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Dive into the research topics where Michael P. Curry is active.

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Featured researches published by Michael P. Curry.


The New England Journal of Medicine | 2015

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis

Michael P. Curry; Jacqueline G. O'Leary; Natalie Bzowej; Andrew J. Muir; K. M. Korenblat; Jonathan M. Fenkel; K.R. Reddy; E. Lawitz; Steven L. Flamm; T. Schiano; L. Teperman; R. Fontana; E. Schiff; Marvin P. Fried; B. Doehle; D. An; J. McNally; A. Osinusi; D. M. Brainard; J. G. McHutchison; Rosalind S. Brown; Michael R. Charlton

BACKGROUND As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).


Gastroenterology | 2015

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Michael P. Curry; Xavier Forns; Raymond T. Chung; Norah A. Terrault; Robert S. Brown; Jonathan M. Fenkel; Fredric D. Gordon; Jacqueline G. O’Leary; Alexander Kuo; Thomas D. Schiano; Gregory T. Everson; Eugene R. Schiff; Alex S. Befeler; Edward Gane; Sammy Saab; John G. McHutchison; G. Mani Subramanian; William T. Symonds; Jill Denning; Lindsay McNair; Sarah Arterburn; Evguenia Svarovskaia; Dilip K. Moonka; Nezam H. Afdhal

BACKGROUND & AIMS Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.


Gastroenterology | 2015

Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation

Michael R. Charlton; Edward Gane; Michael P. Manns; Robert S. Brown; Michael P. Curry; Paul Y. Kwo; Robert J. Fontana; Richard Gilroy; Lewis Teperman; Andrew J. Muir; John G. McHutchison; William T. Symonds; Diana M. Brainard; Brian J. Kirby; Hadas Dvory-Sobol; Jill Denning; Sarah Arterburn; Didier Samuel; Xavier Forns; Norah A. Terrault

BACKGROUND & AIMS Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.


The Journal of Infectious Diseases | 2002

CD4 T Helper Type 1 and Regulatory T Cells Induced against the Same Epitopes on the Core Protein in Hepatitis C Virus-Infected Persons

Angus J. MacDonald; Margaret Duffy; Miriam T. Brady; Susan McKiernan; William W. Hall; J. Hegarty; Michael P. Curry; Kingston H. G. Mills

The factors that determine persistence or clearance of hepatitis C virus (HCV) infection are poorly understood. The CD4 T cell responses to the HCV core protein were examined in a cohort of women infected with a single genotype of HCV. CD4 T cells from HCV-infected patients secreted interferon (IFN)-gamma in response to peptides from 4 immunodominant regions of the core protein, and these responses were stronger in persistently infected women. Interleukin (IL)-10 was also produced by CD4 T cells from HCV-infected subjects in response to the same core peptides. Furthermore, HCV core-specific CD4 T cell clones secreted either IFN-gamma or IL-10 but not IL-4. These findings demonstrate that T helper type 1 and regulatory T cells are induced against the same epitopes on the core protein during HCV infection.


Hepatology | 2004

Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source

Susan McKiernan; Richard Hagan; Michael P. Curry; George S.A. McDonald; Alan Kelly; Niamh Nolan; Anne Walsh; John P. Hegarty; Emer Lawlor; Dermot Kelleher

The role of cytotoxic T lymphocyte responses, restricted by human leukocyte antigen (HLA) class I alleles, is recognized as highly significant in the successful clearance of hepatitis C virus (HCV). The frequency of class I alleles in females inoculated with HCV genotype 1b from a single source was examined for an association with outcome. Class I typing was performed using polymerase chain reaction sequence‐specific primers in 227 female subjects: 141 had chronic infection and 86 had viral clearance. Statistical analysis included χ2 testing and multiple logistic regression analysis. A*03, B*27, and Cw*01 occurred more frequently in those with viral clearance (39.5%, 14%, and 9.3%, respectively) compared with those with chronic infection (19.1%, 2.1%, and 1.4%, respectively; P ≤ .005). B*08 occurred more often in those with chronic infection compared with viral clearance (39.7% vs. 19.8%; P = .002). In combination with previously reported class II allele associations, over 75% that successfully eliminate HCV carry either A*03, DRB1*0101, or *0401, compared with only 37% of those with chronic infection (P < .0001). The haplotypes A*03‐B*07‐DRB1*15‐DQB1*0602 and A*02‐B*27‐Cw*01‐DRB1*0101‐DQB1*0501 are associated with viral clearance (P = .004 and .01, respectively). By multiple logistic regression analysis, the alleles A*03, B*27, DRB1*0101, *0401, and *15 are associated with viral clearance, and B*27 has the strongest association (odds ratio [OR] 7.99). The haplotype A*01‐B*08‐Cw*07‐DRB1*03011‐DQB1*0201 is associated with chronic infection (P = .002), being independent for DQB1*0201 (OR 0.27). In conclusion, certain class I alleles are associated with outcome in this homogenous cohort. More significantly, either HLA‐A*03, ‐DRB1*0101, or ‐*0401 are carried by an overwhelming majority of those subjects who successfully clear HCV. (HEPATOLOGY 2004;40:108–114.)


The New England Journal of Medicine | 2017

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

Marc Bourlière; Stuart C. Gordon; Steven L. Flamm; Curtis Cooper; Alnoor Ramji; Myron J. Tong; Natarajan Ravendhran; John M. Vierling; Tram T. Tran; Stephen Pianko; Meena B. Bansal; Victor de Ledinghen; Robert H. Hyland; Luisa M. Stamm; Hadas Dvory-Sobol; Evguenia Svarovskaia; Jie Zhang; K.C. Huang; G. Mani Subramanian; Diana M. Brainard; John G. McHutchison; Elizabeth C. Verna; Peter Buggisch; Charles S. Landis; Ziad Younes; Michael P. Curry; Simone I. Strasser; Eugene R. Schiff; K. Rajender Reddy; Michael P. Manns

BACKGROUND Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct‐acting antiviral agents (DAAs) have limited retreatment options. METHODS We conducted two phase 3 trials involving patients who had been previously treated with a DAA‐containing regimen. In POLARIS‐1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. In POLARIS‐4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir‐velpatasvir‐voxilaprevir (163 patients) or sofosbuvir‐velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. RESULTS In the three active‐treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS‐1, the rate of sustained virologic response was 96% with sofosbuvir‐velpatasvir‐voxilaprevir, as compared with 0% with placebo. In POLARIS‐4, the rate of response was 98% with sofosbuvir‐velpatasvir‐voxilaprevir and 90% with sofosbuvir‐velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active‐treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS Sofosbuvir‐velpatasvir‐voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS‐1 and POLARIS‐4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)


Journal of Hepatology | 2002

Decrease in hepatic CD56+ T cells and Vα24+ natural killer T cells in chronic hepatitis C viral infection

Tina Deignan; Michael P. Curry; Derek G. Doherty; Lucy Golden-Mason; Yuri Volkov; Suzanne Norris; Niamh Nolan; O. Traynor; Gerry McEntee; J. Hegarty; Cliona O'Farrelly

BACKGROUND/AIMS The intrahepatic immune system is likely to play a key role in determining the outcome of hepatitis C virus (HCV) infection. The hepatic lymphocyte repertoire is characterised by high CD8/CD4 T cell ratios and large numbers of gamma delta T cells, natural killer (NK) cells, NK T cells and NK receptor-positive T cells. It is not known which of these populations contribute to immunity against HCV or immune pathology. METHODS To explore the relative contributions of lymphocyte subpopulations, we have compared the intrahepatic lymphocyte repertoires and cytokine expression in 13 patients with mild chronic hepatitis C infection, 14 with end-stage hepatitis C cirrhosis and five histologically normal livers by flow cytometry and immunohistochemistry. RESULTS CD4(+) T cells bearing alpha beta T cell receptors (TCR) were significantly expanded in livers with chronic HCV infection while CD56(+) alpha beta T cells and V alpha 24 TCR-positive T cells were significantly depleted. Expanded CD4(+)T cells were predominantly Th1 cells, producing interferon-gamma but not interleukin-4. CONCLUSIONS Failure to resolve HCV infection may be due to deficient innate and/or memory immune responses, while Th1 cells may mediate immune pathology.


Gastroenterology | 2012

Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon.

Josh Levitsky; Maria Isabel Fiel; John P. Norvell; Kymberly D. Watt; Michael P. Curry; Sumeet K. Tewani; Timothy M. McCashland; Maarouf Hoteit; Abraham Shaked; Samuel Saab; Amanda C. Chi; Amy Tien; Thomas D. Schiano

BACKGROUND & AIMS Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD) characterized by plasma cell hepatitis or rejection. METHODS We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG-IGD. Data from each patient were compared with those from 2 matched patients who did not develop PEG-IGD (n = 104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. RESULTS Overall incidence of PEG-IGD during a 10-year study period was 7.2%. Risk factors included no prior PEG therapy (odds ratio = 5.3; P < .0001), therapy with PEGα-2a (odds ratio = 4.7; P = .03), and immune features (mainly plasma cell hepatitis) on pre-PEG therapy liver biopsies (odds ratio = 3.9; P = .005). The PEG-IGD group had lower long-term patient (61.5% vs 91.3% of controls) and graft (38.5% vs 85.6% of controls) survival and higher rates of retransplantation (34.6% vs 6.7% of controls) (all, P < .0001), without increases in sustained virologic response. Variables associated with increased mortality included acute rejection as the PEG-IGD sub-type (hazard ratio [HR] = 2.4; P = .002), a high level of alkaline phosphatase at PEG initiation (HR = 1.003; P = .005), and lack of a sustained virologic response (HR = 3.3; P = .04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR = 1.002; P = .04) and lack of a sustained virologic response (HR = 2.1; P = .04). CONCLUSIONS PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.


Transplantation | 2008

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

Karen J. Ho; Christopher D. Owens; Scott R. Johnson; Khalid Khwaja; Michael P. Curry; Martha Pavlakis; Didier A. Mandelbrot; James J. Pomposelli; Shimul A. Shah; Reza F. Saidi; Dicken S.C. Ko; Sayeed K. Malek; John Belcher; David Hull; Stefan G. Tullius; Richard B. Freeman; Elizabeth A. Pomfret; James F. Whiting; Douglas W. Hanto; Seth J. Karp

Background. Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. Methods. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Results. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Conclusions. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.


Hepatology | 2004

Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV.

Camilla S. Graham; Michael P. Curry; Qi He; Nezam H. Afdhal; David Nunes; Catherine Fleming; Robert Horsburgh; Donald E. Craven; Kenneth E. Sherman; Margaret James Koziel

Persons with human immunodeficiency virus (HIV) and hepatits C virus (HCV) coinfection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV‐specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. We examined intrahepatic cellular immune responses to HCV antigens to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4‐enriched, liver‐infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon γ (IFN‐γ), tumor necrosis factor α (TNF‐α), and interleukin (IL) 10 was determined using enzyme‐linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN‐γ or TNF‐α in response to HCV or recall antigens. However, there was a significant increase in IL‐10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinfection. In conclusion, subjects with coinfection have an alteration of intrahepatic HCV‐specific IL‐10 cytokine response that may have implications for HCV‐related disease progression. (HEPATOLOGY 2004;40:125–132.)

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Nezam H. Afdhal

Beth Israel Deaconess Medical Center

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Kris V. Kowdley

Virginia Mason Medical Center

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Douglas W. Hanto

Beth Israel Deaconess Medical Center

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Douglas T. Dieterich

Icahn School of Medicine at Mount Sinai

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Michael R. Charlton

Intermountain Medical Center

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