RESUMEN
Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.
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Hemofilia A , Hemostáticos , Biomarcadores , Factor VIII , Hemofilia A/tratamiento farmacológico , Humanos , Inmunoglobulina G , Estudios ProspectivosRESUMEN
INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.
Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Niño , Preescolar , Factor VIII/farmacología , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Lactante , Proteínas Recombinantes de Fusión/farmacología , Estudios RetrospectivosRESUMEN
Although hemophilia B affects 1 in 25,000 males there may be 3 female hemophilia B carriers per affected male. This clinical review highlights the unique challenges faced by hemophilia B carriers including the under-recognition of bleeding symptoms associated with and without FIX deficiency, discrepancies in correlation between genotype and bleeding phenotype and therapeutic considerations utilizing clinical vignettes of common scenarios.
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Hemofilia B/complicaciones , Hemorragia/etiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Hemofilia B/patología , Hemorragia/patología , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes. In anticipation of future studies in FVIII-deficient dogs, we investigated the efficacy of FIV-delivered canine FVIII (cFVIII). Codon-optimization of the cFVIII sequence increased activity and decreased blood loss as compared to the native sequence. Further, we compared a standard B-domain deleted FVIII cDNA to a cDNA including 256 amino acids of the B-domain with 11 potential asparagine-linked oligosaccharide linkages. Restoring a partial B-domain resulted in modest reduction of endoplasmic reticulum (ER) stress markers. Importantly, our optimized vectors achieved wild-type levels of phenotypic correction with minimal inhibitor formation. These studies provide insights into optimal design of a therapeutically relevant gene therapy vector for a devastating bleeding disorder.
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Factor VIII/genética , Factor VIII/uso terapéutico , Hemofilia A/terapia , Animales , ADN Complementario/genética , Perros , Factor VIII/fisiología , Terapia Genética/métodos , Vectores Genéticos , Hemofilia A/genética , Hepatocitos , Lentivirus/genética , Infecciones por Lentivirus , Hígado/metabolismo , Ratones , FenotipoRESUMEN
In the course of establishing the discourse of public health ethics in Germany, we discuss whether economic efficiency should be part of public health ethics and, if necessary, how efficiency should be conceptualized. Based on the welfare economics theory, we build a theoretical framework that demands an integration of economic rationality in public health ethics. Furthermore, we consider the possible implementation of welfare efficiency against the background of current practice in an economic evaluation of health care in Germany. The indifference of the welfare efficiency criterion with respect to distribution leads to the conclusion that efficiency must not be the only criteria of public health ethics. Therefore, an ethical approach of principles should be chosen for public health ethics. Possible conflicts between principles of such an approach are outlined.
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Programas Nacionales de Salud/economía , Programas Nacionales de Salud/ética , Salud Pública/economía , Salud Pública/ética , Análisis Costo-Beneficio , Alemania , Humanos , Asignación de Recursos/economía , Asignación de Recursos/éticaRESUMEN
BACKGROUND: Analysing a community's needs and requirements is useful for planning a community-based health promotion programme. The literature recommends the analysis of existing population-based data, the discussion with a community's key persons, and standardised surveys among the community members. With regagrd to the latter method, German-language literature is scarce. AIM: A community analysis in the Bavarian rural community Karlshuld (5 000 inhabitants) was intended to provide a starting point for tailored health promotion activities in the community. As a part of the community analysis, a survey among the Karlshuld citizens was intended to inform about (1) health-related knowledge and behaviour of the community members, (2) their utilization and acceptance of existing health-related offers and activities, (3) their possibilities for active participation, their state of empowerment and (4) community-related aspects influencing quality of life. METHODS: A standardised telephone survey was performed with a random sample of Karlshuld community members aged 15 years and older. The questions covered health-related living conditions and activities in Karlshuld, quality of life and participation of community members. In addition, data were collected on knowledge, attitude and behaviour with regard to the issues nutrition, physical activity and tobacco consumption. The sample comprised 314 community members (f=68.8%; age 43.9+/-13.8 years). RESULTS: Shortcomings in knowledge on healthy nutrition were evident, especially among male participants. Whereas the general attitude towards a healthy diet was favourable in the majority of respondents, only 45.9%/58.6% stated that they daily consumed vegetables/fruit. One third of the 27.4% smokers among the respondents had intended but failed to quit smoking in the previous year; 80% stated they were willing to quit. The participants named infrastructure, nature and health-related activities as positive aspects in Karlshuld. Only 50% knew where to get information on health-related issues. 42.9% of respondents felt they could influence decisions on health-related issues in the community. There was no correlation between school education and knowledge or participation. DISCUSSION: The survey among Karlshuld community members identified potential approaches to improving the community environment and to tailor health education activities to the special needs of Karlshuld. A follow-up survey in 2008/2009 will be carried out in order to evaluate whether or not the Karlshuld health promotion programme was successful in building on Karlshuld's strengths and influencing its weaknesses.
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Actitud Frente a la Salud , Servicios de Salud Comunitaria/estadística & datos numéricos , Promoción de la Salud/estadística & datos numéricos , Evaluación de Necesidades/organización & administración , Salud Rural/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Recolección de Datos , AlemaniaRESUMEN
Respiratory syncytial virus (RSV) is an important respiratory pathogen that preferentially infects epithelial cells in the airway and causes a local inflammatory response. Very little is known about the second messenger pathways involved in this response. To characterize some of the acute response pathways involved in RSV infection, we used cultured human epithelial cells (A549) and optimal tissue culture-infective doses (TCID(50)) of RSV. We have previously shown that RSV-induced IL-8 release is linked to activation of the extracellular signal-related kinase (ERK) mitogen-activated protein kinase pathway. In this study, we evaluated the upstream events involved in ERK activation by RSV. RSV activated ERK at two time points, an early time point consistent with viral binding and a later sustained activation consistent with viral replication. We next evaluated the role of protein kinase C (PKC) isoforms in RSV-induced ERK kinase activity. We found that A549 cells contain the Ca(2+)-dependent isoforms alpha and beta1, and the Ca(2+)-independent isoforms delta, epsilon, eta, mu, theta, and zeta. Western analysis showed that RSV caused no change in the amounts of these isoforms. However, kinase activity assays demonstrated activation of isoform zeta within 10 min of infection, followed by a sustained activation of isoforms beta1, delta, epsilon, and mu 24-48 h postinfection. A cell-permeable peptide inhibitor specific for the zeta isoform decreased early ERK kinase activation by RSV. Down-regulation of the other PKC isoforms with PMA blocked the late sustained activation of ERK by RSV. These studies suggest that RSV activates multiple PKC isoforms with subsequent downstream activation of ERK kinase.