Keyur Patel

North Carolina Clinical Research, Raleigh, North Carolina, United States

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Publications (107)870.56 Total impact

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    ABSTRACT: Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance, which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype-1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end of treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response (SVR), n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n= 17 SVR, n=8 relapse). Serum LDL concentration and particle size increased early in therapy, while triglyceride concentration and very low density lipoprotein (VLDL) particle size decreased concomitantly, irrespective of treatment outcome. While LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion: Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. (Hepatology 2014)
    Hepatology 09/2014; · 12.00 Impact Factor
  • Hepatology 06/2014; · 12.00 Impact Factor
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    ABSTRACT: Non-invasive tests cannot differentiate between adjacent stages of fibrosis, which limits assessment of disease progression and regression during therapy. We investigated whether levels of cytokines and extracellular matrix proteins in serum and biopsy samples can be used to determine actual stage of liver fibrosis in patients with chronic hepatitis C (CHC), and in prognosis. We collected data from 383 treatment-naïve patients with CHC from the Duke Hepatology Clinical Research Database and Biorepository, from 2006 through 2009, for use in the training set. Serum samples were obtained from 100 individuals without CHC (controls). We selected 37 serum biomarkers for customized array analysis, using the SearchLight multiplex sandwich ELISA. Data from 434 treatment-naïve patients with CHC, obtained from the Trent HCV cohort, were used in the validation analysis. Multivariable modeling, marker selection, and validation included RandomForest and Obuchowski measures, with independent comparison to FibroSURE. Four serum markers (levels of hyaluronic acid, VCAM1, A2M, and RBP4) and age associated with fibrosis stage (F0-1, F2-3, or F4); these had Obuchowski measures of 0.85-0.89, with misclassification rates of 38% and 29% in training and validation sets, compared to 50% for the FibroSURE test. In the training set, area under the curve (AUC) values for the multiplex markers were similar to those from the FibroSURE test: stages F0 vs F1 (0.51 vs 0.53), F1 vs F2 (0.60 vs 0.59), F2 vs F3 (0.69 vs 0.72), and F3 vs F4 (0.51 vs 0.52). AUC values were similar in the validation cohort. In longitudinal analyses of 133 paired biopsies, 9 markers (level of alanine aminotransferase, γ-glutamyltranspeptidase, hyaluronic acid, ICAM1, interleukin (IL)4, CXCL10, CXCL9, and VCAM1) were associated with change in the histologic activity index (P values ranging from .000 to .049) and 4 (GMCSF, IL12, IL2, and MMP13) were associated with a change in fibrosis stage (P values ranging from .001 to .042). We identified serum biomarkers that can be measured by mutiplex ELISA to determine levels of fibrosis in patients with CHC, although misclassification is frequent and results are comparable with those from the FibroSURE test. Changes in protein levels in biopsy samples associated with progression of fibrosis in patients.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 05/2014; · 5.64 Impact Factor
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    ABSTRACT: Background: Osteopontin (OPN) is a Hedgehog (Hh)-regulated cytokine that is up-regulated during chronic liver injury, and directly promotes fibrosis. We reported that Hh-signaling enhances viral permissiveness and replication in HCV-infected cells. Hence, we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. Methods: We compared expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated if modulating OPN levels using exogenous OPN ligands (upregulate OPN) or OPN-specific RNA-aptamers (neutralize OPN), leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analyzed to determine if OPN levels were associated with disease severity or response to therapy. Results: Compared with Huh7, Huh7.5 support higher levels of HCV replication (15-fold), and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 with OPN ligands led to dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 with OPN-specific RNA-aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (p=0.009), but negatively correlated with end-of-treatment (ET) biochemical-response (BCR), ET virological-response (VR), sustained (S)BCR, and SVR (p=0.007). The OPN-Fibrosis Score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. Conclusions: OPN is upregulated in the liver and serum of patients with chronic HCV, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic HCV.
    Clinical Science 01/2014; · 4.86 Impact Factor
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    Julius Wilder, Keyur Patel
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    ABSTRACT: An important aspect of managing chronic liver disease is assessing for evidence of fibrosis. Historically, this has been accomplished using liver biopsy, which is an invasive procedure associated with risk for complications and significant sampling and observer error, limiting the accuracy for determination of fibrosis stage. Hence, several serum biomarkers and imaging methods for noninvasive assessment of liver fibrosis have been developed. In this article, we review the current literature on an important noninvasive imaging modality to measure tissue elastography (FibroScan(®)). This ultrasound-based technique is now increasingly available in many countries and has been shown to be a reliable and safe noninvasive means of assessing disease severity in chronic liver disease of varying etiology.
    Medical Devices: Evidence and Research 01/2014; 7:107-114.
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    ABSTRACT: Backgrounds & Aims Non-invasive tests cannot differentiate between adjacent stages of fibrosis, which limits assessment of disease progression and regression during therapy. We investigated whether levels of cytokines and extracellular matrix proteins in serum and biopsy samples can be used to determine actual stage of liver fibrosis in patients with chronic hepatitis C (CHC), and in prognosis. Methods We collected data from 383 treatment-naïve patients with CHC from the Duke Hepatology Clinical Research Database and Biorepository, from 2006 through 2009, for use in the training set. Serum samples were obtained from 100 individuals without CHC (controls). We selected 37 serum biomarkers for customized array analysis, using the SearchLight multiplex sandwich ELISA. Data from 434 treatment-naïve patients with CHC, obtained from the Trent HCV cohort, were used in the validation analysis. Multivariable modeling, marker selection, and validation included RandomForest and Obuchowski measures, with independent comparison to FibroSURE. Results Four serum markers (levels of hyaluronic acid, VCAM1, A2M, and RBP4) and age associated with fibrosis stage (F0–1, F2–3, or F4); these had Obuchowski measures of 0.85–0.89, with misclassification rates of 38% and 29% in training and validation sets, compared to 50% for the FibroSURE test. In the training set, area under the curve (AUC) values for the multiplex markers were similar to those from the FibroSURE test: stages F0 vs F1 (0.51 vs 0.53), F1 vs F2 (0.60 vs 0.59), F2 vs F3 (0.69 vs 0.72), and F3 vs F4 (0.51 vs 0.52). AUC values were similar in the validation cohort. In longitudinal analyses of 133 paired biopsies, 9 markers (level of alanine aminotransferase, γ-glutamyltranspeptidase, hyaluronic acid, ICAM1, interleukin (IL)4, CXCL10, CXCL9, and VCAM1) were associated with change in the histologic activity index (P values ranging from .000 to .049) and 4 (GMCSF, IL12, IL2, and MMP13) were associated with a change in fibrosis stage (P values ranging from .001 to .042). Conclusions We identified serum biomarkers that can be measured by mutiplex ELISA to determine levels of fibrosis in patients with CHC, although misclassification is frequent and results are comparable with those from the FibroSURE test. Changes in protein levels in biopsy samples associated with progression of fibrosis in patients.
    Clinical Gastroenterology and Hepatology. 01/2014;
  • Hans L Tillmann, Keyur Patel
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    ABSTRACT: Although new hepatitis B virus (HBV) infections are decreasing due to improving vaccination coverage, patients without vaccination coverage can still suffer from manifestation of acute hepatitis B with jaundice and (although rarely) liver failure. No treatment is indicated for mild acute hepatitis B; however, antiviral therapy should be initiated for patients showing signs of significant liver impairment as exemplified by deterioration of prothrombin time to an equivalent of 1.5 or 50% of the 'Quick test'. For fulminant hepatitis, there is no complete agreement on whether antiviral treatment would alter the course, but it should still be started, as it would reduce the risk of reinfection in case there is a need for liver transplantation. Patients in danger of progression towards acute liver failure should be referred to transplant centers as early as possible. © 2014 S. Karger AG, Basel.
    Intervirology 01/2014; 57(3-4):181-8. · 1.89 Impact Factor
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    ABSTRACT: It is estimated that there are 350-400 million individuals with chronic hepatitis B virus infection (HBV) worldwide. The natural course of HBV infection is variable with a number of individuals developing no or only mild disease, while others will die from liver-associated complications if left untreated. It is estimated that 25 % of individuals with HBV infection will eventually die from the complications of HBV-associated liver disease. Several viral and host variables including hepatitis B e antigen status, HBV genotype, viral load, hepatitis B surface antigen and transaminase levels, and viral mutations have been identified as determinants of disease outcomes. The personalized approach to the treatment of chronic hepatitis B might include mere monitoring of the disease in some patients but aggressive treatment in others. Individuals who require treatment should have close monitoring to help ensure maximum medication compliance, to watch for adverse events, and to monitor virologic and biochemical responses. Therefore, management of patients with chronic HBV infection requires a practical setting to demonstrate the relevance of personalized medicine, the roles and limitations of genetic and non-genetic factors, and the risks and benefits of individualized patient care. This article provides an overview of the viral and host genetics of chronic HBV and reviews the clinical utility of serum quantitative hepatitis B surface antigen in the management of patients with chronic HBV infection.
    Molecular diagnosis & therapy. 12/2013;
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    ABSTRACT: Hepatitis C virus-a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma-affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
    Molecular diagnosis & therapy. 09/2013;
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    ABSTRACT: Background Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. Methods We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. Results Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). Conclusions In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850 , respectively.).
    New England Journal of Medicine 04/2013; · 51.66 Impact Factor
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    ABSTRACT: Background The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. Methods In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Results Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome. Conclusions The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420 .).
    New England Journal of Medicine 03/2013; · 51.66 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation. Our aims were to determine the role of APOE regional polymorphisms on host lipids, IL28B genotype and disease severity in chronic HCV (CHC) patients. The study cohort included 732 CHC patients with available DNA for genotype determination of four polymorphisms in the chromosome 19 region that encompasses the TOMM40, APOE and APOC1 genes. Serum lipid analysis and apolipoproteins levels were measured using an immunoturbidimetric assay. APOE rs7412 polymorphism (capturing the ε2 isoform) was significantly associated with serum ApoE levels in both Caucasians and African-American patients (p = 2.3 × 10(-11)) and explained 7 % of variance in serum ApoE. Among IL28B-CC patients (n = 196), the rs429358 (defines ε4 isoform) and TOMM40 '523' S polymorphisms were associated with 12 % of variance in ApoB levels. Patients homozygous for the APOE ε3 isoform had a greater than twofold increased odds of F2-F4 fibrosis (p = 1.8 × 10(-5)), independent of serum lipid and lipoprotein levels. There were no associations between APOE polymorphisms and serum HDL-C, APO-CIII and triglycerides. In CHC patients, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region.
    Human Genetics 08/2012; · 4.63 Impact Factor
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    ABSTRACT: Label-free quantitative proteomics holds a great deal of promise for the future study of both medicine and biology. However, the data generated is extremely intricate in its correlation structure, and its proper analysis is complex. There are issues with missing identifications. There are high levels of correlation between many, but not all, of the peptides derived from the same protein. Additionally, there may be systematic shifts in the sensitivity of the machine between experiments or even through time within the duration of a single experiment. We describe a hierarchical model for analyzing unbiased, label-free proteomics data which utilizes the covariance of peptide expression across samples as well as MS/MS-based identifications to group peptides-a strategy we call metaprotein expression modeling. Our metaprotein model acknowledges the possibility of misidentifications, post-translational modifications and systematic differences between samples due to changes in instrument sensitivity or differences in total protein concentration. In addition, our approach allows us to validate findings from unbiased, label-free proteomics experiments with further unbiased, label-free proteomics experiments. Finally, we demonstrate the clinical/translational utility of the model for building predictors capable of differentiating biological phenotypes as well as for validating those findings in the context of three novel cohorts of patients with Hepatitis C. Mass-spectrometry proteomics is quickly becoming a powerful tool for studying biological and translational questions. Making use of all of the information contained in a particular set of data will be critical to the success of those endeavors. Our proposed model represents an advance in the ability of statistical models of proteomic data to identify and utilize correlation between features. This allows validation of predictors without translation to targeted assays in addition to informing the choice of targets when it is appropriate to generate those assays.
    BMC Bioinformatics 05/2012; 13:74. · 3.02 Impact Factor
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined. We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy. A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR). IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR. IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.
    Digestive Diseases and Sciences 04/2012; 57(8):2213-21. · 2.26 Impact Factor
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    ABSTRACT: Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. CONCLUSION: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.
    Hepatology 02/2012; 56(2):444-54. · 12.00 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P(adj) = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P(adj) = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P(adj) = 0.0015], 7DHC [Δ0.0075 mg/dL; P(adj) = 0.0026], lathosterol [Δ0.0430 mg/dL P(adj) = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). CONCLUSION: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.
    Hepatology 02/2012; 56(1):49-56. · 12.00 Impact Factor
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    ABSTRACT: The rapid growth of internet usage has led to an explosion of social networking sites for discussion of health issues. This provides a forum for subjects to communicate with one another during the course of the studies. Previous studies have raised concerns about the quality of health information on social networking sites, although none have evaluated content related to ongoing clinical trials. We reviewed material posted in virtual communities by self-identified clinical trial participants. We identified material posted in online health forums that could introduce bias into clinical research studies; we believe that this issue warrants further study and discussion. Physicians and others who conduct clinical trials should be aware of this issue. Study investigators and research teams should also talk to their study subjects about where and how they are obtaining information in order to prevent behaviors and correct misinformation that could put a subject's safety or the study objectives at risk. Given the rapid increase in Internet use for health care, a broader evaluation of both the benefits and potential risks of social networking among research participants during the course of a clinical trial appears warranted.
    Journal of Empirical Research on Human Research Ethics 02/2012; 7(1):71-80. · 1.49 Impact Factor
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    ABSTRACT: Hepatic elastography (HE) is a noninvasive technique that measures liver stiffness and is used to diagnose hepatic fibrosis. It can help patients who are thought to have early-stage disease avoid a staging liver biopsy, but only when confounding variables that increase liver stiffness are excluded. Chronic inflammation from hepatitis C virus (HCV) infection is not considered to be one of these variables. We identified 684 patients with HCV and METAVIR fibrosis scores of 0-2 from a prospective, multi-institutional study of liver stiffness in 2880 patients with chronic liver disease. Patients were 49.6 ± 9.0 years old, 64.3% were male, and they had an average body mass index of 26.7 ± 4.1 kg/m(2). In a multivariate analysis, inflammation (based on histologic analysis) and level of alanine aminotransferase (ALT) were associated with liver stiffness. The chances of a patient having a level of stiffness that indicates cirrhosis increased with grade of inflammation and level of ALT. By using a conservative 14.5-kPa cutoff for the diagnosis of cirrhosis, grade 3 inflammation had an odds ratio of 9.10 (95% confidence interval, 2.49-33.4). Likewise, levels of ALT greater than 80 and 120 IU/L had odds ratios of 3.84 (95% confidence interval, 2.10-7.00) and 4.10 (95% confidence interval, 2.18-7.69), respectively. The effect of the level of ALT persisted when analysis was restricted to patients with fibrosis scores of F0 to F1. In patients with HCV infection and early-stage fibrosis, increased levels of ALT correlate with liver stiffness among patients in the lowest strata of fibrosis (METAVIR scores 0-2). Patients without fibrosis but high levels of ALT could have liver stiffness within the range for cirrhosis. Inflammation should be considered a confounding variable in analysis of liver stiffness.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2012; 10(8):932-937.e1. · 5.64 Impact Factor
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    ABSTRACT: To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus (HCV) cohort. Patients with chronic HCV were randomized to receive interferon-based therapy for 24 (genotypes 2/3) or 48 (genotype 1) wk. FibroSURE™ (FS) was assessed at baseline and at week-12 post-treatment follow-up. Baseline biopsy for METAVIR was assessed by a single pathologist. FibroScan(®) transient elastography (TE) was performed during treatment in a patient subset. Two thousand and sixty patients (n = 253 in Asia) were classified as METAVIR F0-1 (n = 1682) or F2-4 (n = 378). For F2-4, FS (n = 2055) had sensitivity and specificity of 0.87 and 0.61, respectively, with area under the receiver-operating curve of 0.82; corresponding values for TE (n = 214) and combined FS/TE (n = 209) were 0.77, 0.88 and 0.88, and 0.93, 0.68 and 0.88. Overall FS/TE agreement for F2-4 was 71% (κ = 0.41) and higher in Asians vs non-Asians (κ = 0.86 vs 0.35; P < 0.001). Combined FS/TE had 97% accuracy in Asians (n = 33). Baseline FS (0.38 vs 0.51, P < 0.001) and TE (8.0 kPa vs 11.9 kPa, P = 0.006) scores were lower in patients with sustained virological response than in nonresponders, and were maintained through follow-up. FS and TE may reliably differentiate mild from moderate-advanced disease, with a potential for high diagnostic accuracy in Asians with chronic HCV.
    World Journal of Gastroenterology 11/2011; 17(41):4581-9. · 2.55 Impact Factor
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    ABSTRACT: Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.
    Gut 08/2011; 61(1):128-34. · 10.73 Impact Factor

Publication Stats

4k Citations
870.56 Total Impact Points

Institutions

  • 2008–2014
    • North Carolina Clinical Research
      Raleigh, North Carolina, United States
  • 2002–2013
    • Duke University Medical Center
      • • Department of Medicine
      • • Duke Clinical Research Institute
      • • Institute for Genome Sciences and Policy
      Durham, NC, United States
  • 2010–2012
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • University of Florida
      Gainesville, Florida, United States
  • 2006–2012
    • Duke University
      Durham, North Carolina, United States
  • 2008–2009
    • University of Leipzig
      Leipzig, Saxony, Germany
  • 2004
    • United HealthCare Services
      Chicago, Illinois, United States