Keyur Patel

Duke University Medical Center, Durham, North Carolina, United States

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Publications (118)967.01 Total impact

  • 12/2015; 2(2). DOI:10.5430/crcp.v2n2p89
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    ABSTRACT: miR-122 is the predominant liver miRNA that regulates hepatic lipid metabolism and inflammation. Hepatitis C virus (HCV) modulates host intracellular lipid metabolism. HCV stability and propagation also depend on an interaction between virus and miR-122. Our aims were to examine the associations between miR-122, apolipoproteins, and serum makers of fibrosis in chronic hepatitis C (CHC) patients. We evaluated baseline sera from 36 CHC genotype 1 patients who completed the Phase IIa study of miravirsen (LNA oligonucleotide targeting miR-122). Samples were assessed for liver transaminases, IL 28B genotype, IP-10, and lipid profiles. The noninvasive markers of liver fibrosis, APRI, and FIB-4, were calculated using standard formulae. miR-122 levels were measured using RT-PCR and expressed as fold-change compared to normal healthy controls. CHC patients were mostly male (61%) with mean age 47.5 ± 11.6 years. Patients with higher ApoB (ApoB/ULN ≥ 0.5) has significantly lower miR-122 levels in compared to patients with lower ApoB (ApoB/ULN < 0.5). (8.28 ± 6.23 vs. 16.28 ± 13.71; P = 0.02). There were no similar associations between miR-122 and ApoA-1 or between HCV RNA and lipoproteins. There were no differences in miR-122 levels between patients with different stages of fibrosis determined by APRI or FIB-4. Patients with lower ApoB had higher serum miR-122 levels. However, we cannot identify significant association between miR-122, ApoA-1, or fibrosis markers in this small cohort of CHC genotype 1 patients. The mechanism of HCV dyslipidemia is complex and could partly relate to the effect of miR-122 on lipid metabolism which requires further evaluation in a larger study. J. Med. Virol. 9999: 1-15, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2015; DOI:10.1002/jmv.24230 · 2.22 Impact Factor
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    ABSTRACT: Liver biopsy is invasive and associated with complications, sampling errors, and observer variability. Vibration-controlled transient elastography (VCTE) with FibroScan can be used to immediately assess liver stiffness (LS). We aimed to define optimal levels of LS to identify patients with chronic viral hepatitis and significant fibrosis, advanced fibrosis, or cirrhosis. In a prospective, 2-phase study, patients with chronic hepatitis C or B underwent VCTE followed by liver biopsy analysis from January 2005 through May 2008 at 6 centers in the US. In phase 1 we identified optimal levels of LS for identification of patients with stage F2-F4 or F4 fibrosis (the development phase, n=188). In phase 2 we tested these cut-off values in a separate cohort of patients (the validation phase, n=560). All biopsies were assessed for METAVIR stage by a single pathologist in the Phase 1 analysis and by a different pathologist in the Phase 2 analysis. Diagnostic performances of VCTE were assessed by area under the receiver operating characteristic curve (AUROC) analyses. In phase 1 of the study, LS measurements identified patients with ≥F2 fibrosis with an AUROC value of 0.89 (95% confidence interval [CI], 0.83-0.92), and identified patients with F4 fibrosis with an AUROC value of 0.92 (95% CI, 0.87-0.95). LS cut-off values (kPa) in phase 1 were 8.4 for ≥F2 (82% sensitivity, 79% specificity) and 12.8 for F4 (84% sensitivity, 86% specificity). In the phase 2 analysis, the LS cut-off values identified patients with ≥F2 fibrosis with 58% sensitivity (P<.0001 vs phase 1) and 75% specificity (non-significant difference vs phase 1); they identified patients with F4 fibrosis with 76% sensitivity (P<.0001 vs phase 1) and 85% specificity (non-significant differences vs phase 1). VCTE had an inter-observer agreement correlation coefficient of 0.98 (n=26), and an intra-observer agreement correlation coefficient of 0.95 (n=34). In a large US multicenter study, we confirmed that VCTE provides an accurate assessment of liver fibrosis in patients with chronic viral hepatitis. Our findings are similar to those from European and Asian cohorts. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 12/2014; 13(4). DOI:10.1016/j.cgh.2014.12.014 · 6.53 Impact Factor
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    ABSTRACT: Background & AimsFibrogenesis results in release of certain extracellular matrix protein fragments into the circulation. We evaluated the diagnostic and prognostic performance of two novel serological markers, the precisely cleaved N-terminal propeptide of type III collagen (Pro-C3) and a peptide of helical collagen type III degradation (C3M), in chronic hepatitis C (CHC) patients.Methods Pro-C3 and C3M were measured by ELISA in plasma from CHC patients (n=194) from a prior phase II antifibrotic trial (NCT00244751). Plasma samples and paired liver biopsies were obtained at baseline and after 1-year. Patients were stratified according to Ishak stages 2-4. Internal cross-validation was performed by bootstrap analysis.ResultsPro-C3 levels were significantly higher in CHC patients in Ishak stage 4 compared to stage 2 (p<0.001) or 3 (p<0.01). Pro-C3 could significantly distinguish moderate (stage 4) from mild fibrosis (stage 2/3) (AUC=0.72, p<0.001). Importantly, an overall significance in Pro-C3 (p=0.007) levels was observed between the groups of -1, 0, +1 and +2 change in Ishak stage at 12 months. Pro-C3 was significantly increased in group +1 (p=0.030) and +2 (p=0.021) compared to group 0. No significant differences were observed for C3M. In multivariate analysis, only baseline Pro-C3, but not FibroTest, had an independent association with fibrosis progression.Conclusions Pro-C3 is a useful test to predict fibrogenesis and monitor disease progression. Moreover, it could differentiate mild from moderate disease. Pro-C3 may become a promising blood parameter be included in future studies for monitoring disease progression and eventually for evaluation of potential antifibrotic therapies.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 10/2014; 35(2). DOI:10.1111/liv.12700 · 4.41 Impact Factor
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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; 61(3). DOI:10.1002/hep.27424 · 11.19 Impact Factor
  • Hepatology 08/2014; 60(2). DOI:10.1002/hep.27213 · 11.19 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; 12(12). DOI:10.1016/j.cgh.2014.04.037 · 6.53 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 05/2014; 7(1):107-114. DOI:10.2147/MDER.S46943
  • Keyur Patel, Nicholas A Shackel
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    ABSTRACT: Improved understanding of the pathophysiology of fibrosis and recent technological advances have resulted in the development of several serum biomarkers and imaging tools as noninvasive alternatives to biopsy. Most of these markers have been developed in chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) patients. This review highlights some of the recent advances and potential clinical application of these modalities. Many noninvasive approaches initially developed for binary disease staging in CHC continue to be refined for diagnostic use in other chronic liver disease such as NAFLD. A combination of serum markers and imaging tools appears useful in reducing the need for biopsy for the diagnosis of cirrhosis, and providing functional assessment in advanced stage disease. Cytokeratin-18 fragments, controlled attenuation parameter (CAP), real-time elastography, and magnetic resonance imaging approaches appear promising for NAFLD, but require further validation. Current noninvasive tests of fibrosis provide good diagnostic and prognostic utility for advanced stage liver disease, and have been adapted into clinical practice for CHC. Reliable biomarkers for steatosis, nonalcoholic steatohepatitis, and assessment of fibrosis progression in chronic liver disease are still required. Continued advances in bioimaging and functional genomics will be important for quantitative assessment of fibrosis and future biomarker development.
    Current opinion in gastroenterology 03/2014; 30(3). DOI:10.1097/MOG.0000000000000059 · 3.66 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; DOI:10.1042/CS20130473 · 5.63 Impact Factor
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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.
  • Julius Wilder, Keyur Patel
    North American journal of medicine & science 01/2014; 07(01):001. DOI:10.7156/v07i01p001
  • 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. DOI:10.1159/000360939 · 1.77 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.
    12/2013; DOI:10.1007/s40291-013-0072-1
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    ABSTRACT: Background: Hepatitis C (HCV) modulates the intrahepatic VLDL synthetic pathway as part of its natural life cycle. Chronic HCV (CHC) infection is associated with an altered metabolic state including dyslipidemia and insulin resistance, contributing to disease progression and reduced response to therapy. The interactions between HCV replication and host lipid pathways are incompletely understood. Methods: Sixty CHC genotype-1, treatment-naive patients were treated with 24 weeks of the HCV NS5B inhibitor sofosbuvir in combination with low or full dose ribavirin. Serum lipids and hemoglobin A1C (HbA1c) were measured at various time points. Targeted quantitative RT-PCR for lipid and glucose metabolism related genes was performed on paired liver biopsy specimens obtained from 7 patients before and at end-of treatment (EOT). Results: Of 55 patients who completed the study, 38 patients achieved a sustained virologic response (SVR24) and 17 patients relapsed after EOT. Between baseline and week 4 of therapy, LDL significantly increased (91 4 to 104 5 mg/dl, p=.0027) and triglycerides decreased (137 10 to 98 8 mg/dl, p<.0001) which persisted through EOT. Compared to patients who achieved SVR24, LDL was significantly lower in patients who eventually relapsed both at baseline (97 5 vs 78 7 mg/dl; p=0.031) and at week 48 (109 6 vs 82 7mg/dl; p=0.005), while there was no difference during or at EOT (Fig 1A). Triglycerides differed by treatment outcome only after EOT (Fig 1B). No changes in HDL were observed. HbA1C decreased significantly (5.58 to 5.45) in the 39 patients with paired values obtained at baseline and 24 weeks after EOT (p=0.0033) and this was independent of treatment outcome (Figure 1C). Intrahepatic gene expression of lipid transport genes (APOB, APOC3, APOL3) was significantly up-regulated, while lipid assembly and signaling genes (LEPR, MTTP) were down-regulated at EOT in 7 patients with paired liver biopsies (all achieved SVR24). Conclusion: Our data demonstrate changes in lipid metabolism pathways and glucose homeostasis in CHC genotype-1 infection following interferon-free antiviral therapy. The early changes in LDL and triglycerides associated with treatment implicate a direct effect of viral clearance on lipid homeostasis.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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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.
    09/2013; 18(1). DOI:10.1007/s40291-013-0053-4
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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; 368(20). DOI:10.1056/NEJMoa1214854 · 54.42 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; 368(18). DOI:10.1056/NEJMoa1209026 · 54.42 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; DOI:10.1007/s00439-012-1220-0 · 4.52 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 08/2012; 56(2):444-54. DOI:10.1002/hep.25647 · 11.19 Impact Factor

Publication Stats

5k Citations
967.01 Total Impact Points

Institutions

  • 2002–2015
    • Duke University Medical Center
      • • Department of Medicine
      • • Duke Clinical Research Institute
      Durham, North Carolina, United States
    • Bar Ilan University
      Gan, Tel Aviv, Israel
  • 2014
    • University of Sydney
      • Centenary Institute
      Sydney, New South Wales, Australia
  • 2008–2014
    • North Carolina Clinical Research
      Raleigh, North Carolina, United States
  • 2006–2014
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
  • 2009
    • Segal Institute for Clinical Research
      Miami, Florida, United States
  • 2004
    • United HealthCare Services
      Chicago, Illinois, United States
    • University of California, San Francisco
      • Division of Gastroenterology
      San Francisco, California, United States