P. Bernard; M. Salzmann; G. Moisset; W. Merrouche; P. Couzigou.

 

Background & aim:

Liver stiffness measurement using FibroScan and Fibrotest are non-invasive methods for fibrosis evaluation in HCV patients. The aim of this longitudinal study was to evaluate liver fibrosis using FibroScan and Fibrotest in very long-term HCV responder patients compared to (1) fibrosis stage before treatment, and (2) a control group of patients without fibrosis (liver biopsy F0).

 

Methods:

A total of 88 very long-term HCV responder patients (42 males, mean age 56 ± 11 years) who undergone fibrosis evaluation using non-invasive methods more than one year after the end of HCV treatment (mean time between the end of treatment and fibrosis evaluation: 3.8 ± 2.1 years, range: 2-13 years) were studied. 85 of these patients had a liver biopsy before treatment. This group was compared to a control group of 72 patients (33 males, mean age 49 ± 15 years) who undergone non-invasive evaluation of fibrosis at the time of liver biopsy with a F0 Metavir fibrosis score.

 

Results:

Before treatment, according to liver biopsy, liver fibrosis was F0F1 in 19%, F2 in 43%, F3 in 19% and F4 in 19% cases. At the end of very long-term follow-up, according to published FibroScan and Fibrotest cutoffs for fibrosis stages, fibrosis was F0F1 in 82% and 71%, F2 in 2% and 9%, F3 in 8% and 8%, F4 in 8% and 12%, respectively. Using FibroScan and Fibrotest, fibrosis regression was observed in 95% and 78% of patients with F2 fibrosis at liver biopsy before treatment, 87% and 75% of F3 patients. In the group of cirrhotic patients before treatment (according to liver biopsy), fibrosis regression was observed using FibroScan and Fibrotest in 68% and 53% of patients, respectively. No statistical difference was observed between HCV responders and the control group for liver fibrosis. Indeed, in HCV responders and F0 patients, mean values of FibroScan and Fibrotest were 7.2 ± 6.0 and 5.8 ± 3.7 kPa (NS), 0.36 ± 0.24 and 0.32 ± 0.24 (NS), respectively.

 

Conclusion:

More than 80% of very long-term HCV responder patients have no or mild fibrosis. Moreover, more than 50% of cirrhotic patients before treatment have fibrosis < F4 at the end of very long term follow-up. These results confirm that complete regression of fibrosis is observed in very long-term HCV responders. FibroScan and Fibrotest are sensitive and reliable tools for non invasive evaluation of liver fibrosis and monitoring of histological response after antiviral treatment in HCV patients.

 


#342. Effect of drug exposure on sustained virological response (SVR) in patients with chronic hepatitis C virus genotype 2 or 3 treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for 16 or 24 weeks.

M. Shiffman; S. Pappas; S. Greenbloom; R. Sola; L. Nyberg; J. Bronowicki; D. Crawford; A. Lin; G. Hooper; S. Zeuzem.

 

Introduction:

Previous studies have demonstrated that exposure to both peginterferon and ribavirin (RBV) impacts SVR in HCV genotype 1 pts. The aim of the present study was to examine the effect of cumulative drug exposure on SVR in genotype 2 (GT2) and GT3 pts enrolled in ACCELERATE, a large prospective randomized trial (n=1469) which compared peginterferon alfa-2a (40KD) 180 µg/wk plus RBV 800 mg/d for 16 or 24 wks. The primary results of this study demonstrated that SVR was significantly greater with 24 wks of treatment [EASL 2006;A734].

 

Methods:

Complete data was available in 1373 pts. The cumulative exposure to PEG-IFNα-2a and RBV on the probability of SVR was assessed, while simultaneously controlling for other potential predictors (age, gender, race, bodyweight, cirrhosis, genotype, baseline ALT and HCVRNA) using logistic regression models. PEG-IFNα-2a dose was expressed as a multiple of the standard 180µg dose; RBV was expressed as mean daily dose.

 

Results:

Cumulative PEG-IFNα-2a dose, mean daily RBV dose, genotype, baseline HCVRNA, cirrhosis status, age and baseline ALT significantly and independently predicted SVR (Table). SVR increased stepwise with increasing cumulative PEG-IFNα-2a duration regardless of RBV dose. In patients with mean RBV dose of <8.4 mg/kg/d (lowest quartile of RBV exposure), SVR increased from 42% in pts who received ≤16 PEG-IFNα-2a doses to 67% in pts with ≥17 PEG-IFNα-2a doses. In patients with RBV exposure of ≥11.5 mg/kg per day (top quartile of RBV exposure), SVR was 77% and 87% in pts receiving ≤16 and ≥17 PEG-IFNα-2a doses respectively.

 

Conclusion:

Total exposure to both PEG-IFNα-2a and RBV affected SVR in pts with GT2 and GT3 independent of other factors. The highest SVR (87%) was observed in pts who received the longest duration of therapy and the highest mean dose of RBV based upon body weight. Since all pts in this trial received an 800 mg/d fixed dose of RBV; the reduction in RBV exposure was a function of increasing body weight. Whether increasing RBV exposure in heavier GT2 and GT3 pts will improve SVR remains uncertain.

 

Predictor

SVR
(univariate)

Odds ratio [95% CI]
(multivariate)

Cumulative PEG-IFNα-2a dose
<17 x 180µg
≥17 or more x 180µg

63% (423/673)
77%(542/700)

1.0
2.1 [1.6–2.7] (p<0.0001)

RBV average daily dose
<9.9 mg/kg
≥9.9 mg/kg

62% (429/693)
79% (536/680)

1.0
2.3 [1.7–2.9] (p<0.0001)

HCV genotype
3
2

68% (465/688)
73% (500/685)

1.0
2.2 [1.6–2.9] (p<0.0001)

HCV RNA at baseline
>400’000 IU/ml
≤400’000 IU/ml

66% (715/1086)
87% (250/287)

1.0
3.8 [2.5–5.5] (p<0.0001)

Histological status
cirrhosis / bridging fibrosis
no cirrhosis / no bridging fibrosis

55% (182/332)
75% (783/1041)

1.0
2.3 [1.7–3.1] (p<0.0001)

Age
>47 years
≤47 years

66% (413/625)
74% (552/748)

1.0
1.5 [1.1–1.9] (p=0.0051)

ALT quotient at baseline (x ULN)
≤2.3 x ULN
>2.3 x ULN

70% (491/703)
71% (474/670)

1.0
1.4 [1.1–1.8] (p=0.0091)

 


#343. Improved Virologic Response Rates With Treatment Extension To 72 Weeks Of Peginterferon Alfa-2B Plus Weight-Based Ribavirin In A Difficult-To-Treat Population Of Genotype 1-Infected Slow Responders.

B. Pearlman; C. Ehleben; S. Saifee.

 

Introduction:

 

In genotype 1-infected HCV patients, the duration of interferon-based therapy is a critical determinant of achieving sustained virologic response(SVR). Slow virologic responders may benefit from an extended treatment course; improved SVR and relapse rates were demonstrated when therapy was extended from 48 weeks to 72 weeks (Gastroenterol 130:1357, 2006). However, previous studies utilized suboptimal doses of ribavirin for genotype 1 infection (800 mg daily). Furthermore, it is unclear if treatment extension could benefit more treatment-resistant patients like African-Americans. We sought to determine if treatment extension could improve response rates in a difficult-to-treat population of slow responders using weight-based ribavirin dosing.

 

Methods:

86 treatment-naďve, chronically-infected HCV patients with elevated ALT and genotype 1 were enrolled in this single center study. Patients were treated with 1.5 mcg/kg/week of peginterferon alfa-2b and 800-1,400 mg/day of ribavirin, dosed according to weight. All patients examined were slow-responders to therapy, defined by achieving at least a 2-log decrement in HCV RNA from baseline value, yet, having detectable HCV RNA at 12 weeks (PCR, TaqMan, Roche, detection limit 10 IU/ml). Patients were randomized 1:1 to continue treatment to complete a total of 48 or 72 weeks. HCV RNA was rechecked at week 24, at the end of treatment, and at the end of a 24 week treatment-free follow-up interval.

 

Results:

Demographic, biochemical and virologic baseline characteristics were not statistically different between groups. Overall, 48% of patients were African-American; 79% had high viral load; 24% had F3/4 fibrosis, and 31% had a body mass index of 30 or above. All patients had undetectable HCV RNA at 24 weeks of therapy. Dose reductions and treatment discontinuations for adverse events or laboratory abnormalities were similar between groups. The end-of-treatment response rates were significantly higher in the 72-week group compared to those in the 48-week group (54% versus 33%, respectively; p=0.04). Relapse rates were 28% in the 72 week treatment group compared to 46% in the 48 week treatment group (p=ns). Overall, the rate of SVR was superior in patients treated for 72 weeks versus 48 weeks (39% versus 18%, respectively; p=0.03).

 

Conclusions:

Extending the treatment duration from 48 weeks to 72 weeks in genotype-1 infected patients with slow virologic response to peginterferon alfa-2b and weight-based ribavirin significantly improves SVR rates. Treatment extension does not seem to increase the rate of dose reduction or therapy discontinuation. Results need to be confirmed in larger studies.

 


#344. Efficacy and tolerability of citalopram in interferon-induced depression: a randomized, placebo-controlled double-blind study on the antidepressant treatment in HCV patients with antiviral therapy.

M. R. Kraus; A. Schaefer; M. Scheurlen.

 

Background and Aims:

Interferon (IFN) - induced depression represents a major complication in the antiviral treatment of chronic hepatitis C virus (HCV) infection. According to several studies, selective serotonin reuptake inhibitors (SSRIs) appear to be useful in the treatment and prevention of cytokine-induced depressive symptoms. However, efficacy and tolerability of SSRIs - given only after the onset of IFN-associated depression - have not been demonstrated in a placebo-controlled study setting.

 

Methods

In a randomized and placebo-controlled single-center study, we included a total of 100 HCV outpatients with chronic hepatitis C infection and antiviral combination therapy (peginterferon alfa-2b and ribavirin). Before, during, and after interferon therapy, depression was monitored using the Hospital Anxiety and Depression Scale (HADS). When showing clinically relevant on-treatment depression scores (HADS ≥ 9), patients were randomly assigned to either placebo or citalopram (SSRI, 20 mg daily) treatment. Moreover, this patient subgroup underwent close psychometric follow-up (1, 2, and 4 weeks after the depression event). Rescue-medication (citalopram, 20 mg daily) was started in the case of exacerbation of depressive symptoms.

 

Results

Of 28 patients with clinically relevant depression scores during IFN therapy, 14 received placebo and 1 received verum. In five patients with exacerbating depressive symptoms, rescue-medication had to be initiated, leading to a significant relief of IFN-induced depression (P = 0.008). Unblinding revealed that all of the 5 patients had been allocated to the placebo condition. Analysis of variance (2-way ANOVA: time x treatment condition) demonstrated a statistically significant decline in HADS scores in verum patients within 4 weeks (P < 0.001). Depression scores did not decrease significantly over time in the placebo subgroup (n=14) and remained markedly higher than in citalopram-treated patients (main effect therapy: P = 0.032). All patients receiving citalopram medication were able to continue and terminate IFN combination therapy as scheduled.

 

Conclusions:

Our findings clearly demonstrate that citalopram treatment is both well tolerable and highly effective in the treatment of IFN-induced depressive symptoms. The results from our placebo-controlled study imply that antidepressant treatment is safe when initiated after the onset of clinically relevant depressive symptoms. A general SSRI prophylaxis can not be recommended because this strategy would require subjecting the majority of patients, who will not develop depression, to potential adverse events and for no benefit.

 


#345. HCV Treatment Response Rates in an Incarcerated Population-Influence of Race, Compliance and Pegylated Interferon.

W. Cassidy; A. Windham; R. Horswell.

 

Background:

Reportedly, incarcerated African Americans (AA) chronically infected with HCV who are treated with interferon and ribavirin (INF/RIB) have treatment response rates similar to non-African Americans (non-AA). This raises the possibility that elimination of racial differences in quality of care, access to medicine, control of co-morbidities & compliance with INF/RIB therapy eliminates differences in treatment response rates between AA and non-AA. To assess, we examined a quality assurance database used to monitor care given to inmates in the Louisiana Department of Corrections. Unique to this population is directly observed therapy with treatment discontinuation if an inmate is non-compliant. There is minimal use of alcohol and non-prescribed drugs.

 

Methods:

Information on genotype (GT) 1 infected patients from the aforementioned database was examined. Response to therapy was defined as undetectable viral load on the most recent HCV viral load test, at least 12 weeks after starting therapy. The sample was accrued over 5 years and includes equal numbers treated with non pegylated interferon (P-INF) + RIB & P-INF + RIB. Response rates were compared between AA and non-AA patients after adjustment for covariates, including biopsy stage and grade (Metavir), age, GT 1a vs 1b & use or non-use of P-INF. No gender adjustment was made, as the sample was 99% male. A statistical model based on propensity score methods was used to compare adjusted odds ratios.

 

Results:

250 patients were included. 144 (70%) were AA. There were no statistical differences between AA & non-AA patients in age, GT 1a vs 1b, grade, stage, & fraction receiving P-INF. The first row of the table shows the raw response rates by racial group, as well as adjusted odds ratio (AA vs non-AA.) The 2nd & 3rd rows show results separately for those who did & did not receive P-INF.

 

Conclusion:

Overall, there is a significant difference in response rates between AA & non-AA even in the prison setting with directly observed therapy. Use of P-INF increased positive response in both AA & non AA. Among those receiving P-INF, the AA vs non-AA difference is not statistically significant. This could be due to the disappearance of racial response differences with use of P-INF, but may stem from insufficient power to detect a racial difference in response among those receiving P-INF.

 

Treatment Response by Race (N)

 

AA

Non AA

Odds ratio
(p-value)

Total sample (250)

39%

63%

0.37(0.001)

Non P INF/RIB (108)

16%

46%

0.19(0.001)

P INF/RIB (142)

58%

73%

0.64(0.395)

 


#346. Evaluation of the efficacy of an 18 week short treatment duration in HCV type 1 infected patients based upon early viral kinetics: an approach to recognise “super-responders”.

T. Berg; V. Weich; G. Teuber; H. Klinker; B. Möller; J. Rasenack; H. Hinrichsen; G. Pape; U. Spengler; P. Buggisch; H. Balk; M. Zankel; C. Sarrazin; S. Zeuzem.

 

Introduction:

A number of ongoing studies in patients with HCV infection have been recently concerned with the evaluation of the optimal dose and duration of pegylated IFN and ribavirin. In a multicenter randomized controlled study, HCV type 1-infected patients received an individualized treatment duration from 18 up to 48 weeks tailored according to early viral kinetics.

 

Aim:

The aim of the present analysis was to find out whether there are conditions which allow a reduction of the treatment duration to 18 weeks.

 

Study design:

433 patients have been randomized to receive either 1.5 ug/kg body weight PEG-IFNa-2b per week plus 800-1400 mg ribavirin daily for 48 weeks (n=225, group A) or an individualized tailored treatment duration ranging between 18 to 48 weeks (n=208, group B). In the latter group treatment duration was calculated by the time required to become for the first time HCV-RNA negative as defined by bDNA assay (detection limit 615 IU/mL) multiplied by the factor 6. Patients being found to be HCV-RNA negative by this test were subjected to another test, the highly sensitive TMA assay (detection limit <5.3 IU/mL).

 

Results:

When HCV RNA levels were quantified at baseline and weekly using the bDNA assay it turned out that 45 out of the 208 group B patients became already negative by week 3 and therefore received only 18 weeks of therapy. SVR rates in these rapid responders were 62% (28/45) and consequently significant lower than in the control group A rapid responders being treated for 48 weeks (87%; 48/58). Furthermore group B patients with a baseline viral load (VL) ≤800.000 IU/mL had significantly higher SVR rates (76%; 25/33) than patients with a VL >800.000 IU/mL (31%; 4/13). When applying the TMA assays 31 of the 45 patients became HCV RNA negative (<5.3 IU/mL) within the first 5 treatment weeks. SVR rates after 18 weeks of treatment in these TMA negative patients were 81% (25/31) but reached 95% in those with low baseline viremia (≤800.000 IU/mL; 21 out of 22 patients) and only 44% in those with high VL at baseline (>800.000 IU/mL; 4 out of 9 patients). In contrast patients being still positive with the sensitive TMA assay at week 5 hardly had any change to achieve SVR when treated for 18 weeks (29%; 4 out of 14 patients).

 

Conclusion:

This analysis underlines the importance to determine viral kinetics at an early phase during treatment using quite sensitive HCV RNA assays. By that means a subgroup of HCV genotype 1 infected rapid responder patients (“super-responders”) may be identified (around 10% of the total population) which can achieve a SVR above 90% within a treatment duration of 18 weeks.

 


#347. Fatigue in Patients with Hepatitis C and Non-Viral Chronic Liver Disease.

F. Barakat; M. D. Carlson; D. L. Oliver; K. Edwards; N. Karlen; R. Hilsabeck; W. Perry; T. I. Hassanein.

 

Introduction:

Fatigue is a common complaint in patients with Chronic Liver Disease (CLD) and may cause impaired quality of life. Numerous studies have described fatigue in patients with hepatitis C (HCV) and non-viral liver disease such as Primary Biliary Cirrhosis (PBC); however, comparisons between etiologies have not yet been conducted. The goal of this study was to evaluate self-reported fatigue in patients with HCV versus Non-Viral CLD.

 

Methods:

Patients completed a set of questionnaires including the Fatigue Severity Scale (FSS). The FSS is a 9-item questionnaire designed to assess the impact of self-reported fatigue on daily functioning. The measure is scored on a 7-point Likert-type scale resulting in an average fatigue score (range 1-7). Our group defined impairment as an average score > 2 standard deviations above published reports of normal healthy adults (2.3±0.7). Liver disease etiology, histology, and history of psychiatric disease were also collected.

 

Results:

313 subjects completed the FSS questionnaire between 1999 and 2004. After excluding patients with HCV/HIV and those on antiviral therapy, 227 patients were included in this analysis. The mean age was 49±8 years, 55% were male, and 62% were Caucasian. 52% showed evidence of cirrhosis, and 85 (40%) reported a history of psychiatric disease.  Etiology of CLD was HCV in 180 patients and Non-Viral CLD in 47 patients (i.e., ETOH, NASH, AIH, PBC, PSC, Cryptogenic). Demographic and FSS scores for both groups are reported in Table 1. Overall, 68% of patients reported significant fatigue (Mean FSS score = 4.7±1.8). There was a significant difference in FSS scores between the HCV and Non-Viral CLD groups (p=0.013). There was no significant difference in FSS scores between patients with cirrhosis (4.7±1.8) versus no-cirrhosis (4.6±1.9) (p=0.87). Patients reporting a history of psychiatric disease had significantly greater FSS scores than patients without psychiatric history (5.4±1.4 & 4.3±1.9, respectively; p<0.001).

 

Conclusions:

·        68% of patients with chronic liver disease, regardless of etiology, reported significant fatigue (mean FSS score 4.7 ± 1.8)

·        Patients with HCV reported significantly higher fatigue scores than in patients with non-viral chronic liver disease

·        Patients with chronic liver disease and psychiatric report significant fatigue irrespective of liver disease etiology

 

HCV
n = 180

Non-viral CLD
n = 47

p-value

Age

49 ± 8

48 ± 14

0.60

Education

13 ± 3

12 ± 4

0.81

% Male

55%

53%

0.82

% Caucasian

61%

47%

0.09

% Cirrhosis

52%

81%

0.002

% Psych History

40%

32%

0.31

FSS Score

4.8 ± 1.8

4.1 ± 1.7

0.013

 


#348. Progression of Fibrosis and Interferon Treatment in Liver Transplant Recipients with Hepatitis C Infection.

S. Habib; C. H. Chang; J. Ahmad; D. Sass; T. Shaw-Stiffel; A. J. Demetris; M. De Vera; P. Fontes; A. Marcos; O. S. Shaikh.

 

Introduction:

Hepatitis C in the liver allograft recipient has an aggressive course. A significant proportion of such recipients develop graft fibrosis and cirrhosis within five years of transplantation. Treatment efficacy with standard or pegylated interferon and ribavirin is also suboptimal compared to the immunocompetent individuals. However, the effect of such therapy on graft fibrosis remains unknown.

 

Objectives:

To determine the efficacy of interferon based therapies in liver transplant recipients with recurrent hepatitis C, and to determine the effect of interferon treatment on progression of graft fibrosis.

 

Methods:

We retrospectively analyzed 864 hepatitis C patients, who underwent liver transplantation at Thomas E Starzl Transplantation Institute, University of Pittsburgh between January 1992 and April 2006. Three hundred and twenty two patients received either interferon (all kinds) monotherapy, combination therapy or ribavirin monotherapy. The primary end point was stage of fibrosis (4-6) on last available liver biopsy.

 

Results:

Both treated and untreated groups were similar in clinical characteristics at the time of transplantation, and their post transplant course was also similar. In treatment group 78% received prednisone based immunosuppression as compared to 71% in no treatment group. 58% of patients in treatment group had HCV RNA >1 million units/ml after transplantation. Only those variables were included in multi-variable, which were significant on uni-variable analysis. Treatment was categorized in multiple ways and AIC statistics was used to select best multivariable analysis. Patients were categorized into four groups; no treatment (n=525), <24 weeks of treatment (n=78), 25-48 weeks of treatment (n=68) and >48 weeks of treatment (176). Patient’s age, AST at 6 months, AST/ALT ratio of >1 at 6 month of transplantation, warm ischemia time of >one hour, cumulative prednisone >1000 mg and treatment status are multi-variably associated with the progression of fibrosis . Patients, who received treatment for <24 weeks has significantly decreased chances of progression of fibrosis to stage 4-6 (HR 0.45,p=<.005) regardless of viral response. Further analysis will be performed regarding progression of fibrosis in patients, who achieved sustained viral response.

 

Conclusion:

Among liver transplant recipients with recurrent hepatitis C, treatment with any interferon with or without ribavirin significantly reduces fibrosis progression to stage 4 and above regardless of viral response. Long term treatment >48 weeks did not show any benefit on progression of fibrosis. Further prospective trials are indicated to confirm these findings.

 


#349. Prospective Analysis of Sustained Virologic Response (SVR) to Peg-interferon (PEG IFN) Alfa-2b and Ribavirin Treatment in Asian and Hispanic Patients with Chronic Hepatitis C: Results from the WIN-R Trial.

B. Freilich; K. Hu; I. Jacobson; R. Brown; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; D. Pound; E. Godofsky; R. Strauss; D. Bernstein; S. Flamm; N. Bala; V. Araya; L. Griffel; C. Brass.

 

Background:

Retrospective data suggest a higher SVR in Asian patients (APs), but a lower SVR in Hispanic patients (HPs) than in Caucasian patients (CPs) to interferon (IFN) and ribavirin (RBV) treatment for chronic hepatitis C (CHC). Prospective studies are needed to determine SVR in APs and HPs with CHC treated with PEG IFN and RBV. Aim: To evaluate the rates of SVR to PEG IFN alfa-2b and RBV in APs and HPs with CHC enrolled in the WIN-R trial, a large U.S. multicenter study comparing RBV in a fixed dose (FD) vs. a weight based dose (WBD) combined with PEG IFN alfa-2b.

 

Methods:

Patients with CHC were randomized to PEG IFN alfa-2b 1.5 µg/kg once weekly combined with RBV 800 mg (FD) or RBV 800-1,400 mg WBD. Treatment was for 48 weeks with 24 weeks follow-up. The SVR was based on intent-to-treat (ITT) and defined as undetectable HCV RNA by central quantitative TaqMan assay (LLD is <29 IU/ml or 100 copies/ml-Schering-Plough Research Institute) 24 weeks post-treatment. Dose reductions of RBV were required for hemoglobin (Hgb) < 10 g/dL and discontinuation for Hgb < 8.5. Erythropoietin was permitted concomitant with RBV dose reduction for Hgb < 10.

 

Results:

5,519 patients were randomized in this trial. 

Between-Group Analysis

Overall SVR rates.

— Among patients receiving WBD ribavirin, the SVR rates were lower in Hispanic patients (32% vs 47% for Caucasian patients, P = .0013 and 32% vs 66% for Asian patients, P = .00008). There was no significant difference in SVR rates between Caucasian patients and Asian patients receiving WBD ribavirin.

— Among patients receiving FD ribavirin, the SVR rates among Asian patients were not significantly different than those among Caucasian or Hispanic patients. However, SVR rates were lower among Hispanic patients (35% vs 44% for Caucasian patients, P = .0410 and 35% vs 39% for Asian patients, P = .6299).

SVR rates by genotype.

— Among patients with G1 receiving WBD or FD ribavirin, there was no significant difference between patients of different ethnic origin.

— Similar results were observed among patients of different ethnic origin with G2/3 receiving WBD or FD ribavirin.

— SVR rates were lower among Hispanic patients.

·        SVR Rates by Baseline Characteristics

— SVR rates were lower in patients with high baseline viral load (>600,000 IU/mL).

— Among Asian patients, WBD ribavirin (P = .037) and G2/3 (P = .017) were significantly associated with improved SVR rates.

— Among Hispanic patients, G2/3 (P < .0001) and baseline METAVIR fibrosis stage F0-F2 (P = .038) were significantly associated with higher SVR rates.

— Among Caucasian patients, high baseline viral load (P< .0001) and G1 were significantly associated with lower SVR rates.

 

Conclusions:

Hispanic patients with chronic hepatitis C represent a particularly treatment-resistant population. Additional studies are required to identify factors that will improve SVR rates in this ethnic group.

• Overall WBD ribavirin is more effective than FD ribavirin.

• Asian patients achieve overall SVR rates than are at least equivalent to those observed among Caucasian patients.

   WBD ribavirin is more effective among Asian patients, especially among G2/3

   Additional studies among a greater number of Asian patients are required to confirm results observed in this study.

This study was supported by Schering-Plough Corp.

 


#350. Definition of a pre-treatment viral load cut-off for an optimized prediction of treatment outcome in patients with genotype 1 infection receiving either 48 or 72 weeks of peginterferon alfa-2a plus ribavirin.

T. Berg; M. von Wagner; H. Hinrichsen; T. Heintges; P. Buggisch; T. Goeser; J. Rasenack; G. Pape; W. Schmidt; B. Kallinowski; H. Klinker; U. Spengler; U. Alshuth; S. Zeuzem.

 

Introduction:

Viral load (VL) has become an important predictor for treatment outcome in patients with chronic hepatitis C virus (HCV) infection but its determination becomes also relevant with respect to the individualization of treatment duration. Thus while in previous studies a HCV RNA cut-off of 800.000 IU/ml has been proposed to define high and low pre-treatment VL recent observations imply that this cut off is not sensitive enough to govern critically individual treatment strategies. In the present exploratory analysis we now identified a baseline HCV RNA cut-off level that obviously can predict most effectively sustained virologic response (SVR) as well as relapse rates. The population investigated were treatment-naive, HCV genotype 1 patients (n=455) receiving peginterferon alfa-2a (180µg/week) plus ribavirin (800 mg/day) for either 48 (n=230) or 72 weeks (n=225) during the course of a phase III, randomized, clinical trial.

 

Results:

Based on the ROC analyses, the baseline level which most effectively differentiated between a high and low probability of SVR in the total population was 400,000 IU/ml with a sensitivity and specificity of 0.43 and 0.78. It could be shown that the SVR rate in patients with VL ≤400,000 IU/ml was 70%, as compared to 46% in patients with baseline VL >400,000 IU/ml (p<0.0001). In contrast choosing the 800,000 IU/mL VL cut-off, SVRs were 58% and 45% in patients with low and high VL (p=0.007). Furthermore analyzing the 72 weeks treated patients only the 400.000 IU/mL VL cut-off was predictive for SVR (66% vs. 48% in low vs. high VL, p=0.01), but not the 800.000 IU/mL cut off (57% vs. 48% in low vs. high VL, p=0.2). Also in predicting virologic relapses the 400,000 IU/mL pre-treatment VL cut-off proved to be superior to the 800.000 IU/mL cut-off. Thus we could show in the 72 weeks treatment group that the virologic relapse rates were statistically highly different when comparing the baseline VL ≤400,000 vs. >400,000 IU/mL (6% vs. 29% in low vs. high VL;p=0.001). These clear differences disappeared when a baseline cut-off of 800,000 IU/mL was used (17% vs. 29% in patients with low and high VL; p=0.11). In the 48 week group the relapse rates with respect to low vs. high VL cut-off of 400,000 or 800,000 IU/mL were 15% vs. 36% (p=0.004) or 24% vs. 36% (p=0.08), respectively.

 

Conclusion:

This analysis shows that a baseline HCV RNA level of approximately 400,000 IU/mL has the highest statistical power to predict SVR as well as relapse rates in HCV type 1-infected patients treated for either 48 or 72 weeks with peginterferon-alpha-2a plus ribavirin. Use of this cut-off point will allow treatment optimization in genotype 1 patients.

 


#351. Treatment with peg-interferon and ribavirin therapy in dialysis patients with chronic hepatitis C.

A. C. Tan; R. A. de Vries; R. Adang; S. Konings; N. Cnossen; S. W. Schalm; R. van Leusen.

 

Background and aims:

In hemodialysis patients, it is advisable to eliminate HCV before transplantation as reactivation after kidney transplantation and decreased survival has been described. Standard therapy consists of pegylated interferon (PEG-IFN) with ribavirin for 48 weeks in genotype 1/4 and for 24 weeks in genotype 2/3. Sustained response (negative HCV-RNA 6 months after treatment) is reached in 50 – 80 %. Ribavirin is discouraged in renal insufficiency due to accumulation and severe (hemolytic) anemia. We studied the effectiveness of low doses of ribavirin, titrated by measuring serum levels and hemoglobin (Hb), combined with PEG-IFN-alfa 2a (40kd).

 

Methods:

7 caucasian patients on chronic hemodialysis participated in the study; 4 patients with genotype 1b, 1 with 4c/d, 1 with 2a, and 1 with 3a. Ribavirin was started at a low dose of 200 mg each other day. Subsequent dose changes were based on Hb and ribavirin serum level monitoring (target range 1.5 – 2.5 mg/ml). PEG-IFN-alfa 2a was given in a dose of 135 microgram weekly. Treatment was continued for 48 weeks in genotype 1 and 4, and for 24 weeks in genotype 2 and 3.

 

Results:

In 5 patients the ribavirin dose was increased to a max of 200 mg each day. In the other 2 the dose was kept at 200 mg each other day.The PEG-IFN dose was reduced to 90 microgr/week in one patient.Despite an increase of the weekly erythropoietin dose a max of 2 red cell transfusions was given to 4 patients. HCV-RNA showed an end-of -treatment response in all patients.Sustained response was accomplished in 5 of them.There were no serious adverse events.

 

Conclusion:

Using PEG-IFN alfa 2a (40 kd) and ribavirin, dosed using serum levels, a sustained response was accomplished in 5 out of 7 chronic hemodialysis patients. An acceptable Hb-level could be maintained by an increase of the erythropoetin dose in all and a max of 2 blood donations in 4 patients. The treatment was tolerated quite well. This result is well-matched with the result in normal kidney function. Keeping the ribavirin levels in the therapeutic range contributes to the tolerability and safety of the treatment.

 


#352. IL-10 levels during treatment with PegIFN-alpha 2b and Ribavirin in patients with Chronic Hepatitis C of different genotypic constitution.

K. Kaligeros; N. Margetis; E. Vergopoulos; V. Arseniou; D. Tsakalia; M. Kokkinou; E. Karkantzos; M. Demonakou; M. Agioutantis.

 

Aim:

The aim of this study was to demonstrate if IL-10 levels vary in relation to hepatitis C genotypes (1, 4-2,3) and to identify their correlation with a better response to the treatment of genotypes 2 and 3.

 

Methods:

80 patients with chronic hepatitis C, with at least 6 months abstinence from treatment, without any comorbidities (42 men, 38 women, average age 40) were divided into Group A: 36 patients genotype 1,4 and Group B: 44 patients genotype 2,3. There were no differences in sex and age between the groups. Eleven subjects free of hepatitis C served as control.

 

All patients had liver biopsy and viral load was measured by Roche Cobas Amplicor. They received pegylated interferon a-2b 1.5 ug/kg and ribavirin 800-1200 mg/d. The IL-10 levels were measured using Elisa Biosource immunoenzymatic method before treatment and at 8 and 24 weeks during treatment.

 

Results:

Before treatment, the IL-10 levels showed no considerable differences between the groups with no correlation to the viral load, degree of hepatic fibrosis or the transaminases levels. (Group A: average value 30 pg/ml, Group B: average value 25 pg/ml). The average value of IL-10 levels in the control group was 1.5 pg/ml.

 

At 8 weeks during treatment the average values of IL-10 were 20 pg/ml in group A and 8 pg/ml in group B and at 24 weeks 15 pg/ml and 8 pg/ml respectively. SVR in group A was 51% and 89% in group B.

 

Conclusions:

The rapid decline of IL-10 levels in group B compared to group A seems to boost the antiviral action of Th1 cytokines (interferon-γ, IL-2, IL-12, TNF-a) which in turn, cause an early increase of longer duration in CD4 and CD8 lymphocytes activity.

 

This may result in a more prolonged response to therapy in patients with chronic hepatitis C genotypes 2 and 3 compared to genotypes 1 and 4.

 

 


#353. Efficacy And Safety Of Peginterferon Alfa-2a Administrated Every Five Days In Combination With Ribavirin In HCV Genotype 1-Infected Patients With Severe Fibrosis Not Responding To Weekly Administrations Of Peginterferon In Combination With Ribavirin.

C. Hezode; M. Bouvier-Alias; F. Roudot-Thoraval; E. Zafrani; D. Dhumeaux; A. Mallat; J. Pawlotsky.

 

Introduction:

Weekly administration of pegylated interferon (PEG-IFN) alfa in combination with ribavirin is the standard therapy for chronic hepatitis C. Failure of this combination to clear infection is frequent in patients with HCV genotype 1. Viral kinetics studies have suggested that a rebound of viral replication often occurs at the end of each week, i.e. before the new PEG-IFN injection. This rebound could be responsible for treatment failures and could theoretically be prevented by more frequent PEG-IFN administrations.

 

Methods:

We tested the hypothesis in 3 male and 4 female patients, mean age 54.0 + 10.1 years, with HCV genotype 1 with severe fibrosis (F3, METAVIR), who did not clear infection after weekly administrations of PEG-IFN alfa-2b in combination with ribavirin. All patients were retreated by PEG-IFN alfa-2a, 180 µg administered every 5 days for 12 weeks, followed by 180 µg/week for an additional 36 weeks, combined with ribavirin (1,000 mg/day < 75 kg and 1,200 mg/day > 75 kg) for 48 weeks.

 

Results:

An early virological response (> 2 log HCV RNA drop at week 12) and an end-of-treatment virological response (HCV RNA < 50 IU/ml) were observed in 6 out of the 7 patients. As shown in the Table, the mean HCV RNA decline at week 12 was significantly more pronounced during the second treatment (frequent PEG-IFN administration) than during the first one (weekly PEG-IFN administration): 3.66 ± 1.35 log IU/ml versus 0.70 ± 0.46 log IU/ml, respectively. Overall, 4 patients achieved a sustained virological response, 2 patients relapsed and 1 patient did not respond to therapy.

 

Tolerance was similar to previous reports with weekly administrations of PEG-IFN combined with ribavirin. No dose interruptions or treatment discontinuations were needed due to adverse events or laboratory abnormalities.

 

Conclusion:

In conclusion, more frequent administrations of PEG-IFN alfa in combination with ribavirin induce a sustained virological response in a substantial proportion of patients with HCV genotype 1 infection and severe fibrosis who did not respond to prior standard PEG-IFN-ribavirin combination. Prospective, randomized controlled studies are now needed to confirm the interest and evaluate the global results of frequent PEG-IFN injections in difficult-to-treat patients with chronic hepatitis C.

 

Patients

First treatment
Viral load
Baseline

First treatment
Viral load
Week 12

First treatment
Log viral load decline
Baseline-W12

Second treatment
Viral load
Baseline

Second treatment
Viral load
Week 12

Second treatment
Log viral load
decline
Baseline-W12

1

6.34

5.08

1.26

6.42

<1.70

≥4.72

2

5.67

5.44

0.23

5.65

3.62

2.03

3

5.40

4.32

1.08

5.89

<1.70

≥4.19

4

6.42

6.25

0.17

6.27

> 1.70
<2.79

≥3.48

5

5.96

4.80

1.16

6.25

<1.70

≥4.5

6

5.39

4.92

0.47

5.31

<1.70

≥3.61

7

6.41

5.91

0.50

6.75

5.15

1.59

 

 


#354. Transient elastography (Fibroscan©) in chronic hepatitis c. Will it modify the assessment and the follow-up of treated patients?

F. Serejo; R. Marinho; A. Costa; J. Velosa; A. Fernandes; M. Carneiro de Moura.

 

Aims:

To evaluate the interest of hepatic elastography for the assessment and monitoring of histological response in chronic HCV patients submitted to antiviral therapy, comparing with a control group.

 

Methods:

25 normal individuals and 158 chronic hepatitis C patients with liver biopsy (less then 3 years) were included, 69 treated with Peginterferon+ ribavirin (SVR- 30; Relapsers (RR)- 7; NR- 32). Histological activity index (HAI) was graded according Knodell / Peter Scheuer: 47 patients F3/4; 111 patients F0/2. Liver stiffness was measured using Fibroscan©, median in 25 controls= 4.5 Kpa (3.30 – 5.69) and was correlated with clinical and laboratorial data including serum aminoterminal propeptide of procollagen type III (PIIIP RIA 25 controls= 0.4 ± 0.2 U/L).

 

Results:

A significant correlation was found between liver stiffness and HAI (p< 0.003). Median liver stiffness was 12.55 Kpa (9.10 - 16.24): F0,1 - 4,92 kPa (4,21-6,17) vs F2,3,4 - 6,81 kPa (5,14-15,95), P =0,006; F0,1,2 - 5.90 kPa (4,85 – 7,25) vs F3/F4 – 12,55 kPa (9,10-16,24), P =0,001. Median liver stiffness for detection of cirrhosis: 13.75 KPa (11.44-27.05), p=0.001. Optimal stiffness cut-off values for fibrosis stage assessment were determined by ROC curve analysis in 60 patients with concomitant liver biopsy specimens that contain more then 10 portal tracts. Optimized cutoff: F≥ 2 - 5,43 (AUC- 0,79; Se- 0,78; sp- 0,67; PPV- 0,98; PNV- 0,25); F≥3 – 8,18 (AUC- 0,96; se- 0,95; sp- 0,93; PPV- 0,87; PNV- 0,97); F4- 10,08 (AUC- 0,98; se- 0,93; sp- 0,93; PPV- 0,82; PNV- 0,98). The cut-off level of PIIIP for exclusion cirrhosis was 0.65 U/ml (se- 83%; sp- 60%; NPP= 96%). A significant correlation of liver stiffness was seen with age (p= 0.009), cholesterol (p= 0.04), triglycerides (p= 0.04), HOMA (p< 0.03), GGT (p= 0.006), AST (p< 0,0005); ALT (p< 0,0005) and PIIIP (p< 0.001). After therapy, median Liver stiffness in SVR was 5.13 Kpa (4.27-6.05), lower then in NR- 8.02 Kpa ( 5.78-22.06), p< 0.0005 and similar to the control group-4.5 Kpa (3.30 – 5.69)

 

Conclusions:

These preliminary results suggest that Fibroscan® is able to differenciate the different stages of fibrosis and correlates with other parameters of progressive liver fibrosis (age, GGT, HOMA, PIIIP). In sustained virological response values were similar to those observed in controls. Fibroscan may become a useful and reliable method for the non invasive follow-up of treated HCV patients. Evaluation of the early response to antiviral therapy (1 and 3 months) in patients with genotype 1 should be investigated.

(The authors would like to thanks Dr Vasco Lança and Mauro Conde for statistical analysis).

 


#356. Development of HCC in Patients who Achieve SVR to IFN-Based Therapies is Associated with Cirrhosis and Prior HBV Exposure.

M. J. Tong; S. Tu; J. Chen; L. M. Blatt.

 

Introduction:

The long term benefit of IFN-alpha + ribavirin therapy in chronic Hepatitis C patients who achieve an SVR is largely unknown however; previous studies have reported evolution of hepatocellular carcinoma (HCC) in some patients.

 

Methods:

To assess clinical benefit of SVR in our community practice, we examined 236 patients with SVR following standard IFN, standard IFN + ribavirin or Peg-IFN + ribavirin therapy. Patients were assessed for HCV RNA and development of cirrhosis and HCC during follow-up. The mean follow-up time was 46.96 ± 2.5 months. All but one patient (99.57%) remained HCV RNA negative throughout the follow-up. At baseline 40% of patients were HCV Genotype 1, mean HCV RNA was 5.94 ± 0.8 log10 copies/mL, 46 (20%) patients had cirrhosis and 42 (37%) were anti-HBc and/or anti-HBe positive (all patients were HBV DNA negative).

 

Results:

During follow-up, no patient developed cirrhosis however 9 patients with cirrhosis (4%) developed HCC and 2 patients (0.8%)with cirrhosis developed liver failure and required liver transplant. Univariate analysis of variables significantly associated with HCC revealed lower mean serum albumin and platelet counts, prior HBV exposure (anti-HBc and/or anti-HBe +), presence of cirrhosis prior to therapy and HCV genotype 1 as significant (p<0.05 for all observations). Multivariate analysis revealed anti-HBc and/or anti-HBe positivity and cirrhosis as independent predictors of HCC (anti-HBc and/or anti-HBe + OR 12.5 (1.9-248) cirrhosis at baseline OR 13 (2.5-99) p<0.05 for all observations).

 

Conclusion:

·        Chronic hepatitis C patients who achieve SVR may still be at risk for development of HCC.

·        Patients with prior exposure to HBV and cirrhosis prior to obtaining an SVR are 12.5 and 13 times more likely to develop HCC, respectively, compared with patients without these risk factors.

·        Patients with these risk factors should be monitored closely for development of HCC even if they achieve an SVR following therapy.

·        Further study is warranted.

 


#357. Homeostasis Model Assessment (HOMA) as a Measurement of Insulin Resistance is Related to Race, Stage, Grade, Body Mass Index but not to Virologic Response to Treatment.

W. Cassidy; B. Yoffe; J. Phillips; J. McCone; R. Muhumuza; N. Bailey; E. Britton; A. Lambert; R. Horswell.

 

Goal:

Increasing insulin resistance (IR) is thought to lessen immunologic response. This is an interim analysis of a study looking at the influence of IR upon virologic response rates seen in chronic hepatitis C infected patients treated with pegylated interferon alfa 2b (P-INF) & weight-based ribavirin (RIB).

 

Methods:

Data accumulated as part of a multicenter trial that examined the relationship between HOMA score, other clinical factors & response to P-INF/RIB therapy. Of the 400 patients, 395 enrolled. Of that number, 241 were genotype (GT) 1 patients with at least week 12 data. IR was assessed using HOMA score calculated as (fasting glucose (mg/dl) / 18.5) x (fasting insulin level/22.5). HOMA & viral load were measured at baseline, weeks 12, 24, 48, 72 or 24 weeks after last dose in a 12 week responder with early discontinuation. Biopsies were performed within 2 years of beginning therapy. An instrumental variables statistical model was used to assess the marginal relationship of HOMA on viral response after adjusting for other covariates, including African American race (AA) vs. non-AA, age, gender, biopsy grade & stage (Metavir), body mass index (BMI) & baseline viral load. As most patients do not yet have week 72 data, response to therapy (dependent variable in the model) was defined as an undetectable viral load at the latest available test (for those with viral load tests at 24 weeks or longer) or a 2+ log decline in viral load from baseline to week 12 for those with only week 12 follow-up viral loads available.

 

Results:

The unadjusted HOMA relationship to viral response was not statistically significant (p = 0.349) & the adjusted HOMA effect was even less (p = 0.788). HOMA scores are related to covariates that appear to assess burden of HCV-related liver disease. For example, there is a monotonic relationship between stage & HOMA (p < 0.001). This relationship appears to hold for AA & non-AA regardless of BMI. HOMA is also independently related to BMI (p < 0.001).

 

Conclusion:

These results suggest that HOMA score (& IR) are influenced by degree of HCV-related liver damage and also by BMI, but HOMA was not found to be related to virologic suppression after adjusting for other factors related to treatment success.

 

Relationship of mean HOMA score and Stage

 

All Patients

AA

Non AA

BMI≤27

BMI>27

Stage 0

2.07

3.66

1.83

2.09

2.05

Stage 1

2.47

2.46

2.47

2.02

2.85

Stage 2

3.06

3.52

2.90

2.44

3.46

Stage 3

3.43

3.50

3.34

2.45

4.40

Stage 4

3.97

4.43

3.67

3.05

4.54

Total

2.97

3.48

2.75

2.35

3.47

 


#358. An Interim Analysis of the Canadian POWeR Program (Peginterferon alfa-2b Prospective Optimal Weight-Based Dosing Response): Consistent SVR Rates Across All Weight Categories.

P. Marotta; S. V. Feinman; C. Ghent; L. Scully; M. Varenbut; J. Daiter; H. Witt-Sullivan; J. Robert; R. J. Bailey; B. Romanowski; J. Farley; N. Abadir.

 

Introduction:

• Pegylated interferon (PEG-IFN) alfa–based therapy in combination with ribavirin (RBV) is the current gold standard of treatment for patients with chronic hepatitis C.

• Numerous studies have shown an inverse relationship between body weight and virologic response when PEG-IFN alfa alone or in combination with RBV are administered as flat doses.1-3

• A recent study showed that a weight-based approach to PEG-IFN alfa and RBV dosing may improve treatment outcomes in patients with higher body weight without compromising the responses of patients with lower body weight.

• The WIN-R study, a large community-based trial conducted in the United States, showed a significantly improved response in patients receiving weight-based PEG-IFN alfa-2b (PegIntron®) in combination with weight-based RBV compared with those who received flat RBV dosing.5 Response rates were consistent across all weight categories.

 

Aim:

The Pegetron Prospective Optimal Weight-Based Dosing Response program (POWeR) is a large, open-label, mixed community- and academic-based clinical outcomes program that evaluates the impact of baseline

viral and patient factors on sustained virologic response (SVR) in patients with chronic hepatitis C who received treatment with weight-based PEG-IFN alfa-2b and weight-based RBV.

 

Methods:

Study Design

• Open-label, prospective, community- and academic-based therapeutic outcomes study conducted in treatment-naive patients with chronic hepatitis C.

• Patients were enrolled at 138 academic and community clinics across Canada between December 2002 and August 2005.

• Patients were treated, followed up, and managed according to current treatment guidelines and standard of care at each site, with no study-related intervention beyond collection of data.

Patients

• At baseline the following patient characteristics were recorded:

— Body weight: <50 kg, 50 to <64 kg, 64 to <75 kg, 75 to <85 kg, ≥85 kg.

— Hepatitis C virus (HCV) genotype (G): G1, G2, G3, or other.

— Extent of fibrosis (METAVIR score F0-F4 determined by liver biopsy).

• PEG-IFN alfa-2b (1.5 μg/kg/wk) plus weight-based RBV (800-1200 mg/d) was given according to standard of care (for 24 weeks in G2/3 patients and for up to 48 weeks in G1 patients).6,7 Early in the program, a week 12 virologic assessment was introduced as a standard of care in G1 patients. G1 patients who did not have undetectable HCV RNA or at least a 2 log10 drop from baseline viral load by week 12 were generally discontinued from treatment.

Efficacy Assessments

• Two separate analyses were conducted to determine response:

— Outcomes analysis: Patients with completed and queried case report forms, including those who discontinued for any reason, including nonresponse. In this analysis, patients who had detectable

HCV RNA at end of treatment (EOT) and for whom no SVR data were available were considered nonresponders.

— Completer analysis: Study population for whom both final EOT and SVR data were available.

• EOT response was defined as undetectable HCV RNA (<50 IU/mL) after completion of therapy.

• SVR was defined as undetectable serum HCV RNA (<50 IU/mL) 24 weeks after EOT.

Baseline Demographics

• A total of 2194 patients were enrolled in POWeR.

• Patient demographics were similar in both analyses (Table 1). Most patients had HCV G1 (~60%); 58% of these patients had high viral load at baseline (defined as >600,000 IU/mL or >2 million copies/mL

according to the local laboratory).

• A sizable proportion of patients had severe fibrosis or cirrhosis (F3-F4, ~37%) and approximately 60% of patients enrolled

 

Overall Virologic Response and Discontinuation

• SVR was attained in 64% of patients in the completer analysis and in 55% of patients in the outcomes analysis.

• 459 (25%) of 1820 patients included in the outcomes analysis discontinued treatment prematurely (ie, did not receive a full 24 or 48 weeks of treatment) and were nonresponders in the analysis.

SVR by Body Weight and Degree of Fibrosis

• Chi-square analysis was performed comparing the lowest SVR weight class (75-85 kg) to the mean of the other weight categories. Consistent with data previously reported there was no statistically significant difference in SVR rates across patient weight categories (P = .17) in either analysis.

• SVR rates decreased with increasing levels of hepatic fibrosis. In the patients with available biopsy data, there was an inverse relationship between SVR rates and baseline fibrosis stage. SVR rates (completers

and outcomes analysis) were highest in patients with F0-F1

SVR by Genotype

• Response rates for G1 patients were 52% and 42% in completer and outcomes analyses, respectively.

• G2 patients exhibited the highest SVR rates (87% and 80%, respectively).

• Response rates in G3 patients were 80% and 72%, respectively.

 

Relapse rates

• Recognizing the limitations of an interim analysis, relapse rates were calculated using the same patients for whom both EOT and SVR data are available as of September 2006 (best-case scenario).

— When PEG-IFN alfa-2b and RBV both were dosed by weight, the overall relapse rate was low (11%).

— When stratified by genotype, relapse rates were higher in G1 patients (16%) than in G2 and G3 patients (7% each).

Conclusion:

 In this large, population-based study, treatment-naive patients with chronic hepatitis C were enrolled to receive weight-based PEG-IFN alfa-2b (1.5 μg/kg/wk) plus weight-based RBV (800-1200 mg/d).

— Patients did not conform to any inclusion/exclusion criteria and were managed by individual physicians by standard of care only.

— At baseline, more than one third of patients had advanced fibrosis (35%, >F3) and 58% of G1patients had high viral load.

• Even with these poor prognostic characteristics, interim results of the POWeR study revealed excellent SVR rates. Importantly, the SVR rates were consistent across all weight categories.

• Patients with G2 chronic hepatitis C had the highest SVR rates, followed by patients with G3 and G1.

• Further analysis is required to complete the program and report SVR in all patients enrolled. More accurate relapse rates will then be defined.

 

 

 

Weight, kg (n = 1476)

<50

50-<64

64-<75

75-<85

>85

SVR (%)

57

56

54

52

56

Patients (number)

54

291

394

449

621

 


#359. Therapy A la Carte Is More Cost-Effective Than Standard Combination Therapy For Naive Patients With Chronic Hepatitis C.

M. Buti; M. A. Casado; R. Esteban.

 

Purpose:

Monitoring rapid virological response (RVR; undetectable HCV RNA at week 4) and early virological response (EVR; undetectable HCV RNA at week 12) rates are important tools that can be used to tailor duration of peginterferon and ribavirin therapy in patients, limiting side effects and costs. The purpose of this study was to analyze the financial impact of therapy a la carte (TALC) compared with standard combination therapy (SCT) for a population of treatment-naive patients infected by genotype 1 (G1, 74%), 2, and 3 (G2/3, 26%) from the perspective of the Spanish Health Care System.

 

Methods:

A budgetary impact model was constructed using a decision-tree analysis to compare (a) SCT: peginterferon alfa-2b and weight-based ribavirin for 24 weeks (G2/3) or 48 weeks (G1) with a 12-week stopping rule for non-EVR and (b) TALC: the same therapy dosage but different duration depending on RVR and HCV genotype: G1 and RVR, 24 weeks of therapy; G1 and no RVR, 48 weeks; G2/3 and RVR, 12 weeks; G2/3 and no RVR, 24 weeks. SVR results and costs were assumed from published studies.

 

Results:

·        STC and TALC strategies both resulted in similar SVR rates.

o       50% of patients receiving SCT and 55% of those receiving TALC

·        Total costs were higher with SCT than with TALC

o       Total costs were $301,527,236 for SCT and $226,318,631 for TALC

o       Overall, TALC would save $301,527,235 for SCT and $226,318,631 for TALC

·        Cost per patient who achieved an SVR was lower with TALC than with SCT

o       Cost per patient who achieved an SVR was $22,657 for SCT and $15,662 for TALC

o       TALC would result in saving of $6995 per patient who achieved an SVR, corresponding to $31% savings per SVR

o       Cost savings per patient who achieved an SVR are greater in patients with G1 than in patients with G2/3 ($10,125 vs. $2657).

 

Conclusions:

·        RVR is an important predictor of treatment outcome in patients receiving PEG-IFN alfa-2b plus RBV.

·        Healthcare costs associated with the treatment of chronic hepatitis C can be reduced by monitoring RVR to determine treatment duration.

·        TALC represents an effective approach for minimizing the healthcare costs associated with treatment of chronic hepatitis C without compromising SVR rates.

 

 

SCT

TALC

Difference

Overall SVR (%)

50

55

–5

SVR G1 (%)

41

46

–5

SVR G2/3 (%)

Cost

76

79

-3

Overall Cost (US$)

 

 

 

100 pts

1,160,624

972,623

188,001

74 G1 pts

939,133

799,933

139,200

26 G2/3 pts

221,491

172,690

48,801

Cost/patient with SVR (US$)

21,509

16,863

4,646

G1 pts

30,217

21,522

8,695

G2/3 pts

9,681

8,420

1,261

 


#361. Re-infection following successful treatment for Hepatitis C virus Infection with either alpha interferon or pegylated interferon/ribavirin combination therapy.

J. D. Farley; Y. Al-Khafaji; T. Mikami; W. Shum; T. A. Farley.

 

Background:

Until recently, there has been much reluctance to treat hepatitis C virus (HCV) infection in illicit intravenous drug users (IVDU) who now account for most of the chronic and new infections in Canada. One of the reasons advanced for not treating, has been because of the likelihood of re-infection. However, current treatment recommendations do not routinely monitor these individuals after sustained virologic response (SVR): following the end of treatment (EOT).

 

Objective:

To access the likelihood of re-infection in individuals who were successfully treated with either alpha interferon or pegylated interferon / ribavirin combination therapy.

 

Method:

We reviewed the medical charts of all the patients who were treated for and became re-infected with HCV.  173 pateints were identified as followed up for a range of six month to four years.  We assumed that re-infection happened halfway between the date of the last negative test result and the date of the first subsequent positive test result for HCV.

 

Results:

We identified eight (7) IVDUs, who became re-infected with HCV after SVR.   There were all former IVDUs.  Four likely resulted from IVDU, two from tattoos and one from blood splash (during a fight).  On an average, reinfection occurred 43.23 weeks after checking for SVR.

 

Conclusion:

·        We have documented seven cases of re-infection of HCV in former intravenous drug users following successful treatment for their chronic HCV.

·        We feel that re-infection may be a more frequent occurrence than is currently reported.

·        Current protocols do not usually emphasize any type of counselling (or monitor and following-up) after SVR/EOT.

·        We believe that patients (especially IDUs) should be counselled before, during and after treatments about the possibility of re-infection.  Counseling should include risk factors such as tattooing, sexual and direct blood contact.  There should also be ongoing monitoring and follow-up of these patients for more than six months post treatment (probably a minimum of two to four years) to reinforce harm reduction.

 


#362. Title: A Meta – Analysis of HCV Treatment in HIV Co – infected Patients.

A. Bonder; B. B. Shah; J. B. Wong.

 

Background and Aims:

Treatment of HCV/HIV co-infected patients has been associated with high rates of intolerance and low response rates. The aim of this study was to assess the efficacy of combination therapy with peginterferon plus ribavirin (PegIFN+RBV) versus interferon plus ribavirin (IFN+RBV) in co–infected patients.

 

Methods:

We performed a systematic review of MEDLINE from 1966-2006. Sustained virological response (SVR) was pooled using the DerSimonian and Laird random effects model. Subgroup analyses of SVR by study population characteristics were explored.

 

Results:

13 trials:  6 randomized controlled trials (RCT) = 7 Non-RCT

 

RCT (n=1216)

Non-RCT (n=216)

Age (mean, range)

38 (33.45)

35 (25-47)

Men (mean, range)

79% (43-100%)

75% (64-95%)

HAART (mean, range)

86% (68-100%)

90 (70-100%)

 

RCT Results:

 

IFN+RBV

SVR (95% CI)

PEG+RBV Risk

Difference (95% CI)

Intention to Treat

(n=1216)

 

16% (12-22%)

 

16% (0.036-31%)

Treatment Completers

(n=853)

 

33% (27-83%)

 

16% (0.36-31%)

 

 

IFN+RBV (95% CI)

PEG+RBV Risk

Difference (95% CI)

Early Viral Response

(2 trials, n=957)

 

33% (27-83%)

 

20% (-0.04-44%)

 

RCT

IFN+RBV

N=599

PEG+RBV Risk

Difference (95% CI)

n=617

Adverse Events*

13% (11-16%)

2.3% (-1.5-6.2%)

Withdrawals

  Adverse effects

  Insufficient response

Decline continuation

 

13% (11-16%)

4.6% (3.0-7.0%)

2% (4.2 -8.8%)

 

2.3 (-1.5-6.2%)

3.2% (-7.4-1.1%)

1.9% (-4.8-8.8%)

Most common:  flu-like illness, depression and haematological complications

 

 

SVR (95% CI)

 

IFN+RBV

4 studies (n=89)

PEG+RBV

3 studies, n=127

Non-RCTs

33% (20-49%)

38% (20-59%)

 

Conclusions:

·        Compared with IFN+RBV, PegIFN+RBV significantly improves SVR in HCV/HIV co-infected patients.

·        The largest benefit occurs in men, CD4>500, HCV RNA>1 million and patients who do not drink.

·        Close psychiatric and hematological monitoring may improve response rates further.

 


#363. Therapeutic Efficacy of 24 Weeks’ Antiviral Treatment in Addicted Patients on Methadone Maintenance Therapy Who Have Chronic Hepatitis C, Genotype 1, With Low Baseline Viremia.

M. Simonova; K. Katzarov; D. Takov; N. Tomov; D. Z. Aleksieva; G. N. Vasilev; E. Belokonski; N. Vladov.

 

Introduction:

Despite the high prevalence of HCV, there are few data about its treatment in injection drug users. Methadone maintenance therapy (MMT) is currently the most effective pharmacological treatment for chronic heroin addiction. It dramatically reduces recidivism and assists the majority of those taking it to achieve medical, psychological, and psychosocial stability. This study aimed to assess the therapeutic efficacy of 24-week combination therapy with pegylated interferon alfa 2b and ribavirin in addicted patients on methadone maintenance therapy who had chronic hepatitis C, genotype 1, low baseline viremia.

 

Patients and Methods:

Of 150 addicted patients on MMT with naive G1 low viral load chronic HCV infection, aged 17-36 years and screened for the study, 68 fulfilled the enrollment criteria: ALT >1.5 ULN, baseline HCV RNA < 600 000 IU/ml (Amplicor® HCV test; Roche), genotype 1, naive to interferon, HBV/HIV-negative, methadone dose up to 150 mg/daily. Liver biopsies were performed in all patients and assessed by METAVIR. Early virological response was measured quantitatively at week 12, end-of- treatment (ETR) and sustained virologic response (SVR) was measured qualitatively at 24 weeks and 24 weeks after treatment, respectively. Patients were treated with pegylated interferon alfa 2b 1.5 μg/kg/weekly and ribavirin 800-1200 mg/daily according to body weight for 24 weeks.

 

Results:

63 patients completed full treatment and follow-up duration periods. ETR was observed in 49/63 patients (78%) and SVR was observed in 42/63 patients (67%). 51/63 patients (81%) who had RNA HCV <600 IU/ml at week 12 achieved SVR and no initial non-responder at week 12 achieved SVR. Dose reductions for adverse events were required in 14/68 (20%) patients, mainly on methadone dose higher than 100 mg/daily. Discontinuation of the therapy was observed in 5/68 patients (7%) – 2 SAE and 3 for noncompliance to treatment regiment.

 

Conclusion:

Twenty-four weeks of treatment with pegylated interferon alfa 2b 1.5 μg/kg/weekly and Ribavirin 800-1200 mg/daily appears to be an acceptable regimen for the addicted patients on MMT with chronic hepatitis C, genotype 1, low baseline viremia.

 


#364. PREDICTORS OF RELAPSE AND OF SUSTAINED VIROLOGIC RESPONSE IN PATIENTS WITH HCV GENOTYPE 3 WITH AND WITHOUT HIV CO-INFECTION: BASIS FOR AN “A LA CARTE” TREATMENT.

M. Puoti; E. Minola; B. Zanini; G. Quinzan; A. Spinetti; S. Zaltron; L. Biasi; M. Antonini; M. Airoldi; C. Baiguera; P. Pagani; K. Prestini; F. Zacchi; P. Nasta; O. Fracassetti; S. Fredy; G. Carosi.

 

Aim:

In order to optimise anti-HCV treatment in patients with HCV G3 infection we analysed data of all consecutive HCV G3 infected patients with and without HIV coinfection who underwent anti HCV treatment in 2 infectious diseases departments with pegylated interferons (Pegasys 180 mcg/w or Pegintron 1-1.5 mcg/w) in combination with weight adjusted ribavirin (10,6-15 mg/Kg/day) from 2001 to 2005. Logistic regression analysis has been used for multivariate analysis.

 

Results:  

Three hundred and twelve patients have been studied: age was > 40 years in 31%, 25% were female, 72% were previous IDU, 40% HIV coinfected, 38% with METAVIR F3-F4, 49% with HCVRNA > 600.000 IU/mL, 32% with ALT > 3x UNL. Median treatment duration was 17.5 weeks in HIV - patients (IQR 14-26) and 27 weeks in HIV+patients (IQR 22-28). Treatment was stopped prematurely in 18% for adverse events and in 20% voluntarily Seventy percent showed SVR; 13% of 256 patients with End Of Treatment Response (EOTR) treated for at least 8 weeks after HCVRNA clearance relapsed : 3% of HIV- and 38% of HIV+(p<0.0001) Logistic regression analysis showed that SVR was independently and significantly associated with: HIV co-infection (AOR 0.21 95% CI 0.10-0.46) and with 4 baseline characteristics: HCVRNA > 600.000 IU/mL at baseline (AOR 0.45 95% CI 0.20-0.47), advanced fibrosis (AOR 0.39 95% CI 0.18-0.93), ALT > 3 x UNL (AOR 0.35 95% CI 0.16-0.76), female gender (AOR 2.79 95% CI 1.01-7.16). HCVRNA clearance at 4 weeks was also independently associated with SVR (AOR 4.49 95%CI 2.49-8.10). In patients with EOTR treated for at least 8 weeks after HCVRNA clearance relapse was significantly associated with HIV infection (AOR 18.92 95%CI 5.99-79.80), clearance of HCVRNA for <20 consecutive weeks during treatment (AOR 0.11 95% CI 0.04-0.25) and at least 2 predictors of poor response (PPR) at baseline ( AOR 5.06 AOR 1.42-17.99). Only 14% of 29 patients with >2 PPR treated for < 20 weeks after HCVRNA clearance relapsed (p<0.01 vs. other subgroups). In patients with HIV infection treated for < 20 weeks after HCVRNA clearance relapse was observed in 37% of those with <2 PPR and in 52% of those with >2 PPR (p>0.05). In HIV+ treated for > 20 weeks after HCVRNA clearance relapse was observed in 16% of those with >2 PPR but in none of those with <2 PPR (p= 0.02).

 

Conclusion:

Our data suggest that anti HCV treatment should be conducted for 8-16 weeks after HCVRNA clearance in HIV- without more than 1 PPR (male gender, high baseline HCVRNA, advanced fibrosis and ALT > 3 x UNL) , for 20 weeks after HCVRNA clearance in HIV- with 2 or more PPR, in all HIV+ for at least 20 weeks after HCVRNA clearance .

 


#365. The PRESCO trial: impact of higher ribavirin doses and longer duration of therapy with peginterferon alfa-2a plus ribavirin in HIV-infected patients with chronic hepatitis C.

M. Nunez; J. Garcia-Samaniego; M. Romero; J. Portu; P. Barreiro; L. Bonet; M. Cordero; M. Gonzalez; P. Lopez-Serrano; V. Soriano.

 

Background:

The treatment of chronic HCV infection has become a priority in HIV+ patients, given the faster progression to end-stage liver disease in the coinfected population. Poorer response in this group of patients compared to HCV-monoinfected individuals has been reported.

 

Methods:

In a prospective, multicenter, open, comparative trial, HCV/HIV-coinfected patients with elevated ALT who had not previously been exposed to interferon were treated with pegylated interferon alfa-2a (180 mcg per week) plus ribavirin (1,000 mg daily if body weight <75 Kg; 1,200 mg daily if >75 kg). Patients with HCV genotypes 1 and 4 (61%) were treated for 48 or 72 weeks, while patients with HCV genotypes 2 and 3 (39%) were treated for 24 or 48 weeks. Patients without early virological response discontinued therapy at 12-24 weeks.

 

Results:

Out of 389 patients included in the trial, 137(61%) were infected by HCV-1/4 and 67% had high HCV RNA levels. Treatment was prematurely discontinued in 46%, due to: virologic failure 17%, serious adverse events 7%, voluntary withdrawal or lost-to-follow-up 22%. In an intent-to-treat analysis, sustained virological response (SVR) was achieved in 49.6% patients, significantly more frequently in patients infected with HCV-2/3 (72.4%) than 1 (35.6%) and 4 (32.6%). No significant differences in SVR were observed when comparing short and extended treatment arms. Relapses according to length of therapy and HCV genotype are displayed in the table. Infection with HCV-2/3, lower baseline HCV-RNA, and negative serum HCV RNA at week 12 were independent predictors of SVR in the multivariate analysis.

 

Conclusion:

Nearly half of HIV/HCV-coinfected patients treated with RBV 1,000-1,200 mg/daily plus pegylated interferon alfa-2a 180 mcg per week achieved SVR. Response was twice higher in HCV-2/3 than HCV-1/4 carriers. The use of higher doses of ribavirin rather than extended duration of therapy seems to account for the good results obtained in this study.

 

Relapses according to length of therapy and HCV genotype

Treatment

HCV-1/4

HCV-2/3

All*

Short

(35.9%)

(21.0%)

(28.9%)

Extended

(27.3%)

(17.8%)

(21.3%)

All**

 (33.6%)

(19.7%)

(26.3%)

 

 


#366. Barriers to Treatment of Hepatitis C Virus in Human Immunodeficiency Virus Infected Patients in the Real Life: Modifications in Two Large Surveys between 2004 and 2006.

P. Cacoub; P. Halfon; E. Rosenthal; G. Pialoux; Y. Benhamou; C. Perronne; S. Pol.

 

Aim:

To analyse the barriers to HCV treatment in HIV-HCV co-infected patients and their evolution between 2004 and 2006 in France.

 

Patients and Methods:

Three hundred and eighty HIV-HCV co-infected patients were prospectively included by 71 physicians, specialists in the care of HIV infected patients during the period November 22 to 29, 2004 (2004 survey = Prospecth1), whereas in the second phase of the study 58 physicians included 416 patients seen from April 3 to 10, 2006 (2006 survey = Prospecth2). A standard data collection form was used.

 

Results:

Demographic characteristics were similar in the 2004 and 2006 surveys: male gender (71%), mean age (42 vs. 44 years), transmission via injection drug use (77% vs. 82%). Patients had more often undetectable HIV viral load (70% vs. 63%) and negative HCV RNA (24% vs. 12%) in 2006 than in 2004, with a similar distribution of HCV genotypes (genotype 1 or 4 in 65%). Patient management has changed between 2004 and 2006. Liver biopsy was done less frequently in 2006 (38% vs. 56%) while 24% had had a non invasive liver damage assessment. The rate of previous treatment for HCV infection was higher in 2006 than in 2004 (51% vs. 26%). Main reasons for the non treatment of HCV have changed between 2004 and 2006: HCV treatment deemed questionable (55% vs. 44%), no liver biopsy (34% vs. 18%), contraindication to treatment (30% vs. 26%), physician conviction of poor patient compliance (30% vs. 20%), and patient refusal (16% vs. 21%). In both surveys, patients having received HCV treatment compared to those who had never received any were more commonly of European origin, had better control of HIV infection, were followed by a hepatologist more often, were less frequently infected by a genotype 4, and had had a liver damage assessment more often. In the 2006 survey treated versus non treated patients were less frequently alcohol consumers (31% vs. 40%), particularly for high consumption > 50 g/d (6% vs. 23%) and more commonly receiving antiretroviral treatment with NRTI plus boosted PI (72% vs. 61%)(p<0.05).

 

Conclusion:

Following the 2005 European Consensus Conference, the care of HIV-HCV co-infected patients have changed significantly in "the real life" in France. Compared to 2004, more patients in 2006 have received HCV treatment (HCV treatment deeming less questionable), patients had more liver damage assessment, treatment was less contraindicated, while physicians’ conviction of poor patient compliance was lower. These results underline the importance of continuing efforts to educate physicians and patients to increase the access of HIV-HCV co-infected patients to HCV treatment.

 


#367. Contraction of HCV-Specific CD4+ T cell Responses in Patients Undergoing Antiviral Therapy Irrespective of Race and Virologic Outcome.

J. R. Burton; J. Klarquist; K. Im; S. Smyk-Pearson; L. Golden-Mason; H. R. Rosen.

 

Introduction:

Individuals who spontaneously clear HCV infection have vigorous HCV-specific cellular immune responses, whereas persistent infection is associated with weak responses. The effect of antiviral treatment on cellular immunity is not clearly defined. We examined the effect of antiviral therapy on HCV- and CMV-specific immunity according to race and viral outcome.

 

Methods:

Virahep-C is a multicenter NIH funded study of response to up to 48 weeks of peg-IFN and ribavirin in 205 Caucasian and 196 African American naďve, genotype 1 patients. Therapy was stopped in patients with detectable HCV RNA after 24 weeks of therapy. Primary end-point was sustained virologic response (SVR) defined as undetectable HCV RNA at 24 weeks after completing therapy. CD4+ T cell responses were quantified by IFN-γ enzyme linked immunospot (ELISPOT) assays in a subset of 60 patients selected to be evenly distributed by race and viral kinetic groups at baseline, treatment week (TW) 8, 24 and 48 and 24 weeks after stopping therapy (FU24). Briefly, 2.5x105 peripheral blood mononuclear cells (PBMCs) were incubated with HCV core (aa 1-115), E2 (383-715), NS3 (1007-1534), NS4 (1569-1931), NS5 (2054-2995), and both positive (CMV, PHA/SEB) and negative (SDS/SOD) control antigens for 40 hours with IL-2. Non-parametric Wilcoxon or Kruskal-Wallis signed rank tests were used for paired comparisons at each study time point. A random coefficients model was used to examine the longitudinal pattern of CD4+ T cell responses over time.

 

Results:

Overall, there were significant decreases from baseline at TW8 (median difference 38.7 ELISPOTS/2.5x105 PBMCs, p<0.0001; 85% decrease from baseline) that remained below baseline throughout therapy, not returning to baseline responses at FU24 (median difference 27.2 ELISPOTS/2.5x105 PBMCs, p=0.007; 40% decrease from baseline). These decreases were comparable across the different groups in terms of race, viral kinetics and SVR status. Though not statistically significant, there was a trend for higher median total IFN-γ ELISPOTs at follow-up in patients with HCV relapse after therapy (n=9) compared to patients with SVR (n=28) (92.3 vs. 34.2 total median ELISPOTs/2.5x105 PBMCs; p=0.076). Responses directed against CMV were relatively preserved during antiviral therapy.

 

Conclusions:

Combination antiviral therapy results in contraction of immune responses specifically directed against HCV. These decreases in the memory population are independent of race and virologic outcome.

 

This study is funded by the NIDDK through a cooperative agreement with partial support from Roche Laboratories Inc. through a CRADA with the NIH.

 


#368. Better prediction of SVR in patients with HCV genotype 1 (G1) with peginterferon alfa-2a (PEGASYS) plus ribavirin: Improving differentiation between low (LVL) and high baseline viral load (HVL).

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

 

Introduction:

Recently, baseline VL has become an important predictive factor in the development of a treatment algorithm in pts with G1; however, it is unclear whether the cut-off should be 600,000 or 800,000 IU/mL HCV RNA. Both were derived historically from 2 x 106 cps/mL using different conversion factors for the PCR assay used. In an analysis of predictive factors using data from a German observational study (DDW 2006, abs #219003), developed by the Association of German Independent Gastroenterologists (bng) and Roche Pharma AG, categorized baseline VL (800,000 IU/mL cut-off) was not significant in uni- or multivariate analyses. Therefore, this analysis investigated the optimal VL cut-off for SVR prediction.

 

Methods:

Analyses included 916 naive patients with G1 who received treatment with peginterferon alfa-2a + ribavirin for 48 weeks according to current guidelines and for whom complete relevant data was recorded. The influence of logarithmic VL on SVR was estimated as a continuous variable in univariate logistic regression (ULR) and by analyzing the receiver operating characteristic curve (ROC). The optimized cut-off was then compared to both existing cut-offs using multivariate logistic regression (MLR) analysis.

 

Results:

In ULR, continuous VL was a strong predictor of SVR (p<.0001; OR=0.79; CI: 0.69–0.89), but the effect of VL was non-linear. The ROC-plot revealed a cut-off level of VL of 5.6 log10 IU/mL (~400,000 IU/mL). According to this result, the predictability of baseline VL using a cut-off level of 400,000 IU/mL, 600,000 or 800,000 IU/mL was compared by MLR. Of the three, 400,000 IU/mL best predicted SVR (p<.0001; OR=0.48; CI:0.37–0.63). Using this cut-off, 62.0% of patients with LVL and 43.7% with HVL had an SVR. SVR rates according to VL cut-off are shown in the table. While in pts with LVL, SVR rate increased with decreasing cut-off, in pts with HVL, the SVR rate was 43% regardless of cut-off, i.e. pts with VL >400,000 IU/mL had low SVR rates similar to pts with VL>800,000/mL and belong in the same VL category.

 

Conclusion:

The well-accepted former cut-off of 2 x 106 copies/mL was statistically optimized for treatment with standard interferon. In the era of pegylated interferon, this cut-off is not the best way to differentiate between LVL and HVL with regard to likelihood of SVR. These data suggest that to use VL as a reliable predictor of successful treatment outcome, the optimized cut-off of 400,000 IU/mL should be used.

 

400,000 IU/mL

600,000 IU/mL

800,000 IU/mL

LVL

HVL

LVL

HVL

LVL

HVL

267/431

212/485

323/552

156/364

355/628

124/288

62.0

43.7

58.5

42.9

56.5

43.1

SVR rate by VL cut-off, n (%)

 

 

#369. Response to Peginterferon Alfa-2b and Ribavirin for Chronic Hepatitis C in Patients with Body Weight >125 kg: Results from the WIN-R Trial.

I. M. Jacobson; R. Brown; B. Freilich; N. Afdhal; P. Kwo; J. Santoro; S. Becker; A. Wakil; L. Griffel; C. Brass; W. The.

 

Introduction/Aim:

In WIN-R, a US study of >4900 HCV patients from community and academic sites that prospectively compared PEG-IFN alfa-2b 1.5ug/kg/wk + fixed dosing (FD; 800 mg/d) or weight-based dosing (WBD; 800-1400 mg/d) of ribavirin (RBV), sustained virological response (SVR) rates were significantly greater with WBD than FD of RBV (AASLD’05). WBD patients weighing >105-125 kg received RBV 1400 mg/d and had SVR rates similar to other WBD patients. The current study evaluated SVR rates among patients weighing >125 kg, for whom data are limited, who entered the study as protocol exceptions.

 

Methods:

In WIN-R, patients were randomized to PEG-IFN alfa-2b 1.5ug/kg/wk (max: 150 ug/wk) + FD RBV 800 mg/d or WBD RBV: <65 kg, 800 mg/d; 65-<85kg, 1000 mg/d; 85-<105 kg, 1200 mg/d; 105-125 kg, 1400 mg/d. Genotype 1 (G1) patients received 48 wks of therapy, and G2/3 patients were randomized to 24 or 48 wks of therapy. All patients were monitored for 24 wks post-treatment. HCV RNA levels were determined by PCR (Taqman/SPRI, LLQ 29 IU/ml) at wks 0, 24, 48 and 72. RBV dose reductions and discontinuation were required for hemoglobin <10 gm/dl and <8.5 gm/dl.

 

Results:

In total, 51 patients >125 kg were enrolled in the trial; 28 received FD RBV (800 mg/d) and 23 received WBD RBV (1400 mg/d). SVR occurred in 47% of patients—30% of G1 and 67% of G2/3 patients, rates nearly identical to those for the overall study cohort. SVR rates for the 28 FD RBV patients and the 23 WBD RBV patients were 30% and 61% overall (P=.0342); 15% and 43% in G1 (P=.1315), and 50% and 79% in G2/3 (P=.1524). Only 3/49 (6%) had nadir Hgb <10 gm/dl and 30/50 (6%) had neutrophils <750/mm3; for the overall study cohort (n = 4913) these percentages were 16% and 19%. Dose reductions of PEG-IFN occurred in 9/51 (18%) patients and 10/51 (20%) had dose reductions of RBV.

 

Conclusion:

• Patients with very high body weight (≥125 kg) and high BMI (mean, 41.0 kg/m2) achieved SVR rates similar to those of patients weighing <125 kg.

• Patients weighing ≥125 kg were at least as likely to achieve an SVR as patients weighing ≤125 kg with weight-based ribavirin therapy.

• Patients weighing ≥125 kg were much more likely to achieve an SVR with weight-based ribavirin than with flat-dose ribavirin.

• Low rates of anemia and neutropenia and low dose-reduction rates probably reflect lower levels of ribavirin exposure.

• These results suggest that severe obesity should not preclude consideration of antiviral therapy for patients with chronic hepatitis C.

 

Supported by Schering Plough.


#370. Hepatitis C screening and treatment among drug users in Amsterdam: interim results of the inclusion procedure in the Dutch C project.

K. Lindenburg; C. Weegink; J. Schinkel; P. Jansen; M. Beld; A. Krol; G. Casteelen; G. van Santen; R. Coutinho; M. Prins.

 

Objective:

Although injecting drug users (IDU) are at high risk for Hepatitis C Virus (HCV) infection, they are less likely to be treated than other populations. We started to offer HCV testing and treatment combined with methadone programs in a setting where active drug use is tolerated. Here, we evaluate the inclusion procedure 1.5 year after the start of our pilot project.

 

Methods:

The study population comprises DU participating in the Amsterdam Cohort Studies (ACS) in 2005. Hepatologists, methadone specialists, cohort staff and a special project-nurse collaborate closely to provide optimal HCV care. DU chronically infected with HCV are offered additional medical and psychiatric screening. HCV treatment is directly observed and combined with methadone provision.

 

Results:

493 DU were offered HCV screening: 60% male, 8% homeless and median age 45 years. HCV screening was refused by 110/466 (24%). An additional 10% (49/466) was willing but lacked medical insurance, leaving 383 (78%) to be tested. HCV antibodies were found in 224 (59%), 144 (64%) were chronically infected. Of these, 127 (88%) returned to obtain their test result. Of 76 HIV-negative HCV-infected DU, 77 (85%) were willing to undergo additional medical screening which was completed by 65 (84%). For 39 (60%) a final treatment decision was made: 18 (47%) started treatment, 9 (23%) refused, for 6 (15%) treatment was not indicated based on a liver biopsy, and for 6 (15%) there were medical and/or social contraindications. For 26 (40%) the decision on HCV treatment initiation is pending.  8 (44%) finished treatment, 5 (28%) are still on treatment and 5 (28%) stopped treatment--2 virological non-responders (genotype 1) and 3 from side effects. 5 achieved SVR (genotype 2 and 3)

 

Among the 18 treated subjects 14/18 (78%) were active DU, 4/18 (22%) reported injecting over the last 6 months and 16/18 (89%) were on methadone.  Compliance for HCV treatment was 98%.

 

Conclusions:

78% of the participants of the ACS among DU is willing to undergo HCV screening and has medical insurance.  We observed a high return rate among screened DU and great willingness to undergo additional medical screening.  Screening appears to be time-consuming, but once DU start HCV therapy they are fully compliant.  Interim end of treatment response in the Dutch-C project are very good.  These findings suggest that active DU can successfully undergo treatment for HCV in a multidisciplinary approach.  However, social, medical, psychiatric and abuse related problems postpone or interfere with HCV treatment.

 


#371. Pegylated interferon and ribavirin in haemodialyzed patients with chronic hepatitis C: a prospective study.

P. Deltenre; V. Canva; F. Provôt; F. Glowacki; S. Dharancy; H. Ben Ali; A. Louvet; J. Boitard; J. Henrion; C. Noël; P. Mathurin.

 

Introduction:

In haemodialyzed patients, ribavirin is contraindicated due to a high risk of hemolytic anemia related to the end-stage renal failure. HCV eradication before kidney transplantation may be an attractive option when considering the deleterious impact of HCV after kidney transplantation.

 

Aims: 

1.     to determine the tolerance of combinative therapy with pegylated interferon (Pegasys) and a weekly individual schedule of ribavirin;

2.     to provide preliminary data on virological response.

 

Patients and methods:

Fourteen haemodialyzed HCV patients waiting for renal transplant were treated with combinative therapy with Pegasys and weekly dose of ribavirin for 6 or 12 months according to genotype. Doses of ribavirin and erythropoietin (EPO) were adjusted according to hemoglobin level (Hb) to maintain levels up to 10 g/dl. There were 9 patients with genotype 1, 5 with non-1 genotype. Median viral load was 962000 IU/mL (95 % CI: 146000-3610000). Liver fibrosis was mild or moderate (≤F2) in all but 1 patient. Mean time on dialysis was 16 years.

 

Results:

Median doses of Pegasys was 180µg/week (95 % CI: 135-180 µg) and of ribavirin 800 mg/week (95 % CI: 600-1000 mg). Before initiation of antiviral therapy, 11 out of 14 patients were already treated by EPO. After 2 months of treatment, 13 out of 14 patients received EPO. As compared to baseline, the median increase of EPO dose was 200 % (95 % CI: 100-305%, range: 92-525%). Median Hb levels decreased during the first 2 months of treatment from 11.9 (95 % CI: 10.2-12.8) to 10.2 g/dl(95 % CI: 8.9-11.1, p=0.03) and remained stable throughout the period of treatment. Five patients required transfusion but only 2 of them had Hb level lower than 7 g/dl. Eleven patients completed treatment. Treatment was withdrawn in the 3 remaining patients for severe asthenia (n=2) and retinal hemorrhage (n=1). After 1 and 3 months of treatment, more than 2 log decrease in viral load was reached in 86% (12 out of 14 patients) and in 92% (11 out of 12 patients), respectively. End-of-treatment virological response (ETR) was reached in 11 out of 14 patients and sustained virological response (SVR) in 6 out of the 10 patients reaching 6 months post-treatment follow-up.

 

Conclusions:

Despite a theoretical contraindication, ribavirin may be used in haemodialyzed HCV patients, a particular high-difficult-to-treat group of patients. This use required a weekly adaptation of ribavirin dose and 200 % increase of EPO. This combinative therapy with an individualized schedule of ribavirin permits to reach ETR and SVR in 79 % (11 out of 14) and 60 % (6 out of 10) of cases, respectively. These results are similar to those observed in non-haemodialyzed HCV patients.

 


#372. Economic Evaluation of Individualized versus Standard Treatment Approach for Patients with Chronic Hepatitis C Virus Genotype-1 (G1) Low Viral Load (LVL) Using Peginterferon Alpha-2b Plus Ribavirin in the United Kingdom.

S. Zeuzem; N. Naoumov; N. Tatman; L. Cragin; S. Sorensen.

 

Purpose:

A 24-week course of therapy for G1 LVL patients who become viral negative after 4 weeks of treatment with peginterferon alpha-2b + ribavirin was recently approved by the EMEA. Clinical evidence suggests sustained virologic response (SVR) in this population is comparable to a 48-week course of therapy. The long-term clinical and economic impacts of shorter treatment duration are unknown. This study evaluated the cost-effectiveness of 24-week treatment for 4-week responders + 48-week treatment for 12-week responders (individualized strategy) vs. 48-week treatment for both 4- and 12-week responders (standard strategy) in the context of current UK management guidelines, which recommend 12-week non-responders stop treatment.

 

Methods:

Decision analytic and Markov models for the treatment and disease progression phases, respectively, were designed to reflect potential clinical events for G1 LVL patients. Response at weeks 4 and 12, SVR, discontinuation, adherence, and disease progression rates were obtained from published literature. Clinical data were adjusted to reflect current medical practice. Costs included drug therapy, monitoring, adverse events, and disease progression. Resource use data were collected from published literature and supplemented by clinical experts. Unit costs were obtained from available UK sources. Incremental costs per quality-adjusted life-year (QALY) gained were calculated using short-term (2-year) and long-term (lifetime) timeframes to account for long-term complications of chronic HCV.

 

Results:

The model predicted SVR rates of 70% (standard) and 68% (individualized) based on 4- and 12-week response rates and assumptions for discontinuation and adherence. Due to the shorter duration of therapy, the results indicate short-term cost-savings of Ł52,527 per QALY for the individualized strategy. In addition, this strategy resulted in fewer discontinuations and adverse events as well as improved adherence. The long-term incremental cost per QALY was Ł43,595 for the standard vs. individualized strategy. Probabilistic sensitivity analysis demonstrated the model was robust with respect to incremental costs but showed considerable uncertainty for incremental effectiveness.

 

Discussion:

·        MNodleing is a useful tool for guiding treatment decisions when head-to-head clinical trials have not been conducted or when predicting events that extend beyond the trial period.

·        To our knowledge, this is the first cost-effectiveness analysis evaluating individualized versus standard treatment strategies for HCV-1 patients with low pre-treatment viral load.

·        Analysis incorporates discontinuation and adherence rates and reflects current UK medical practice.

·        Several limitations of this analysis deserve mention:  use of small historical control group (n=38) consisting of HCV-1 LVL patients from Manns et al, historical control group treated with suboptimal RBV dose due to concerns about anemia at the time study was conducted, and exclusion of relapse patients who might be re-treated.

 

Conclusions:

·        For treatment of G1 LVL patients in the UK, the individualized strategy has similar efficacy to the standard strategy and is expected to be cost-effective.

·        Probabilistic sensitivity analyse demonstrated that the model, overall, is robust.

 

 

Costs

QALYs

ST

LT

ST

LT

Standard

Ł13,046

Ł21,679

1.62

19.56

Individualized

Ł9,202

Ł18,429

1.69

19.49

Difference

Ł3,844

Ł3,250

-0.07

0.07

 

Abbreviations: ST, short-term; LT, long-term

 


#373. THE INTERNATIONAL AUTOIMMUNE HEPATITIS GROUP SCORING SYSTEM IN PATIENTS WITH CHRONIC HEPATITIS C AND SERUM AUTOANTIBODIES UNDERGOING INTERFERON/RIBAVIRIN THERAPY: A PROSPECTIVE VALIDATION STUDY.

V. Monti; A. Aghemo; M. G. Rumi; M. F. Donato; E. Arosio; R. D'Ambrosio; P. Lampertico; R. Soffredini; M. Colombo.

 

Background:

Non organ specific autoantibodies (NOSA) circulate in approximately 40% of patients with chronic hepatitis C virus (HCV) infection marking a risk for autoimmunity.

 

Aim:

To clarify whether HCV patients with NOSA lacking a diagnosis of Autoimmune Hepatitis (AIH) according to the International Autoimmune Hepatitis Group (IAHG) score system can be safely and effectively treated with interferon (IFN)/ Ribavirin (Rbv). Material and methods: All consecutive patients with chronic hepatitis C due to genotype 1 or 4 who between 2000 and 2005 underwent IFN/Rbv therapy were studied. NOSA were looked for at baseline by indirect immunofluorescence on cryostat 4 μ sections from rat liver, stomach and kidney at 1:80 dilution. The antinuclear antibody (ANA) was further characterized on Hep-2 cells. In all patients with NOSA the IAHG was calculated.

 

Results:

37 patients received standard IFN and 216 received pegylated IFN. 82 (32%) circulated NOSA: 28 had ANA, 13 ANA + smooth muscle antibodies (SMA), 31 SMA and 10 liver-kidney microsomal antigen antibody type 1 (LKM-1). All patients with NOSA had less or equal to 15 IAHG score (no definite AIH). NOSA were associated with female sex (p=0.02). A sustained virological response (SVR) was obtained in 72 (28%) patients, 34 (42%) with NOSA vs 38 (22%) without NOSA (p=0.01). None of patients developed an autoimmune reaction following IFN/RBV therapy. By logistic regression a SVR was associated to NOSA, absence of cirrhosis and low basal viremia (<800.000 IU/ml).

 

Conclusions:

IAHG scoring system is useful for selecting patients with genotype 1 or 4 chronic hepatitis C with NOSA who are candidable to IFN/RBV therapy and likely to respond well to therapy.

 


#374. Overcoming barriers to treatment of hepatitis C in Italian drug users. The importance of a co-management model of care.

R. Brigada; M. Bonasso; G. Borroni; M. Orso; M. C. Vivirito; G. Orofino; C. Magni; A. Cividini; G. Pennisi.

 

Introduction:

Despite the high prevalence of hepatitis C virus (HCV) infection among drug users (DU) enrolled in the methadone/buprenorphine maintenance treatment programs (MTP), only few DU are being treated with antiviral therapy.

 

Methods:

No treatment guidelines are available in Italy for management of HCV infection among DU. Thus, experts in addiction medicine, hepatologists, psychiatrists and psychologists organized a “Working Group on HCV Infection in DU” to implement a multidisciplinary model of care and to draft recommendations. The model includes screening and treatment for HCV infection among DU, counselling pre, on and post-treatment, psychiatric evaluation and enhanced cooperation with infectious disease specialists.

 

Results:

We describe the results of a pilot program designed to integrate care for HCV infection in a setting of MTP. All patients (pts) selected at 4 MTP centres of Northern Italy were screened for HCV antibodies and those with positive results were tested for HCV RNA. Counselling addressing minimization of transmission and value of treatment was offered. Enrolled pts were treated with peg interferon and ribavirin for 24 or 48 weeks, according to genotype, blood tests were performed and virological response assessed. The 90 treated pts (78 males,12 females, mean age 36, range 22-61) were evaluated with a depression scale. The mean duration of HCV infection was 10 years. The most frequent genotype was 3 (45 pts; 50%) followed by genotypes 1 (28 pts; 31%), 4 (10 pts;11%) and 2 (7 pts; 8%). Forty pts (44%) received methadone and 11 ( 12%) buprenorphine. Therapy was discontinued early in 11 pts (12%); in 4 pts (4%) because of side effects and in 7 pts (8%) because of non-compliance. The dropout rate was highest during the first 2 months of therapy. Of the 82 pts (90%) that ended the treatment, 62 (76%) were HCV RNA negative. Ten pts (12%) developed depression after the 2nd month of treatment and 3 pts (4%) reported craving for drugs or alcohol. However, none of them had to stop the treatment. The symptoms were controlled with antidepressants or changes in substitutive treatment. Six months after the end of therapy, only one patient (1%) experienced a relapse.

 

Conclusion:

Caring for pts who use illicit drugs presents challenges to the health-care team as it requires patience, experience and understanding of the dynamics of addiction and HCV infection. Improved provider-patient communication, counselling, follow-up at frequent intervals and the work of a multidisciplinary team helped to control the dropout rate and the psychiatric side effects. Further effort is warranted to increase the proportion of DU who initiate treatment for HCV infection.

 


#375. Successful hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants.

G. P. Jeffrey; G. MacQuillan; F. Chua; S. Galhenage; J. Bull; E. Young; G. Hulse; G. O'Neil.

 

Introduction:

The effectiveness of HCV antiviral therapy in patients who have undergone recent drug dependency treatment and continue to inject drugs sporadically is presently not clear.

 

Methods:

Patients attending a community based drug rehabilitation and naltrexone implant clinic from October 2002 until March 2005 were screened for HCV infection and if positive offered further assessment and treatment with interferon and ribavirin therapy. The first 50 patients to commence HCV therapy and complete at least six months follow up were prospectively studied. 49 underwent liver biopsy.

 

Results:

ETR response (HCV PCR negative) was 34/50 (68%) and SVR 6 months post-treatment was 31/50 (62%). Viral eradication was maintained in those 22 patients that have had 12 months or more post-treatment follow up. The presence of F3/F4 fibrosis or previous heavy alcohol intake (>100g/day) were associated with non response (p<0.05), however logistic regression anaylsis found that only prior heavy alcohol intake was associated with non response. 11 (22%) patients stopped therapy early due to side effects or poor compliance. Only two patients with an ETR re-infected due to unsafe injection practices. One was re-treated and achieved an SVR. Of the patients achieving a 6 month SVR, 17 of 31 patients reported no further IDU and 13 of 31 patients occasional IDU during treatment and this was maintained after HCV treatment cessation. 46% of patients received antidepressant and/or antipsychotic medication during treatment.

 

Conclusion:

In conclusion this prospective study of HCV treatment in a community based subcutaneous naltrexone implant clinic found antiviral therapy resulted in a 62% SVR. This result is comparable to that reported in hospital based clinics in non IDU patients. The side effect profile and compliance was also similar. HCV antiviral therapy should be offered to this large and currently under treated group.

 


#376. Late treatment of chronic hepatitis C in renal transplant recipients: an open pilot study.

G. Pageaux; G. Mourad; F. Chermak; H. Audin; V. Garrigue; S. Deleuze; D. Larrey.

 

Introduction:

Renal transplantation is associated with a more severe evolution of chronic hepatitis C as compared with HCV-infected immunocompetent patients. This results in a decrease in survival of patients and allografts. Treatment of hepatitis C in renal transplant recipients remains a controversial issue, since interferon therapy has been associated with a high risk of rejection and a low efficacy. There is very few data in the literature, since interferon is considered as contra-indicated in these patients.

 

Aim:

In an open pilot study, we assessed the efficacy and the safety of late use of interferon or PEG-interferon, associated or not to ribavirin, in renal transplant recipients with chronic hepatitis C.

 

Patients:

Seven kidney recipients were treated with interferon a monotherapy (n = 1), PEG-interferon a2a or a2b monotherapy (n = 3), or PEG-interferon a2b associated to ribavirin (n = 3). Liver biopsy was performed before therapy and classified according to the Metavir score.

 

Results:

There were 6 male and 1 female, mean age 55.4 years (36-75), mean time between transplantation and antiviral treatment 14 years (1.6-24). The virological and histological parameters were as follows : genotype 1 (n = 2), genotype 2 (n = 3), genotype 5 (n = 2) ; the mean viral load was 830 000 UI/ml ( 140 000 - 2 500 000) ; according to the Metavir score, 1 patient was F1, 2 patients were F2, 3 patients were F3, 1 patient was F4. Antiviral treatment was withdrawn in 4 patients, at week 35, week 28, week 12, week 20, respectively, for the following reasons : anemia (n = 1) , depression (n = 2), hemolytic and uremic syndrome (n = 1). End of treatment and sustained virological responses were observed in 4 and 2 patients, respectively. The characteristics of the 2 patients with sustained virological response were as follows : one male with genotype 2, viral load 1 300 000 UI/ml, Metavir score F1 and one female with genotype 2, viral load 140 000 UI/ml, Metavir score F2. The 2 other patients with only end of treatment response were genotype 2 and 5, Metavir score F2 and F3. Mean baseline serum creatinine value was 171.8 µmol/l (83-268) and end of treatment serum creatinine value was 167.7 µmol/l (74 – 275). No patient developed graft rejection.

 

Conclusion:

In this pilot study, interferon a or PEG interferon, associated or not ribavirin, was used in renal transplant recipient with chronic hepatitis C without inducing graft rejection. A significant portion of patients achieved end of treatment and sustained virologic response.

 


#377. The risk of hepatocellular carcinoma and decompensation following hepatitis C treatment with interferon based therapy.

K. Jamil; W. Cheng; L. Tarquinio; L. Adams; L. Mollison; G. MacQuillan; B. DeBoer; M. McInerney; S. Nazareth; C. Connelly; J. Flexman; N. Kontorinis.

 

Introduction:

Patients with advanced hepatic fibrosis due to hepatitis C virus (HCV) are at high risk of hepatocellular carcinoma (HCC) and hepatic decompensation (HD). We evaluate their incidence following interferon therapy in patients with F3/4 fibrosis, and study the effect of SVR.

 

Methods:

A cohort of patients with F3-4 fibrosis (METAVIR) treated with IFN therapy from 1995 to 2006 was identified from the HCV databases at 3 centres in WA. All patients had compensated (Childs A) liver disease. The incidences of HD, diagnosis of HCC and mortality were recorded. Frequency of HCC screening with U/S and AFP were assessed. Statistical methods used were: χ2 test, Fischer’s exact test and Welch’s unpaired t-test.

 

Results:

135 patients (104 males & 31 females) were followed for a median of 983 days (0-3513) Mean age was 48 years (SD 7.8). 13 had IFN monotherapy (SVR 31%), 33 had IFN/RBV combination therapy (SVR 42%) and 87 had PEG-IFN/RBV therapy (SVR 46%). Asian ethnicity was associated with development of HCC (p=0.02). Incidence of HCC was 1.4%/year overall (5.1%/year in Asians, 0.7%/year in non-Asians). There was a reduction in HCC and mortality following SVR (see table) but this was not statistically significant. There was no difference in development of complications between F3 (7/75, 9%) and F4 (5/60, 8%) patients. Overall, 102 patients had HCC screening of which 69% was sporadic, 28% was annual and 3% was 6 monthly. 52 are currently in a screening schedule.

 

Conclusions:

HCV eradication in this high risk population may reduce the risk of HCC and mortality. Patients with F3 fibrosis are at similar risk to F4 for HCC and decompensation and require analogous screening. Asian patients are at greater risk of HCC from HCV-related cirrhosis. There is a need for standardised screening methods and follow up in all patients.

 

Complication

Asian

Non Asian

p

SVR

No SVR

p

%/Yr

HCC

3/19 (16%)

2/116 (2%)

0.02

1/51 (2%)

4/84 (5%)

0.65

1.4

HD

0/19 (0%)

6/116 (5%)

0.59

2/51 (4%)

4/84 (5%)

1.00

1.7

Death

1/19 (5%)

4/116 (3%)

0.54

0/51 (0%)

5/84 (6%)

0.16

1.4

Total

3/19 (16%)

9/116 (8%)

0.37

3/51 (6%)

9/84 (11%)

0.53

3.4

 


#378. Maintenance pegylated IFN given once every three weeks prevents relapse of hepatitis C virus (HCV) in decompensated cirrhosis.

V. K. Thorat.

 

Background & Aim:

Successful eradication of HCV results in improvement of liver tests and liver histology, and reduction in hepatocellular carcinoma. However, there is limited data on the impact of anti-viral therapy in patients with advanced liver disease. In the present study, we assessed the effect of maintenance treatment in patients with decompensated liver disease who had relapsed after initial anti-viral therapy.

 

Methods:

28 patients with HCV (genotype 2/3) and Child-Pugh score of ≥7 were included in the study. Exclusionary criteria included recurrent episodes of spontaneous bacterial peritonitis, severe encephalopathy, serious comorbid illnesses, HIV co-infection, platelets <50,000/ mm3, white cells <2x109 liter and hemoglobin <10g/dl. All patients were treated with 1.5 MU of interferon (INF) for 2 weeks, then 3MU of IFN for two weeks followed by pegylated IFN alfa-2a 180 µg once a week for 20 weeks (total 24 weeks). In addition, all patients received ribavarin 800-1200 mg/day (weight based). Patients who became HCV –ve at week 24 were followed for one year. Those patients who relapsed were retreated with the same regimen as above for another 24 weeks. Patients who again became HCV –ve were started on maintenance pegylated IFN alfa-2a 180 µg once every three weeks.

 

Results:

Of the 28 patients, treatment was discontinued in 4 patients due to adverse effects and 9 patients were treatment failures. The remaining 15 patients became HCV –ve initially but 13 relapsed on follow up and 12 of these were retreated with a second course of therapy for 24 weeks. Eleven patients became HCV –ve after the second course and of these 10 were placed on maintenance pegylated IFN alfa-2a. One patient relapsed while on treatment, the remaining 9 patients remained HCV free at the end of 1 year of follow up. In these 9 patients, the mean Child-Pugh score improved from 7.3 to 6.2 after one year of treatment, the difference was statistically not significant. All patients tolerated the treatment well.

 

Conclusions:

Maintenance pegylated IFN given once every 3 weeks in previous relapsers maintains remission in the majority (90%) of patients, prevents disease progression, and in some patients improves the Child-Pugh score. Our findings suggests that maintenance treatment can be given successfully even to patients with decompensated liver disease. Further studies are required to determine whether the observed beneficial effect is maintained over longer duration of treatment.


#379. A Randomized Double-Blind Placebo-Controlled Trial of Paroxetine to Prevent Interferon-α-Induced Depression in Patients with Hepatitis C.

B. J. Morasco; M. A. Rifai; J. M. Loftis; D. W. Indest; E. E. Kizer; J. K. Moles; P. Hauser.

 

Background & Aims:

Prior research suggests that the prophylactic use of antidepressant medication may prevent the development of depression induced by treatment with interferon-α (IFN-α) in patients with hepatitis C (HCV). However, no prior studies have assessed this in a randomized double-blind study. The aim of the present study was to determine whether treatment with paroxetine in a sample of patients with HCV would decrease the likelihood of developing IFN-α-induced depression.

 

Methods:

In a double-blind, placebo-controlled study, 33 patients with HCV were randomized to receive paroxetine (n=14) or placebo (n=19) four weeks prior to beginning IFN-α and ribavirin treatment for HCV. Patients were evaluated for psychiatric symptoms prior to HCV treatment, regularly throughout treatment, and up to six months follow-up. The primary outcome measure was the development of major depression, as assessed by the Structured Clinical Interview for DSM-IV. The study blind was broken for any patient who developed IFN-α-induced depression; these patients were put into the rescue arm of the study and treated with paroxetine in an open-label fashion.

 

Results:

The rate of IFN-α-induced depression in the entire sample was 33.3%. The prophylactic use of paroxetine did not decrease the likelihood of developing IFN-α-induced depression (35.7% in the paroxetine group vs. 31.6% in the placebo group, p>0.10). In those patients who developed IFN-α-induced depression and were treated in an open-label fashion, paroxetine was effective in reducing depressive symptoms (assessed with the Hamilton Depression Rating Scale) below the level of clinical significance in 10 of 11 patients.

 

Discussion:

These results suggest that when administered prophylactically, the use of paroxetine does not prevent the development of IFN-α-induced depression in patients with HCV. However, when administered in an open-label fashion, paroxetine may be beneficial in treating depression induced by IFN-α.

 


#380. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in HCV patients with complete cirrhosis (Knodell score F4).

S. Bruno; P. Maisonneuve; P. J. Pockros; M. Sarracino; M. Diago; S. Zeuzem; M. Rizzetto; P. Marcellin; S. J. Hadziyannis.

 

Introduction:

Patients with chronic hepatitis C (CHC) with fully developed cirrhosis have a higher risk of developing severe complications, including hepatocellular carcinoma, than patients without cirrhosis, and thus represent a population with a great need for HCV treatment. However, few studies have assessed the benefits of interferon-based therapy in this population. Here we examined the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin (RBV) treatment in patients with cirrhosis. Predictors of sustained virological response (SVR) in this population were also identified.

 

Methods:

This post-hoc analysis from a randomised, multinational, phase III study evaluated the efficacy and tolerability of peginterferon alfa-2a (40KD) 180 μg/week plus RBV standard-dose (1000/1200 mg/day) or low-dose (800 mg/day) for 24 or 48 weeks [Ann Int Med 2004, 140:346]. Patients from the study were included in this analysis if they had histologically proven cirrhosis (Knodell score F4). Due to small patient numbers, data from all 4 treatment arms were pooled.

 

Results:

Of 1311 patients enrolled in the phase III study, 90 with complete cirrhosis (Knodell score F4) were included in this analysis. Most patients (72%) were infected with HCV genotype 1 (G1). 56 (62%) were male and median age was 49 years (range 32-76). No patient had oesophageal varices. The overall SVR rate was 36% (28% in G1, 70% in G2 and 46% in G3 patients). Of the 28 patients (31%) who did not complete treatment, 4 were due to laboratory abnormalities and 24 due to other adverse events (4 severe). There were no deaths during treatment or follow-up. Multivariate analysis showed that the only independent predictive factors associated with SVR were G1 infection(Odds ratio[OR]=3.2,95%CI:1.16–8.8,p<0.01) and albumin level ≥4 g/dL (OR=4.4,95%CI:1.26–15.48,p<0.02). In G1 patients, the SVR rate was 35% in those with albumin ≥4 g/dL but only 14% in those with albumin <4 g/dL (NPV=86%).

 

Conclusions:

Overall in CHC patients with fully developed cirrhosis (Knodell score F4), who have a high treatment need, peginterferon alfa-2a (40KD) plus RBV was effective in over one third of patients. Although 31% of patients needed to discontinue treatment, only a small number of serious adverse events were observed. Pre-treatment albumin level was the strongest predictor of SVR. This could be used to allow the identification of subjects more likely to benefit from treatment, although this should be confirmed. Further studies should also be performed to determine the most appropriate schedule of treatment for these patients with difficult-to-treat disease.

 


#381. Effect of hepatic steatosis in patients with chronic hepatitis C virus genotype 2 or 3 treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for 16 or 24 weeks.

M. Rodriguez-Torres; S. Govindarajan; S. Shafran; T. Morgan; B. S. Anand; K. Barange; F. Suter; A. Lin; G. Hooper; S. Zeuzem; M. Shiffman.

 

Introduction:

Although data suggest that steatosis contributes to progression of liver fibrosis, its impact on anti-HCV treatment efficacy is less clear. Lower SVR rates in GT3 pts (vs. GT2) may perhaps be related to higher levels of steatosis (J Hep 2004;40:993). Here we evaluated the impact of steatosis on SVR in GT2/3 pts with peginterferon alfa-2a (40KD) plus ribavirin using the ACCELERATE database (n=1469).

 

Methods:

Naďve GT2/3 pts received PegIFNα-2a 180µg/wk + RBV 400mg bid for 16 or 24wks with 24wk follow-up. Liver biopsy was performed on all pts ≤24mo of therapy and reviewed by one central (blinded) pathologist. Effect of steatosis on SVR was evaluated, controlling for: steatosis grade, cirrhosis, baseline (BL) ALT, age, gender, race, bodyweight, BL HCVRNA and treatment duration.

 

Results:

BL steatosis data were available for 885 pts. 614 pts (69%) had some degree of steatosis. GT3 pts were more likely to have steatosis than GT2 (79% vs. 59%, p<0.001) and more advanced (19% and 6%; p<0.001; Table 1). In univariate analysis, steatosis led to a significant SVR reduction in GT3 pts, but not GT2; and SVR declined with increasing severity (Table 2). However, this relationship was not significant in the multivariate analysis (p=0.48 in GT2; p=0.20 in GT3 pts). Pts treated for 24wks had a significantly higher SVR (vs. 16wks), regardless of degree of steatosis. In GT3 pts, steatosis was strongly associated with higher BL HCVRNA than no steatosis (r=0.35; p<0.001). Steatosis effect became significant when BL HCVRNA was removed from the logistic regression model (p=0.01).

 

Conclusions:

We confirm a higher prevalence of steatosis among GT3 than GT2 pts. GT2 and GT3 pts achieved higher SVR rates with 24wks than 16wks, regardless of the degree of steatosis. When other factors are accounted for, steatosis did not affect SVR in either GT2 or GT3 pts suggesting that other factors associated with steatosis may have accounted for the inverse association seen previously.

 


#382. Assessment of Th1 and Th2 cytokines during antiviral therapy for HCV Mixed Cryoglobulinemia.

R. R. Meidinger; M. R. Shey; Z. K. Ballas; W. N. Schmidt.

 

Introduction:

Mixed Cryoglobulinemia (MC) occurs in 40-50% of patients with chronic HCV infection. MC results from expansion of rheumatoid factor producing B cells and formation of cryoglobulin complexes which are useful markers for liver and extrahepatic diseases caused by chronic HCV infection. Recent evidence has suggested that cytokines are important for development of MC, HCV disease progression, and successful antiviral therapy for HCV. The aim of this study was to evaluate representative Th1 and Th2 cytokine profiles in the blood of patients with and without MC to determine changes before and after pegylated antiviral therapy. The correlation of cytokine levels with other variables known to be important for SVR was also compared between the two patient groups.

 

Methods:

Forty patients, 20 with and 20 without MC, were randomly recruited for study. Half of the patients in each group achieved SVR while the other half were non-responders (NR) to standard dosages of pegylated interferon and Ribavirin. Using Bio-Plex 100 system, Th1 (IL-2, IF-γ) and Th2 (IL-10, IL-5) cytokines were measured in patient plasma samples before and at the end of antiviral therapy. Inter- and intra-assay variation for patient cytokine levels was less that 5%.

 

Results:

Patients with MC who achieved SVR showed significant reductions of IL-2 and IL-10 from pre to post therapy (p < 0.025 in both cases), in contrast to SVR patients without MC who had no significant changes in cytokine levels. NR to antiviral therapy did not show significant changes from pre to post antiviral therapy for any cytokine level in either group. Overall, MC was associated with significantly higher levels of IL-2 than patients without MC (p <0.025). Assessment of host and viral factors known to be important for SVR to antiviral therapy revealed a significant association of IL-2 pretreatment levels with the amount of cryoglobulin (p < 0.03). No significant association was found in either group between any cytokine level and pre-treatment viral load. However, both Th1 cytokines showed significant negative correlations with Metavir fibrosis scores for patients without MC (p < 0.03) but not for patients with MC.

 

Conclusions:

These results reveal differences in the baseline cytokine profiles of HCV patients with and without MC as well as changes in cytokine levels occurring during successful antiviral therapy and progressive liver disease. The findings support the hypothesis that enhanced levels of Th1 cytokines such as IL-2 dominate in HCV patients with MC as compared to patients without MC thus suggesting differences in immune response and response to therapy in the two groups.

 


#383. Standard and Pegylated Interferon alfa-2b plus Ribavirin as initial treatment for HCV genotype 2 chronic hepatitis: analysis of a large single center cohort.

M. Rumi; A. Aghemo; R. D'Ambrosio; G. Ronchi; S. Gallus; M. Colombo.

 

Background:

Patients with chronic infection with hepatitis C virus (HCV) genotype 2c achieve the highest rates of SVR (80%) following Interferon/Ribavirin treatment (IFN/Rbv). In these patients phase III registration studies showed no superiority of PegIFN alfa-2b (PegIFN) over standard IFNalfa-2b (IFN), nor they identified any predictor of treatment failure.

 

Aim:

To assess the effectiveness of Rbv combination therapy with PegIFN and IFN in genotype 2c patients and to identify predictors of non response. Methods: All naďve patients with genotype 2c who consecutively received weight-dosed Rbv combined with standard IFN 3MU t.i.w. and after 2001 PegIFN 1.5 mcg/Kg week.

 

Results:

Epidemiological and clinical characteristics were similar at baseline in the 94 patients who received IFN/Rbv compared to the 136 receiving PegIFN/Rbv. By intention to treat analysis (ITT), 211 (95%) had an end of treatment response (ETR), that was maintained in 183 (SVR=80%). Drop out rates were similar in the 2 treatment schedules (8/136 PegIFN vs 1/94 IFN, p=0.06). According to ITT and per protocol analysis, PegIFN was not superior to IFN in terms of SVR rates (ITT: 78% vs 82%; per protocol: 83% vs 83 %). SVR rates obtained in cirrhotic patients were similar in the 2 treatment groups (70% PegIFN vs 74% IFN, p=ns), however, in the PegIFN subset, higher relapse rates were seen in patients with cirrhosis (30%) than in those with less fibrosis (10%) (OR 3.8 C.I. 95% 1.3-11.1). SVR was independent from sex, age, BMI, modality of infection, disease duration, disease severity, adherence to therapy and IFN type. By unconditional multiple logistic regression analysis, treatment failure was predicted by pre-treatment HCV-RNA >800.000 IU/mL (OR: 2.3 C.I. 95% 1.2-4.7), persistence of HCV-RNA at week 4 (OR: 6.1 C.I. 95% 2.9-12.7) and at week 12 (OR: 13.2 C.I. 95% 5.1-34.1).

 

Conclusions:

Combination therapy with PegIFNalfa-2b is not superior to standard IFNalfa-2b in the treatment of HCV-2 patients. Cirrhotic patients receiving PegIFNalfa-2b are at increased risk of post-treatment relapse.

 


#384. HCV-RNA in the fourth week as a predictive factor of sustained virological response (SVR) in genotype 1 hepatitis C patients treated with Peg-Interferon-α2b(PEG-IFN-α2b)and Ribavirin.

J. Segadas-Soares; C. Villela-Nogueira; R. M. Perez; L. Nabuco; C. Brandăo-Mello; H. M. Coelho.

 

Background:

Currently it is not yet defined if an earlier response, defined as a negative HCV-RNA in the fourth week of treatment, could better foresee a SVR. Objective: The aim of this study was to evaluate the HCV-RNA in the fourth week of treatment as a predictive factor of SVR in genotype 1 hepatitis C patients treated with PEG-IFN-α2b and Ribavirin.

 

Methods:

A hundred and sixty seven genotype 1 hepatitis C patients who were treated with PEG-IFN-α2b and Ribavirin and had an HCV-RNA performed 24 weeks after the end of treatment were included. An HCV-RNA at the 4th week of treatment was performed in all patients (Amplicor Roche). The exclusion criteria were HBV and/or HIV co-infection. Patients were treated for at least 12 weeks and if the HCV-RNA was undetectable on week 12, treatment was continued until week 48. Those with a detectable HCV-RNA on week 12 had their treatment canceled and were considered as non-responders. For comparative analysis patients were categorized in two groups as follows: G1- those with an undetectable HCV-RNA in week 4, and G2- those with a detectable HCV-RNA in the 4th week of treatment.

 

Results:

The mean age was 50±11yrs, 59% female. Naďve patients (n=103) comprised 62% of the total sample. Sixty four patients have been previously submitted to treatment with conventional IFN and Ribavirin and, among these, 22 (13%) were relapsers (R) and 42 (25%) were non-responders (NR). The HCV-RNA in the 4th week of treatment was undetectable in 51/167 of the total sample (31%)-G1 and among these patients, 38 (75%) had a SVR. However, among the 116/167 (69%) patients with a detectable HCV-RNA in the fourth week (G2), only 27 (23%) had a SVR (p<0.001). Among the 103 naďve patients, the SVR was obtained in 71% from G1 and in 29% from G2 (p<0.001). Considering the relapsers, the SVR was 92% in G1 and 40% in G2 (p=0.002). Among non-responders, SVR was 50% in G1 and 8% in G2 (p=0.06).

 

Conclusion:

A negative HCV-RNA in the fourth week of treatment is an excellent predictive factor for SVR in naďve and relapsers and should be an important tool in genotype 1 hepatitis C treatment.

 


#386. Efficacy and safety of IFN treatment for the 70 year-old or over patients with chronic hepatitis C.

H. Kodama; S. Takahashi; S. Takaki; K. Yamashina; A. Hiramatsu; S. Tei; Y. Kawakami; H. Aikata; K. Chayama.

 

Background:

Despite the beneficial effects of IFN monotherapy or IFN and ribavirin (IFN/Rib) combination therapy for chronic hepatitis C patients, these treatments have several adverse events which are not tolerable, especially for older patients. Although it used to be considered that the patients who was 60 years old or over with chronic hepatitis C should not be treated with IFN therapy before, the mean age of the patient with chronic hepatitis C is currently more than 60 years old in Japan.

 

Aim:

The aim of this study was to evaluate the efficacy and safety of IFN monotherapy or IFN/Rib therapy for patients whose age were 70 years old or over with chronic hepatitis C.Objective: The number of chronic hepatitis C patients treated with IFN therapy was 360 between 2001 on January and 2004 on September. Patients were classified into non-older group : younger than 70 years old (n=309) and older group : 70 years old or over (n=51).

 

Result:

The completion rate of IFN monotherapy was similar in both non-older and older group (86% in non-older vs. 87% in older). Whereas the completion rate of IFN/Rib therapy in older group was lower than that in non-older group (81% in non-older vs. 62% in older, p<0.05), mainly due to anemia. With IFN/Rib therapy, the SVR rate for the patients with genotype 1b and high viral load was 29% in non-older group and 6% in older group, and the SVR rate for the patients with genotype 2 or low viral load was 67% in non-older group and 50% in older group. Whereas with IFN monotherapy, the SVR rate for the patients with genotype 1b and high viral load was 13% in non-older group and 17% in older group, and the SVR rate for the patients with genotype 2 or low viral load was 68% in non-older group and 63% in older group. Therefore, based on intention to treat analysis, while SVR rate was much lower in the older group with genotype 1b and high viral load, even with IFN/Rib therapy, SVR rate in the older group with genotype 2 or low viral load was similar to that in the non-older group, which reflects that there were more discontinuation cases in older group with IFN/Rib therapy. SVR rate in the patients with genotype 1b and high viral load was 35% in non-older group and 9% in older group with IFN/Rib therapy, suggesting that SVR rate would be still low even though IFN/Rib therapy was completed.

 

Conclusion:

Our results suggest that IFN monotherapy is effective for older patients of 70 years old or over with genotype 2 or low viral load, and that it is difficult to achieve SVR for older patients of 70 years old or over with genotype 1b and high viral load.

 


#388. Exposure to ribavirin (RBV) predicts EVR and SVR in patients with HCV genotype 1 infection: analysis of the Canadian Pegasys Expanded Access Program (EAP).

V. G. Bain; S. S. Lee; K. Peltekian; E. Yoshida; M. Deschęnes; M. Sherman; R. Bailey; H. Witt-Sullivan; R. Balshaw; M. Krajden.

 

Introduction:

Analyses of phase III trials have shown that drug exposure is a significant predictor of SVR. We examined the relationship between exposure to PEG-IFNα2a and RBV and the probability of EVR and SVR in patients enrolled in the Canadian Pegasys EAP.

 

Methods:  

This exploratory analysis was restricted to treatment-naďve genotype 1 patients who were assigned to PEG-IFNα2a 180 µg/wk + RBV for 48 wks. In the initial phase of the EAP all patients received RBV 800 mg/d, and 1000 (≤75kg) or 1200 (>75kg) mg/d in later phases.

 

We considered RBV 1000/1200 mg/d to be 'optimal' (100%) in accordance with current guidelines. Dose adjustments for AEs or lab abnormalities were recorded, and included in a continuous measure of exposure (%). EVR was defined as a ≥2-log drop in HCV RNA at wk12. SVR was defined as undetectable HCV RNA (<50 IU/mL) at the end of untreated follow-up. Only patients with known SVR status were included. The impact of baseline factors and exposure to PEG-IFNα2a and RBV on EVR and SVR was evaluated by multiple logistic regression analysis. Drug exposure was considered as a continuous variable.

 

Results:  

720 patients were included, of whom 318 (44%) and 402 (56%) were assigned to RBV 800, 1000, and 1200 mg/d, respectively. At wk12 the mean exposure, expressed as a percentage of the optimal dose, was 70%, 97%, and 96% in patients assigned to ribavirin 800, 1000 and 1200 mg/day, respectively.  During the first 12 wks, the mean administered dose of PEG-IFNα2a was 94% of the planned dose.

 

Among patients assigned to RBV 800, 1000,and 1200 mg/d an EVR was achieved in 73%, 80%, and 76%, respectively, and an SVR in 47%, 65%, and 58% respectively. 

 

Significant and independent predictors of SVR included RBV exposure (p<0.0001), baseline HCV RNA (p<0.0001), race (p<0.0001), metavir score (p=0.0001) and age (p=0.006).

 

PEG-IFNα2a exposure was not associated with SVR (p=0.818), but showed a strong trend for the prediction of EVR (p=0.051). The failure to demonstrate an association with SVR is not surprising given the consistently high exposure to PEG-IFNα2a.

 

Conclusion:  

·        In treatment-naďve HCV genotype 1 patients, ribavirin (COPEGUS) exposure from baseline to week 12 was significantly correlated with the probability of achieving and EVR and, especially, an SVR.

·        Exposure to peginterferon alfa-2a (40KD) (PEGASYS) was not a statistically significant predictor of outcomes;  this may have been due to near optimal exposure in all groups.

 


#389. Antiviral therapy for HCV-associated mixed cryoglobulinemia vasculitis : a long term follow-up.

D. Saadoun; M. Resche Rigon; V. Thibault; J. Piette; P. Cacoub.

 

Objective:

To describe the long-term follow-up of anti-hepatitis C virus (HCV) therapy in patients with mixed cryoglobulinemia (MC).

 

Methods:

Monocentric study of seventy-two consecutive HCV-MC patients who received treatment with IFNα-2b (n=32) (3 millions IU x 3/week) or Peg-IFNα-2b (n=40) (1.5 µg/kg/week), both combined with oral ribavirin (600 to 1,200 mg/day) for at least 6 months. Logistic regression was used to assess factors associated with clinical remission of MC.

 

Results:

The mean follow-up after discontinuing antiviral therapy was 39.7 ± 24.4 months. Eight (11%) deaths were noted, primarily from cardiovascular disease, liver disease or infection. Forty-five (62.5%) patients achieved a complete clinical response of MC, 58% had a sustained virological response and 45.8% cleared cryoglobulin. Compared with patients treated with IFNα-2b/ribavirin, those receiving Peg-IFNα-2b/ribavirin had a higher sustained clinical (67.5% vs. 56.2%), virological (62.5% vs. 53.1%) and immunological (57.5% vs. 31.2%) response, regardless of HCV genotype and viral load. In multivariate analysis, an early virologic response [(odds ratio (OR), 3.53; 95% CI 1.18 to 10.59)] was independently associated with a complete clinical response of MC. A glomerular filtration rate lower than 70 ml/min (OR 0.18; 95% CI 0.05 to 0.67) was negatively associated with a complete clinical response of MC.

 

Conclusion:

Peg-IFNα plus ribavirin should be considered the induction therapy for HCV-MC vasculitis. An early virological response and the absence of renal insufficiency are the key factors of clinical response.

 


#390. Customizing treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) in patients with HCV genotype 1 or 4 infection. Interim results of a prospective randomized trial.

P. Ferenci; H. Laferl; T. Scherzer; A. Maieron; M. Gschwantler; H. Brunner; R. Hubmann; M. Bischof; K. Staufer; C. Datz; P. Steindl-Munda; H. Kessler.

 

Introduction:

The rapidity and magnitude of response to therapy in GT1 and GT4 pts is variable. Pts who have an RVR (undetectable HCVRNA at 4wks) with peginterferon alfa plus RBV may achieve SVR after only 24wks (Hepatol 2006;43:954, J Hep 2006;44:97), while pts with no RVR may benefit from prolonged therapy (Diago, Gastroenterol. in press). This prospective study investigates customization of PegIFNα-2a + RBV in GT1/4 pts based on HCVRNA level at wk4 and 12.

 

Methods:

Naďve GT1/4 pts were initially treated with PegIFNα-2a 180μg/wk +RBV 1000/1200 mg/d, before allocation to 1 of 4 treatments based on HCVRNA level at wk4 and 12. At wk4, ‘super-responders’ (HCVRNA <50IU/mL) were assigned to a further 20wks (Gp D). All other pts continued to receive therapy until wk12 when HCVRNA was retested. Pts with an EVR (unquantifiable [<600IU/mL] or ≥2log drop in HCVRNA) were randomized to 48wks (Gp A) or 72 wks (Gp B) therapy. Remaining pts without an EVR were assigned to Gp C and treated for 72wks. In Gps A–C therapy was terminated if HCVRNA remained detectable at wk24. Due to the high number of pts with an RVR (28%; expected 15%), the target of 444pts was increased to 565 to power the study (Gp A vs B).The study is fully recruited.

 

Results:

Of 401pts recruited at Jun 30 2005, 28 dropped out before assignment. Outcomes in Gp D pts have been reported (Hepatol;44:S6). Pts in Gps A and B had similar outcomes (Table); the lower SVR in the ITT analysis was due to the higher no. of drop outs in the 72wk arm. Overall, relapse rates in Gps A and B were similar (24 vs 21%). In pts with an EVR (Gps A & B), those with HCVRNA <50IU/mL at wk12 had similar relapse rates (A,17%; B,18.5%); however, in those with HCVRNA ≥50IU/mL at wk12, longer treatment lowered relapse rate (A,50%; B,27%). Very few pts without an EVR (Gp C) obtained an SVR, even with a longer duration, confirming the high NPV of an EVR.

 

Conclusion:

These interim results suggest that customizing duration of therapy based on undetectable HCVRNA at wk4 and 12 is likely to be beneficial in maximizing the probability of an SVR in GT1/4 pts.

 

 

A (n105)
No RVR
EVR
48wks

B (n108)
No RVR
EVR
72wks

C (n58)
No RVR
no EVR
72wks

D (n-104)
RVR

24wks

BL Characteristics  (± data are mean ± SD)

Male, n (%)

68 (65)

72 (67)

39 (70)

63 (61)

Age, y

45.3 ± 10.2

44.5±9.7

46.6 ± 10.1

40.8 ± 11.5

BMI, kg/m2

26.3±4.2

25.1±4.0

25.8±3.3

25.0 ± 4.4

Caucasian, n (%)

 

96 (91)

 

100 (93)

 

55 (98)

 

104 (100)

HCV RNA (IU/ml x 106

 

1.64 ± 2.64

 

1.57 ± 2.24

 

1.05 ± 2.32

 

1.02 ± 2.64

HCVRNA <800000 IU/mL, n (%)

 

 

47 (45)

 

 

50 (46)

 

 

24 (43)

 

 

71 (68)

Genotype 1, n (%)

 

96 (91)

 

99 (92)

 

48 (86)

 

81 (78)

F3-4, n (%)

26 (24)

26 (24)

21 (36)

21 (20)

Response

SVR % (intent to treat)

 

56.4

 

42.9

 

3.9

 

77.2

SVR %( per protocol)

 

75.9

 

78.9

 

N/A

 

87.9

Relapse rate

24

21

N/A

12

 


#391. Evaluation of fibrosis evolution using non-invasive methods according to sustained virological response in HCV patients. A pilot prospective controlled study.

V. de Ledinghen; L. Castera; J. Foucher; R. Tournan; P. Bernard; G. Moisset; X. Moncoucy; J. Bertet; P. Couzigou.

 

Introduction:

FibroScan (FS) and Fibrotest (FT) are non-invasive methods for the evaluation of fibrosis in HCV patients. The usefulness of non-invasive methods, especially FS, for the follow-up of fibrosis in treated patients, according to long-term virological response (LTR), is unknown. The aim of this prospective study was to evaluate liver fibrosis evolution using FS and FT in treated HCV compared to untreated HCV patients.

 

Methods:

236 consecutive patients were evaluated: 82 treated HCV patients (43 males, age 51 ys) who undergone fibrosis evaluation (FS and FT) before treatment and 6 months after the end of treatment and 154 untreated HCV patients (49 males, age 54 ys) who undergone FS and FT every years.

 

Results:

Sustained virological response (SVR), relapse response (RR), non response (NR) were observed in 45, 14, 23 cases, respectively. Mean values of FS and FT at day 0 and LTR are indicated in the figure. FS and FT values were significantly higher at day 0 in treated compared to untreated patients (p<0.05). No statistical difference was observed between untreated patients and SVR or RR at the end of follow-up. 87% of cirrhotic SVR had FS values < 10 kPa at the end of follow-up. Only NR had higher values of FS and FT than untreated patients at the end of follow-up (p<0.01). Between untreated and SVR patients, FS evolution between day 0 and LTR was significantly different (+12% vs -14%, p=0.001). This difference was lower between untreated and RR or NR patients (+12% vs -17% or -12%, p=0.04). For FT evolution between day 0 and LTR, no difference was observed between untreated patients and SVR, RR or NR. By logistic regression, only treatment was associated with regression of FS (OR 2.89, 95%CI 1.6-5.1, p<0.0001) and FT (1.83, 1.0-3.3, p=0.04).

 

Conclusion:

SVR and RR patients have fibrosis regression. FS seems the best non-invasive method for the evaluation of fibrosis regression and should be evaluated in a large controlled study.

 

 


#392. Treatment of subjects with chronic hepatitis C infection (HCV) and end stage renal disease (ESRD) using low dose pegylated interferon alpha 2 a (PEG-IFN) and Ribavirin (RBV).

D. Carriero; A. J. Uriel; D. T. Dieterich.

 

Introduction:

Up to 20% of patients (pts)with ESRD also have chronic HCV. Tolerability of IFN and RBV in this population limits effective treatment. In small cohort studies, sustained viral response (SVR) rates were less than 20%. HCV is associated with poorer clinical outcomes after renal transplantation (RT); Antiviral therapy is therefore indicated for RT candidates.

 

Aim:

To evaluate the efficacy and tolerability of modified dose PEG-IFN a 2a and low dose RBV in a cohort of pre-RT candidates with HCV.

 

Methods:

Data was collected both retrospectively and prospectively on 15 patients with ESRD awaiting renal transplant, who had completed, or were currently on therapy for HCV.  PEG-IFN a2a was administered once week post-dialysis.  15 patients received modified dose of 135 ug, 1 patient received full dose (180 ug).  All patients received ribavirin 200 mg daily.

 

Results:

Mean age of the cohort was 50.5 yrs (25–68), 57% were male, 67% were African-American; 12 pts were on hemodialysis and 3 on continuous ambulatory peritoneal dialysis.

 

In 11 ESRD patients were secondary to diabetes or hypertension (HTN); 2 were secondary for glomerulonephritis.   12 pts had HCV genotype (gt) 1, 2 had gt 2.

 

3 patients were coinfected with HIV, all were on stable snit-retroviral therapy at baseline, with undetectable HIV RNA levels and median absolute CD lymphocyte count of 411 cell/mm3 (range 319-620).  The majority of the cohort (10/15) had hypertension, 6 patients had a history of coronary artery disease, and four patients had other cardiac pathology (aortic valve disease, congestive cardiac failure, pulmonary hypertension and left ventricular hypertrophy).

 

Median baseline (bl) HCV-RNA level was 554,500 IU/mL (range 3380-12,100,000) 809,000 IU/ml (190,000–12,100,000),  median ALT was 38 (range 7-140); AST (30 (10-265).  Mean fibrosis score (out of 4) n=11 was 2 (range 0-2).  2 patients had cirrhsois. 

11/15 (73%) of patients were on Erythropoietin (EPO) at baseline, 4 started during therapy.  All patients on EPO at baseline required increased doses during therapy.

Seven patients (47%) required transfusion, 4 patients required ribavirin dose reduction for anemia, 3 subsequently discontinued at 6,8, and 16 weeks respectively.  No dose reductions were required for neutropenia or thrombocytopenia. 

 

Two patients required hospitalization and discontinuation of therapy (1 for hip fracture, 1 for bacteremia).  One patient with cardiomyopathy died of acute CHF at week 14.  One patient died at week 6 of intra-cerebral bleed due to uncontrolled HTN.

 

To date 14 out of 15 patients have completed therapy.  Median length of treatment was 25 weeks (range 4-76), one subject is at week 5.

 

12/14 (86%) complete 12 weeks, 7/11 (44%) had an EVR.  Two subjects are not year evaluable for SVR (1 patient is HCV RNA undetectable at end of treatment, 1 subject is still on therapy.  On an ITT analysis—4/13 (31%) achieved and SVR; 7/13 are non-responders (2 of 7 relapsed after discontinuation of therapy).

 

Conclusion

·        The majority of the cohort (85%) were able to complete 12 weeks of therapy, with SVR being achieved in 31%.

·        Therapy was well tolerated by over 60% of patients

·        Both deaths during therapy were related to underlying cardiovascular disease, which has a high prevalence in this population.

·        Well controlled HIV should not be an exclusion to HCV therapy in patients with ESRD.

·        ESRD should not preclude a trial of HCV therapy in carefully selected patients, given the benefit of viral clearance prior to renal transplantation, and the difficulties in treating HCV post transplant.


#393. A Prospective, Double-Blinded Neuropsychiatric Comparison of Pegylated Interferons Alfa-2a and Alfa-2b.

D. Sylvestre; A. Smith; L. Barrett; D. Greene.

 

Background:

Inter-study evidence using interferon alfa as a standard suggests that pegylated interferons alfa-2a (PI2a) and alfa-2b (PI2b) may have different neuropsychiatric toxicity profiles. Because of its potential importance to the many HCV-infected patients with comorbid mental illness, we conducted a prospective, double-blinded pilot study of PI2a vs. PI2b in patients undergoing treatment for HCV. Endpoints included psychiatric discontinuations; initiation and adjustment of psychiatric medications; monthly Beck Depression Inventory (BDI) and SF-36 Quality of Life scores, and self-reported depression (D), anxiety (A), and irritability (I).

 

Methods:

40 patients were randomized to treatment with ribavirin and either PI2a or PI2b at standard dosing. Self-reported D, A, and I scored on a 0-10 scale were recorded weekly. The BDI and SF-36 were administered every 4 weeks.

 

Results:

39 subjects initiated treatment and 1 was discontinued due to inadvertent unblinding. The average age was 48, 23 (57%) were male, and 27 (67%) had genotype 1. None of these measures differed between the cohorts. 15 in each cohort (75%) reported a pre-existing psychiatric diagnosis. 26 were taking a psychiatric medication at treatment initiation, 12 (67%) in the PI2a cohort and 14 (70%) in the PI2b cohort (p=0.55).

 

27 (71%) completed treatment and there were 11 (29%) discontinuations. 4 patients had psychiatric discontinuations, 1 taking PI2a and 3 taking PI2b (p=0.32). New psychiatric medications were initiated in 9 (50%) taking PI2a and 14 (70%) taking PI2b (p=0.18), and they were adjusted in 12 (67%) taking PI2a and 15 (75%) taking PI2b (p=0.41). BDI, SF-36, and self-reported depression, anxiety, and irritability scores were not statistically different at baseline, nor were there significant differences when analyzed on a monthly basis. However, the PI2b cohort had a significantly higher cumulative BDI score, 16.3 vs 13.1 (p=0.01), and a lower SF-36 score, 40.8 vs 48.5 (p=0.004). Additionally, those taking PI2b reported significantly higher overall depression, 2.4 vs 2.1 (p=0.04), and anxiety, 2.8 vs 2.2 (p <0.001), but not irritability, 2.9 vs 2.7 (p=0.32).

 

Conclusion:

This small but rigorous study provides the first direct evidence that PI2a and PI2b may elicit small but measurable differences in depression, anxiety, and quality of life during HCV treatment. It is unclear, however, whether these will translate to meaningful differences in major neuropsychiatric outcomes. A larger study is needed to assess the magnitude of the differences in the psychiatric toxicity profiles of these medications and to assess any impact on HCV outcomes.

 


#394. Treatment with Peginterferon alfa 2b and Ribavirin of Chronic Hepatitis C Patients on Substitution Therapy and Outcome in the Clinical Setting in Germany.

D. Hueppe; E. Zehnter; M. P. Manns; S. Mauss; R. Prinzing.

 

Introduction:

Peginterferon (PEG-IFN alfa) and Ribavirin (RBV) are the standard of care for hepatitis C virus (HCV) treatment. The efficacy and safety of PEG-IFN alfa-2b and RBV was observed in Germany under daily life conditions.

 

Methods:  

249 active sites (117 with substitution patients) have treated a total of 2912 HCV patients (490 on substitution and 2422 without substitution).

 

Results:  

The 490 substituted patients had a mean age of 35.1 years, mean weight of 73.8 kg and 71.6% were male. 48.1% of patients were genotype 3, 42.8% were genotype 1/4/5 or 6, and 9.1% were genotype 2. 2.2% of patients showed cirrhosis, 4.5% had a HIV co-infection, and 5.1% had a HBV co-infection. 9.0% of patients were treated in hospitals, 10.4% in BNG practices, and 80.6% in other practices. 46.3% of patients were substituted with methadone, 13.5% with buprenorphine, 4.1% with other agents, and in 36.1% no according specification was present.

 

The majority of patients (92.7%) received PEG-IFN and RBV as primary therapy, only 7.3% were relapse patients after IFN mono-therapy. 39.9% received the intended PEG-IFN doses, 34.8% received lower and 25.3% higher doses of PEG-IFN. 65.9% of patients received appropriate RBV doses.

 

The project is ongoing so all follow-up (FU) and end of treatment (EOT) data for patients are not available. To date, 299 substituted patients reached EOT and 158 the end of FU.

 

A normalization of ALT was seen in 71.6% of substituted patients at EOT and 61.4% at FU compared to 72.6% at EOT and 61.9% at FU for nonsubstituted patients. Of 158 substituted patients who completed FU, 67.7% reached a sustained viral response (SVR), 9.5% relapsed, 8.9% were non-responders, and 13.9% were either lost to FU or had no documentation.

 

Comparison of the 490 substituted with 2422 nonsubstituted patients showed 16.9% and 19.7%, respectively, discontinued the study; reasons for discontinuation included adverse events (3.1% vs. 4.5%), lack of efficacy (3.9% vs 8.8%), loss to FU (2.7% vs 2.1%), patient wish (3.3% vs 1.6%,), or other reasons (4.1% vs 2.5%, respectively).

 

Conclusion:  

The preliminary results for the difficult-to-treat substituted patients regarding sustained viral response and relapse rates are very encouraging and show a high standard of treatment in Germany. The reason for the exceptionally good outcome may be that substituted patients have frequent visits and a closer link to their physicians compared with nonsubstituted patients.

 


#395. Early predictors of anemia in patients with HCV genotype 1 treated with peginterferon alfa-2a (40KD) plus ribavirin 1000-1200 mg/day.

D. Jensen; N. Reau; S. J. Hadziyannis; D. Messinger; M. W. Fried.

 

Introduction:

Although RBV dose adherence is critical in the treatment of HCV genotype 1 (G1) pts, higher doses can be associated with hemolytic anemia. In studies with peginterferon plus RBV, hematologic abnormalities were common: hemoglobin (Hb) level <12g/dL in 52% of pts and Hb <10g/dL in 13%. Also, RBV dose reduction was required in 22% of pts receiving combination therapy for 48wks. However, pre-treatment predictors of considerable anemia (CA; Hb decrease ≥2.5 g/dL from baseline [BL]) were inadequate to guide therapeutic intervention. Analysis of 59 G1 pts showed an Hb decrease ≥1.5 g/dL from BL at wk2 significantly correlated with CA at wk4. Thus, to test the predictive value of wk-2 Hb drop, we analyzed data from 2 prospective, randomized, phase III trials of PegIFNα-2a + RBV (NEJM,2002;347:975; Ann Int Med,2004;140:346).

 

Methods:

We analyzed BL characteristics (gender, race, age, bodyweight, BMI, fibrosis, genotype, Hb, platelets, WBC, creatinine, creatinine clearance (CLR), wk2 Hb drop ≥1.5g/dL, and RBV and PegIFNα-2a doses) of 555 G1 pts receiving PegIFNα-2a 180µg/wk + RBV 1–1.2g/d for 48wks, to determine their predictability for CA at wk4 using univariate (Wald χ2 test) and multiple logistic regression analyses.

 

Results:

Significant factors associated with CA at wk4 in 236 pts exhibiting a ≥2.5 g/dL decrease in Hb are listed (table). CA at wk4 was also significantly associated with more/earlier drug dose reductions due to anemia (p<0.0001) and lower cumulative dose of RBV (p<0.001). An SVR in pts with CA at wk4 was only marginally reduced (47.5% vs 51.7% in pts without CA).

 

Conclusions:

Important predictors of CA at wk4 included a wk2 Hb drop ≥1.5g/dL, non-Black/Asian race, and cirrhosis. Pts with a wk2 Hb drop experienced more dose reductions and sub-therapeutic RBV doses than those with no wk2 drop. Early anemia intervention in pts with a wk2 Hb drop >1.5g/dL may avoid RBV dose reduction, thereby improving the chance of achieving an SVR.

 

Factors associated with considerable anemia at week 4

Univariate

Multivariate

p-value

Odds ratio (95% CI)

Age (10 yrs)*

<0.001

ns

Gender (female vs. male)

0.0426

ns

Race (Black/Asian vs. other)

0.0046

0.0035

0.31 (0.14–0.68)

Baseline Hb (1 g/dL)*

<0.0001

0.0087

1.34 (1.08–1.66)

CLR (10mL/min)*

<0.0001

0.0003

0.82 (0.73–0.91)

Cirrhosis (yes vs. no)

0.0808

0.0121

2.06 (1.17–3.61)

Wk 2 Hb drop (≥1.5 g/dL vs. other)

<0.0001

<0.0001

23.2 (14.1–38.1)

PegIFNα-2a exposure wk 1–4 (1 µg/wk/kg)*

0.0275

0.0293

1.77 (1.06–2.95)

 

*For continuous variables, the odds ratio presented relates to a one unit change (eg the odds of having a Hb drop of ≥2.5g/dL in a patient with a baseline Hb of 11 g/dL is 34% higher than in a patient with a Hb of 10g/dL)


#396. Substitute opiate use in intravenous drug users (IVDUs) does not adversely effect sustained virological response(SVR) following treatment of chronic hepatitis C (CHC) with pegylated interferon alpha (PEG- IFN) and ribavirin.

H. Hussaini; E. Cole; A. Flynn; J. Bergin.

 

Background:

Many treatment programs for CHC exclude IVDUs who currently use intravenous or oral opiate substitution. Aims: To determine the effect of a joint hepatology and drug team pathway on CHC SVR to treatment, in IVDUs on concurrent opiate substitution.

 

Methods:

A retrospective analysis over a 4-year period of 118 treatment naďve patients:

·        Group A with no history of IVDU (n=22),

·        Group B with a past history of IVDU (n=30) and,

·        Group C with substitute opiate use in IVDUs (n=66).

Patients were treated with either Peg IFN 2a/2b and ribavirin (800-1200mg) for 6–12 months according to standard protocols. Data was analysed on an intention to treat basis. Patients with negative hepatitis C RNA 6 months post-therapy had a SVR. Data was stratified according to genotype (G 2-3 vs non G 2-3) and fibrosis score (Knodell < 4 vs > 4; n=80).

 

Results:

The proportion of patients with genotype 2-3 was not significantly different in Groups A (36%), B (37%) and C (53%). Group C compared to Group A had a lower advanced (> 4) fibrosis score (18.4 vs 42.6%, p< 0.04) but not compared to group B (41.4%).

The overall and group SVR rates with stratification for genotype and fibrosis are shown in the table below. In the entire cohort the SVR was 53%, with a significantly higher SVR in patients with G 2-3 and less advanced fibrosis. In Group C, SVR was also significantly greater in G 2-3 patients. However, the comparative SVRs in the three groups were similar, as were SVR based on genotype and fibrosis score within each group. Compliance, non-response and relapse rates were similar in all groups.

 

In contrast, treatment discontinuation (overall 7.6%) was commoner in former IVDUs (n=3) and substitute opiate use IVDUs (n=4) compared to non-IVDUs (n=1). Six-month post treatment HCV RNA data was not available in 3 former IVDUs and 4 substitute opiate users, but complete in all non-IVDUs.

 

Conclusions:

·        Concurrent opiate substitution in IVDUs does not adversely affect treatment response rates for CHC, although SVR may be underestimated in ex- and concurrent IVDUs, due to lack of post-treatment data.

·        In our experience, patients with opiate substitution are compliant to therapy and should not be excluded from CHC treatment.


#397. Effectiveness of Antiviral Therapy in Patients with Chronic Hepatitis C Treated in Daily Clinical Practice.

Goulis; S. Manolakopoulos; S. Savvidou; P. Tsekoura; G. V. Papatheodoridis; C. Triantos; O. Anagnostou; N. Chrysanthos; K. Thomopoulos; V. Nikolopoulou; A. Archimandritis; D. Chrysagis; D. Tzourmakliotis; C. Arvanitakis.

 

Background:

Standard treatment of patients with chronic hepatitis C consists of pegylated interferon (PegIFN) α in combination with ribavirin. Information outside clinical practice is limited. Our aim was to determine the efficacy and safety of PegIFN plus ribavirin in routine clinical practice.

 

Patients and Methods:

356 consecutive treatment-naďve hepatitis C patients from five centers in Greece who fulfilled the following criteria age >18 years, absence of HBV or HIV coinfection, adherence to treatment duration above 80%, absence of other comorbid conditions were included in the study. Patients were treated with either PegIFNα2a (n=104) or PegIFNα2b (n=251) and ribavirin for 24 weeks (HCV genotype 2,3) and 48 weeks (HCV genotype 1,4) respectively. Multiple logistic regression analysis was used to identify baseline factors of SVR. The influence of age, gender, alcohol use, BMI, infection duration, mode of transmission, baseline viral load, serum ALT, genotype, liver histology (inflammation and fibrosis), hepatic steatosis and type of interferon were analysed.

 

Results:

Demographic characteristics: 56.8% male, IV drug abuse 31.1%, mean BMI 23.6+4 kg/m2, distribution of genotypes: GT1 46.1%, GT2 7.3%, GT3 34% and GT4 12.6%, median HCVRNA 5.27x105 (0.02-6050x105) IU/mL, mean HAI 7.51+2.39, severe fibrosis (Ishak > 4) 15.3%, steatosis >33% 30.1%.

 

Sustained Virological Response (SVR) was achieved in 254/356 patients (71.3%) According to genotype: GT1 112/164 (68.3%), GT2 20/26 (77%), GT3 105/121 (86.7%), GT4 17/45 (37.8%). Multiple logistic regression analysis showed that cirrhosis (OR 4.88), genotype 1 or 4 (OR 3.38), age >40 (OR 2.19) and hepatic steatosis on liver biopsy (OR 2,24) were baseline factors independently associated with a significant lower chance of SVR. Patients with GT4 had a significant lower SVR compared to patients with GT1 (37.8 vs 68.3%, p<0.05) although there was no difference in patient age, median infection duration, gender, mode of transmission, BMI, alcohol consumption, baseline viral load, treatment adherence or histological activity and stage.

 

Conclusion:

·        Our results clearly show that in clinical practice patients with >80% adherence to the current treatment regimens of PegIFN-α and ribavirin could achieve response similar or even better to those of controlled clinical trials.

·        Hepatic steatosis is a baseline factor independently associated with poor response to treatment.

·        GT4 has a significant lower response rate compared to GT1 in Greek naďve chronic hepatitis C patients.

 


#398. Plasma ribavirin quantification in patients with chronic hepatitis C, genotype 1, treated with peginterferon and ribavirin.

J. SALMERON; P. Muńoz de Rueda; L. Rodriguez; J. Candel; R. Quiles; R. Andrade; M. Diago; J. Navarro.

 

Background:

The ribavirin (RBV) association to peginterferon (Peg-IFN) is very important in order to increase the rate of sustained virological response (SVR). But one of the side effect of RBV is anemia (9% to 13%) related to HCV therapy, that induces a dose modification and discontinuation of RBV.

 

Aim.

To study the relation ship between plasma RBV concentration (RBV-C) with the anemia and SVR in patients with chronic hepatitis C (HCC), genotype 1, treated with 180 μg Peg-IFN α-2a and 1.000-1.200 mg RBV during 48 weeks.

 

Patients and Methods.

Prospective study of 62 patients with HCC. RBV-C was determined in 52 patients during treatment in 1, 2, 3, 4, 6, 8, 10 y 12 months. RBV-C was carried out with serum samples drawn before the morning administration of RBV by high-performance liquid chromatography (HPLC) with commercially available reagents. Patients were classified as sustained virologic response (SVR) (n=28) and non responders NR (n=24).

 

Results.

RBV-C was between 2 and 2,5 µg/ml during treatment, but within 2 months was higher than 2,5 µg/ml. Body weight average before treatment was 69 kg, and at the end of treatment decreased to 63 kg (0-19 kg), with rapid recovery after treatment (71 kg, P< 0.001). Patients with weight loss >7 kg had a higher RBV-C within 2 months period, and they had a higher hemoglobin decrease. Hemoglobin reduction was between 0,2 and 8,6 g/dL during treatment, and in men the reduction was higher (P=0.09). 55% of patients had a hemoglobin decrease >2 g/dL during the first month. 48% of patients had a drop in Hb between 3-5 g/dL, and 11% >5 g/dL. There was a negative correlation between the RBV-C and the hemoglobin of following month (P<0.05). Also patients with a RBV-C peack of >3 mcg/ml had a higher decrease of hemoglobin concentration than patients with < 3mcg/mL (P=0.002). Early virological response and SVR was not correlated with RBV-C. But patients with SVR received a higher doses of RBV (mg/kg).

 


#399. Managing HCV infection in injecting drug users: a community model.

K. Jack; M. Varnam; B. J. Thomson.

 

Introduction

Injecting drug use is the dominant risk factor for the acquisition of HCV and by far the most important route for ongoing transmission. The identification and provision of treatment to this vulnerable population, however, remains a major challenge. Non-attendance rates of over 40% are common in hospital based HCV clinics in the UK and are highest in the drug using population. In a recent study in Nottingham, only 1 of 61 new HCV positive individuals identified by Drug and Alcohol Services over a two year period received antiviral therapy.

 

Aim:

Against this background, we have initiated a pilot study to assess the feasibility, safety and efficacy of a nurse led HCV service for injecting drug users based entirely in the community.

 

Methods:

The study focused initially on 212 clients attending a shared care clinic in an inner city primary care facility between 31 August 2004 and 1 September 2005. 147 were male and 65 were female. All were receiving prescribed opiates and many continued to inject. 187 of 192 offered serological testing for HCV agreed to the procedure. No sample could be obtained from 1 patient. Of the remaining 186, 95 (51%) were HCV antibody positive. Sixty of the 95 HCV positive clients were positive for HCV RNA as determined by RT-PCR. All HCV PCR positive clients were counselled and assessed for treatment according to a set of criteria developed with the primary aim of maintaining patient safety while on antiviral therapy. These criteria were based on pattern of drug use, physical and mental health, social circumstances and housing. All candidates for treatment were reviewed in the primary care clinic by a hospital consultant.

 

Results:

22 of the 60 PCR positive clients were assessed as suitable for treatment. 

·        15 patients have commenced treatment with PEG-RBV

·        1 patient achieved SVR

·        6 patients completed treatment with end of treatment response

·        1 withdrew for lack of virologic response

·        1 patient withdrew because of side effects

·        1 patient withdrew for psychiatric side effect

·        5 patients still on treatment.

Attendance rates at the nurse led clinic exceeded 80%.

Conclusion

This study found a large pool of HCV infected individuals attending a single primary care clinic, the great majority of whom would either not have been referred to, or would not have attended, a secondary care facility. Our results so far indicate that HCV services, including anti-viral therapy, can be safely delivered to this high risk group on the community. Our study may constitute a new model for the delivery of care to this important population.

 


#400. Pegylated interferon plus ribavirin in chronic hepatitis C patients with liver lesions related to alcohol intake.

J. Perez Poveda; M. Trapero-Marugan; N. Syong-Hyung ; J. Moreno-Monteagudo; M. Borque; L. Garcia-Buey; X. Salcedo-Mora; R. Moreno-Otero.

 

Aims:

To establish the prevalence of lesions related to alcohol intake (LA) in patients with CHC. To analyse the sustained virological response (SVR) to pegylated interferon alpha (PEG-IFNα-2b) plus ribavirin. To correlate the existance of LA with liver fibrosis and treatment response.

 

Patients/Methods:

We analysed liver biopsies of 62 consecutive patients (49 males, 79%) with CHC according to METAVIR score before starting antiviral combination therapy. LA were considered when two or more items (Mallory bodies, megamitochondries, polimorphonuclear infiltrate, steatosis, perivessel fibrosis and siderosis) were detected. All parameters were evaluated as: 0: none, 1: mild, 2: moderate and 3: intense. All of liver biopsies was evaluated by the same pathologist. Viral genotype and quantitative viraemia were assessed. Patients received PEG-IFNα-2b plus ribavirin (adjusted to weight) during six or twelve months according to genotype. Statistics: Student's t test, U Mann-Whitney, chi-squared and ANOVA test.

 

Results:

LA were detected in 54/62 patients (87%). Single parameters appeared in liver biopsy as follows: 46/62 steatosis, 3/62 megamitochondries, 2/62 Mallory bodies, 41/62 infiltrate by polimorphonuclear cells, 42/62 perivessel fibrosis and 28/62 siderosis. Patients with LA presented higher GGT levels than patients without LA (72 ± 51 vs 34 ± 33 U/L; p<0.05), but no differences were found regarding viraemia (1024629 ± 916092 vs 748750 ± 415982 IU/mL; p=0.4), AST levels (74 ± 47 vs 63 ± 71 U/L; p=0.5) and ALT levels (124 ± 93 vs 121 ± 133 U/L;p=0.9). Nevertheless patients with LA show more intense fibrosis (F3-F4) than patients without LA but with no statistical significance (37% vs 25%; p=0.7). All patients finalised therapy and follow-up period: 54 with LA and 8 without LA. The global SVR rate was 46.8% (29/62): the SVR rate in patients with LA was 46.3% and 50% in patients without LA.

 

Conclusion:

1.     A high prevalence of LA in CHC patients exists

2.     LA may be associated to an increase in hepatic fibrogenesis.

3.     LA presence does not determine a worse virological response to combination therapy.

 


#402. The Therapeutic Effect of Ribavirin plus Pegylated Interferon in Chronic Hepatitis B and C.

R. Chien; C. Hu; I. Sheen; Y. Liaw; C. Yen; J. Chang.

 

Background/Aims:

Concurrent chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection appears to increase the risk of progressive liver disease. Studies with conventional interferon-alfa and/ or ribavirin combination in patients with HBV-HCV coinfection have been carried out. The efficacy is not satisfactory. Therefore, we retrospectively analyze the therapeutic effect of ribavirin plus pegylated interferon in the treatment of chronic hepatitis B and C.

 

Patients:

Forty patients with chronic hepatitis B and C were enrolled. They are filled with the following criteria: 1). age, 18-70 years; 2). seropositive for HBsAg and antri-HCV > 6 months; 3). elevated alanine aminotransferase (ALT) 2 times upper limit of normal twice one month apart; 4). alcohol, autoimmune, toxic and hepatitis delta coinfection were excluded.

 

Methods:

All patients received pegylated interferon alfa 2a or 2b subcutaneous injection once weekly plus oral ribavirin 800-1200 mg daily for 24 weeks. Regularly clinical assessment, hemogram, biochemical and virological checked up. The efficacy assessment was performed at end of 24-week treatment (EOT) and at end of 24-week follow-up (EOF). Statistical analysis was performed using Chi-square test, Fisher’s exact test and stepwise logistical regression model where appropriate.

 

Results:

They were 65% male with a mean age of 56 years. Fifteen percent of them were cirrhosis and 66 % were infected with HCV genotype 1b. All patients were seropositive for HCV RNA, but only 11% were seropositive for HBV DNA. The mean pretherapy biochemical tests levels were: ALT 133 U/L; total bilirubin 0.9 mg/dL; albumin 4.4 gm/dL. At EOT, the ALT nomalization rate (biochemical response, BR), HCV and HBV seroclearance (virological response; VR) or both (complete response; CR) were 65%, 84% and 56% respectively. At EOF, the BR, VR and CR were 67%, 50% and 44% respectively. Stepwise logistical regression analysis showed no clinical predictor to response. However, patients infected with HCV genotype non-1b showed superior response than those with genotype 1b at EOF (CR, 80% vs 20%; P=0.089).

 

Conclusion:

Combination therapy using ribavirin plus pegylated interferon is effective in patients with chronic hepatitis B and C, especially those with HCV genotype non-1b. Further large scale clinical study is warranted.

 


#403. Improvement in immunological abnormalities in patients with chronic hepatitis C who have a sustained virological response to therapy.

A. A. Modi; J. Feld; R. Loomba; B. Borg; T. Heller; M. Ghany; E. Doo; J. Liang; J. Hoofnagle.

 

Background:

Patients with chronic hepatitis C often have immunological abnormalities such as elevations in serum immunoglobulin G (IgG), rheumatoid factor (RF) and antinuclear antibody (ANA), which usually correlate with more advanced disease. The effects of successful antiviral treatment on these abnormalities has not been well defined.

 

Aim:

To evaluate the effect of interferon-based antiviral therapy and sustained virological response (SVR) on immunological markers in chronic hepatitis C virus (HCV) infection.

 

Methods:

179 patients with chronic hepatitis C treated at the Clinical Center of the NIH were available for analysis. Patients had been treated with either standard or pegylated interferon and ribavirin within genotype appropriate regimens. Patients were categorized as having an SVR (HCV RNA-negative 24 wks after stopping therapy) or non-response (which included both non-responders and relapsers). Values for RF, ANA and IgG from before and 24 weeks after stopping therapy were obtained from retrospective chart review. Comparisons were performed using χ2 analysis.

 

Results:

The 179 patients were predominantly men (59%) and Caucasian (76%) with an average age of 48 (range = 28 to 73) yrs. Genotype 1 accounted for 71%, genotype 2 for 17%, genotype 3 for 11% and genotype 4 for 1% of cases. Both pre- and post-treatment values for RF were available in 160, ANA in 157 and IgG in 53 patients. RF was present in 77 patients before therapy and declined in 44% of patients with an SVR but in only 18% of non-responders (p=0.001). Similarly, IgG levels declined in 74% of patients with an SVR but in only 43% of non-responders (p=0.038). Finally, ANA was present in 24 patients before treatment and declined in 14% of patients with an SVR, but in only 6% of non-responders (p=ns).

 

Conclusion:

Patients with chronic hepatitis C who achieve an SVR frequently have improvements in RF and IgG levels which may be surrogate markers for immune activation and disease activity that decrease following viral eradication.

 


#404. Pegylated Interferon alfa-2b Plus Ribavirin in Patients With Genotype 1 Chronic Hepatitis C With a Slow Virologic Response: An Early Enrollers Analysis of the SUCCESS Study.

M. Buti; Y. Lurie; N. Blokhina; G. Teuber; W. Halota; J. Sumskiene; Z. Vozianova; F. Wong; R. Winkler; R. Esteban.

 

Aim:  

To assess the efficacy of 72 vs 48 weeks' therapy with peginterferon (PEG-IFN) alfa-2b plus ribavirin (RBV) in G1, treatment-naive, chronic hepatitis C patients who have slow virologic response.

 

Methods: 

This is an open-label study involving treatment-naive G1 patients with hepatitis. Patients will receive PEG-IFN alfa-2b 1.5µg/kg QW + weight-based RBV (800–1400mg/day) for 12 weeks (Fig.). HCV RNA levels at weeks 12 and 24 will determine whether patients are discontinued or assigned to 48 to 72 weeks of treatment. Patients will be followed for 24 weeks after treatment. Early virologic response (EVR) is defined as ≥2 log decrease in HCV RNA or undetectable HCV RNA levels at week 12. Primary endpoint is SVR 24 weeks after therapy. HCV RNA levels are measured using TaqMan assay (LLQ, 29IU/mL) at screening, baseline, weeks 4, 12, 24, 48, 72, and follow-up.

 

Results:  

As of September 2006, 1033 patients have been screened and 1428 patients are enrolled at 133 sites in Europe, Canada, and Israel. Of these, 12-3 patients have been treated until week 12, and 190 until week 24. Most (63.3%) patients are men, white (96.2%), and have a mean age of 43 years and a mean body weight of 76kg (range, 45–124kg).

Virologic Response

• RVR was observed in 188 (17%) of 1129 patients with available data for week 4 and EVR was observed in 726 (78%) of 934 patients with available data for week 12 as of May 2006

• EVR was observed in 1044 (87%) of 1203 of patients with available week 12 HCV RNA data as of September 2006.

— 781 (75%) of 1044 had undetectable levels of HCV RNA.

— 263 (25%) of 1044 had a ≥2 log10 decrease from baseline in HCV RNA levels.

• Of those with available 12- and 24-week HCV RNA data as of September 2006, 126 (66%) of 190 had a ≥2 log10 decrease from baseline in HCV RNA levels at week 12 and undetectable HCV RNA at week 24 and were classified as slow responders

Conclusions:   

Preliminary observations from SUCCESS are encouraging and indicate that most (87%) G1 patients treated with PEG-IFN alfa-2b plus ribavirin attain an EVR.

 

Upon completion of the study, data from SUCCESS may determine whether extending duration of therapy with PEG-IFN alfa-2b plus ribavirin from 48 weeks to 72 weeks improves SVR in slow responder G1 patients.

 


#406. The Antiviral Efficacy of an HCV Polymerase Inhibitor in the Chimpanzee Model: Genotypic and Phenotypic Analyses.

C. Chen; Y. He; L. Lu; B. Lim; R. L. Tripathi; A. Roth; T. Middleton; T. Pilot-Matias; L. E. Hernandez; D. W. Beno; M. A. Long; H. Mo; W. M. Kati; T. D. Bosse; D. P. Larson; R. Wagner; R. E. Lanford; W. E. Kohlbrenner; D. J. Kempf; A. M. Molla.

 

Background:

A-837093 is a novel, potent inhibitor of HCV NS5B polymerase. In replicon–based cell culture assays, the EC50 values of A-837093 for HCV genotypes 1a and 1b are 11 nM and 3 nM, respectively. This compound also demonstrates good pharmacokinetic properties, with oral bioavailability ranging from 63-77% in rats and 90-100% in dogs.

 

Methods:

The antiviral efficacy of A-837093 was evaluated in chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg BID for 14 days followed by a 14-day post-treatment observation. Serum samples were withdrawn at various times throughout the study period to determine viral load, plasma drug levels, and for clinical chemistry analysis.

 

The NS5B genes were cloned into a subgenomic replicon-based shuttle vector to evaluate their phenotypic response. Individual clones were isolated and sequenced to compile a detailed analysis of the viral population composition.

 

Results:

At day 2 of therapy, viral load reductions of 1.4 and 2.5 log10 copies/ml for 1a and 1b chimpanzees, respectively, were observed. After this initial drop in viral load, rebound of plasma HCV RNA was observed in the genotype 1b-infected animal while the genotype 1a-infected chimpanzee experienced a sustained viral load reduction throughout the treatment period. Clonal sequencing revealed the presence of several mutations associated with resistance to A-837093, such as C316Y and G554D in samples from the genotype 1b-infected animal.

 

Conclusion:

These findings validate the in vivo antiviral efficacy of benzothiadiazine HCV polymerase inhibitors. The outgrowth of resistant strains in the genotype 1b-infected animal is consistent with in vitro studies showing the presence of preexisting resistant mutants, and suggests that this compound would be optimally useful in combination with other HCV antiviral agents.

 


#408. Mutagenic effect of ribavirin on NS5B quasispecies heterogeneity in vitro and in patients with chronic hepatitis C.

W. Hofmann; A. Polta; E. Herrmann; U. Mihm; B. Kronenberger; T. Sonntag; V. Lohmann; B. Schoenberger; S. Zeuzem; C. Sarrazin.

 

Introduction:

The addition of ribavirin to (pegylated) interferon alfa has substantially increased sustained virologic response rates in the treatment of chronic hepatitis C. Ribavirin is suggested to act as an RNA virus mutagen thereby reducing the viral fitness which results in lethal mutagenesis and error catastrophe. However, data on the mutagenic effect of ribavirin in chronic hepatitis C (CHC) are controversial.

 

Methods:

We studied the non structural (NS)5B quasispecies heterogeneity (1041 base-pair fragment, mean number of clones, n=18) in HCV replicon cells (subgenomic HuH7 replicon system, HCV-con1) treated with increasing doses of ribavirin or, as a control, with its L-enantiomer levovirin. Furthermore, NS5B quasispecies heterogeneity was determined from stored serum samples of 14 patients with CHC genotype 1b infection, who received ribavirin alone (n=7) or in combination with pegylated interferon alfa (n=7), both at baseline and during the first weeks of therapy.

 

Results:

Cultivation of the HCV replicon cells per se resulted in an increase of the NS5B mutational frequency. However, ribavirin at a concentration of 500µM, but not levovirin induced a further increase with a maximum of 2.5 fold after 48h. In patients undergoing ribavirin monotherapy, the total NS5B mutational frequency was higher during the first weeks of therapy as compared to baseline (p=0.01) but only 5 out of 7 patients had an increase when paired serum samples were analyzed (p=n.s.). Genetic complexity (p=0.043) and the proportion of specific G-to-A transitions increased significantly (p=0.003). Serum ribavirin concentration was positively correlated with evolution of NS5B genetic diversity (p=0.039). In patients receiving pegylated interferon alfa and ribavirin combination therapy a decrease of mutational frequency (p=0.002), unchanged genetic complexity and a lower proportion of G-to-A mutations (p=0.002), respectively, were detectable.

 

Conclusion:

Ribavirin, but not its clinically non effective L-enantiomer levovirin possesses a dose-dependent mutagenic effect in HCV replicon cells. In patients with chronic hepatitis C undergoing monotherapy, ribavirin exhibits moderate mutagenic effect early during therapy which may escape detectability in patients undergoing interferon alfa and ribavirin combination therapy.

 


#409. Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon.

M. Imamura; N. Hiraga; M. Tsuge; C. Noguchi; S. Takahashi; E. Iwao; C. Tateno; M. Honda ; S. Kaneko; T. Wakita; K. Yoshizato; K. Chayama.

 

Purpose:

Studies of hepatitis C virus (HCV) infection and replication in vivo have been hampered by the lack of a small animal mode with long-term HCV infection. A mouse model of HCV has been developed using human hepatocyte chimeric mouse and the cell line producing genotype 2a HCV has been shown to infect this mouse. As an extension of this model, we attempted to develop an infectious model of molecularly cloned both genotype 1a and 2a HCV RNA, and evaluated its susceptibility to interferon (IFN)-α.

 

Methods:

HCV was infected to the human hepatocyte chimeric mice by following methods. 1) intravenous inoculation of genotype 1b HCV-infected human serum, 2) intrahepatic injection of genotype 1a molecular clone, 3) intravenous inoculation of culture medium collected from hepatoma cell lines transfected with genotype 2a HCV genome. The HCV-infected mice were intramuscularly administrated with consecutive daily injection of 7000 IU/g/day of IFN-α, and mice serum HCV RNA titer were analyzed.

 

Results:

The mice inoculated with HCV-infected human serum developed measurable viremia 2 weeks after inoculation. The viremia reached a plateau 6 to 8 weeks after infection and persisted high titer of HCV RNA for more than 12 weeks. IFN-α-treatment reduced HCV RNA titer in HCV-infected mice. The mice inoculated with in vitro generated HCV RNA also developed high level of viremia in both genotype 1a and 2a. With 1 week-IFN-α treatment, the viral load reduced to undetectable limit in genotype 2a-infected mouse. However, only 1 log decrease was seen in genotype 1a-infected mice.

 

Conclusion:

We have established a genetically engineered genotype 1a and 2a HCV-infected mice model, and the mice pronounced different susceptibility to IFN-α. These animal models would be useful for studies of HCV virology and resistance of HCV against IFN.

 


#412. Identification of human monoclonal antibodies against HCV E1 that broadly neutralize retroviral pseudoparticles and JFH1-based viruses.

J. Meunier; S. Takikawa; R. Russell; J. Bukh; V. Goossens; G. Maertens; E. Depla; S. Emerson; R. Purcell.

 

Background:

Hepatitis C virus infection is a major cause of chronic liver disease worldwide. Unfortunately, development of an effective vaccine has proven to be very challenging. Passive immunoprophylaxis using monoclonal antibodies to both glycoproteins would be an attractive alternative to prevent or control HCV infections, but thus far, only mAbs against E2 have been shown to neutralize.

 

Methods:

A large panel of mAbs against E1 or E2 was derived from mice, chimpanzees or humans immunized with recombinant envelope proteins. In addition, mAbs were also retrieved from HCV patients that cleared infection. In an initial screening all mAbs were evaluated for neutralization of a genotype 1a retroviral pseudoparticle (HCVpp). Antibodies showing at least 50% neutralization in this first assay were further characterized with respect to neutralization of other genotype HCVpp, JFH1 HCVcc neutralization and epitope mapping.

 

Results:

Out of a panel of more than 50 mAbs, only 3 monoclonal antibodies neutralized retroviral pseudoparticles (HCVpp). The neutralization titers of two human mAbs against E1 and one chimpanzee mAb against E2 were determined with HCVpp representing each of the six HCV genotypes. All three mAbs reacted against the HCVpp 1a, with neutralization titers from 1:800 to 1:3200. Surprisingly, all three mAbs also reacted strongly against HCVpp of genotypes 4 and 5 (neutralization titers from 1:400 to 1: 3200), and almost as well against HCVpp 6a (1:100 to 1:1600). All three mAbs reacted weakly or not at all against HCVpp 3a and HCVpp 2a, respectively. However, all three mAbs neutralized cell-culture grown HCVcc JFH1 (genotype 2a) by 80% to 90%. Especially the E1 specific mAbs recognize an epitope region which has so far not been associated with HCV entry.

 

Conclusion:

For the first time, E1 neutralizing mAbs were identified. The antibodies show an unexpectedly broad and strong cross-genotype neutralization activity. Therefore, the results of this study may contribute to the understanding of HCV replication and may be used in novel clinical approaches for the control of HCV infection.

 


#417. In vitro antiviral effects of combinations of Abbott HCV polymerase inhibitors with IFN or NS3/4A protease inhibitors.

G. Koev; T. Dekhtyar; L. Han; P. Yan; J. M. Beyer; T. Ng; C. Lin; D. P. Larson; T. D. Bosse; H. Chen; K. F. McDaniel; L. L. Klein; R. Wagner; W. M. Kati; D. J. Kempf; H. Mo; A. M. Molla.

 

Aim:  

In search of an alternative to the standard IFN-RBV treatment of HCV infection, we have discovered a series of potent inhibitors of the HCV NS5B RNA polymerase. While monotherapy often leads to resistance development, drug combinations have proven to deliver superior results in HIV therapy, and are almost certain to be most effective in treatment of HCV. In this study, we examined the short-term and long-term antiviral activity of Abbott HCV polymerase inhibitors in combination with IFN and NS3 protease inhibitors.

 

Methods:  

The antiviral effects of compound combinations were studied in the HCV 1b-N replicon cell culture system. In the short-term combination assays, serial dilutions of one compound were combined with dilutions of another compound in a checkerboard manner. The level of HCV replication was determined by the SEAP reporter assay 4 days after compound addition. In the long-term combination assays, replicon cells were grown in the presence of the compounds for 16-20 days being passaged every 4 days. Replicon RNA levels were determined by Real-Time RT-PCR at each passage.

 

Results:   

A-837093 and A-848837 are benzothiadiazine NS5B inhibitors discovered at Abbott. They exhibit replicon EC50s in the 1b-N HCV replicon of 5 nM and 2 nM, respectively. A-837093 showed additive to synergistic antiviral interactions with human IFN and the HCV protease inhibitor BILN-2061 at most concentrations tested. Treatment with either A-837093 or BILN-2061 alone in a long-term assay resulted in an HCV RNA drop of ~4 logs and ~3 logs, respectively, but did not completely clear RNA in the course of the 16-day treatment. Replicon RNA sequence analysis revealed development of specific resistance mutations in response to A-837093 (Y448H, G554D, D559G, in NS5B) and BILN-2061 (D168V in NS3). On the other hand, the combination treatment with the two compounds at concentrations of 10 times their respective EC50s resulted in a replicon RNA drop of over 7 logs, which led to undetectable HCV RNA within 12 days of treatment. Combination of A-848837 with the protease inhibitor SCH503034 also cleared HCV replicon RNA in a long-term assay.

 

Conclusions:  

Our results suggest that highly potent benzothiadiazine inhibitors of HCV polymerase such as A-837093 and A-848837 have the potential to be used in combination with different classes of HCV inhibitors for the treatment of HCV infection.

 


#422. The C-terminus of the first structural domain of HCV and GBV-C NS5A protein inhibit HIV replication in Jurkat cells.

J. Xiang; J. H. McLinden; Q. Chang; T. M. Kaufman; J. T. Stapleton.

 

Introduction:

The most closely related human virus to HCV is a nonpathogenic flavivirus initially called hepatitis G virus, but usually referred to as GBV-C because it is not associated with acute or chronic hepatitis. HCV and GBV-C nonstructural phosphoproteins NS5A share several properties including a predicted N-terminal ER membrane anchoring domain, a zinc-binding domain, a region associated with interactions with PKR and subsequent inhibition of phosphorylation of eIF-2a, and two phosphorylation forms. Because co-infection of primary lymphocytes with GBV-C and HIV results in inhibition of HIV replication and because the HCV NS5A protein has pleotropic effects on cells, we examined the effect of HCV and GBV-C NS5A on HIV replication.

 

Methods:

Jurkat (CD4+ T lymphocyte) cell lines were constructed that stably expressed full-length HCV and GBV-C NS5A, or a series of HCV and GBV-C NS5A deletion mutants. Negative control cells contained only the vector (which expresses GFP). NS5A expression was regulated by doxycycline, and was measured by immunoblot and immunofluorescence microscopy. HIV replication was measured by p24 antigen release or infectivity.

 

Results:

HIV replication was potently and significantly inhibited in Jurkat cell lines expressing full-length HCV and GBV-C NS5A proteins compared to vector control cell lines (> 95% reduction p24 antigen days 4-6, > 2.5 log10 reduction in infectivity on day 6 post-infection; p< 0.01 for each). GBV-C NS5A deletions that contained amino acids 1 to 182 inhibited HIV, whereas C-terminal deletions expressing GBV-C aa’s 1 – 152 or regions expressing aa’s 237 – 414 did not. Mutants containing HCV structural domain I (aa’s 1 - 213) inhibited HIV while domains II (aa’s 214 – 342) and III (aa’s 343 – 447) did not. Comparison of HCV NS5A with the GBV-C NS5A region involved in HIV inhibition reveals a region that is predicted to share hydrophobic and secondary structure, despite little sequence homology. This domain is currently being expressed in Jurkat cells to determine if it too mediates HIV inhibition in Jurkat cells. In addition, expression of these peptides in non-lymphocyte cell lines is underway to determine if this effect is cell-specific. In conclusion, a region at the C-terminus of domain I of HCV and GBV-C NS5A protein inhibits HIV replication in Jurkat cells. Further characterization and mapping of NS5A effects on gene expression and identification of cellular proteins that interact with this protein are underway.

 

Conclusions:

HCV and GBV-C NS5A proteins may lead to a novel, cellular-based approach to inhibiting HIV replication.

 


#423. A comprehensive system for consistent numbering of HCV sequences, proteins and epitopes.

C. Kuiken; C. Combet; J. Bukh; G. Deleage; M. Mizokami; R. Richardson; E. Sablon; K. Yusim; J. Pawlotsky; P. Simmonds.

 

Introduction:

In October 2004, an expert meeting was convened in parallel with the 11th Symposium on Hepatitis C and Related Viruses to resolve current issues in HCV nomenclature and numbering. Inconsistent and inaccurate numbering of locations in DNA and protein sequences is a problem in the HCV literature and may become clinically problematic. A standardized numbering system will circumvent these problems in the future. We present a simple numbering scheme to facilitate the identification of the position number or precise location of interest in HCV DNA or proteins.

 

Discussion:

The proposed numbering system was adapted from the Los Alamos HIV database (1), with elements from the hepatitis B virus numbering system (2). The system comprises both nucleotides and amino acid sequences and epitopes. It uses the full length genome sequence of the H77 strain as a reference, and includes a method for numbering insertions and deletions relative to this reference sequence.

 

1. Korber B, Foley B, Kuiken C, Pillai S, Sodroski J: Numbering Positions in HIV Relative to HXB2CG. In: Korber BK, C.L.; Foley,B.; Hahn,B; McCutchan,F.; Mellors J.W.; Sodroski,J., ed. Human Retroviruses and AIDS. Los Alamos: Los Alamos National Laboratory, 1998.

2. Stuyver LJ, Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, Schinazi RF. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology 2001;33:751-757.

 


#425. Rapid Decline of Hepatitis C Viral (HCV) RNA and Very Early Virologic Responses (VEVR) Are Associated With Low Sequence Diversity in the NS5A Region.

M. K. Jain; H. Yuan; A. Reeck; N. Attar; D. S. Carney; M. Gale; W. M. Lee.

 

Background:

Early events in interferon (IFN) treatment of HCV impact overall outcome. HCV viral kinetic studies show great variation in initial responses thought to result from direct IFN-mediated effect on replication of IFN-sensitive HCV quasispecies. The level of sequence diversity within the NS5A coding region has been associated with HCV treatment outcome in some studies. We hypothesized that lower sequence diversity in NS5A might be associated with more rapid responses to HCV therapy.

 

Methods:

Ten HCV genotype 1 patients were treated with pegylated interferon alfa 2a and ribavirin, sera collected at 0, 24, 48, and 7 days(d) and clone analysis was performed for the entire NS5A (10 to 13 for each time point).

 

Results:

Five patients had fast viral load (VL) decline [>0.8 log at 72 hours(h)]; 5 had slow VL decline. Four of 5 of those with fast VL decline had VEVR (bDNA neg at wk 4) compared to none of those who had a slow VL decline (p=0.05). All 5 with fast VL decline also demonstrated EVRs at 12 wks compared to 2 of 4 slow decliners; 1 patient in the slow decline group withdrew prior to 12 wks. Of the 5 patients with fast VL decline clinical outcomes showed: 3 SVRs, 1 relapse and 1 ETR. Of the patients with slow viral decline: 1 SVR, 2 NR, and 1 relapse. Sequence diversity at baseline was narrow (median 0.009) in the fast viral decliners compared to a median of 0.024 in the slow viral decliners (p=0.03). One patient with higher sequence diversity at baseline had a fast VL decline but failed to achieve VEVR. No other patients with high sequence diversity at baseline had a 72h rapid response or VEVR. Phylogenetic analysis showed a closely related cluster of clones at 7d when compared with baseline in 4/5 patients with fast VL decline. No clonal clustering was observed in patients with slow VL decline. We observed varying degrees of sequence diversity between the previously described ISDR/PKR binding domain and V3 regions in most patients, suggesting that these regions are under different selective pressures. Summary: Rapid VL decline during the initial 72h of interferon treatment predicts a VEVR at 4 wks. Those showing VEVR had lower sequence diversity at baseline; this group appeared to develop an even more closely related cluster of clones connoted by changes within NS5A by 7d of therapy than did non-VEVRs.

 

Conclusions:

Low sequence diversity of NS5A may be important in obtaining VEVR. IFN therapy appears to be more effective in patients with limited diversity at baseline and when even more closely related clones emerge. Screening for clonal diversity at baseline and at 7 days might provide additional insights to predict later viral responses.

 


#429. FIBROSIS IS ASSOCIATED WITH INSULIN RESISTANCE AND STEATOSIS IN CHRONIC HEPATITIS C PATIENTS WITH GENOTYPE 1 AND 4 BUT NOT GENOTYPE 3.

R. Moucari; T. Asselah; V. Paradis; H. Voitot; D. Cazals-Hatem; M. Martinot-Peignoux; S. Maylin; M. Nicolas-Chanoine; D. Valla; M. Vidaud; P. Bedossa; P. Marcellin.

 

Aim:

To assess the impact of the metabolic syndrome and insulin resistance on steatosis and fibrosis severity according to genotype and viral load in a cohort of patients with chronic hepatitis C.

 

Patients and Methods:

300 consecutive patients with chronic hepatitis C were evaluated. Presence of the metabolic syndrome was assessed in all patients on the day of liver biopsy. Insulin resistance was defined as HOMA >3. Necroinflammation and fibrosis were evaluated using the METAVIR score. Severe fibrosis was considered with fibrosis stage F2-F4. Steatosis was graded as absent, moderate (<30%) or severe (>30%). Serum HCV RNA (Bayer's VERSANT® HCV RNA 3.0 Assay) and genotype (sequencing) were determined for all patients.

 

Results:

Patients characteristics were: male sex (n=173), mean age 47.6 years, mean BMI 24.9(BMI> 28, n=60; BMI > 30, n=28). Eighty- two patients had central obesity. Metabolic syndrome was present in 44 patients and insulin resistance in 110 patients. Steatosis was present in 162 patients (54%) (mild in 53, moderate in 57 and severe in 48 patients). Genotype distribution was: 1 (n=164), 3 (n=57), 4 (n=50) and 2 (21 patients). Mean serum HCV RNA was 1.1 106 IU/ml and 117 patients had viral load>800 000 IU/ml.

 

In patients with genotype1and 4, insulin resistance, steatosis and fibrosis distribution were similar and analysis of pooled data showed:

 

·        Severe Fibrosis was more frequent in patients with insulin resistance (61/84 vs. 54/127, p<0.001) and severe steatosis (43/66 vs. 54/127, p=0.003)

·        Insulin resistance was associated with metabolic syndrome (27/36 vs. 58/177, p<0.001), severe steatosis (42/69 vs. 42/142, p<0.001) and severe fibrosis (61/115 vs. 23/96, p<0.001)

·        Severe Steatosis was associated with metabolic syndrome (21/3vs. 47/175, p<0.001), insulin resistance (43/97 vs. 23/96, p<0.001) and severe fibrosis (45/107 vs. 26/110, p=0.004).

·        In genotype 3 patients, severe steatosis was significantly more frequent (29/57 vs. 69/211, p=0.01) and was associated with high viral load (serum HCV RNA >800 000 IU/ml) (12/16 vs. 13/36, p=0.01) but not with fibrosis neither with insulin resistance. Prevalence of the metabolic syndrome as well as insulin resistance was significantly lower compared to other genotypes.

 

Conclusion:

·        Fibrosis was associated with both steatosis and insulin resistance in chronic hepatitis C patients with genotypes 1 and 4. I

·        Steatosis is associated with the metabolic syndrome, insulin resistance  in HCV genotypes 1 and 4.

·        Steatosis is associated with viral replication in HCV genotype 3.

 


#430. STEATOSIS IS ASSOCIATED WITH INTRAHEPATIC HCV RNA LEVEL IN GENOTYPE 3 CHRONIC HEPATITIS C.

R. Moucari; S. Maylin; M. Martinot-Peignoux; T. Asselah; H. Voitot; D. Cazals-Hatem; V. Paradis; M. Vidaud; M. Nicolas-Chanoine; D. Valla; P. Bedossa; P. Marcellin.

 

Background and Aim:

In chronic hepatitis C patients, the relationship between intrahepatic viral load and histological features is not well known. The aim of this study was to analyze the impact of intrahepatic HCV RNA level on insulin resistance, steatosis and fibrosis.

 

Patients and Methods:

Eighty six patients with absent or severe steatosis were selected from a prospective series of 300 patients with chronic hepatitis C who underwent a liver biopsy between September 2005 and May 2006, and had available frozen samples (-80°C). Severe steatosis was defined as affecting more than 50% of hepatocytes. Insulin resistance was defined as HOMA >3. Necroinflammation and fibrosis were evaluated using METAVIR score. Serum HCV RNA (HCV RNA Quantiplex v3.0) and genotype (sequencing) were determined for all patients. RNA was extracted from liver biopsy (Qiagen-Rneasy Mini Kit) and HCV RNA was quantified (Bayer’s VERSANT ® HCV RNA Quantiplex 3.0 assay).

 

Results:

There was no significant correlation between serum and intrahepatic viral load (r2= 0.28). Patients with genotype 1 had significantly higher viral load in serum (1.6 106 IU/ml vs. 0.6 106 IU/ml, p=0.003) and in liver (7.2 106 IU/g vs. 2.4 106 IU/g, p=0.04) in comparison with patients with other genotypes. Intrahepatic viral load was not significantly different between patients with or without insulin resistance (4.9 106 IU/g vs. 4.0 106 IU/g, p=0.7). Intrahepatic viral load was also not different in patients with mild or moderate fibrosis (F1-F2) compared to those with bridging fibrosis or cirrhosis (F3-F4) (4.9 106 IU/g vs. 1.9 106 IU/g, p=0.3). In patients with genotype 3, intrahepatic viral load was associated with severe steatosis (6.0 106 IU/g vs. 1.0 106 IU/g, p=0.01). This difference was not found in patients with other genotypes

 

Conclusion:

We found no correlation between serum and intrahepatic viral load. Genotype 1 was associated with higher serum and intrahepatic viral load compared to other genotypes. Intrahepatic viral load was associated neither with insulin resistance, nor with fibrosis severity. Intrahepatic viral load was associated with severe steatosis in genotype 3.

 


#432. Selection And Characterization Of Hepatitis C Virus Replicons Resistant To A Potent Polymerase Inhibitor A-837093.

L. Lu; P. Krishnan; R. Pithawalla; T. Dekhtyar; T. Ng; W. He; T. Pilot-Matias; D. Larson; T. Bosse; R. Wagner; D. Kempf; A. Molla; H. Mo.

 

Purpose:

We undertook this study to characterize the resistance profile of A-837093, a potent HCV RNA dependent RNA polymerase (RdRp) inhibitor.

 

Methods:

The anti-HCV activity of A-837093 was determined in HCV replicon cells by the reduction of HCV RNA. HCV replicon colonies resistant to the inhibitor were selected by treating the HCV subgenomic 1b-N replicon cells with A-837093 at a concentration 10 times above its EC50. Genotypes of the resistant colonies were determined by sequencing the NS5B polymerase gene. Individual mutations were introduced into a luciferase-expressing replicon by site-directed mutagenesis. The susceptibility of the mutants was evaluated by a transient replication assay.

 

Results:

A-837093 displayed excellent activity in HCV replicon with EC50 of 3 and 11 nM against HCV genotype 1b and 1a, respectively. Replicon colonies selected by A-837093 exhibited substantial decreases in susceptibility to A-837093. Genotypic analysis demonstrated that each colony contained one of the following mutations: S368A, Y448H, G554D or D559G in the NS5B gene. Molecular clones containing the above single mutations conferred moderate (Y448H, 19-fold) to high-level (200-300 fold) resistance to A-837093. In contrast, all four mutants retained susceptibility to a thiophene-2-carboxylic acid polymerase inhibitor (Shire 2), the HCV protease inhibitor BILN2061 and interferon. Mutant replicons showed significantly impaired fitness compared with the wild-type replicon.

 

Conclusion:

This study suggests that monotherapy with the polymerase inhibitor A-837093 may lead to the development of resistance. However, the lack of cross-resistance may allow this agent to be used in combination with different classes of polymerase inhibitors, protease inhibitors or interferon.

 


#436. Mutations in the Natural Strains of NS3 Protease Domain of HCV in HIV/HCV Coinfected Patients Under Antiretroviral Therapy Including or Not HIV Protease Inhibitors.

G. Morsica; S. Bagaglio; L. Alagna; C. Lodrini; G. Gallotta; L. Galli; S. Dispinseri; A. Lazzarin; C. Uberti-Foppa.

 

Introduction:

HCV Protease inhibitors (HCV-PI) have been recently identified as potential candidates for new-anti-HCV therapy. In vitro studies have shown mutations within replicon system that confer resistance to VX-950 and SCH503034 HCV-PI.

 

Methods: 

Mutations within NS3 protease gene were investigated by direct sequencing in 38 HIV/HCV coinfected patients, harboring HCV genotype-1. Nineteen of 38 patients were treated with HIV protease inhibitors (HIV-PI) at time of samples collection whereas the remaining 19 patients received antiretroviral therapy (ART) without HIV-PI since two years from samples examination.

 

Results:

The comparison of mutations between HIV/HCV coinfected patients and a pool of 250 sequences obtained from Genbank as control group, showed that the presence of amino acid (aa) change at position 156, conferring resistance to HCV-PI, was higher in HIV positive patients than in the control group (3/38 vs 2/250; p=0.0177). HIV infected patients under ART with PI showed a mutational profile significantly different from that detected in the control group (3/19 vs 2/250; p=0.0028). On the contrary, HIV infected patients under ART without PI exhibited a mutational profile similar to that detected in the control group (0/19 vs 2/250; p=ns). An aa change A156G or A156T, was found in 3 (15.7%) HIV infected patients under ART regimen including HIV-PI and in none of HIV infected patients under ART without HIV-PI, but the difference was not statistically significant (p=0.2297). The aa substitution at position 170 of NS3 was prevalently detected in HIV infected patients under ART than in the reference group of sequences obtained from Genbank (5/38 vs 0/250; p<0.0001). However, this aa substitution did not result differently distributed between patients treated or not with HIV-PI (2/19 vs 3/19; p=ns).

 

Conclusions:

In this small cohort of HIV/HCV coinfected patients, the natural strains of the NS3 protease domain exhibited mutations that were related to resistance to HCV-PI. This finding could have implication for the treatment with HCV-PI of HIV/HCV coinfected patients with naturally selected drug-resistant variants.