132 results on '"Eyster ME"'
Search Results
2. Correction to: DOAC compared with warfarin for VTE in patients with obesity: a retrospective cohort study conducted through the VENUS network.
- Author
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Martin KA, Lancki N, Li C, Eyster ME, Sanfilippo K, Woller IA, Woller SC, Kreuziger LB, and Rosovsky RP
- Published
- 2023
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3. DOAC compared with warfarin for VTE in patients with obesity: a retrospective cohort study conducted through the VENUS network.
- Author
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Martin KA, Lancki N, Li C, Eyster ME, Sanfilippo K, Woller IA, Woller SC, Kreuziger LB, and Rosovsky RP
- Subjects
- Adult, Humans, Anticoagulants adverse effects, Retrospective Studies, Rivaroxaban adverse effects, Hemorrhage chemically induced, Hemorrhage drug therapy, Obesity complications, Obesity drug therapy, Administration, Oral, Warfarin adverse effects, Venous Thromboembolism etiology, Venous Thromboembolism chemically induced
- Abstract
The effectiveness and safety of direct oral anticoagulants (DOAC) compared with warfarin remains uncertain in obese patients. We assessed the comparative effectiveness and safety of DOACs with warfarin for the treatment of VTE among obese patients. This multi-center retrospective cohort study included adults with a BMI ≥ 35 kg/m
2 or weight ≥ 120 kg prescribed either DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin for a VTE diagnosis. The primary outcome was the 12-month rate of recurrent VTE. The secondary outcome was the 12-month rate of major bleeding. Among 5626 patients, 67% were prescribed warfarin and 33% were prescribed a DOAC. The 12-month VTE recurrence rate was 3.6% (67/1823) for patients treated with DOAC compared with 3.8% (143/3664) for patients treated with warfarin [odds ratio for recurrent VTE on warfarin versus DOAC (OR) (95% CI).07 (0.80, 1.45)]. The 12-month major bleeding rate was 0.5% (10/1868) for patients on DOAC versus 2.4% (89/3758) on warfarin [OR 4.25 (2.19, 8.22)]. Similar proportions of recurrent VTE occurred across BMI thresholds on DOAC and warfarin: for BMI ≥ 35 kg/m2 (N = 5412), 3.6% versus 3.8%, respectively [OR 1.08 (0.80, 1.46)]; for BMI ≥ 40 kg/m2 (N = 2321), 4.4% versus 3.5%, respectively [OR 0.80 (0.51, 1.26)]; and for BMI ≥ 50 kg/m2 (N = 560), 3.1% versus 3.7%, respectively [OR 1.18 (0.39, 3.56)]. Similar proportions of recurrent VTE occurred in patients with obesity treated for VTE with DOACs and warfarin. DOACs were associated with lower major bleeding compared to warfarin in patients with obesity and VTE., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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4. Physician perceptions and use of reduced-dose direct oral anticoagulants for extended phase venous thromboembolism treatment.
- Author
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Groat D, Martin KA, Rosovsky RP, Sanfilippo KM, Gaddh M, Kreuziger LB, Eyster ME, and Woller SC
- Abstract
Background: The direct oral anticoagulants (DOACs), apixaban and rivaroxaban, have been studied for extended-phase treatment of venous thromboembolism (VTE). Yet, scant evidence exists surrounding clinician practice and decision-making regarding dose reduction., Aims: Report clinician practice and characteristics surrounding dose reduction of DOACs for extended-phase VTE treatment., Methods: We conducted a 16-question REDCap survey between July 14, 2021, and September 13, 2021, among ISTH 2021 Congress attendees and on Twitter. We explored factors associated with dose reduction using logistic regression. We used k-means clustering to identify distinct groups of dose-reduction decision-making. Random forest analysis explored demographics with respect to identified groups., Results: Among 171 respondents, most were attending academic physicians from North America. Clinicians who treated larger volumes of patients had higher odds of dose reduction. We identified five clusters that showed distinct patterns of behavior regarding dose reduction. Cluster 1 rarely dose reduces and likely prescribes rivaroxaban over apixaban; cluster 2 dose reduces frequently, does not consider age when dose-reducing, is least likely to temporarily reescalate dosing, and prescribes apixaban and rivaroxaban equally; cluster 3 dose reduces <50% of the time, and temporarily reescalates dosing during increased VTE risk; cluster 4 dose reduces frequently, temporarily reescalates dosing, and is most likely to prescribe apixaban over rivaroxaban; and cluster 5 dose reduces most frequently, and takes the fewest risk factors into consideration when deciding to dose reduce., Conclusions: Most clinicians elect to dose-reduce DOACs for extended-phase anticoagulation. The likelihood of a clinician to dose reduce increases with volume of patients treated. Clinician prescribing patterns cluster around VTE risk factors as well as reescalation during high-risk periods., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
- Published
- 2022
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5. Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study.
- Author
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Kleiboer B, Layer MA, Cafuir LA, Cuker A, Escobar M, Eyster ME, Kraut E, Leavitt AD, Lentz SR, Quon D, Ragni MV, Thornhill D, Wang M, Key NS, and Buckner TW
- Subjects
- Anticoagulants therapeutic use, Humans, Postoperative Complications prevention & control, Postoperative Hemorrhage prevention & control, Prospective Studies, Retrospective Studies, Antifibrinolytic Agents, Arthroplasty, Replacement, Hip adverse effects, Hemophilia A complications, Hemophilia A drug therapy, Venous Thromboembolism prevention & control
- Abstract
Background: Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function., Objectives: This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA)., Patients/methods: We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24-h period, or transfusion of two or more units of packed red blood cells., Results: One hundred thirty-one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non-use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk., Conclusions: The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk., (© 2022 International Society on Thrombosis and Haemostasis.)
- Published
- 2022
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6. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.
- Author
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George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, and High KA
- Subjects
- Adolescent, Adult, Follow-Up Studies, Genotype, Glucocorticoids adverse effects, Glucocorticoids therapeutic use, Hemophilia A genetics, Hemophilia A prevention & control, Hepatocytes metabolism, Humans, Immunosuppression Therapy, Male, Middle Aged, Young Adult, Dependovirus, Factor VIII genetics, Factor VIII metabolism, Genetic Therapy, Genetic Vectors, Hemophilia A blood
- Abstract
Background: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose., Methods: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 10
11 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII., Results: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration)., Conclusions: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.)., (Copyright © 2021 Massachusetts Medical Society.)- Published
- 2021
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7. Diagnosing dehydrated hereditary stomatocytosis due to a KCNN4 Gardos channel mutation: understanding challenges through study of a multi-generational family.
- Author
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Waldstein S, Arnold-Croop S, Carrel L, and Eyster ME
- Abstract
Competing Interests: The authors have declared no conflict of interest.
- Published
- 2021
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8. Prothrombotic variants as modifiers of clinical phenotype in four related individuals with haemophilia A.
- Author
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Carrel L, Arnold-Croop S, Achtermann T, Chen F, Cheng Y, Liu D, and Eyster ME
- Subjects
- Humans, Phenotype, Hemophilia A complications, Hemophilia A genetics
- Published
- 2021
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9. Investigation of discordant phenotype in mild Hemophilia A using whole exome sequencing.
- Author
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Cygan PH, Arnold-Croop SE, Weidman EA, Chen F, Liu DJ, Eyster ME, and Carrel L
- Subjects
- Factor VIII genetics, Humans, Phenotype, Hemophilia A genetics, Exome Sequencing
- Abstract
Competing Interests: Declaration of competing interest The authors state that they had no interests which might be perceived as posing a conflict or bias. M.E. Eyster has received research support from Bayer, Baxalta, Spark Therapeutics, Novo Nordisk, and Sanofi.
- Published
- 2020
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10. Total knee replacement with and without emicizumab: a unique comparison of perioperative management.
- Author
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Evans MS, Davis C, and Eyster ME
- Published
- 2020
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11. A novel type 2N VWF gene mutation: a case report.
- Author
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Evans MS and Eyster ME
- Subjects
- Diagnosis, Differential, Genetic Testing, Hemorrhage, Humans, Male, Mutation, Hemophilia A diagnosis, von Willebrand Disease, Type 2 diagnosis, von Willebrand Factor genetics
- Abstract
: Men and boys who present with bleeding associated with low factor VIII levels and normal von Willebrand studies are assumed to have hemophilia A until proven otherwise. However, routinely available coagulation assays cannot easily distinguish mild hemophilia A from the 2N variant of von Willebrand disease. We present a case that highlights the difficulties of recognizing this diagnosis, the role of genetic testing, and the identification of a 2N variant that has not been previously described.
- Published
- 2018
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12. A cross-sectional analysis of cardiovascular disease in the hemophilia population.
- Author
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Sood SL, Cheng D, Ragni M, Kessler CM, Quon D, Shapiro AD, Key NS, Manco-Johnson MJ, Cuker A, Kempton C, Wang TF, Eyster ME, Kuriakose P, von Drygalski A, Gill JC, Wheeler A, Kouides P, Escobar MA, Leissinger C, Galdzicka S, Corson M, Watson C, and Konkle BA
- Subjects
- Aged, Cross-Sectional Studies, Female, Hemophilia A complications, Hemophilia B complications, Humans, Male, Middle Aged, Electrocardiography, Hemophilia A epidemiology, Hemophilia B epidemiology, Myocardial Infarction epidemiology, Myocardial Infarction etiology, Myocardial Infarction physiopathology, Stroke epidemiology, Stroke etiology, Stroke physiopathology
- Abstract
Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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13. Development of an inhibitor in a man with mild haemophilia A.
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Evans MS and Eyster ME
- Subjects
- Aged, 80 and over, Factor VIII immunology, Factor VIII therapeutic use, Humans, Male, Hemophilia A drug therapy, Hemophilia A immunology, Isoantibodies immunology
- Published
- 2017
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14. Development of a novel automated screening method for detection of FVIII Inhibitors.
- Author
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Evans MS, Donaldson KJ, and Eyster ME
- Subjects
- Automation, Blood Coagulation Tests, Factor VIII analysis, Factor VIII immunology, Female, Hemophilia A diagnosis, Humans, Male, Predictive Value of Tests, Sensitivity and Specificity, Autoantibodies blood, Factor VIII antagonists & inhibitors, High-Throughput Screening Assays methods
- Abstract
Introduction: Factor VIII activity is routinely determined by measuring the activated partial thromboplastin time (aPTT) of a patient plasma sample and determining percent activity from a standard curve. To maximize the detection of a clotting factor inhibitor, a subjective assessment of parallelism of a patient curve compared with a standard curve is performed. We developed and validated an automated objective method to assess parallelism as a rapid screening tool for detection of an inhibitor to factor VIII during routine FVIII assays., Methods: We performed FVIII assays on a subset of FVIII-deficient patients with hemophilia A with and without inhibitors. Utilizing a ratio of the slopes from parallelism curves obtained by an independent Microsoft excel program in patients compared with a normal standard curve, we determined a cutoff ratio predictive for presence of an inhibitor., Results: A cutoff ratio of patient to control slopes of <0.45 for the detection of an inhibitor to FVIII was 100% sensitive and 91.6% specific, with a positive predictive value of 92.3% and a negative predictive value of 100%., Conclusion: Utilizing a ratio of the slopes from parallelism curves in patients with and without an inhibitor, we developed and validated a rapid, automated, and objective method to assess parallelism as an added screening tool for detection of an inhibitor to factor VIII during routine FVIII assays on a STAGO-based coagulation platform. This simple automated method has the potential to detect inhibitors to other clotting factors., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2017
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15. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.
- Author
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Reding MT, Ng HJ, Poulsen LH, Eyster ME, Pabinger I, Shin HJ, Walsch R, Lederman M, Wang M, Hardtke M, and Michaels LA
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- Adolescent, Adult, Aged, Body Weight, Child, Drug Administration Schedule, Half-Life, Humans, Male, Middle Aged, Patient Safety, Protein Domains, Severity of Illness Index, Treatment Outcome, Young Adult, Factor VIII pharmacology, Hemophilia A drug therapy, Hemorrhage drug therapy, Polyethylene Glycols pharmacology
- Abstract
Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg
-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds., (© 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)- Published
- 2017
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16. Moderate X-chromosome inactivation skewing underlies factor VIII activity in symptomatic carriers from a family with mild haemophilia A.
- Author
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Cygan PH, Carrel L, and Eyster ME
- Subjects
- Humans, Factor VIII genetics, Hemophilia A genetics, X Chromosome Inactivation genetics
- Published
- 2016
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17. Long term survival in persons with hemophilia and chronic hepatitis C: 40 year outcomes of a large single center cohort.
- Author
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Eyster ME, Kong L, Li M, and Schreibman IR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antiviral Agents therapeutic use, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Follow-Up Studies, HIV Infections mortality, Hemophilia A therapy, Hemorrhage, Hepatitis C, Chronic mortality, Humans, Infant, Male, Middle Aged, Survival Rate, Treatment Outcome, Young Adult, von Willebrand Diseases, HIV Infections drug therapy, Hemophilia A complications, Hepatitis C, Chronic drug therapy
- Abstract
We studied the course of chronic HCV infections in a cohort of 222 persons with hemophilia (PWH) and von Willebrand disease followed at our center since 1973. Twenty two (10%) developed end stage liver disease (ESLD). Forty years after HCV infection, cumulative incidence of ESLD was 12.3% and overall survival was 45.5%. Those who were infected with HCV only (n = 100) had a survival of 75.2%, while those infected with HIV (n = 122) had a survival of 24% (P < 0.001). Survivals were significantly longer for those infected with HCV at younger age (< 15 years) compared to those infected over age 30 years (P = 0.014). Cause specific deaths for ESLD and bleeding were 8.8% and 8.3% respectively. For HIV negative subjects, the annual hazard of death from ESLD and bleeding was near zero for the first 10 years, and then rose slowly over the next 20 years to 0.4/100py for ESLD and 0.2/100py for bleeding. Sixty subjects completed 79 treatment episodes. Sustained viral response rates increased from 7/21 (33%) between 1990 and 2001, to 17/29 (58%) between 2002 and 2011, and to 27/29 (93%), since 2012 with the advent of the directly acting antiviral agents. These results confirm the very slow ESLD progression rate in HIV negative PWH. However, the risk of death from both ESLD and bleeding increases steadily with longer duration of HCV infection. More aggressive surveillance to detect those with early fibrosis is needed now that curative treatment is possible in >95% of individuals. Am. J. Hematol. 91:E335-E340, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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18. Prospective, multicenter study of postoperative deep-vein thrombosis in patients with haemophilia undergoing major orthopaedic surgery.
- Author
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Buckner TW, Leavitt AD, Ragni M, Kempton CL, Eyster ME, Cuker A, Lentz SR, Ducore J, Leissinger C, Wang M, and Key NS
- Subjects
- Adult, Arthroplasty, Replacement, Hip adverse effects, Arthroplasty, Replacement, Knee adverse effects, Cohort Studies, Hemophilia A therapy, Hemophilia B therapy, Humans, Male, Middle Aged, Postoperative Complications prevention & control, Postoperative Hemorrhage etiology, Postoperative Hemorrhage prevention & control, Prospective Studies, Venous Thromboembolism etiology, Venous Thromboembolism prevention & control, Venous Thrombosis diagnostic imaging, Venous Thrombosis prevention & control, Hemophilia A complications, Hemophilia A surgery, Hemophilia B complications, Hemophilia B surgery, Postoperative Complications etiology, Venous Thrombosis etiology
- Abstract
Perioperative clotting factor replacement is administered to reverse the inherent haemostatic defect in persons with haemophilia (PWH), potentially increasing their risk for developing venous thromboembolism (VTE) postoperatively. It was our objective to determine the prevalence of VTE in PWH undergoing total hip or knee arthroplasty (THA, TKA). Patients with haemophilia A or B who underwent THA or TKA were enrolled in this prospective, multicentre observational cohort study. Lower extremity venous duplex ultrasound was performed prior to surgery and 4-6 weeks after surgery. Eleven centres enrolled 51 subjects, 46 of whom completed the study. Six subjects (13.0 %) were treated with bypass agents perioperatively; the remaining 40 subjects received factor VIII or IX replacement. Intermittent pneumatic compression devices were utilised postoperatively in 23 subjects (50 %), and four subjects (8.7 %) also received low-molecular-weight heparin prophylaxis. One subject (2.2 %) with moderate haemophilia A was diagnosed with symptomatic distal deep-vein thrombosis (DVT) on day 6 following TKA. One subject (2.2 %) with severe haemophilia A was diagnosed with pulmonary embolism on day 9 following bilateral TKA. No subjects had asymptomatic DVT. Eighteen subjects (39.1 %) had major bleeding, and three subjects (6.5 %) experienced minor bleeding. The observed prevalence of ultrasound-detectable, asymptomatic DVT in PWH following TKA or THA in this study was low, but the incidence of symptomatic VTE (4.3 %, 95 % CI, 0.5-14.8 %) appeared similar to the estimated incidence in the general population without thromboprophylaxis.
- Published
- 2016
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19. Anemia and the Need for Intravenous Iron Infusion after Roux-en-Y Gastric Bypass.
- Author
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Kotkiewicz A, Donaldson K, Dye C, Rogers AM, Mauger D, Kong L, and Eyster ME
- Abstract
The frequency of anemia, iron deficiency, and the long-term need for IV iron following Roux-en-y gastric bypass (RYGB) surgery has not been well characterized. Three-hundred and nineteen out of 904 consecutive subjects who underwent RYGB at Penn State Hershey Medical Center from 1999 to 2006 met the inclusion criteria for a preoperative complete blood count (CBC) and at least one CBC >6 months following surgery. Cumulative incidence of anemia 7 years post procedure was 58%. Menstruation status and presence of preoperative anemia were predictive of anemia by univariate analysis and multivariable Cox regression (P = 0.0014 and 0.044, respectively). Twenty-seven subjects, primarily premenopausal women, representing 8.5% of the cohort and 22% of the 122 anemic subjects, needed intravenous (IV) iron a mean of 51 months postoperatively for anemia unresponsive or refractory to oral iron. The risk for development of anemia necessitating IV iron therapy following RYGB is highest in menstruating women and continues to increase for many years, even in post-menopausal women. Well-designed prospective studies are needed to identify the incidence of iron deficiency anemia and the patient populations at increased risk for requiring IV iron replacement after RYGB surgery.
- Published
- 2015
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20. Evaluation of von Willebrand factor phenotypes and genotypes in Hemophilia A patients with and without identified F8 mutations.
- Author
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Boylan B, Rice AS, De Staercke C, Eyster ME, Yaish HM, Knoll CM, Bean CJ, and Miller CH
- Subjects
- Adolescent, Adult, Biomarkers blood, Blood Coagulation Tests, Case-Control Studies, Child, DNA Mutational Analysis, Factor VIII metabolism, Genetic Predisposition to Disease, Hemophilia A blood, Hemophilia A diagnosis, Hemorrhage blood, Hemorrhage diagnosis, Hemorrhage genetics, Heterozygote, Homozygote, Humans, Male, Phenotype, Predictive Value of Tests, Protein Binding, United States, Young Adult, von Willebrand Factor metabolism, Blood Coagulation genetics, Factor VIII genetics, Hemophilia A genetics, Mutation, von Willebrand Factor genetics
- Abstract
Background: Hemophilia A (HA) is an X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII). von Willebrand disease (VWD) is characterized by a quantitative or qualitative defect in von Willebrand factor (VWF). Patients with VWD with severely low VWF or VWD Type 2N (VWD2N), a VWD subtype distinguished by defective VWF binding to FVIII, may have reduced FVIII levels secondary to their VWD. These patients superficially resemble patients with HA and pose a potential for misdiagnosis., Objectives: To investigate the unexplained cause of bleeding in HA patients without known FVIII mutations by assessing plasma VWF antigen (VWF:Ag), FVIII binding capacities and VWF genotypes., Patients/methods: Thirty-seven of 1027 patients with HA studied as part of the Hemophilia Inhibitor Research Study lacked identifiable F8 mutations. These patients (cases) and 73 patients with identified F8 mutations (controls) were evaluated for VWF:Ag, a patient's VWF capacity to bind FVIII (VWF:FVIIIB) and VWF sequence., Results: Four cases had VWF:Ag < 3 IU dL(-1) and VWF mutations consistent with Type 3 VWD. Six cases and one control were heterozygous for mutations previously reported to cause Type 1 VWD (VWD1) (n = five cases and one control) or predicted to be deleterious by Polyphen2 and SIFT prediction tools (n = 1 case). One control had VWF:Ag < 30 IU dL(-1) and seven patients (four cases and three controls), including two cases who were heterozygous for a known VWD2N mutation, had reduced VWF:FVIIIB., Conclusions: These data emphasize that some patients diagnosed with HA require VWF assessments in order to achieve a comprehensive diagnosis and an optimal treatment strategy., (© 2015 International Society on Thrombosis and Haemostasis.)
- Published
- 2015
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21. Correlates of high hepatitis C virus RNA load in a cohort of HIV-negative and HIV-positive individuals with haemophilia.
- Author
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Gadalla SM, Preiss LR, Eyster ME, and Goedert JJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, HIV Infections blood, HIV Infections drug therapy, Hemophilia A blood, Hepatitis C blood, Humans, Liver Function Tests, Logistic Models, Lymphocyte Count, Male, Middle Aged, Platelet Count, Viral Load, Viremia blood, Viremia virology, Young Adult, HIV isolation & purification, HIV Infections virology, Hemophilia A virology, Hepacivirus genetics, Hepatitis C virology, RNA, Viral blood
- Abstract
Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV-RNA load. Correlates of high HCV-RNA load in individuals with haemophilia are largely unknown. Among 1266 interferon naïve HCV-infected individuals with haemophilia, we compared those with high (> 2 x 10⁶ HCV-RNA copies/mL) to lower viral load, overall and stratifying on HIV co-infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Overall, high HCV load was independently associated with longer duration of HCV infection (P(trend)=0.0001), body mass index ≥ 25 kg/m² (OR=1.4, 95% CI=1.1-1.9), and HIV co-infection (OR=1.4, 95% CI=1.0-1.8). Among 795 HIV-negative participants, high HCV-RNA load was associated with older age at HCV acquisition (OR=1.9 for > 15 years vs ≤ 2 years, P(trend)=0.008), and lower AST/platelet ratio (P(trend)=0.01), in addition to longer duration of HCV infection (P(trend)=0.0008), and body mass index ≥ 25 kg/m² (OR=1.6, P=0.005). Among 471 HIV-positive individuals, anti-retroviral therapy (ART) was the only variable associated with high HCV-RNA load (OR=1.8, CI=1.1-2.9 for combination ART; OR=1.8, CI=0.9-3.4, for other ART vs no treatment). High HCV-RNA load with haemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end-stage liver disease., (© 2010 Blackwell Publishing Ltd.)
- Published
- 2011
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22. Coping with the HIV epidemic 1982-2007: 25-year outcomes of the Hershey Haemophilia Cohort.
- Author
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Eyster ME
- Subjects
- Adult, Child, Cohort Studies, Disease Outbreaks, HIV Infections complications, HIV Infections transmission, Hemophilia A complications, Humans, Male, Pennsylvania epidemiology, Prognosis, Survival Analysis, Transfusion Reaction, HIV Infections epidemiology, Hemophilia A epidemiology
- Published
- 2008
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23. Chronic hepatitis B and other correlates of spontaneous clearance of hepatitis C virus among HIV-infected people with hemophilia.
- Author
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Melendez-Morales L, Konkle BA, Preiss L, Zhang M, Mathew P, Eyster ME, and Goedert JJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, CD4 Lymphocyte Count, Female, HIV Infections immunology, Hepacivirus isolation & purification, Hepatitis C, Chronic transmission, Hepatitis C, Chronic virology, Humans, Male, Middle Aged, RNA, Viral blood, Remission, Spontaneous, Viral Load, HIV Infections complications, Hemophilia A complications, Hepatitis B, Chronic complications, Hepatitis C, Chronic complications
- Abstract
Objective: To identify correlates of spontaneous hepatitis C virus (HCV) clearance among people with human immunodeficiency virus (HIV) co-infection., Design: Baseline (2001-2004) analysis of a cohort study of people with hemophilia., Methods: Detailed questionnaire data were used to identify dates of primary HCV and HIV infections and to categorize sex; race; alcohol use; interferon treatment; hepatitis B virus (HBV) status; and HIV/AIDS history, treatment and current status. Spontaneous HCV clearance was defined as nondetection of HCV RNA by polymerase chain reaction assay in paired annual plasma, excluding those treated with interferon. Chi-squared, Fisher exact test, and logistic regression were used to identify correlates of clearance., Results: Among 478 HIV-infected participants, 61 (12.8%) had cleared HCV. Among the 31 participants with chronic HBV (as well as HIV), 16 (51.6%) had cleared HCV. With chronic HBV, HCV clearance was increased 11.2-fold (95% confidence interval, 5.1-24.8), after adjusting for sex, race, and hemophilia severity. Excluding the participants with chronic HBV, the prevalence of HCV clearance was 10.1%; and it was significantly reduced among males (9.7%, P = 0.05), blacks (1.6%, P = 0.01), and participants with severe hemophilia (8.2%, P = 0.02). HCV clearance was not associated with HIV RNA detection in plasma, CD4 cell count, anti-HIV therapy, AIDS history, ages at or years of HIV or HCV infection, or alcohol consumption., Conclusions: HCV clearance is unambiguously and markedly increased with chronic HBV infection among HIV co-infected people.
- Published
- 2007
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24. Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs.
- Author
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Eyster ME, Asaad SM, Gold BD, Cohn SE, and Goedert JJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Female, Gastrointestinal Hemorrhage etiology, Hemarthrosis drug therapy, Hemophilia A drug therapy, Humans, Male, Middle Aged, Multicenter Studies as Topic, Prospective Studies, Risk Factors, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Gastrointestinal Hemorrhage chemically induced, Helicobacter pylori, Hemarthrosis complications, Hemophilia A complications
- Abstract
This multicentre study sought to estimate the incidence of upper gastrointestinal (UGI) bleeding in haemophiliacs and its relationship to use of non-steroidal anti-inflammatory drugs (NSAIDs). Cox models were used to estimate relative hazards (RH) with 95% confidence intervals (CI) for postulated risk factors. Conditional logistic regression and stored sera were used to assess UGI bleeding risk with Heliobacter pylori seropositivity in cases compared with closely matched controls. During a mean of 17.4 months (range 2-34), 2285 participants, ages 13-89 (mean 36.5) were followed for 3309 person-years (py). Forty-two experienced a UGI bleeding event (incidence 1.3 per 100 py), most from ulcer (11), gastritis (four), varices (five) and Mallory Weiss tears (eight). RH was significantly increased with traditional NSAID use for <1 month (OR: 3.66; 95% CI: 1.1-11.9), but not with coxibs use. RH was significantly and independently increased with age >46 years (3.5; 95% CI: 1.1-10.6) and hepatic decompensation (4.4; 95% CI: 1.7-11.6). Likelihood of bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. These findings suggest that coxibs are a safer alternative than traditional NSAIDs in the treatment of haemophilic arthropathy.
- Published
- 2007
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25. HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia.
- Author
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Shire NJ, Horn PS, Rouster SD, Stanford S, Eyster ME, and Sherman KE
- Subjects
- AIDS-Related Opportunistic Infections complications, AIDS-Related Opportunistic Infections virology, Adult, Alanine Transaminase blood, Antiviral Agents pharmacology, CD4-Positive T-Lymphocytes drug effects, Female, Follow-Up Studies, HIV Infections complications, HIV Infections drug therapy, HIV-1 genetics, Hepatitis C complications, Hepatitis C virology, Humans, Interferon-alpha pharmacology, Male, Middle Aged, RNA, Viral analysis, Remission Induction, Ribavirin pharmacology, Viral Load, AIDS-Related Opportunistic Infections drug therapy, Antiviral Agents therapeutic use, Hemophilia A complications, Hepacivirus drug effects, Hepatitis C drug therapy, Interferon-alpha therapeutic use, Ribavirin therapeutic use
- Abstract
Hepatitis C virus (HCV) treatment response rates remain low in HCV/HIV-1-coinfected individuals compared with those with HCV alone. Persons with inherited coagulation disorders have high rates of HCV and HIV-1 infection, but HCV treatment trials in this patient population are scarce. We hypothesized that differences by infection status in HCV viral kinetics would be associated with differences in HCV quasispecies complexity over time and with treatment response disparities. Coinfected and monoinfected patients were enrolled in a treatment trial for pegylated-interferon alpha-2a (peg-IFN) + ribavirin. Patients were treated for 48 weeks and followed for an additional 24. Quantitative HCV RNA was tested at multiple times during and after treatment. Viral kinetic parameters associated with response were estimated with a mathematical model. Quasispecies emergence was determined via heteroduplex complexity assay. Twenty-two patients were HCV RNA-positive at baseline, with no significant demographic or virological differences by infection status. Five of eleven (45%) of monoinfected and 3 of 11 (27%) of coinfected patients achieved sustained viral response (SVR). Peg-IFN efficacy (epsilon) of 90% or greater was associated with probability of end-of-treatment response (ETR) (P = .001) and SVR (P = .06). Patients with SVR had lower baseline quasispecies complexity than those without SVR (P = .07). Those with epsilon of 90% or greater also had lower baseline complexity (P = .07). Coinfection status mediated changes in complexity over time (P = .04). In conclusion, low pretreatment quasispecies complexity may predict peg-IFN response; early peg-IFN response is critical for sustained HCV clearance and is altered in coinfection. Further studies are warranted.
- Published
- 2006
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26. Evaluation of the efficacy and safety of etoricoxib in the treatment of hemophilic arthropathy.
- Author
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Tsoukas C, Eyster ME, Shingo S, Mukhopadhyay S, Giallella KM, Curtis SP, Reicin AS, and Melian A
- Subjects
- Adolescent, Adult, Aged, Child, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors adverse effects, Double-Blind Method, Etoricoxib, Female, Headache etiology, Hemarthrosis complications, Hemarthrosis enzymology, Humans, Lactones administration & dosage, Lactones adverse effects, Male, Membrane Proteins antagonists & inhibitors, Middle Aged, Pyridines adverse effects, Respiratory Tract Infections etiology, Sulfones adverse effects, Treatment Outcome, Cyclooxygenase 2 Inhibitors administration & dosage, Hemarthrosis drug therapy, Hemophilia A complications, Hemophilia A enzymology, Pyridines administration & dosage, Sulfones administration & dosage
- Abstract
This 2-part, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of etoricoxib, a COX-2 selective inhibitor, for the treatment of hemophilic arthropathy. In part 1 (6 weeks), 102 patients (> or = 12 years old) with hemophilic arthropathy were randomized to receive 90 mg etoricoxib once daily or placebo (1:1 ratio). In part 2 (6 months), 51 patients taking placebo in part 1 were randomized to receive 90 mg etoricoxib or 25 mg rofecoxib once daily; patients taking etoricoxib in part 1 continued the same treatment. Efficacy end points included Patient Assessment of Arthropathy Pain, Patient Global Assessment of Arthropathy Disease Status, and Investigator Global Assessment of Arthropathy Disease Status. Safety was evaluated at each study visit. Etoricoxib provided significant improvement in all end points versus placebo (P < .001). Fewer patients taking etoricoxib discontinued due to a lack of efficacy versus placebo (P = .048). During part 2, efficacy was maintained; etoricoxib and rofecoxib demonstrated similar results. The most common adverse experiences were upper respiratory infection and headache. The incidence of joint bleeding during part 1 was similar between etoricoxib (66.7%) and placebo (72.6%) and during part 2 between etoricoxib (77.0%) and rofecoxib (78.9%). We conclude that etoricoxib provided superior efficacy versus placebo for the treatment of hemophilic arthropathy and was generally safe and well tolerated.
- Published
- 2006
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27. Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia.
- Author
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Zhang M, Rosenberg PS, Brown DL, Preiss L, Konkle BA, Eyster ME, and Goedert JJ
- Subjects
- Adolescent, Adult, Age Factors, Blood Component Transfusion, Child, Child, Preschool, Cohort Studies, Female, Hemophilia A complications, Hemophilia A therapy, Hemophilia B complications, Hemophilia B therapy, Humans, Male, Middle Aged, Plasma, Remission, Spontaneous, Retrospective Studies, Virus Inactivation, Hemophilia A blood, Hemophilia B blood, Hepacivirus, Hepatitis C blood, RNA, Viral blood
- Abstract
People with hemophilia were formerly at very high risk of infection with hepatitis C virus (HCV). Approximately 20% of HCV-infected patients spontaneously clear the virus. To identify correlates of spontaneous clearance of HCV, we studied a cohort of HCV-infected hemophilic subjects without human immunodeficiency virus infection who had never been treated with interferon. Plasma HCV RNA was persistently undetectable in 192 (27.0%) of 712 HCV-seropositive subjects. In multivariate analyses, HCV clearance was more likely in subjects infected with HCV at younger age, especially with infection before age 2 years (40.1%) compared with after age 15 years (14.9%, P(trend) < .0001), and with relatively recent infection, especially after 1983 (42.8%) compared with before 1969 (18.2%, P(trend) < .0001). HCV clearance was marginally reduced with African ancestry (19%) and greatly increased with chronic hepatitis B virus (HBV) infection (59.1%, P = .001). Resolved HBV infection, coagulopathy types and severity, types of clotting factor treatment, and sex were not associated with HCV clearance. In conclusion, hemophilic subjects coinfected with chronic HBV and those infected with HCV before age 2 years or after 1983 were significantly more likely to spontaneously clear HCV viremia. These data highlight and clarify the importance of nongenetic determinants in spontaneous recovery from HCV infection.
- Published
- 2006
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28. Knee and hip arthroplasty infection rates in persons with haemophilia: a 27 year single center experience during the HIV epidemic.
- Author
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Powell DL, Whitener CJ, Dye CE, Ballard JO, Shaffer ML, and Eyster ME
- Subjects
- Adult, Aged, Antiretroviral Therapy, Highly Active methods, Escherichia coli Infections etiology, HIV Infections drug therapy, HIV Infections mortality, HIV Seropositivity complications, HIV Seropositivity microbiology, HIV-1, Hemarthrosis etiology, Hemophilia A mortality, Hemophilia A surgery, Hip Joint microbiology, Humans, Joint Diseases etiology, Joint Diseases microbiology, Joint Diseases mortality, Knee Joint microbiology, Male, Middle Aged, Postoperative Hemorrhage etiology, Postoperative Hemorrhage microbiology, Postoperative Hemorrhage mortality, Staphylococcal Infections etiology, Surgical Wound Infection mortality, Treatment Outcome, Arthroplasty, Replacement, Hip methods, Arthroplasty, Replacement, Knee methods, HIV Infections complications, Hemarthrosis surgery, Hemophilia A complications, Surgical Wound Infection etiology
- Abstract
Total joint replacement (TJR) is an option for the management of chronic haemophilic arthropathy. Because surgery is technically challenging, there is a high rate of deep prosthetic infections, particularly in human immunodeficiency virus (HIV)-infected individuals. We determined the incidence of deep infection rates following total knee and hip arthroplasties in HIV-seropositive and HIV-seronegative persons with haemophilia. Fifty-one primary joint replacements were performed on 32 patients seen at a regional comprehensive haemophilia care center from 1975 to 2002. Thirty prostheses were placed in patients who were HIV-seropositive prior to surgery (n = 14) or seroconverted later (n = 16). Median age at the time of surgery was 33 years (range: 20-61) among 19 HIV-seropositive patients and 35 years (range: 26-74) among 13 HIV-negative patients. Median duration of follow-up was 83 months (range: 2-323). Rate of primary joint infection per artificial joint-year by HIV status was compared by Poisson regression. Main outcome measures were the incidence of primary replacement joint infections by HIV status. Deep infections developed in five (9.8%) of 51 replacement joints. There were two infections during 204.15 joint-years without HIV infection and three infections during 205.28 joint-years with HIV infection. The incidence rate of joint infection (0.98 vs. 1.46 per 100 joint-years) was not increased with HIV (relative risk, RR: 1.49, 95% CI: 0.25-8.93, P = 0.66). We conclude that HIV infection is not a contraindication to knee or hip replacement arthroplasty in the appropriate clinical setting.
- Published
- 2005
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29. HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV.
- Author
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Qin H, Shire NJ, Keenan ED, Rouster SD, Eyster ME, Goedert JJ, Koziel MJ, and Sherman KE
- Subjects
- Amino Acid Sequence, Cohort Studies, Disease Progression, Evolution, Molecular, Genetic Variation, Hepatitis C, Chronic virology, Humans, Liver Failure virology, Longitudinal Studies, Molecular Sequence Data, Species Specificity, HIV Infections epidemiology, Hemophilia A epidemiology, Hepacivirus genetics, Hepatitis C, Chronic epidemiology, Liver Failure epidemiology
- Abstract
Patients with inherited bleeding disorders who received clotting factor concentrates before 1987 have high rates of hepatitis C virus (HCV) or HCV/HIV infection. We evaluated HCV quasispecies evolution in longitudinally collected specimens comparing those from patients with progression to end-stage liver disease (ESLD; cases) to those with compensated chronic hepatitis (controls). Plasma samples were obtained from the National Cancer Institute Multicenter Hemophilia Cohort Study. Controls were matched for age, sex, infection duration, and presence/absence of HIV. Samples from early infection were compared to those obtained after onset of ESLD in the cases. The first hypervariable (HVR1) and core proteincoding regions were amplified, subcloned, and sequenced. Complexity and diversity were determined. More than 700 sub-clones from 10 pairs of patients (8 with HIV) followed over approximately 9.3 years were evaluated. HVR1 complexity narrowed over time in the cases, whereas it increased in controls (P = .01). Similar trends were observed for diversity within HVR1 and the core region (P = .04). HCV-infected patients with inherited bleeding disorders undergo quasispecies evolution over time. Evolution patterns differ for progressors and nonprogressors. Further understanding of these mechanisms may help identify factors related to progression rate and treatment response.
- Published
- 2005
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30. Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C.
- Author
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Theodore D, Fried MW, Kleiner DE, Kroner BL, Goedert JJ, Eyster ME, Faust SP, Sherman KE, Kessler CM, Francis C, and Aledort LM
- Subjects
- Biopsy, Contraindications, Humans, Hemophilia A complications, Hepatitis C, Chronic pathology, Liver pathology
- Abstract
Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.
- Published
- 2004
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31. Viral clearance occurs very early during the natural resolution of hepatitis C virus infection in persons with haemophilia.
- Author
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Eyster ME, Sanders J, and Goedert JJ
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Hemophilia A complications, Hepacivirus genetics, Humans, Middle Aged, Polymerase Chain Reaction methods, RNA, Viral blood, Remission, Spontaneous, Viral Load, Hemophilia A virology, Hepatitis C complications
- Abstract
We studied spontaneous hepatitis C virus (HCV) RNA clearance in 12 haemophilic patients. In their earliest anti-HCV positive samples, HCV RNA was undetectable in eight patients (66%), positive by polymerase chain reaction (PCR) but negative by branched-DNA (bDNA) in three others, and quantifiable by bDNA (4839 IU/mL) in only one patient. In contrast, in earliest anti-HCV positive samples from eight matched controls who had persistent viremia, HCV RNA was quantifiable by bDNA in seven (P = 0.0008) and at higher levels (range 4644-678 515 IU/mL; median 43 532 IU/mL). From initial HCV infection, HCV RNA cleared in 7 months or less in four patients and in 1-2 years in six others. HCV persisted for 5 years before clearance in the absence of repeated exposure in one patient. We conclude that HCV clearance usually but not always occurs within 1-2 years after infection and is more likely in those with lower than in those with higher early viral loads.
- Published
- 2004
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32. End-stage liver disease in persons with hemophilia and transfusion-associated infections.
- Author
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Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC 2nd, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, and Hatzakis A
- Subjects
- Adolescent, Adult, Age Factors, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, HIV Infections etiology, HIV Infections physiopathology, Hepatitis B etiology, Hepatitis B physiopathology, Humans, Incidence, Infant, Liver Failure, Acute virology, Male, Prospective Studies, Hemophilia A therapy, Hepatitis C etiology, Hepatitis C physiopathology, Liver Failure, Acute etiology, Transfusion Reaction
- Abstract
Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of these, 624 were HIV(-) and 1192 were HIV-coinfected; 135 had persistent HBV surface antigenemia, 1374 had resolved HBV infection, and 287 were HBV-uninfected. ESLD was defined as bleeding esophageal varices, hepatic encephalopathy, persistent ascites, or death excluding nonhepatic causes of these conditions. Competing risk models were used to estimate the annual hazard rate and cumulative incidence of ESLD. Proportional hazards models were used to estimate relative hazards of ESLD with covariates. ESLD developed in 127 of the HCV/HIV-coinfected participants, with an estimated 16-year cumulative incidence of 14.0% (95% confidence interval [CI], 11.6%-16.4%). Without HIV, 10 HCV-infected participants developed ESLD, for a significantly lower cumulative incidence of 2.6% (95% CI, 1.0%-4.3%, P <.0001). ESLD risk increased steeply with age in both groups. With HIV, ESLD risk was increased 8.1-fold (95% CI, 1.9-35.2) with HBV surface antigenemia, 2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 x 10(9)/L (200/microL) CD4(+) lymphocytes, and 1.04-fold (95% CI, 1.03-1.06) per year of age. Thus, HIV is associated with a markedly increased risk of HCV-related ESLD for persons with hemophilia, particularly with HBV infection, low CD4(+) lymphocytes, or older age.
- Published
- 2002
33. Hepatitis C viral clearance and antibody reactivity patterns in persons with haemophilia and other congenital bleeding disorders.
- Author
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Messick K, Sanders JC, Goedert JJ, and Eyster ME
- Subjects
- Adolescent, Adult, Age Distribution, Blood Coagulation Disorders complications, Blood Coagulation Disorders congenital, Blood Coagulation Disorders virology, Child, Child, Preschool, Cohort Studies, Epitopes blood, HIV Infections complications, HIV Infections diagnosis, HIV Infections etiology, Hemophilia A complications, Hepacivirus genetics, Hepatitis C complications, Hepatitis C etiology, Hepatitis C Antigens, Humans, Infant, Middle Aged, Prognosis, RNA, Viral blood, Viral Core Proteins immunology, Hemophilia A virology, Hepacivirus growth & development, Hepatitis C diagnosis, Hepatitis C Antibodies blood
- Abstract
We studied hepatitis C virus (HCV) clearance and antibody reactivity patterns in a cohort of 100 haemophiliacs exposed to unsterilized blood products, of whom 25 were antiHCV negative and 75 were antiHCV positive [49 human immunodeficiency virus (HIV) negative and 26 HIV positive]. HCV RNA was measured by the 2.0 bDNA assay and an 'in-house' polymerase chain reaction assay. Antibody reactivity patterns were examined using a recombinant immunoblot assay (RIBA). Prior HCV infection was found in two (8%) of 25 antiHCV negative patients. HCV viraemia persisted in all 26 antiHCV+ patients who were coinfected with HIV. HCV RNA clearance was found in 12 (25%) of 49 antiHCV+, HIV- patients. Viral clearance was associated with younger current age (P < 0.01) and age at infection (P < 0.001), but not with duration of infection or with dose or frequency of clotting factor use. RIBA ratios reflecting an index of each patient's overall reactivity to four HCV epitopes were significantly lower in those with viral clearance (P < 0.0001). Over a period of 15 years, those with viral clearance demonstrated significant loss of reactivity to the NS3, NS4 and NS5 epitopes, while those with viral persistence demonstrated relatively stable reactivities to all epitopes. We conclude that spontaneous HCV RNA clearance in haemophiliacs is age-related and is unlikely to occur in those coinfected with HIV. The loss of antibody reactivity for some epitopes, especially c22 (core), may be a marker for the natural resolution of chronic HCV infection.
- Published
- 2001
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34. Activity of HIV-1 integrases recovered from subjects with varied rates of disease progression.
- Author
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Katzman M, Harper AL, Sudol M, Skinner LM, and Eyster ME
- Subjects
- Acquired Immunodeficiency Syndrome blood, Conserved Sequence, DNA metabolism, Disease Progression, HIV Integrase genetics, Humans, Substrate Specificity, Acquired Immunodeficiency Syndrome enzymology, HIV Integrase metabolism
- Abstract
We recently described 102 HIV-1 integrase sequences that were amplified from blood cells or plasma obtained up to 18 years ago from 5 hemophiliacs who later died of AIDS and 5 hemophiliacs subsequently classified as slow or nonprogressors ( J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:99-110). Although the region of the HIV-1 genome that encodes integrase was highly conserved, none of the deduced protein sequences of the patient-derived enzymes matched that of the clade B consensus or standard laboratory integrases. To test the hypothesis that the activity of HIV-1 integrases prevalent within an infected person contributes to the rate of disease progression, we have now expressed and purified these proteins and compared them in various assays. Most of the 75 unique full-length integrase proteins from the 102 clones were enzymatically active. Comparison of proteins derived from samples obtained soon after infection showed that the specificity and extent of viral DNA processing and the amount of DNA joining (the two biologically relevant activities of integrase) did not differ between the two groups of patients. In addition, the relative usage of alternative nucleophiles for processing and the amount of nonspecific nicking catalyzed by the proteins were indistinguishable between the patient groups. Although the patient-derived enzymes often exhibited different patterns of target site preferences compared with the laboratory integrase, there was no correlation with clinical course. Thus, the activities of HIV-1 integrases prevalent within these infected individuals, at least as reflected by standard assays, did not influence or predict the rate of disease progression.
- Published
- 2001
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35. Lack of association of hepatitis C virus load and genotype with risk of end-stage liver disease in patients with human immunodeficiency virus coinfection.
- Author
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Goedert JJ, Hatzakis A, Sherman KE, and Eyster ME
- Subjects
- Cohort Studies, Disease Progression, Genotype, Hemophilia A complications, Hepacivirus classification, Hepacivirus genetics, Hepacivirus isolation & purification, Hepatitis C physiopathology, Hepatitis C virology, Humans, Liver Failure physiopathology, Prospective Studies, RNA, Viral blood, Risk Factors, HIV Infections complications, Hepacivirus physiology, Hepatitis C complications, Viral Load
- Abstract
In hepatitis C virus (HCV) infection, virus load and the risk for HCV-related end-stage liver disease (ESLD) are increased among persons with human immunodeficiency virus (HIV) coinfection. To clarify these relationships, 42 hemophilic patients who developed ESLD and random samples from 164 hemophilic patients with HCV infection alone and 146 with HCV-HIV coinfection were tested for HCV load and genotype. HCV genotype was unrelated to HIV and age. In contrast, HCV load was higher with older age (P(trend)=.0001) and with HIV coinfection (6.2 vs. 5.9 log(10) genome equivalents/mL, P=.0001). During 16 years of follow-up of dually infected patients, ESLD risk was unrelated to HCV load overall (P(trend)=.64) or separately to HCV genotype 1 and genotypes 2 or 3 (P(trend)> or =.70). Irrespective of virus load, incidence of ESLD was marginally increased 2-fold (95% confidence interval, 0.8-5.6) with HCV genotype 1. Understanding the discordance between HCV load and ESLD, despite HIV's link to each of these, may help clarify the pathogenesis of HCV-related disease.
- Published
- 2001
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36. Intra- and interlaboratory variabilities of results obtained with the Quantiplex human immunodeficiency virus type 1 RNA bDNA assay, version 3.0.
- Author
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Kellogg JA, Atria PV, Sanders JC, and Eyster ME
- Subjects
- Branched DNA Signal Amplification Assay standards, HIV Infections virology, Humans, RNA, Viral genetics, Reference Values, HIV Infections diagnosis, HIV-1 genetics, HIV-1 isolation & purification, RNA, Viral analysis
- Abstract
Normal assay variation associated with bDNA tests for human immunodeficiency virus type 1 (HIV-1) RNA performed at two laboratories with different levels of test experience was investigated. Two 5-ml aliquots of blood in EDTA tubes were collected from each patient for whom the HIV-1 bDNA test was ordered. Blood was stored for no more than 4 h at room temperature prior to plasma separation. Plasma was stored at -70 degrees C until transported to the Central Pennsylvania Alliance Laboratory (CPAL; York, Pa.) and to the Hershey Medical Center (Hershey, Pa.) on dry ice. Samples were stored at < or =-70 degrees C at both laboratories prior to testing. Pools of negative (donor), low-HIV-1-RNA-positive, and high-HIV-1-RNA-positive plasma samples were also repeatedly tested at CPAL to determine both intra- and interrun variation. From 11 August 1999 until 14 September 2000, 448 patient specimens were analyzed in parallel at CPAL and Hershey. From 206 samples with results of > or =1,000 copies/ml at CPAL, 148 (72%) of the results varied by < or =0.20 log(10) when tested at Hershey and none varied by >0.50 log(10). However, of 242 specimens with results of <1,000 copies/ml at CPAL, 11 (5%) of the results varied by >0.50 log(10) when tested at Hershey. Of 38 aliquots of HIV-1 RNA pool negative samples included in 13 CPAL bDNA runs, 37 (97%) gave results of <50 copies/ml and 1 (3%) gave a result of 114 copies/ml. Low-positive HIV-1 RNA pool intrarun variation ranged from 0.06 to 0.26 log(10) while the maximum interrun variation was 0.52 log(10). High-positive HIV-1 RNA pool intrarun variation ranged from 0.04 to 0.32 log(10), while the maximum interrun variation was 0.55 log(10). In our patient population, a change in bDNA HIV-1 RNA results of < or =0.50 log(10) over time most likely represents normal laboratory test variation. However, a change of >0.50 log(10), especially if the results are >1,000 copies/ml, is likely to be significant.
- Published
- 2001
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37. Characterization of high-risk HIV-1 seronegative hemophiliacs.
- Author
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Salkowitz JR, Purvis SF, Meyerson H, Zimmerman P, O'Brien TR, Aledort L, Eyster ME, Hilgartner M, Kessler C, Konkle BA, White GC 2nd, Goedert JJ, and Lederman MM
- Subjects
- Adolescent, Adult, Chemokine CCL4, Chemokine CCL5 blood, Child, Cohort Studies, Drug Contamination, Factor VIII adverse effects, Factor VIII isolation & purification, Factor VIII therapeutic use, Female, Genetic Predisposition to Disease, Genotype, HIV Infections epidemiology, HIV Infections transmission, HIV Seropositivity, Hemophilia A genetics, Hemophilia A therapy, Hot Temperature, Humans, Immunity, Innate, Isoantibodies blood, Lymphocyte Activation, Macrophage Inflammatory Proteins blood, Male, Polymorphism, Genetic, Receptors, CCR5 genetics, Risk, HIV Seronegativity, HIV-1, Hemophilia A epidemiology
- Abstract
Mechanisms that protect most high-risk HIV-1 seronegative (HRSN) persons are not well understood. Among hemophiliacs from the Multicenter Hemophilia Cohort Study who remained HIV-1 seronegative despite a high (94%) risk for acquisition of HIV-1 infection, only 7/43 were homozygous for the protective CCR5 Delta32 polymorphism. Among the remainder, neither CCR5 density nor beta-chemokine production, nor in vitro susceptibility to infection with the HIV-1 isolate JR-FL could distinguish HRSN hemophiliacs from healthy controls. When compared to lymphocytes of healthy controls not at risk for HIV-1 infection, diminished spontaneous lymphocyte proliferation was seen in lymphocytes of HRSN hemophiliacs as well as in lymphocytes of hemophiliacs not at risk for HIV-1 infection. Surprisingly sera/plasmas obtained from high-risk HIV-1 seropositve hemophiliacs prior to seroconversion more often contained alloreactive antibodies than date-matched sera/plasmas obtained from HRSN hemophiliacs. Thus alloreactivity may predispose to acquisition of HIV-1 infection after parenteral exposure., (Copyright 2000 Academic Press.)
- Published
- 2001
- Full Text
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38. Increased liver decompensation risk with atypical hepatitis C virus antibody levels.
- Author
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Goedert JJ, Hatzakis A, Maloney EM, and Eyster ME
- Subjects
- Case-Control Studies, Cohort Studies, Hepacivirus isolation & purification, Hepatitis C blood, Humans, Viral Load, HIV Infections complications, Hemophilia A complications, Hepatitis C complications, Hepatitis C Antibodies blood, Liver Failure complications
- Abstract
Knowledge of serum markers of liver decompensation would facilitate care of patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. HCV load and anti-c33c and anti-NS5 levels did not distinguish 28 HCV- and HIV-positive predecompensation patients from 28 matched control patients, whereas more patients than controls had high anti-c100(p) and low anti-c22(p). In multivariate analysis, decompensation was associated with high anti-c100(p) titer (>/=1:4050; odds ratio [OR], 3. 4; 95% confidence interval [CI], 1.1-11.5) and low anti-c22(p) (<1:36,450; OR, 3.0; 95% CI, 1.0-10.2) and with antibody band strength at 1:50 dilution (anti-c100[p] OR, 7.0; 95% CI, 1. 7-48.9; anti-c22[p] OR, 7.1; 95% CI, 1.7-49.2). With high anti-c100(p) or low anti-c22(p), sensitivity for decompensation was 86%-96% and specificity was 21%-36%; with both markers, sensitivity was 29%-32% and specificity was 93%-96%. Although the mechanisms for these associations are unknown, if these findings are verified in other populations, anti-c100(p) and anti-c22(p) might be valuable surrogate markers for liver decompensation risk.
- Published
- 2000
- Full Text
- View/download PDF
39. Phenotypic expressions of CCR5-delta32/delta32 homozygosity.
- Author
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Nguyêñ GT, Carrington M, Beeler JA, Dean M, Aledort LM, Blatt PM, Cohen AR, DiMichele D, Eyster ME, Kessler CM, Konkle B, Leissinger C, Luban N, O'Brien SJ, Goedert JJ, and O'Brien TR
- Subjects
- Adult, Antibodies, Viral blood, Cohort Studies, Genotype, HIV Infections genetics, HIV-1, Hemophilia A complications, Hemophilia A genetics, Hepatitis C complications, Hepatitis C enzymology, Hepatitis C genetics, Homosexuality genetics, Humans, Hypertension epidemiology, Hypertension genetics, Liver enzymology, Lymphocyte Count, Male, Phenotype, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Prevalence, Prospective Studies, Homozygote, Receptors, CCR5 genetics, White People genetics
- Abstract
Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1., Design: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis., Results: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype., Conclusions: CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.
- Published
- 1999
- Full Text
- View/download PDF
40. Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease.
- Author
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Paul IM, Sanders J, Ruggiero F, Andrews T, Ungar D, and Eyster ME
- Subjects
- Adult, Child, Cohort Studies, Female, Hepatitis C, Chronic physiopathology, Hepatitis C, Chronic virology, Humans, Leukemia physiopathology, Leukemia therapy, Male, Middle Aged, Prevalence, Transfusion Reaction, Viral Load, Hepacivirus isolation & purification, Hepatitis C, Chronic etiology, Leukemia complications, Leukemia virology
- Abstract
The natural history of chronic hepatitis C (HCV) infections in long-term leukemia survivors has not been well characterized. We studied the prevalence of HCV infections, measured HCV RNA levels, and evaluated the severity of liver disease in patients with leukemia who achieved long-term remissions after intensive chemotherapy or bone marrow transplantation (BMT). HCV antibody tests were performed by the enzyme-linked immunosorbent assay (ELISA) and positive tests confirmed by the recombinant immunoblot assay (RIBA). HCV RNA levels were measured by the branched DNA (bDNA) assay. Seventy-five leukemia survivors with 25 or more blood donor exposures were identified. Nine (12%) were anti-HCV positive. All were infected before 1992 when second generation HCV screening tests were implemented. Mean HCV RNA levels were 10.3 x10(6) eq/mL versus 3.2 x 10(6) eq/mL (P =.056) in a control group of 20 anti-HCV positive immunocompetent individuals of comparable age who were infected twice as long (17.8 +/- 6.5 years v 9.0 +/- 4.4 years in leukemia survivors, P =.001). Liver biopsies were performed on six of the nine anti-HCV positive leukemia survivors. All showed at least moderate portal inflammation and half had evidence of bridging fibrosis. We conclude that viral loads in anti-HCV positive leukemia survivors are markedly higher than in immunocompetent controls. Our results suggest that long-term leukemia survivors with chronic HCV may have more rapidly progressive liver disease than has been previously recognized.
- Published
- 1999
41. Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia. The Multicenter Hemophilia Cohort Study.
- Author
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Eyster ME, Sherman KE, Goedert JJ, Katsoulidou A, and Hatzakis A
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Genotype, HIV Infections complications, Hepacivirus isolation & purification, Humans, Immunoassay methods, Middle Aged, RNA, Viral blood, Reverse Transcriptase Polymerase Chain Reaction methods, Time Factors, Transfusion Reaction, Viremia, Hemophilia A complications, Hepacivirus genetics, Hepatitis C, Chronic complications, Hepatitis C, Chronic virology
- Abstract
The purpose of this study was to determine hepatitis C virus (HCV) genotypes and their relationship to HCV RNA levels over time in a cohort of multitransfused hemophiliacs. Following reverse transcription and polymerase chain reaction amplification of HCV RNA, the product DNAs were genotyped by using the line probe assay. HCV RNA was quantified by the branched-chain DNA assay. Genotyping was done on 109 serum samples from 32 subjects. Genotype 3a had the highest prevalence (41%), followed by genotypes 1a (31%) and 1b (13%). Changes in genotypes were observed in 18 (58%) of the subjects >3-15 years of age. Changes were more common in human immunodeficiency virus (HIV)-positive subjects (13/17) than in HIV-negative subjects (5/15) (P=.014). HCV RNA increased 30-fold in HIV-positive subjects whose genotypes changed. Consensus nucleotide sequencing confirmed genotype changes in 2 patients. We conclude that genotype changes are common in hemophiliacs with chronic HCV, particularly in those who are coinfected with HIV.
- Published
- 1999
- Full Text
- View/download PDF
42. Analysis of a large collection of natural HIV-1 integrase sequences, including those from long-term nonprogressors.
- Author
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Skinner LM, Lamers SL, Sanders JC, Eyster ME, Goodenow MM, and Katzman M
- Subjects
- Acquired Immunodeficiency Syndrome immunology, Adult, Amino Acid Sequence, Base Sequence, CD4 Lymphocyte Count, Cohort Studies, Consensus Sequence, Conserved Sequence, DNA, Viral chemistry, Disease Progression, Humans, Longitudinal Studies, Male, Middle Aged, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, RNA, Viral chemistry, Retrospective Studies, Survivors, Viral Load, Acquired Immunodeficiency Syndrome etiology, HIV Integrase chemistry, HIV Integrase genetics, HIV-1 enzymology, HIV-1 genetics, Hemophilia A complications
- Abstract
A large collection of natural HIV-1 integrase (IN) sequences has not previously been described. We reasoned that analysis of such sequences would address whether natural variation of HIV-1 IN contributes to the pathogenesis of AIDS and might also identify amino acid residues important for IN function. Sequences encoding HIV-1 IN were amplified from cryopreserved lymphocytes or plasma obtained at different times from 10 hemophilia patients who had been observed for up to 17 years. The region of the HIV-1 genome that encodes the 288-amino acid IN protein was sequenced from a total of 102 clones; information was obtained for 99.97% of 29,478 amino acid positions. Phylogenetic analysis indicated that patient samples were unique. Interpatient nucleic acid distances ranged from 0.8% to 4.9%, highlighting the tight conservation of this genomic region. No major differences were found between DNA and RNA or between early and late time points from the same patient. Significantly, no amino acid changes that might account for the variable rate of disease progression between patients were evident. Only one amino acid substitution involved a highly conserved residue known to be important for enzymatic activity. However, several interesting amino acid substitutions were noted, including residues within the C-terminal region of the protein for which sequence comparisons between animal retroviruses have not been very informative. These results should encourage the pursuit of anti-integrase therapies, especially inasmuch as the apparent biologic constraints on the IN sequence may deter the development of drug resistance.
- Published
- 1998
- Full Text
- View/download PDF
43. Thrombocytopenia in HIV-infected and uninfected hemophiliacs. Multicenter Hemophilia Cohort study.
- Author
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Ehmann WC, Rabkin CS, Eyster ME, and Goedert JJ
- Subjects
- Adolescent, Adult, Child, Cohort Studies, HIV Seropositivity physiopathology, Hemophilia A physiopathology, Humans, Middle Aged, Prevalence, Prognosis, Thrombocytopenia etiology, Thrombocytopenia physiopathology, HIV Seropositivity complications, Hemophilia A complications, Thrombocytopenia epidemiology
- Abstract
To determine the incidence and prognostic significance of thrombocytopenia among hemophiliacs, we analyzed clinical and hematologic data from the Multicenter Hemophilia Cohort study. Nineteen percent of HIV-infected subjects had thrombocytopenia (platelet count of <100,000/mm3) noted at least once, compared to 3% of HIV-uninfected subjects. For HIV-infected subjects, the prevalence of thrombocytopenia rose in the first 5 years after seroconversion and was twice as common in subjects age >35 years compared to younger subjects. The risk increased after an AIDS-defining illness, particularly among older subjects, nearly one-half of whom had thrombocytopenia within 1 year after AIDS. When adjusted for age and CD4-positive lymphocyte counts, thrombocytopenia was associated with an increased risk of death [relative risk (RR) 1.7, 95%CI = 1.2-2.3] but with little change in the risk of progression to AIDS (RR = 1.2, 95%CI = 0.8-1.7). Treatment with zidovudine was associated with a decreased risk of thrombocytopenia (RR = 0.5, 95%CI = 0.3-0.7). Although 59 HIV-infected subjects died of hemorrhage, only 11 (19%) of the 59 had a reported platelet count of <50,000/mm3, and only 2 (3%) of the deaths were temporally associated with thrombocytopenia. Thus, the risk of death was increased for thrombocytopenic HIV-infected hemophiliacs but this was not explained by an increased risk of developing AIDS and was rarely associated with death from bleeding.
- Published
- 1997
- Full Text
- View/download PDF
44. Blood safety decisions, 1982 to 1986: perceptions and misconceptions.
- Author
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Zuck TF and Eyster ME
- Subjects
- Blood Banks history, HIV Infections transmission, History, 20th Century, Humans, Transfusion Reaction, United States, Blood Banks standards, Blood Transfusion history, HIV Infections history
- Abstract
Although blood bankers and those who treat persons with hemophilia are supportive of most of the recommendations of the Report, the manner in which the analysis was conducted and some of the general conclusions that were reached appear flawed. The flaws may reflect the deficiencies in the process by which the Committee gathered data more than any bias on the part of its members themselves. The Report may accurately reflect the testimony heard, but it is biased by the committee's acceptance as fact the opinions of critics who claim the AIDS epidemic was mismanaged by the blood-collecting agencies, professional organizations, hemophilia organizations, and the federal government. Countervailing views on the various issues are ignored or incompletely discussed. Much testimony was taken from the victims of the transfusion-associated AIDS epidemic. Reliance seems to have been placed upon hindsight testimony (taken 10 years after the events), rather than on documentation of what was known at the time when events unfolded. The Report states that "[t]he Committee's charge did not include the development of assertions about what should have been done at the time,"l(pl:4) yet that is precisely what was done. These comments address just a few of the misconceptions we perceive in the Report. They are based on our understanding of the state of knowledge--or ignorance--at the time that decisions about the safety of the blood supply were made. If we are to avert future threats to the blood supply from emerging infectious diseases, a goal that is universally embraced, we must learn the lessons the past can teach us, as painful as they may be. However, the hazards of judging history in hindsight should be avoided. Neither allegations nor opinions should be accepted as facts without critical examination and without placement in the context of contemporary knowledge; to accept a lesser standard does a great injustice to all who were touched by this tragedy.
- Published
- 1996
- Full Text
- View/download PDF
45. Causes of death in haemophilia.
- Author
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Ehmann WC, Eyster ME, Aledort LM, and Goedert JJ
- Subjects
- Cause of Death, Cohort Studies, HIV Infections complications, HIV Infections mortality, Hemophilia A complications, Hemorrhage complications, Hemorrhage mortality, Humans, Liver Diseases complications, Liver Diseases mortality, Hemophilia A mortality
- Published
- 1995
- Full Text
- View/download PDF
46. Natural history of HIV-1 cell-free viremia.
- Author
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Henrard DR, Phillips JF, Muenz LR, Blattner WA, Wiesner D, Eyster ME, and Goedert JJ
- Subjects
- Acquired Immunodeficiency Syndrome immunology, Acquired Immunodeficiency Syndrome mortality, Adult, Biomarkers blood, CD4 Lymphocyte Count, Cohort Studies, Disease Progression, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, HIV Core Protein p24 analysis, HIV Infections blood, Humans, Longitudinal Studies, Male, Multivariate Analysis, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Prospective Studies, RNA, Viral analysis, Survival Analysis, Viremia blood, Virus Replication, Acquired Immunodeficiency Syndrome blood, HIV Core Protein p24 blood, HIV Infections physiopathology, HIV-1 isolation & purification, HIV-1 physiology, RNA, Viral blood, Viremia physiopathology
- Abstract
Objective: To characterize the natural history of viremia with human immunodeficiency virus type 1 (HIV-1) and its association with disease progression from infection to acquired immunodeficiency syndrome (AIDS)., Design: Prospective cohort study. Annual specimens were tested for quantitative virion-associated HIV-1 RNA, p24 antigen, and CD4+ lymphocyte levels., Participants: A total of 42 homosexual men who seroconverted to HIV-1 between 1982 and 1985., Main Outcome Measures: Trends over time in serum HIV-1 RNA level, correlations between serum HIV-1 RNA and other markers, and prediction of AIDS using these markers., Results: HIV-1 RNA levels were stable over time, increasing by 10-fold or more in only six (14%) of the 42 subjects during 3 to 11 years of follow-up. Mean HIV-1 RNA levels were 10(3.8) copies/mL if AIDS occurred in less than 4 years, 10(3.07) copies/mL if AIDS developed within 4 through 9 years, and 10(2.27) copies/mL if AIDS did not develop within 6 through 11 years. In both univariate and multivariate models, initial and subsequent HIV-1 RNA levels, p24 antigenemia, and percentage of CD4+ lymphocytes were independently predictive of AIDS., Conclusions: The stability of virion-associated HIV-1 RNA levels suggests that an equilibrium between HIV-1 replication rate and efficacy of immunologic response is established shortly after infection and persists throughout the asymptomatic period of the disease. Thus, defective immunologic control of HIV-1 infection may be as important as the viral replication rate for determining AIDS-free survival. Because individual steady-state levels of viremia were established soon after infection, HIV-1 RNA levels may be useful markers for predicting clinical outcome.
- Published
- 1995
47. Suppression of hepatitis C virus (HCV) replication by hepatitis D virus (HDV) in HIV-infected hemophiliacs with chronic hepatitis B and C.
- Author
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Eyster ME, Sanders JC, Battegay M, and Di Bisceglie AM
- Subjects
- Adult, Child, DNA, Viral analysis, Enzyme-Linked Immunosorbent Assay, HIV genetics, Hepacivirus genetics, Hepatitis Antibodies analysis, Hepatitis Delta Virus immunology, Humans, Male, Middle Aged, RNA, Viral analysis, Antibiosis, HIV Infections complications, Hemophilia A complications, Hepacivirus physiology, Hepatitis B complications, Hepatitis C complications, Hepatitis Delta Virus physiology, Virus Replication, von Willebrand Diseases complications
- Abstract
Most hemophiliacs who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have high serum levels of HCV RNA. To study the impact of multiple hepatitis virus infections, we evaluated all eight chronic carriers of hepatitis B surface antigen (HBsAg) from a previously studied cohort of 99 hemophiliacs with chronic HIV and HCV infections. Stored serum or plasma samples were tested for antibody to hepatitis D virus (anti-HDV) by ELISA; qualitatively for HCV RNA, HBV DNA, and HDV RNA by the polymerase chain reaction (PCR); and quantitively for HIV RNA, HCV RNA, and hepatitis B virus (HBV) DNA by a quantitative branched DNA signal amplification assay. HCV RNA was detected in only one of five patients with HDV infections on a cross-sectional study, and this individual had low levels (< 3.5 x 10(5) genome eq/ml) of HCV RNA. In contrast, all three without HDV infections had high levels (> 1.5 x 10(7) genome eq/ml) of HCV RNA. HIV RNA was present in all eight patients. There was no correlation between the level of HIV RNA and the presence of hepatitis viruses. Three of the eight patients (38%) died of liver failure and another has hypersplenism with hypoprothrombinemia. We conclude that HDV infection appears to suppress HCV replication and that liver failure is common in adult HIV-infected hemophiliacs with chronic HCV and HBV infections. These findings have implications for the therapy of HCV-infected hemophiliacs who are HBsAg positive.
- Published
- 1995
- Full Text
- View/download PDF
48. Idiopathic CD4+ T-lymphocytopenia in HIV seronegative men with hemophilia and sex partners of HIV seropositive men. Multicenter Hemophilia Cohort Study.
- Author
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O'Brien TR, Diamondstone L, Fried MW, Aledort LM, Eichinger S, Eyster ME, Hilgartner MW, White G, Di Bisceglie AM, and Goedert JJ
- Subjects
- Acquired Immunodeficiency Syndrome complications, Adult, Case-Control Studies, Female, HIV Seronegativity, Hepacivirus immunology, Hepatitis Antibodies blood, Humans, Liver Diseases complications, Male, Middle Aged, Prospective Studies, Splenomegaly, CD4-Positive T-Lymphocytes, HIV Seropositivity, Hemophilia A complications, Lymphopenia complications, Sexual Partners
- Abstract
Persons with hemophilia or other HIV-1 risk factors may be more likely to have idiopathic CD4+ T-lymphocytopenia (ICL). We determined the frequency of ICL in prospectively followed cohorts of HIV-1 seronegative hemophilic men and seronegative female sex partners of HIV-1 infected hemophilic men, and examined factors potentially associated with ICL. Seven of 304 (2.3%) seronegative hemophilic men and one of 160 (0.6%) female partners met the ICL definition, but the condition resolved for two of the men and for the sole female partner. All five men with persistent ICL had lymphocytopenia (< 1,200 total lymphocytes/microliters) and < 300 total CD4+ lymphocytes/microliters; only one had a low CD4+ percentage. On the most recent measurement, 14.5% of the 304 seronegative hemophilic men had lymphocytopenia. Compared with matched hemophilic controls, men with persistent ICL more often had a history of liver disease (3/5 cases, 0/21 controls, P = 0.007) or splenomegaly (3/5 cases, 4/21 controls; P = 0.04), but not severe hemophilia, greater clotting factor concentrate exposure, high alanine aminotransferase levels, hepatitis B virus antigenemia, or detectable hepatitis C virus RNA in plasma. All five cases and 20/21 controls had antibodies to hepatitis C virus present in their serum. In this cohort of hemophilic men, ICL was related to lymphocytopenia associated with liver disease rather than selective loss of CD4+ lymphocytes.
- Published
- 1995
- Full Text
- View/download PDF
49. Human immunodeficiency virus (HIV) type 1 infection status and in vitro susceptibility to HIV infection among high-risk HIV-1-seronegative hemophiliacs.
- Author
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Lederman MM, Jackson JB, Kroner BL, White GC 3rd, Eyster ME, Aledort LM, Hilgartner MW, Kessler CM, Cohen AR, and Kiger KP
- Subjects
- Adult, CD4 Lymphocyte Count, CD8-Positive T-Lymphocytes immunology, Disease Susceptibility, Factor IX analysis, Factor VIII analysis, HIV Infections transmission, Hemophilia A blood, Hemophilia A immunology, Humans, Lymphocyte Count, Male, Polymerase Chain Reaction, Risk Factors, HIV Infections epidemiology, HIV Seronegativity, HIV Seropositivity immunology, HIV-1 genetics, HIV-1 isolation & purification, Hemophilia A complications
- Abstract
Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.
- Published
- 1995
- Full Text
- View/download PDF
50. Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and nonhemophilic subjects with asymptomatic human immunodeficiency virus-1 infection. AIDS Clinical Trial Groups.
- Author
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Ragni MV, Amato DA, LoFaro ML, DeGruttola V, Van Der Horst C, Eyster ME, Kessler CM, Gjerset GF, Ho M, and Parenti DM
- Subjects
- Adult, CD4 Lymphocyte Count drug effects, Chemical and Drug Induced Liver Injury etiology, Didanosine administration & dosage, Didanosine adverse effects, Drug Therapy, Combination, Female, HIV Core Protein p24 blood, HIV Infections complications, HIV Infections immunology, HIV Infections virology, HIV-1 isolation & purification, Hemophilia A immunology, Humans, Male, Safety, Treatment Outcome, Viremia drug therapy, Viremia virology, Zidovudine administration & dosage, Zidovudine adverse effects, Didanosine therapeutic use, HIV Infections drug therapy, Hemophilia A complications, Zidovudine therapeutic use
- Abstract
To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.
- Published
- 1995
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