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INTRODUCTION: Nuwiq® [human cell line-derived recombinant factor VIII (human-cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line. AIM/METHODS: This prospective, open-label, multinational phase III study assessed the efficacy and safety of human-cl rhFVIII in 32 adult previously treated patients (PTPs) with severe haemophilia A during standard prophylaxis for ≥6 months and ≥50 exposure days. Efficacy in treating bleeds and during surgical prophylaxis was also assessed. RESULTS: Prophylactic efficacy, based on mean monthly bleeding rate, was rated as 'excellent' or 'good' in 97% of patients for all bleeds and in 100% of patients for spontaneous bleeds. Mean (SD) annualized bleeding rate was 2.28 (3.73) [median = 0.9] for all bleeds, 1.16 (2.57) [median = 0] for spontaneous bleeds and 1.00 (1.79) [median = 0] for traumatic bleeds. There were no bleeds in 50% of patients and there were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in treating 28 (100%) of 28 bleeds. Overall efficacy was rated as 'excellent' during four surgical procedures (three major, one minor) and 'moderate' during one major surgery. Incremental in vivo recovery (IVR) data were comparable with the one-stage and chromogenic assays. IVR was >2.0% per IU kg-1 for all measurements and stable over 6 months. No patients developed FVIII inhibitors and there were no treatment-related serious or severe adverse events. CONCLUSION: These results in adult PTPs indicate that human-cl rhFVIII is effective for the prevention and treatment of bleeds in adults with severe haemophilia A.
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BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes/sangre , Área Bajo la Curva , Pruebas de Coagulación Sanguínea , Coagulantes/farmacocinética , Esquema de Medicación , Factor VIII/análisis , Factor VIII/farmacocinética , Semivida , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. DESIGN: Prospective, multi-centre, large-scale, pan-European registry. SETTING: A total of 117 haemophilia centres in 13 European countries. POPULATION: Pregnancy-associated AHA. METHODS: Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. MAIN OUTCOME MEASURES: Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. RESULTS: The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. CONCLUSIONS: Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.
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Hemofilia A , Complicaciones Hematológicas del Embarazo , Adulto , Antifibrinolíticos/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Quimioterapia Combinada , Europa (Continente)/epidemiología , Factor VIIa/uso terapéutico , Femenino , Estudios de Seguimiento , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Hemofilia A/epidemiología , Hemofilia A/etiología , Hemostáticos/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Embarazo , Complicaciones Hematológicas del Embarazo/diagnóstico , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Complicaciones Hematológicas del Embarazo/epidemiología , Complicaciones Hematológicas del Embarazo/etiología , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Sistema de Registros , Resultado del TratamientoRESUMEN
The clinical picture of haemophilia A patients is often characterised by recurrent bleedings, in particular joint bleeds. Thus far, long-term data on the outcome of haemophilia A patients are scarce as regards the development of target joints, joint replacement, lost days from school or work due to bleedings, and the quality of life, as most previous studies were limited to the aspects of safety and efficacy. The Baxter-initiated AHEAD (Advate in HaEmophilia A outcome Database) study is a multi-centre, prospective, non-interventional observational study of haemophilia A patients. All patients with a residual FVIII activity of £5% who are being treated with ADVATE are eligible. There are no limitations in terms of patient age or treatment regimen. AHEAD is scientifically supported by a renowned interdisciplinary steering board and is intended to yield data on 500 patients in up to 30 haemophilia centres, collected during a period of four years. The large patient population has been chosen in order to ensure a valid database. The objective of the study is to record haemophilia-related arthropathies, which will be defined based on imaging techniques (e. g. MRI, X-ray, ultrasound) and the judgment of the attending physician. In addition, extensive data will be collected on joint replacement surgeries, pseudotumour development, bleeding-related pain, quality of life (age-related questionnaires: Haem-A-QoL, Haemo-QoL, SF10, SF12v2), risk factors (diabetes mellitus, arterial hypertension, nicotine abuse), blood group, gene mutation, physical activity, and on the efficacy and safety of Advate. The patient data will be entered into an electronic CRF system at the centres. Plausibility checks during data entry, regular monitoring visits, and the option of auditing all serve to ensure a high data quality for AHEAD. The first patient was enrolled in the study in early June 2010; recruitment is planned to continue until the end of 2011. The Ethics Committee of the University of Bonn has given its favorable opinion.
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Hemofilia A/terapia , Bases de Datos como Asunto , Factor VIII/metabolismo , Hemofilia A/complicaciones , Humanos , Selección de Paciente , Estudios Prospectivos , Resultado del TratamientoRESUMEN
UNLABELLED: Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information.
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Factor VIII/inmunología , Hemofilia A/sangre , Hemofilia A/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Pruebas de Coagulación Sanguínea , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Curva ROC , Inducción de Remisión , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.
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Factor VII/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Trombastenia/tratamiento farmacológico , Coagulantes/uso terapéutico , Factor VIIa , Femenino , Humanos , Masculino , Transfusión de Plaquetas/efectos adversos , Embarazo , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Complicaciones Hematológicas del Embarazo/terapia , Trombastenia/diagnóstico , Trombastenia/terapiaRESUMEN
CD4+ lymphocyte counts of 91 HIV+ hemophilia patients were monitored for a mean of 4 years (range: 15-69 months). CD4+ lymphocytes decreased in 55 but increased in 36 patients over time. The CD4+ cell increases were persistent in 5 patients, whereas they fluctuated in 31. Of the 36 patients with increasing CD4+ counts 3 developed AIDS and 1 LAS. The other 32 patients were clinically asymptomatic (CDC II), but had immunological abnormalities, such as increased serum neopterin (N = 18) and impaired in vitro T cell responses to pooled allogenic stimulator cells (N = 15) or mitogens (N = 18). In contrast, of the 55 patients whose CD4+ cells decreased, 24 developed AIDS and 5 ARC (P less than 0.0005). Only 2 of these 55 patients had normal mitogen stimulation in vitro and normal serum neopterin levels.
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Linfocitos T CD4-Positivos , Infecciones por VIH/sangre , Hemofilia A/sangre , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Anticuerpos Monoclonales , Autoanticuerpos/inmunología , Biopterinas/análogos & derivados , Biopterinas/sangre , Relación CD4-CD8 , Citometría de Flujo , Infecciones por VIH/inmunología , Seropositividad para VIH/sangre , Seropositividad para VIH/inmunología , Humanos , Recuento de Leucocitos , Activación de Linfocitos/inmunología , Neopterin , PronósticoRESUMEN
OBJECTIVE: There is evidence that HIV induces CD4+ depletion in part by the formation of immune complexes (IC) that attach to CD4+ blood lymphocytes. In the present study we examined the relationship of IC-coated CD4+ blood cells with retroviral replication in HAART-treated patients. PATIENTS AND METHODS: 52 hemophilia patients were studied from 1997 to 1999. Lymphocyte subsets, IgM, IgG and gp120 on CD4+ blood cells, in vitro responses of lymphocytes to mitogens, plasma neopterin and plasma viral load were measured. RESULTS: Patients with detectable viral replication and without ICs on CD4+ blood lymphocytes had a lower viral load (4100 versus 21000 HIV-1 mRNA copies/ml; P = 0.079) and higher CD4+ cell counts (310/microl versus 161/microl; P = 0.035) than patients with ICs on circulating CD4+ lymphocytes. Among patients with < 80 HIV-1 mRNA copies/ml, IC- individuals had slightly higher CD4+ lymphocyte counts than IC+ patients (384/microl versus 316/microl; n.s.). Further evidence for the clinical relevance of the ICs was obtained when 18 patients who had an undetectable viral load at previous investigations were analyzed. Among patients with a stable undetectable viral load, CD4+ counts increased in 6 of 8 IC- but in none of 2 IC+ individuals. In patients whose viral load increased during the observation period, 5 of 6 IC- but none of 2 IC+ individuals showed higher CD4+ cell counts. Impaired virus killing is suggested by lower CD16+ (35/microl versus 107/microl; P = 0.016), higher CD3+ DR+ (178/microl versus 66/microl; P = 0.006), and higher CD8+ DR+ (142/microl versus 34/microl; P = 0.017) cell counts in IC(-) patients compared to IC- patients without detectable viral load. Strong retroviral replication induced strong T cell dysfunctions. Fewer CD3+ 25+ blood lymphocytes (19/microl versus 47/microl; P = 0.006) and a lower in vitro response of T lymphocytes to the mitogens Con A (RR: 0.3 versus 1.2; P=0.023) and CD3 mab (RR: 0.5 versus 2.4; P = 0.012) was observed in IC+ patients with detectable versus undetectable viral load. CONCLUSION: Our data suggest that ICs on circulating CD4+ blood lymphocytes are primarily associated with CD4+ lymphocyte depletion whereas the plasma viral load is primarily associated with decreased T lymphocyte activation, lower CD16+ counts, and higher CD8+ DR+ lymphocytes which might be the effector cells for virus elimination.
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Complejo Antígeno-Anticuerpo/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Hemofilia A/inmunología , Depleción Linfocítica , Receptores de IgG/inmunología , Carga Viral , Recuento de Linfocito CD4 , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , VIH-1/genética , Hemofilia A/complicaciones , Humanos , Estudios Longitudinales , Activación de Linfocitos/inmunología , Recuento de LinfocitosRESUMEN
There is increasing evidence that autoimmune phenomena contribute to the pathogenesis of the acquired immunodeficiency syndrome (AIDS). We investigated the relationship between IgA autoantibodies directed against the Fab part of the IgG molecule and disease progression in 87 HIV-infected hemophilia patients. AIDS patients demonstrated a significantly higher serum IgA-anti-Fab activity than HIV-positive (HIV+) patients with AIDS-related complex (ARC) (P < 0.02), HIV+ patients without AIDS/ARC (P < 0.0001), HIV negative (HIV-) patients (P = 0.0001), or healthy controls (P < 0.0001). Moreover, an inverse association was observed between serum IgA-anti-Fab activity and CD4+ cell counts (r = -0.396, P < 10(-6)). This close association was confirmed in longitudinal studies of symptomatic patients. IgA-anti-Fab antibodies are suggested to play an important role in the immunopathogenesis of AIDS, and their determination may be helpful in the monitoring of HIV-infected patients.
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Síndrome de Inmunodeficiencia Adquirida/inmunología , Autoanticuerpos/biosíntesis , Infecciones por VIH/inmunología , VIH-1/inmunología , Inmunoglobulina A/biosíntesis , Fragmentos Fab de Inmunoglobulinas/biosíntesis , Complejo Relacionado con el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/patología , Linfocitos T CD4-Positivos/inmunología , Ensayo de Inmunoadsorción Enzimática , Seropositividad para VIH/inmunología , Hemofilia A/inmunología , Humanos , Recuento de LeucocitosRESUMEN
OBJECTIVE: We investigated whether the induction of antilymphocyte autoantibodies and immune complexes is associated with the activity of HIV replication. METHODS: Viral HIV-1 RNA was measured in the plasma samples of 84 HIV+ hemophilia patients and correlated with the IgM, IgG, IgM/IgG and IgM/IgG/gp120 load of circulating CD4+ lymphocytes, CD4+ and CD8+ cell counts, plasma neopterin levels and in vitro T-cell responses to mitogens and pooled allogeneic stimulator cells. RESULTS: Compared to patients with no immune complexes, on circulating CD4+ lymphocytes, viral load was increased in patients with IgM, IgM/IgG or IgM/IgG/gp120 complexes. Sequential analysis of HIV+ patients showed that peaks of retroviral activity were associated with the subsequent formation of CD4+ lymphocyte-reactive IgM and IgG autoantibodies and gp120-containing immune complexes. CONCLUSION: The induction of autoantibodies and immune complexes attached to CD4+ lymphocytes is associated with periods of increased viral activity in HIV-infected patients.
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Complejo Antígeno-Anticuerpo/análisis , Autoanticuerpos/análisis , Linfocitos T CD4-Positivos/inmunología , Proteína gp120 de Envoltorio del VIH/análisis , Infecciones por VIH/inmunología , VIH-1 , Hemofilia A/inmunología , Hemofilia A/virología , Carga Viral , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/complicaciones , Hemofilia A/complicaciones , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina M/análisisRESUMEN
The concept of autoimmune mechanisms playing an integral role in the pathogenesis of HIV disease is rapidly gaining ground. In this study, we determined IgM and IgG antibodies, complement fragments and gp120 on the surface of CD4+ lymphocytes using double-fluorescence flow cytometry. Sequential analysis demonstrated an inverse relationship of autoantibodies and CD4+ lymphocyte counts in the peripheral blood. HIV+ patients without autoantibodies (16/104 = 15%) had the highest CD4+ blood cell counts (324 +/- 264/microliters; mean +/- SD). CD4+ counts were successively lower in patients with complement-fixing IgM (243 +/- 240/microliter), complement-fixing IgG and IgM (139 +/- 138/microliter), or gp120-IgM/IgG complement complexes on the surface of CD4+ cells (38 +/- 45/microliter, P = 0.03). Individual patient profiles show that IgM autoantibodies typically are formed early after HIV infection and appear to deplete CD4+ lymphocytes very slowly, whereas complement-fixing IgG autoantibodies are generated at a later stage and deplete CD4+ lymphocytes more efficiently. The presence of both soluble gp120 and complement-fixing autoantibodies on CD4+ lymphocytes is associated with very low CD4+ cell counts and coincides with progression to terminal disease. Early during HIV infection autoantibody production is rather unstable, but it becomes more stable with disease progression and persists in advanced stages of the disease. These data suggest that autoantibody formation against CD4+ lymphocytes is a pathogenic mechanism for CD4+ cell depletion.
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Complejo Antígeno-Anticuerpo/sangre , Linfocitos T CD4-Positivos/inmunología , Complemento C3d/análisis , Seropositividad para VIH/inmunología , Hemofilia A/inmunología , Linfopenia/inmunología , Autoanticuerpos/sangre , Recuento de Linfocito CD4 , Proteína gp120 de Envoltorio del VIH/sangre , Proteína gp120 de Envoltorio del VIH/inmunología , Seropositividad para VIH/sangre , Hemofilia A/sangre , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Linfopenia/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Human immunodeficiency virus (HIV)-induced immune complex load on circulating CD4+ blood lymphocytes is associated with dysfunction and depletion of CD4+ lymphocytes and with increased monocyte/macrophage function. It was investigated whether HAART reduces both the viral load in plasma and the number of immune complex-coated CD4+ lymphocytes in the blood, and whether CD4+ counts are associated with viral load and/or immune complex load. MATERIALS AND METHODS: Twelve HIV+ hemophilia patients before and after conversion to HAART (group 1); eight HIV+ hemophilia patients without antiretroviral therapy (group 2). HIV-1 RNA copies in plasma using NASBA/Nuclisens kits; CD4+ lymphocytes coated in-vivo with immune complexes using flowcytometry on whole blood samples; in-vitro responses of immune complex-coated T lymphocytes in cell culture assays. RESULTS: After conversion to HAART there was a significant reduction of viral load, CD4+ gp120+, CD4+ IgM+, and CD4+ IgG+ circulating blood lymphocytes and plasma neopterin, paralleled by a significant increase of CD4+ and CD8+ counts. The percentage of immune complex-coated CD4+ lymphocytes of converted patients was significantly associated with CD4+ counts, in-vitro responses to concanavalin A (Con A), pokeweed mitogen (PWM), phytohaemagglutinin (PHA), anti-CD3 and pooled allogeneic stimulator cells, and with plasma neopterin levels. CONCLUSION: HAART reduces viral load and HIV-induced immune complex load on circulating CD4+ blood lymphocytes. The results of this study can be interpreted to suggest that HAART increases CD4+ lymphocyte counts in part by counteracting HIV-induced autoimmune phenomena.
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Fármacos Anti-VIH/farmacología , Anticuerpos Antiidiotipos/sangre , Complejo Antígeno-Anticuerpo/sangre , Autoanticuerpos/sangre , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/farmacología , Hemofilia A/inmunología , Inmunoglobulinas/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Viremia/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Autoinmunidad , Linfocitos T CD4-Positivos/virología , Concanavalina A/farmacología , Quimioterapia Combinada , Proteína gp120 de Envoltorio del VIH/sangre , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Hemofilia A/sangre , Hemofilia A/complicaciones , Humanos , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Masculino , Mitógenos/farmacología , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Carga Viral , Viremia/inmunologíaRESUMEN
Previous studies interpreted increases of soluble Fas (sFas) in the plasma during disease progression in HIV-infected patients as evidence of increased apoptosis of CD4(+) lymphocytes. We studied whether sFas and sFas ligand (sFasL) plasma levels are associated with CD4(+) and CD8(+) lymphocyte counts, plasma viral load, and IgM, IgG, C3d, and gp120 complexes on circulating CD4(+) blood lymphocytes in long-term surviving HIV-infected hemophilia patients, most of whom were receiving HAART. Twenty-six hemophilia patients who were infected with HIV in the early 1980s were investigated in 1997, 1998, and 1999. HAART was initiated in 1996 and 1997 in most patients. Lymphocyte subpopulations and immune complex-coated CD4(+) lymphocytes in the blood were investigated by flow cytometry, plasma viral load (HIV-1 mRNA copies/ml plasma) was tested with HIV-1 QT Nuclisens kits, sFas (ng/ml) and sFasL (ng/ml) plasma levels were measured with MBL ELISA kits, and the in vitro response of patient lymphocytes was tested in cell cultures. During the period from 1997 to 1999 we observed an increase in sFas plasma levels (p = 0.003) as well as in CD4(+) (p = 0.004) and CD8(+) (p = 0.023) cell counts; a decrease in IgG (p = 0.047), C3d (p = 0.024), and gp120 (p = 0.001)-coated CD4(+) lymphocytes in the blood; and a decrease in the number of impaired mitogen stimulation assays (p = 0.013). sFas was negatively associated with viral burden (r = -0.662, p = 0.0002) as well as with CD4(+)IgM(+) (r = -0.554, p = 0.004), CD4(+)IgG(+) (r = -0.431, p = 0.031), CD4(+)C3d(+) (r = -0.551, p = 0.041), and CD4(+)gp120(+) (r = -0.430, p = 0.041) blood lymphocytes, CD8(+)DR(+) cell counts (r = -0.700, p = 0.016), and impaired in vitro responses of patient lymphocytes to PHA (r = -0.475, p = 0.016). sFasL was negatively associated with total lymphocyte counts (r = -0.433, p = 0.027), as well as with absolute numbers of CD3(+) (r = -0.492, p = 0.011) and CD8(+) (r = -0.432, p = 0.027) cells. We conclude that, contrary to expectations, sFas plasma levels increased in long-term surviving HIV-infected hemophilia patients receiving HAART, concomitant with increases in CD4(+) and CD8(+) cell counts. Increased sFas may reflect the growing pool of T lymphocytes that recovers because of a decreasing viral burden and a decreasing immune complex load of CD4(+) lymphocytes.
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Complejo Antígeno-Anticuerpo/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/fisiología , Hemofilia A/complicaciones , Receptor fas/sangre , Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Proteína Ligando Fas , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Activación de Linfocitos , Recuento de Linfocitos , Glicoproteínas de Membrana/sangre , ARN Viral/sangre , Carga ViralRESUMEN
The multicenter prospective non-interventional AHEAD study was initiated to obtain long-term outcome data on joint health, HR-QoL, haemophilia-related co-morbidities, and the effectiveness and safety of ADVATE (recombinant anti-hemophilic factor VIII, plasma-free method [octocog alfa]) in routine clinical practice. The German AHEAD study arm aims to enroll up to 500 patients in up to 35 haemophilia treatment centers (HTCs); patient recruitment started in June 2010. The study arm conducted in other European countries is expected to enroll 350 patients from more than 50 HTCs; recruitment started in June 2011. In both study arms, recruitment will continue through the end of 2015, and each enrolled patient will be followed for a total of four years.
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Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia A/mortalidad , Hemorragia/mortalidad , Hemorragia/prevención & control , Artropatías/mortalidad , Artropatías/prevención & control , Comorbilidad , Europa (Continente)/epidemiología , Alemania/epidemiología , Humanos , Incidencia , Selección de Paciente , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
UNLABELLED: An adequate number of qualified haemophilia centres is an essential requirement for effective and cost-efficient haemophilia care. During a reassessment of the delivery of haemophilia care in Germany a broad range of criteria relating to structure and quality of the centres were defined and a questionnaire was developed. RESULTS: Of 137 doctors who received the questionnaire, 113 (82%) replied. Based on data related to diagnostic and treatment services, together with voluntary information from PEI forms (Paul Ehrlich Institut, Germany), 72 haemophilia centres were established. Three levels of haemophilia care were defined by the Medical Advisory Council of the German Haemophilia Society. This is in accordance with criteria defined by European working parties. 17 haemophilia centres were designated CCC (Comprehensive Care Centre), 24 were designated HTC (Haemophilia Treatment Centre) and 31 smallest centres were allocated the status HTR (Haemophilia Treatment Regional). In comparison to the survey in 2007, there was only slight variance in the CCC centres (+ 2 centres/-1 centre). From the previous HTC centres, 7 have withdrawn from this treatment level: 4 maintain treatment on the lower level HTR, and 3 centres had ceased treatment. On the HTR level of treatment, 6 of 29 (21%) had ceased to offer treatment. 9 had been able to increase the number of patients and were designated HTC. 5404 patients with haemophilia and 3047 with the severe form of haemophilia were reported. 67% were treated in CCC, 25% in haemophilia treatment centres and 8% in the 31 smallest centres. 13 of the adult CCC are situated in the department of internal medicine and 4 in the section of transfusion medicine. CONCLUSIONS: The survey and analysis of the haemophilia treatment centres in Germany show that the delivery of haemophilia care through 17 CCC, 24 HCT and 31 HTR appears to be adequately structured. But it is noticeable and alarming, however, that on both HTC and HTR levels of treatment, 32% and 21%, respectively, have left their treatment level. 9 centres (12.5%) have finished working in haemophilia care in the last four years. On the strength of these results, endeavours to maintain haemophilia centres must be intensified. A high level of effective care can be guaranteed only through continued existence of the centres.
Asunto(s)
Instituciones de Atención Ambulatoria/estadística & datos numéricos , Instituciones de Atención Ambulatoria/normas , Atención a la Salud/estadística & datos numéricos , Atención a la Salud/normas , Hemofilia A/prevención & control , Hemofilia A/terapia , Garantía de la Calidad de Atención de Salud/estadística & datos numéricos , Alemania/epidemiología , Encuestas Epidemiológicas , Hemofilia A/epidemiología , Humanos , PrevalenciaRESUMEN
BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. OBJECTIVES: The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. RESULTS: Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. CONCLUSIONS: Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA.
Asunto(s)
Hemofilia A , Hemorragia , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Distribución de Chi-Cuadrado , Europa (Continente)/epidemiología , Factor VIII/inmunología , Femenino , Hemofilia A/diagnóstico , Hemofilia A/inmunología , Hemofilia A/mortalidad , Hemofilia A/terapia , Hemorragia/diagnóstico , Hemorragia/inmunología , Hemorragia/mortalidad , Hemorragia/terapia , Técnicas Hemostáticas , Humanos , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Embarazo , Estudios Prospectivos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
The mechanism of CD4+ cell depletion and functional T helper cell inhibition in HIV-infected individuals is poorly understood. The present study demonstrates that immune complex-covered CD4+ cells are associated with T cell inhibition and macrophage stimulation. We studied 30 patients with ARC/AIDS and 35 asymptomatic HIV+ haemophilia patients. Overall, 20 +/- 3% of peripheral CD4+ lymphocytes were covered with gp120 (range 0-94%). gp120+ cells also exhibited surface-bound IgG (P = 0.0001), IgM (P = 0.0001), and complement (P = 0.0001). Decreased in vitro lymphocyte proliferation was associated with the immune complex load of CD4+ cells. The higher the percentage of CD4+ gp 120+ cells in the blood, the lower the T cell response in vitro (P = 0.001). Moreover, an association was found between immune complex-positive cells and plasma neopterin (P = 0.01). Patients with increased plasma neopterin levels had decreased in vitro responses to pokeweed mitogen (PWM) (P = 0.006), phytohaemagglutinin (PHA) (P = 0.004), concanavalin A (Con A) (P = 0.09), and anti-CD3 MoAb (P = 0.03), and decreased CD4+ cell counts in the blood (P = 0.006). Since maximally 1% of CD4+ lymphocytes are infected with HIV, T cell dysfunction and T cell depletion in HIV-infected patients may also be caused by the release of free gp120 that binds to uninfected CD4+ cells. Our data suggest that the functional inhibition and subsequent elimination of uninfected CD4+ lymphocytes with surface gp120-immunoglobulin-complement complexes may be a pathomechanism in the manifestation of AIDS.
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Proteínas del Sistema Complemento/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Humanos , Inmunoglobulinas/inmunología , Depleción LinfocíticaRESUMEN
It is believed that autoimmune phenomena and apoptosis contribute to CD4 depletion. We investigated 11 long-term (>20 years) HIV-infected haemophilia patients and 10 healthy controls. Using four-colour-fluorescence flow cytometry, we studied the proportions of CD3+CD4+ and CD3+CD4- blood lymphocytes that were CD95+, CD95L+, immune complex+ (IC+, consisting of IgM, IgG, C3d and/or gp120), and were viable or non-viable (propidium iodide+ = PI+). In addition, we studied viability of CD4+IgG+ patient lymphocytes using the apoptosis marker annexin and the permeability indicator 7-amino actinomycin D (7-AAD). HIV+ patients had a higher proportion of CD3+CD4+IgG+PI+ lymphocytes than healthy controls (median: 3.7%versus 0.3%; P = 0.00001). These non-viable IgG-coated lymphocytes might have been killed in vivo by ADCC or complement lysis; 9.1% of the circulating CD3+CD4+ blood lymphocytes were IgG+PI- (controls: 2.5%; P = 0.001). These viable IgG-coated lymphocytes might be targets for phagocytosis or anti-CD95 autoantibody-mediated apoptosis. Because HIV+ patients and healthy controls had similar proportions of PI+ or PI- CD3+CD4+ lymphocytes that carried CD95L on the surface, and because CD3+CD4+CD95L+ cells that were IgG+, C3d+ and/or gp120- were increased in HIV+ patients, the role of CD95L-induced apoptosis in long-term HIV-infected haemophilia patients remains unclear. The findings that HIV+ patients had higher proportions of CD3+CD4+CD95+ (PI+: 6.5%versus 1.4%; P = 0.00002; PI-: 55.8%versus 44.4%; P = 0.04) blood lymphocytes and that the proportion of CD4+IgG+Annexin+7-AAD- blood lymphocytes was associated inversely with peripheral CD4 counts (r = -0.636; P < 0.05) suggest that attachment of IgG to CD4+ blood lymphocytes (anti-CD95?) induces in some lymphocytes apoptosis with subsequent depletion of these IgG-coated apoptotic CD4+ lymphocytes from the circulation. We found supporting evidence for the contention that autoantibody-induced apoptotic and non-apoptotic mechanisms contribute to CD4 depletion in long-term HIV-infected haemophilia patients.
Asunto(s)
Apoptosis/inmunología , Autoanticuerpos/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1 , Adolescente , Adulto , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Recuento de Linfocito CD4 , Citotoxicidad Inmunológica/inmunología , Femenino , Citometría de Flujo , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Hemofilia A/complicaciones , Hemofilia A/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunofenotipificación , Estudios Longitudinales , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Fagocitosis/inmunología , ARN Viral/sangre , Carga ViralRESUMEN
The contribution of autoimmune phenomena to the pathogenesis of acquired immunodeficiency syndrome (AIDS) is poorly understood. We investigated the relationship between IgG-anti-Fab gamma autoantibodies and the main immunologic feature of AIDS, the decrease of CD4+ helper lymphocytes. Sera of 33 human immunodeficiency virus (HIV) infected (HIV+) hemophilia patients with AIDS/AIDS-related complex (ARC), 57 HIV+ patients without AIDS/ARC, 23 HIV-negative (HIV-) patients, and 76 healthy controls were tested for antibody activity against the Fab region of IgG. Patients with AIDS/ARC had significantly higher IgG-anti-Fab gamma activity than HIV+ patients without AIDS/ARC, HIV- patients, or controls (P less than .0001). A striking inverse association was found between IgG-anti-Fab gamma and CD4+ cell counts (r = -.69; P less than 10(-6)). Sequential testing in 16 AIDS/ARC patients showed that an increase in the IgG-anti-Fab gamma activity was invariably accompanied by a decrease in the CD4+ cell count. IgG-anti-Fab gamma antibodies may play an important role in the immunopathogenesis of AIDS.
Asunto(s)
Complejo Relacionado con el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Autoanticuerpos/sangre , Fragmentos Fab de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Linfocitos T Colaboradores-Inductores/patología , Complejo Relacionado con el SIDA/sangre , Síndrome de Inmunodeficiencia Adquirida/sangre , Anticuerpos Antiidiotipos/sangre , Autoantígenos/inmunología , Seropositividad para VIH/sangre , Seropositividad para VIH/inmunología , Humanos , Recuento de LeucocitosRESUMEN
The mechanism of CD4+ lymphocyte depletion, which is the main immunological feature in HIV-infected patients, is unclear. We investigated whether gp120-immunoglobulin-complement complexes on the surface of CD4+ cells might be involved in the elimination of CD4+ lymphocytes. The results obtained in 63 HIV-infected patients show that gp120 is attached to a variable degree to CD4+ cells. Importantly, the percentage of CD4+gp120+ lymphocytes is inversely associated with CD4+ lymphocyte counts in the peripheral blood (p = 0.0004). CD4+gp120+ blood lymphocytes bind IgM (p = 0.0027) and IgG antibodies (p = 0.0001) and complement (p = 0.0005). These results suggest that immune complex-mediated cell elimination is an important mechanism of CD4+ cell depletion in patients with AIDS.