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Biomedical subjects

John G McHutchison

Publications and source records attributed to John G McHutchison.

At least 19 recordsLinked to original sources
PubMed2006

Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naïve patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa.

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFNalpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFNalpha with the long serum half-life of albumin. Interferon alfa (IFNalpha) mediated biological responses stem from the engagement of IFNalpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNalpha naïve patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to1200mug. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained >5-fold median induction on days 7 and 28 of the ISG's- OAS1, IRF7, IFI44 and IFI27. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IFI44 and IRF7 showed significant pair-wise correlation in individual patients (r>0.7 and P<0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFNalpha.

Journal Article↗
PubMed2006

Relationship of smoking and fibrosis in patients with chronic hepatitis C.

BACKGROUND & AIMS: Preliminary studies have suggested that in patients with chronic hepatitis C (CHC), cigarette smoking increases the risk for developing liver fibrosis. Hypoxia caused by smoking may induce expression of the cytokines' vascular endothelial growth factor (VEGF) and VEGF-D and their corresponding soluble tyrosine kinase receptors fms-like tyrosine kinase receptor (s-Flt) and kinase insert domain receptor (s-KDR). These cytokine levels are increased in animals with cirrhosis and in human beings with CHC. We studied whether the concentrations of VEGF, VEGF-D, s-Flt, and s-KDR were increased in CHC smokers with and without hepatic fibrosis. METHODS: A total of 170 CHC patients were identified retrospectively from a single center's database. In 59 patients, serum levels of VEGF, VEGF-D, s-Flt, and s-KDR were measured using an enzyme-linked immunosorbent assay. RESULTS: All 170 patients were hepatitis C virus RNA positive, 117 (69%) were men, 43 (25%) were smokers, and their mean (+/-SD) age was 47 (+/-6) years. Overall, 21% of smokers had Metavir fibrosis scores of 3 and 4 compared with 14% of nonsmokers (P < .01). In an age-weighted multivariate model using step-wise logistic regression, smoking, infection with hepatitis C virus genotype 1, male sex, and increased VEGF-D concentration all were significant independent predictors of more severe liver fibrosis (P < .05 for all observations). CONCLUSIONS: These data suggest that CHC patients who smoke may have more hepatic fibrosis. The data also suggest that increased VEGF and VEGF-D concentrations are associated with smoking and may be involved in the molecular mechanisms of fibrogenesis.

Adult↗
PubMed2006

A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients.

BACKGROUND/AIMS: Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. METHODS: A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1,200 microg. RESULTS: A 2 log(10) IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1,200 microg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log(10) IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141 h consistent with previous alb-IFN data from IFN-alfa-experienced patients. CONCLUSIONS: Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection.

Adult↗
PubMed2006

HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C.

Patients infected with HIV-1 who are heterozygous at HLA class I loci present greater variety of antigenic peptides to CD8+ cytotoxic T lymphocytes, slowing progression to AIDS. A similar broad immune response in chronic hepatitis C (CHC) infection could result in greater hepatic injury. Although specific HLA class II alleles may influence outcome in CHC patients, the role of HLA class I heterogeneity is generally less clearly defined. Our aims were to determine whether HLA class I allelic diversity is associated with disease severity and progression of fibrosis in CHC. The study population consisted of 670 adults with CHC, including 155 with advanced cirrhosis, and 237 non-HCV-infected controls. Serological testing for HLA class I antigens was performed via microlymphocytotoxicity assay. Peptide expression was defined as heterozygous (i.e., a different allele at each locus) or homozygous. Fibrosis staging was determined using METAVIR classification. Heterozygosity at the B locus (fibrosis progression rate [FPR] 0.08 vs. 0.06 units/yr; P = .04) and homozygosity at the A locus (FPR 0.10 vs. 0.08 units/yr; P = .04) predicted a higher median FPR. Age at infection, genotype, and duration of infection were also predictors of FPR. A higher proportion of patients with stage F2-F4 expressed HLA-B18 compared with controls (OR 2.2, 95% CI 1.17-4.23; P = .02). These differences were not observed in patients with advanced cirrhosis. HLA zygosity at 1, 2, or 3 alleles was not associated with fibrosis stage, liver inflammation, or treatment outcome. In conclusion, HLA class I allelic diversity has a minor influence on FPRs and disease severity in CHC.

Adult↗
PubMed2006

Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo.

Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in t he hepaticprogenitor cell population in 16 patients with non-responding chronic hepatitis C Interferon alpha-based treatment significantly reduced the numbers of c-kit-positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murinehepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validatethese results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha-based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation. Supplementay material for this article can

Animals↗
PubMed2006

Definition and management of anemia in patients infected with hepatitis C virus.

Chronic infection with hepatitis C virus (HCV) can progress to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The current best treatment for HCV infection is combination therapy with pegylated interferon and ribavirin. Although this regimen produces sustained virologic responses (SVRs) in approximately 50% of patients, it can be associated with a potentially dose-limiting hemolytic anemia. Hemoglobin concentrations decrease mainly as a result of ribavirin-induced hemolysis, and this anemia can be problematic in patients with HCV infection, especially those who have comorbid renal or cardiovascular disorders. In general, anemia can increase the risk of morbidity and mortality, and may have negative effects on cerebral function and quality of life. Although ribavirin-associated anemia can be reversed by dose reduction or discontinuation, this approach compromises outcomes by significantly decreasing SVR rates. Recombinant human erythropoietin has been used to manage ribavirin-associated anemia but has other potential disadvantages. Viramidine, a liver-targeting prodrug of ribavirin, has the potential to maintain the virologic efficacy of ribavirin while decreasing the risk of hemolytic anemia in patients with chronic hepatitis C.

Anemia↗
PubMed2005

A phase I trial of an antisense inhibitor of hepatitis C virus (ISIS 14803), administered to chronic hepatitis C patients.

BACKGROUND/AIMS: ISIS 14803 is a 20-unit antisense phosphorothioate oligodeoxynucleotide that binds to hepatitis C virus (HCV) RNA at the translation initiation region of the internal ribosome entry site (IRES) and inhibits protein expression in cell culture and mouse models. This Phase I, open-label, dose-escalation trial of ISIS 14803 was performed in chronic HCV patients. METHODS: At least 7 days after receiving an initial single dose, twenty-eight patients received 0.5-3 mg/kg ISIS 14803 thrice weekly for 4 weeks by intravenous infusion or subcutaneous injection. RESULTS: In most patients, the 4-week treatment did not reduce plasma HCV RNA. However, 3 patients receiving > or =2 mg/kg had transient HCV reductions of 1.2-1.7 log(10) that persisted < or =32 days. These reductions were accompanied by asymptomatic, self-resolving elevations in serum alanine transaminase (ALT) levels to >10x the upper limit of normal. Two other patients had ALT flares without plasma HCV reduction. No clinical signs, symptoms of hepatic dysfunction, or laboratory changes in albumin or prothrombin time accompanied ALT elevations. CONCLUSIONS: ISIS 14803 treatment was associated with HCV reductions in only 3/28 patients. ALT flares in 5 patients also occurred. Further studies to evaluate ISIS 14803 treatment and the mechanisms of the ALT flares are now required.

Adult↗
PubMed2005

Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) in the United States. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV. METHODS: We analyzed the United Network for Organ Sharing Liver Transplant Registry database from April 1987 to March 2003 to examine predictors of death or retransplantation in patients with HCV. Univariate models for each predictor were evaluated. Factors significant in the univariate model were used to develop a multivariable model. RESULTS: Of 6,956 patients meeting the inclusion/exclusion criteria, 1,527 (22.0%) died or received retransplants during the first year after transplant. Recipients with graft failure were older, had greater serum creatinine levels, and were more likely to require mechanical ventilation and hemodialysis before transplant. Donors of patients with graft failure were older and more likely to have diabetes mellitus. In the multivariable regression model, predictors of graft failure at 1 year were donor age, recipient age, recipient creatinine greater than 2 mg/dL, and the requirement for mechanical ventilation for the recipient. CONCLUSIONS: Both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV.

Age Factors↗
PubMed2005

Trends in health care resource use for hepatitis C virus infection in the United States.

Chronic hepatitis C virus (HCV) infection affects approximately 3 million people in the United States and places tremendous demands on the health care system. As many observers have predicted, the disease burden continues to grow as the infected population ages. In this study, we analyzed inpatient data from the Healthcare Cost and Utilization Project, outpatient data from the National Ambulatory Medical Care Survey, and drug data from the Verispan Source Prescription Audit. We examined recent growth in the use of health care resources among HCV patients by age group and found average annual increases of 25% to 30% for hospitalizations, charges, hospital days, and physician visits. Corresponding time-trend coefficients were positive (P < .001). From 1994 to 2001, the HCV burden increased among patients aged 40 to 60 years, reflecting the natural history of disease progression. In sensitivity analysis, HCV outcome growth rates remained significant, unless more than 3 out of 4 cases were initially underreported. Also, patients co-infected with HIV and HCV in 2001 constituted 7.5 times as many hospitalizations and incurred 2.9 times the charges in 1994, relative to all HIV hospitalizations and charges. Our findings highlight the urgency concerning HCV outcomes. In conclusion, as patients continue to age and disease burden progresses, suboptimal decisions regarding HCV treatments will bring increasing opportunity costs for the health care system and society.

Adult↗
PubMed2005

Steatosis and chronic hepatitis C virus infection: mechanisms and significance.

Chronic hepatitis C (CHC) and steatosis are common entities that have the potential to interact synergistically and result in significant morbidity. Steatosis is frequently observed in CHC and seems to have a significant impact on the natural history of the disease with respect to development of fibrosis and reducing the virologic response to current therapy. Research efforts should continue to focus on delineating the complex viral and host interactions involved in the pathogenesis of hepatitis C virus (HCV)-related steatosis. This may provide novel future therapeutic strategies that may help modulate disease progression in relation to steatosis in HCV infection.

Body Mass Index↗
PubMed2005

Relationships between hepatic iron content and virologic response in chronic hepatitis C patients treated with interferon and ribavirin.

OBJECTIVES: The aims of this study were to determine the effect of pretreatment hepatic iron concentration (HIC) on response to combination therapy with interferon and ribavirin, and to examine the change in HIC associated with this treatment. METHODS: Patients with hepatitis C who underwent liver biopsy before and after combination therapy were studied retrospectively. HIC was measured from paired pre- and posttreatment liver biopsy specimens, and histologic grade and stage were recorded. RESULTS: Sixty of 112 (54%) patients achieved sustained virologic response (SVR); response varied by genotype (genotype 1 (44%), genotype 2 or 3 (85%)). There was no difference in pretreatment median HIC between responders and nonresponders (404 microg/g and 394 microg/g, respectively; p= 0.31); patients with HIC > or = 500 microg/g were not less likely to achieve SVR (OR = 1.1; 95% CI 0.5-2.3). In a multivariate analysis, factors associated with SVR included genotype 2 or 3 (OR = 12.2; 95% CI 3.1-47.8) and viral load < 2 million copies/ml (OR = 3.6; 95% CI 1.3-10.0). HIC > or = 500 microg/g did not decrease the likelihood of SVR (OR = 0.8; 95% CI 0.3-2.1). There was no significant change in HIC after combination therapy (median increase in HIC = 29.5 microg/g), and the change in HIC did not differ between responders and nonresponders (p= 0.73). CONCLUSIONS: Pretreatment HIC is not an independent predictor of response to therapy with interferon and ribavirin. Combination therapy does not significantly change HIC regardless of baseline histology or virologic response.

Adult↗
PubMed2005

The clinical utility of using Catrimox-14-treated whole blood in detecting hepatitis C virus RNA.

BACKGROUND: Measuring hepatitis C virus (HCV) RNA in serum or plasma may underestimate the true HCV burden. Extracting viral RNA from whole blood (WB) with a cationic surfactant (Catrimox-14) has resulted in HCV RNA concentrations up to 1000-fold higher than from serum or plasma in some studies, but not others. We compared the Catrimox-14 WB assay with a standard serum assay. METHODS: Seventy-two chronic HCV patients received 48 weeks of standard or pegylated interferon alpha-2b and ribavirin therapy. Catrimox-14-treated WB and corresponding serum samples were obtained at baseline and weeks 12, 24, 48 and 72. HCV RNA concentrations from WB and serum were quantified by a previously validated RT-PCR assay. RESULTS: Overall mean (+/- SD) baseline serum log10 HCV RNA concentration was 6.5 ((+/- 0.58) copies/ml. Out of 72 patients, 33 had no detectable virus at 72 weeks. Neither assay detected virus in these patients at 12 weeks and neither WB nor serum assays detected virus at end-of-treatment in the 10 patients who subsequently relapsed at 72 weeks. HCV RNA concentrations from WB and serum assays were linearly correlated (R2 = 0.73; P < 0.001), although mean serum HCV RNA concentrations were 0.5 log10, copies/ml higher in serum than in WB [6.0 (+/- 0.82) vs 5.5 ((+/- 0.84), respectively, P = 0.12]. CONCLUSIONS: Catrimox-14-treated WB assays detect changes in HCV RNA, but do not offer clinical advantage over a conventional serum RT-PCR based assay.

Adult↗
PubMed2005

A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C.

Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.

Administration, Oral↗