Adrian M Di Bisceglie

Saint Louis University, Сент-Луис, Michigan, United States

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Publications (403)3865.43 Total impact

  • Journal of Hepatology 04/2015; 62:S685. DOI:10.1016/S0168-8278(15)31111-9 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S193. DOI:10.1016/S0168-8278(15)30014-3 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S652-S653. DOI:10.1016/S0168-8278(15)31042-4 · 10.40 Impact Factor
  • Jianguo Lin, Weihua Wang, Yanjuan Xu, Adrian M. Di Bisceglie, Xiaofeng Fan
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    ABSTRACT: In chronic hepatitis C virus (HCV) infection, combination therapy of peginterferon and ribavirin does not guarantee viral eradication. Among factors relevant to therapeutic efficacy, the role of humoral immunity has not been examined thoroughly. In the current study, HCV pseudoparticles (HCVpp) were first generated with 80 patient-derived full-length HCV envelope clones, followed by detailed characterization with regard to virus productivity, infectivity and neutralizing activity. Selective HCVpp were used to measure HCV neutralization titers in two independent patient cohorts consisting of 102 patients undergoing antiviral therapy. The HCV neutralization titers at the baseline fitted with a power-law distribution among patients. Pretreatment neutralization titers in both patient cohorts were not correlated with treatment outcomes. In the patient cohort 2 (n = 28) that had samples available at multiple time points, however, HCV neutralization titers displayed clearly distinct patterns over therapeutic course and follow-up. No virological responders (n = 10) had neutralization titers stabilized at low level while it was increased significantly in both sustained virological responders (n = 10) and relapsers (n = 8). High HCV neutralization titers were maintained only in sustained virological responders but not in relapsers after treatment cessation. Therefore, patterns of longitudinal change of HCV neutralization titers, but not pretreatment titers, correlate with the treatment outcome in patients undergoing peginterferon and ribavirin combination therapy. J. Med. Virol. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2015; 87(5). DOI:10.1002/jmv.24120 · 2.22 Impact Factor
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    ABSTRACT: BackgroundHCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres.AimTo assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients.Methods Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points.ResultsOf 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24–40) and 50% (95% CI: 44–56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42–50) and 60% (95% CI: 57–64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients.Conclusions In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811.
    Alimentary Pharmacology & Therapeutics 01/2015; 41(7). DOI:10.1111/apt.13095 · 4.55 Impact Factor
  • Anupam Mukherjee, Adrian M Di Bisceglie, Ratna B Ray
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    ABSTRACT: Hepatitis C virus (HCV) is a serious global health problem which establishes chronic infection in a significant number of infected humans worldwide. IFN and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients and the mechanism is not fully understood. MicroRNAs (miRNAs) have been implicated in the control of many biological processes including IFN signaling. To gain more insights on the role of cellular miRNAs in possible counter measures of HCV for suppression of host antiviral response, a miRNA array was performed using primary human hepatocytes (PHH) infected with in vitro cell culture grown HCV. A group of miRNAs were modulated in HCV infected PHH. We focused on miR-373 as this miRNA was significantly upregulated in HCV infected PHH. Here, we analyzed the function of miR-373 in context to HCV infection. HCV infection upregulates miR-373 expression in hepatocytes and HCV infected liver biopsy specimens. Further, we discovered that miR-373 directly targets Janus kinase1 (JAK1) and IFN regulating factor 9 (IRF9), important factors in the IFN signaling pathway. Upregulation of miR-373 by HCV also inhibited STAT1 phosphorylation, which is involved in ISGF3 complex formation and ISGs expression. Knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression, and reduced HCV RNA replication. Taken together, our results demonstrated that miR-373 is upregulated during HCV infection and negatively regulated type I IFN signaling pathway by suppressing JAK1 and IRF9. Our results offer a potential therapeutic approach for antiviral intervention. Chronic HCV infection is one of the major causes of end stage liver disease worldwide. Although recent introduction of DAA therapy is extremely encouraging, some infected individuals do not respond to this therapy. Further, these drugs target HCV nonstructural proteins and with selective pressure, virus may develop resistant strain. Therefore, understanding the impairment of IFN signals will help in designing additional therapeutic modalities. In this study, we provide evidence of HCV mediated upregulation of miR-373 and show that miR-373 impairs IFN signaling by targeting JAK1/IRF9 molecules. Knockdown of miR-373 inhibited HCV replication by upregulating interferon stimulating genes expression. Together, these results provided new mechanistic insights in understanding the role of miR-373 in HCV infection, and suggest a new potential target against HCV infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 01/2015; 89(6). DOI:10.1128/JVI.03085-14 · 4.65 Impact Factor
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    ABSTRACT: Reactivation of hepatitis B in the context of immunosuppressive therapy may be severe and potentially fatal. The FDA has recently drawn attention to the potentially fatal risk of hepatitis B reactivation in patients receiving the anti-CD20 agents, ofatumumab or rituximab. This action focuses attention on the broader issue of HBV reactivation which may occur with a wide variety of immunosuppressive therapies in benign or malignant disease. This manuscript summarizes the data behind this issue. These data support the recommendation that all patients undergoing chemotherapy, immunosuppressive therapy, HSCT or solid organ transplantation be screened for active or prior HBV infection by testing for HBsAg and anti-HBc in serum. Those who are found to be HBsAg positive should start appropriate antiviral therapy to prevent reactivation. Additionally, even those who have recovered from hepatitis B will benefit from antiviral therapy in certain circumstances because of the risks associated with a form of HBV reactivation referred to as reverse seroconversion. There remain many uncertain areas that warrant further study and further advances will benefit from close interactions between various medical specialties, regulatory agencies and researchers.CONCLUSIONS: There is good evidence to support routine screening of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment. Use of prompt antiviral treatment appears to diminish the risk of severe or fatal reactivation of hepatitis B. This article is protected by copyright. All rights reserved.
    Hepatology 11/2014; 61(2). DOI:10.1002/hep.27609 · 11.19 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV's sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.
    PLoS ONE 07/2014; 9(7):e103748. DOI:10.1371/journal.pone.0103748 · 3.53 Impact Factor
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    ABSTRACT: Objective To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. Methods In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n= 47), with ribavirin ('TRIPLE' regimen; n= 46), or with peginterferon+ribavirin ('QUAD' regimen; n= 59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. Results VX-222 (100 or 400mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ ribavirin, was 67% for TRIPLE (VX-222 400mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400mg twice daily, respectively). Conclusion These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy. (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
    European Journal of Gastroenterology & Hepatology 07/2014; 26(7):761-773. DOI:10.1097/MEG.0000000000000084 · 2.15 Impact Factor
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    ABSTRACT: Background & Aims TG4040 is a Modified Vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα /RBV) in patients with chronic HCV infection. Methods Treatment-naive patients with HCV genotype 1 infection were randomly assigned to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n=31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n=63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n=59). The primary endpoint was complete early virologic response (cEVR), defined as HCV RNA<10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. Results In group C, 64.2% of evaluable patients achieved cEVR, compared to 30.0% in group A and 45.9% in group B (P=.0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were predominantly observed in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα-associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. Conclusions A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared to patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.
    Gastroenterology 07/2014; 147(1). DOI:10.1053/j.gastro.2014.03.007 · 13.93 Impact Factor
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    Hangeun Kim, Keith Meyer, Adrian M Di Bisceglie, Ranjit Ray
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    ABSTRACT: We have previously reported that in vitro HCV infection of cells of hepatocyte origin attenuates complement system at multiple steps, and attenuation also occurs in chronically HCV infected liver, irrespective of the disease stage. However, none of these regulations alone completely impaired complement pathways. Modulation of the upstream proteins involved in proteolytic processing of the complement cascade prior to convertase formation is critical in promoting the function of the complement system in response to infection. Here, we examined the regulation of C2 complement expression in hepatoma cells infected in vitro with cell culture grown virus, and validated our observations using randomly selected chronically HCV infected patient liver biopsy specimens. C2 mRNA expression was significantly inhibited, and classical C3 convertase (C4b2a) decreased. In separate experiments for C3 convertase function, C3b deposition onto bacterial membrane was reduced using HCV infected patient sera as compared to uninfected control, suggesting impaired C3 convertase. Further, iC3b level, a proteolytically inactive form of C3b, was lower in HCV infected patient sera, reflecting impairment of both C3 convertase and Factor I activity. The expression level of Factor I was significantly reduced in HCV infected liver biopsy specimens, while Factor H level remained unchanged or enhanced. Together, these results suggested that inhibition of C3 convertase activity is an additional cumulative effect for attenuation of complement system adopted by HCV for weakening innate immune response.
    PLoS ONE 07/2014; 9(7):e101422. DOI:10.1371/journal.pone.0101422 · 3.53 Impact Factor
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    ABSTRACT: Background & Aims Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the US and Canada might be disproportionately affected. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network. Methods The HBRN collected data on clinical characteristics of 1625 adults with chronic HBV infection who are not receiving antiviral therapy from 21 clinical centers in North America. Results Half of the subjects in the HBRN are male, and the mean age is 42 years; 72% are Asian, 15% are Black, and 11% are White, with 82% born outside of North America. The most common HBV genotype was B (39%); 745 of subjects were negative for the hepatitis B e antigen. The median serum level of HBV DNA when the study began was 3.6 log10 IU/mL; 68% of male subjects and 67% of female subjects had levels of alanine aminotransferase above the normal range. Conclusions The HBRN cohort will be used to address important clinical and therapeutic questions for North Americans infected with chronic HBV and to guide health policies on HBV prevention and management in North America.
    Clinical Gastroenterology and Hepatology 07/2014; DOI:10.1016/j.cgh.2014.06.028 · 6.53 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is a highly mutable RNA virus and circulates as a heterogeneous population in individual patients. The magnitude of such population heterogeneity has long been proposed to be linked with diverse clinical phenotypes, including antiviral therapy. Yet data accumulated thus far are fairly inconclusive. By the integration of long RT-PCR with 454 sequencing, we have built a pipeline optimized for the quantification of HCV genome-wide mutation load at 1% resolution of mutation frequency, followed by a retrospective study to examine the role of HCV mutation load in peginterferon-alpha2a and ribavirin combination antiviral therapy. Genome-wide HCV mutation load varied widely with a range from 92 to 1639 mutations and presented a Poisson distribution among 56 patients (Kolmogorov-Smirnov statistic = 0.078, p = 0.25). Patients achieving sustained virological response (n = 26) had significantly lower mutation loads than that in null responders (n = 30) (mean and standard derivation: 524±279 vs. 805±271, p = 0.00035). All 36,818 mutations detected in 56 patients displayed a power-law distribution in terms of mutation frequency in viral population. The low-frequency mutation load, but not the high-frequency load, was proportional firmly to the total mutation load. In-depth analyses revealed that intra-patient HCV population structure was shaped by multiple factors, including immune pressure, strain difference and genetic drift. These findings explain previous conflicting reports using low-resolution methods and highlight a dominant role of natural selection in response to therapeutic intervention. By attaining its signatures from complex interaction between host and virus, the high-resolution quantification of HCV mutation load predicts outcomes from interferon-based antiviral therapy and could also be a potential biomarker in other clinical settings.
    PLoS ONE 06/2014; 9(6):e100131. DOI:10.1371/journal.pone.0100131 · 3.53 Impact Factor
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    ABSTRACT: Background Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. Methods We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. Conclusions Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286 .).
    New England Journal of Medicine 04/2014; 370(16). DOI:10.1056/NEJMoa1316366 · 54.42 Impact Factor
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    ABSTRACT: Background In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin. Methods We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin. Results A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively. Conclusions Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415 .).
    New England Journal of Medicine 04/2014; 370(17). DOI:10.1056/NEJMoa1401561 · 54.42 Impact Factor
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    ABSTRACT: Background High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. Methods In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. Results The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. Conclusions Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330 .).
    New England Journal of Medicine 04/2014; 370(20). DOI:10.1056/NEJMoa1402355 · 54.42 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S45. DOI:10.1016/S0168-8278(14)60111-2 · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S1. DOI:10.1016/S0168-8278(14)60003-9 · 10.40 Impact Factor
  • Adrian M Di Bisceglie
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; DOI:10.1016/j.cgh.2013.11.027 · 6.53 Impact Factor
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    ABSTRACT: Currently, a surgical approach is the best curative treatment for those with hepatocellular carcinoma (HCC). However, this requires HCC detection and removal of the lesion at an early stage. Unfortunately, most cases of HCC are detected at an advanced stage because of the lack of accurate biomarkers that can be used in the surveillance of those at risk. It is believed that biomarkers that could detect HCC early will play an important role in the successful treatment of HCC. In this study, we analyzed serum levels of alpha fetoprotein, Golgi protein, fucosylated alpha-1-anti-trypsin, and fucosylated kininogen from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. We utilized two different methods, namely, stepwise penalized logistic regression (stepPLR) and model-based classification and regression trees (mob), along with the inclusion of clinical and demographic factors such as age and gender, to determine if these improved algorithms could be used to increase the detection of cancer. The performance of multiple biomarkers was found to be better than that of individual biomarkers. Using several statistical methods, we were able to detect HCC in the background of cirrhosis with an area under the receiver operating characteristic curve of at least 0.95. stepPLR and mob demonstrated better predictive performance relative to logistic regression (LR), penalized LR and classification and regression trees (CART) used in our prior study based on three-fold cross-validation and leave one out cross-validation. In addition, mob provided unparalleled intuitive interpretation of results and potential cut-points for biomarker levels. The inclusion of age and gender improved the overall performance of both methods among all models considered, while the stratified male-only subset provided the best overall performance among all methods and models considered. In addition to multiple biomarkers, the incorporation of age and gender into statistical models significantly improved their predictive performance in the detection of HCC.
    BMC Medical Genomics 11/2013; 6 Suppl 3(Suppl 3):S9. DOI:10.1186/1755-8794-6-S3-S9 · 3.91 Impact Factor

Publication Stats

23k Citations
3,865.43 Total Impact Points

Institutions

  • 2001–2015
    • Saint Louis University
      • • Department of Internal Medicine
      • • Division of Gastroenterology & Hepatology
      Сент-Луис, Michigan, United States
  • 1994–2014
    • Washington University in St. Louis
      • Division of Gastroenterology
      San Luis, Missouri, United States
  • 1995–2013
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 2004–2012
    • St Louis University Hospital
      San Luis, Missouri, United States
    • University of Texas Southwestern Medical Center
      • Division of Digestive and Liver Diseases
      Dallas, Texas, United States
    • Centers for Disease Control and Prevention
      • Division of Viral Hepatitis
      Druid Hills, GA, United States
  • 2011
    • St. Luke's Hospital (MO, USA)
      Сент-Луис, Michigan, United States
  • 2010
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 1988–1999
    • National Institutes of Health
      • • Branch of Digestive Diseases (DDB)
      • • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 1988–1997
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 1991
    • Northern Inyo Hospital
      BIH, California, United States
  • 1990
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 1989
    • Georgetown University
      • Department of Microbiology and Immunology
      Washington, Washington, D.C., United States