RESUMO
Aim: To determine if emicizumab was channeled to clinically complex people with hemophilia A upon approval. Methods: Claims data (16 November 2017, through 31 December 2019) from US-based insurance databases were analyzed to compare the clinical complexity of people with hemophilia A initiating emicizumab with matched individuals receiving factor VIII (FVIII) episodically or prophylactically. People with hemophilia A with evidence of previous bypassing agent use (indicating FVIII inhibitors) were excluded. Outcomes included bleeding events, arthropathy, pain, comorbidities and healthcare costs. Results: A larger proportion of emicizumab users had bleeding events, comorbidities and arthropathy and greater healthcare costs in the year prior to starting emicizumab compared with FVIII users. Conclusion: Claims-based data limitations prevent an absolute conclusion. Nevertheless, emicizumab users appear more clinically complex than FVIII users, suggesting post-approval channeling.
Assuntos
Anticorpos Biespecíficos , Hemofilia A , Hemostáticos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Humanos , PrescriçõesRESUMO
Aim: Compare thrombotic risk in people with congenital hemophilia A (PwcHA) to the general non-hemophilia A (HA) population. Patients & methods: US claims databases were analyzed to identify PwcHA. Incidence rates of myocardial infarction, pulmonary embolism, ischemic stroke, deep vein thrombosis and device-related thrombosis were compared with a matched cohort without HA. Results: Over 3490 PwcHA were identified and 16,380 individuals matched. PwcHA had a similar incidence of myocardial infarction and pulmonary embolism compared with the non-HA population, but a slightly higher incidence of ischemic stroke and deep vein thrombosis. The incidence of device-related thrombosis was significantly higher in PwcHA. Conclusion: This analysis suggests that PwcHA are not protected against thrombosis, and provides context to evaluate thrombotic risk of HA treatments.
Assuntos
Hemofilia A , Infarto do Miocárdio , Embolia Pulmonar , Acidente Vascular Cerebral , Trombose , Hemofilia A/complicações , Hemofilia A/epidemiologia , Humanos , Infarto do Miocárdio/epidemiologia , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Trombose/epidemiologia , Trombose/etiologiaRESUMO
BACKGROUND: As the first non-factor replacement therapy for persons with congenital hemophilia A (PwcHA), emicizumab's safety profile is of particular interest to the community. OBJECTIVES: We applied an algorithm for categorization of fatal events contemporaneous to emicizumab using reporter-assessed causality documented in the Roche Emicizumab Global Safety Database. PATIENTS/METHODS: All fatalities in PwcHA reported to the database (from clinical trials, pre-market access, and spontaneous post-marketing reports) were categorized into: associated with hemophilia A-hemorrhagic, thrombotic, human immunodeficiency virus (HIV)/hepatitis C virus (HCV), hepatic (non-HCV); associated with general population-trauma/suicide, non-HA-associated conditions; or, unspecified. Reported cause of death was not reassessed. RESULTS: As of cut-off May 15, 2020, 31 fatalities in PwcHA taking emicizumab were reported. Median age at death was 58 years; 51% had factor VIII inhibitors. Fifteen fatalities were considered associated with HA; overall, the most frequent category was hemorrhage (11/31). Of these, six had a history of life-threatening bleeds, and four had a history of intracranial hemorrhage. The remaining HA-associated fatalities were related to HIV/HCV (3/31) and other hepatic causes (1/31). No cases were categorized as thrombotic. Of 10 cases considered not associated with HA, two were categorized as cardiovascular (non-thrombotic), five as infection/sepsis, and one each of trauma/suicide, pulmonary, and malignancy. Six cases were unspecified. CONCLUSIONS: No unique risk of death was associated with emicizumab prophylaxis in PwcHA. The data reveal that mortality in PwcHA receiving emicizumab was primarily associated with hemorrhage or non-HA-associated conditions, and was not reported by treaters to be related to emicizumab treatment.
Assuntos
Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemofilia A/mortalidade , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator VIII , Feminino , Hemofilia A/diagnóstico , Humanos , Expectativa de Vida , MasculinoRESUMO
BACKGROUND: Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non-HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk-benefit profiles, timely identification of emerging safety signals, and comparisons between treatments. OBJECTIVES: Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies. PATIENTS/METHODS: We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept. RESULTS: PwcHA share mortality causes with the non-HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%). CONCLUSIONS: A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach.
Assuntos
Hemofilia A/mortalidade , Sistemas de Notificação de Reações Adversas a Medicamentos , Causas de Morte , Comorbidade , Bases de Dados Factuais , Feminino , Hemofilia A/diagnóstico , Humanos , Expectativa de Vida , Masculino , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven® , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra® ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program. OBJECTIVE: Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab. METHODS: The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed. RESULTS: The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 ± 20 µg/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials. CONCLUSION: rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information.
Assuntos
Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Fator VIIa/efeitos adversos , Hemofilia A/tratamento farmacológico , Trombose/induzido quimicamente , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Ensaios Clínicos como Assunto/estatística & dados numéricos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Fator VIII/imunologia , Fator VIIa/administração & dosagem , Fator VIIa/uso terapêutico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Isoanticorpos/imunologia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Hemorragia Pós-Operatória/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Risco , Trombose/prevenção & controleRESUMO
Association of HIV-1-specific T-cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T-cell responses in HIV-1 exposed, but uninfected subjects enrolled in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 envelope-specific T-cell responses were more uniformly IFN-γ+TNF-α+Mip-1ß+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 envelope V2 loop-specific CD8 T-cell responses may help to protect against HIV-1 acquisition.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimioprevenção , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Estudos de Casos e Controles , Estudos Transversais , Humanos , Ativação Linfocitária , Resultado do TratamentoRESUMO
We leveraged data from the Preexposure Prophylaxis Initiative (iPrEx), a global trial of preexposure chemoprophylaxis against human immunodeficiency virus type 1 (HIV-1) infection, to compare T-cell activation between those who remained negative for HIV-1 and those who became infected during the trial. The frequency of CD38(+)HLA-DR(+) CD8(+) T cells was greater in those who seroconverted, relative to the frequency in those who remained uninfected (1.30% vs 0.82%, respectively; P = .005). This translated to an odds ratio of 4.26 (95% confidence interval, 1.54-11.78) for the association between CD8(+) T-cell activation and infection with HIV-1. T-cell activation may be a biomarker for elevated HIV-1 infection risk.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/patologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , ADP-Ribosil Ciclase 1/análise , Adolescente , Adulto , Linfócitos T CD8-Positivos/química , Infecções por HIV/virologia , HIV-1/imunologia , Antígenos HLA-DR/análise , Humanos , Masculino , Glicoproteínas de Membrana/análise , Adulto JovemRESUMO
HIV-1-specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case-control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1-negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19-0.66 and HR = 0.52, 95% CI = 0.28-0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1-specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Imunidade Celular/imunologia , Leucócitos Mononucleares/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/virologia , Soropositividade para HIV/imunologia , HIV-1/metabolismo , HIV-1/fisiologia , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Leucócitos Mononucleares/metabolismo , Modelos Logísticos , Masculino , Análise Multivariada , Adulto JovemRESUMO
OBJECTIVE: To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME). DESIGN: A population approach of nonlinear mixed-effect pharmacokinetics modeling based on serum concentrations of ranibizumab measured at various times after intravitreal administration. PARTICIPANTS: Patients with RVO (n = 441) and DME (n = 435) from 4 large, randomized, phase 3 clinical trials of monthly ranibizumab intravitreal administration. METHODS: A 1-compartment pharmacokinetics model with first-order absorption and elimination rate constants previously developed in patients with age-related macular degeneration (AMD) was fitted separately to RVO and DME data. Population pharmacokinetic parameters and interindividual variability were estimated for each model. Baseline covariates were evaluated for potential effects on systemic pharmacokinetics. Model performance was validated using general diagnostic plots and a visual predictive check. MAIN OUTCOME MEASURES: Ranibizumab disposition was determined in RVO and DME patients and compared with that previously seen in AMD patients. RESULTS: The AMD pharmacokinetics model correctly predicted the measured serum ranibizumab concentration data for RVO and DME patients. Most observed data points were within the simulated 90% confidence interval, indicating that systemic ranibizumab concentrations were comparable among AMD, RVO, and DME patients. No disease-related covariates were identified by the population pharmacokinetics analysis. CONCLUSIONS: The systemic pharmacokinetics of ranibizumab were similar among patients with AMD, RVO, or DME. Disease-related differences and patient demographics, measured in this study, did not lead to variability in ocular elimination or in systemic exposure of ranibizumab after intravitreal administration. In all disease processes tested, ranibizumab exits the eye slowly and then is eliminated rapidly from the circulation, thus minimizing systemic exposure.
Assuntos
Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais Humanizados/farmacocinética , Retinopatia Diabética/metabolismo , Edema Macular/metabolismo , Oclusão da Veia Retiniana/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Meia-Vida , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Ranibizumab , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto JovemRESUMO
The genetic background of HIV-1-infected subjects, particularly the HLA class I haplotype, appears to be critical in determining disease progression rates, thought to be a result of the role of HIV-1-specific CD8(+) T cell responses. The HLA-B*57 allele is strongly associated with viremic suppression and slower disease progression. However, there is considerable heterogeneity in HIV-1 disease progression rates among HLA-B*57-positive subjects, suggesting that additional factors may help to contain viral replication. In this report, we investigated the association between host restriction factors, other established immunological parameters, and HLA type in HIV-1-seronegative individuals. Our results demonstrate that healthy, uninfected HLA-B*57-positive individuals exhibit significantly higher gene-expression levels of host restriction factors, such as APOBEC3A, APOBEC3B, BST-2/tetherin, and ISG15. Interestingly, HLA-B*57 individuals have significantly lower CD4(+) T cell frequencies but harbor slightly more activated CD4(+) T cells compared with their HLA-B*35 counterparts. We detected significant correlations between CD4(+) T cell activation and expression of several APOBEC3 family members, BST-2/tetherin, SAMHD1, and TRIM5α in HLA-B*57-positive individuals. To our knowledge, this is the first report showing distinct associations between host restriction factors and HLA class I genotype. Our results provide insights into natural protection mechanisms and immunity against HIV-1 that fall outside of classical HLA-mediated effects.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , HIV-1/imunologia , Antígenos HLA-B/genética , Linfócitos T CD4-Positivos/imunologia , Citidina Desaminase/fisiologia , Feminino , Antígeno HLA-B35/genética , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Proteínas Monoméricas de Ligação ao GTP/fisiologia , Proteínas/fisiologia , Receptores CCR5/fisiologia , Receptores de HIV/análise , Proteína 1 com Domínio SAM e Domínio HDRESUMO
PURPOSE: To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS: A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS: A TOTAL OF 696 CONCENTRATION-TIME RECORDS FROM 229 SUBJECTS WITH ONE OR MORE MEASURABLE TOTAL SERUM RANIBIZUMAB CONCENTRATIONS WERE ANALYZED. THE SYSTEMIC CONCENTRATION-TIME DATA FOR RANIBIZUMAB WERE BEST DESCRIBED BY A ONE-COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION INTO AND FIRST-ORDER ELIMINATION FROM THE SYSTEMIC CIRCULATION. VITREOUS ELIMINATION HALF-LIFE (T1/2) WAS CALCULATED TO BE 9 DAYS AND THE INTRINSIC SYSTEMIC ELIMINATION T1/2 WAS CALCULATED TO BE APPROXIMATELY 2 HOURS. FOLLOWING ITV ADMINISTRATION, RANIBIZUMAB EGRESSES SLOWLY INTO THE SYSTEMIC CIRCULATION, RESULTING IN AN APPARENT SERUM T1/2 OF 9 DAYS. SYSTEMIC-TO-VITREOUS EXPOSURE RATIO WAS ESTIMATED TO BE 1: 90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steady-state for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times. CONCLUSIONS: Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.).
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Degeneração Macular/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Meia-Vida , Humanos , Injeções Intravítreas , Masculino , Ranibizumab , Corpo Vítreo/metabolismoRESUMO
Psoriasis is a hyper-proliferative disease of the skin in which immunological mechanisms play a direct pathogenetic role. There have been limited studies of natural killer (NK) cells in psoriasis. The aim of this study was to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells from patients with psoriasis and healthy controls. CD56(+) CD16(-) and CD56(+) CD16(+) NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A and NKG2C was assessed by flow cytometry. NK cells in psoriasis skin lesions were skewed in their expression of CD57, a marker of NK cell maturity, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. These data suggest that in this patient cohort, NK cells could be isolated from psoriasis lesions and exhibit an immature phenotype.
Assuntos
Antígenos CD57/metabolismo , Células Matadoras Naturais/metabolismo , Psoríase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Diferenciação Celular , Humanos , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fenótipo , Psoríase/sangue , Receptores de IgG/metabolismo , Pele/citologia , Pele/imunologia , Adulto JovemRESUMO
An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis.
Assuntos
Genes MHC da Classe II , Genes MHC Classe I , Psoríase/genética , Psoríase/imunologia , Genes MHC Classe I/imunologia , Genes MHC da Classe II/imunologia , Estudos de Associação Genética , Predisposição Genética para Doença , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/patogenicidade , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Polimorfismo Genético , Ligação Proteica , Receptores KIR3DS1/genéticaRESUMO
Previous genetic and functional studies have implicated the human endogenous retrovirus K (HERV-K) dUTPase located within the PSORS1 locus in the major histocompatibility complex region as a candidate psoriasis gene. Here, we describe a variant discovery and case-control association study of HERV-K dUTPase variants in 708 psoriasis cases and 349 healthy controls. Five common HERV-K dUTPase variants were found to be highly associated with psoriasis, with the strongest association occurring at the missense single-nucleotide polymorphism (SNP) rs3134774 (K158R, P=3.28 × 10(-15), odds ratio =2.36 (95% confidence interval: 1.91-2.92)). After adjusting the association of the HERV-K dUTPase variants for the potential confounding effects of HLA alleles associated with psoriasis, the HERV-K SNPs rs9264082 and rs3134774 remained significantly associated. Haplotype analysis revealed that HERV-K haplotypes containing the non-risk alleles for rs3134774 and rs9264082 significantly reduced the risk of psoriasis. Functional testing showed higher antibody responses against recombinant HERV-K dUTPase in psoriasis patients compared with controls (P<0.05), as well as higher T-cell responses against a single HERV-K dUTPase peptide (P<0.05). Our data support an independent role for the HERV-K dUTPase on psoriasis susceptibility, and suggest the need for additional studies to clarify the role of this dUTPase in the pathogenesis of psoriasis.
Assuntos
Retrovirus Endógenos/enzimologia , Psoríase/etiologia , Pirofosfatases/fisiologia , Alelos , Linfócitos B/imunologia , Estudos de Casos e Controles , Suscetibilidade a Doenças , Retrovirus Endógenos/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Linfócitos T/imunologiaRESUMO
BACKGROUND: In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied. METHODOLOGY/PRINCIPAL FINDINGS: We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) CD4+ T cells compared to LTS-SS subjects (pâ=â0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells compared to slow progressing subjects (p<0.0001). CONCLUSIONS/SIGNIFICANCE: Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Infecções por HIV/imunologia , Infecções por HIV/transmissão , HIV-1/patogenicidade , Transmissão Vertical de Doenças Infecciosas , Adolescente , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Progressão da Doença , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Humanos , MasculinoRESUMO
BACKGROUND: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (pâ=â0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. CONCLUSIONS/SIGNIFICANCE: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Progressão da Doença , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Epitopos Imunodominantes/imunologia , Transmissão Vertical de Doenças Infecciosas , Adolescente , Alelos , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/fisiologia , Degranulação Celular , Diferenciação Celular/imunologia , Estudos de Coortes , Citocinas/metabolismo , Feminino , Antígenos HLA/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , Especificidade da Espécie , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
(R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (GDC-0834) is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK), investigated as a potential treatment for rheumatoid arthritis. In vitro metabolite identification studies in hepatocytes revealed predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. The formation of M1 appeared to be NADPH-independent in human liver microsomes. M1 was found in only minor to moderate quantities in plasma from preclinical species dosed with GDC-0834. Human clearance predictions using various methodologies resulted in estimates ranging from low to high. In addition, GDC-0834 exhibited low clearance in PXB chimeric mice with humanized liver. Uncertainty in human pharmacokinetic prediction and high interest in a BTK inhibitor for clinical evaluation prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial. GDC-0834 plasma concentrations in humans were below the limit of quantitation (<1 ng/ml) in most samples from the cohorts dosed orally at 35 and 105 mg. In contrast, substantial plasma concentrations of M1 were observed. In human plasma and urine, only M1 and its sequential metabolites were identified. The formation kinetics of M1 was evaluated in rat, dog, monkey, and human liver microsomes in the absence of NADPH. The maximum rate of M1 formation (V(max)) was substantially higher in human compared with that in other species. In contrast, the Michaelis-Menten constant (K(m)) was comparable among species. Intrinsic clearance (V(max)/K(m)) of GDC-0834 from M1 formation in human was 23- to 169-fold higher than observed in rat, dog, and monkey.
Assuntos
Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinonas/metabolismo , Pirimidinonas/farmacocinética , Tiofenos/metabolismo , Tiofenos/farmacocinética , Tirosina Quinase da Agamaglobulinemia , Amidas/metabolismo , Animais , Células Cultivadas , Ensaios Clínicos Fase I como Assunto , Cães , Método Duplo-Cego , Feminino , Hepatócitos/metabolismo , Humanos , Hidrólise , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
OBJECTIVE: The majority of infants born, in developed countries, to HIV-1 positive women are exposed to the HIV-1 virus in utero or peri/post-partum, but are born uninfected. We, and others, have previously shown HIV-1 specific T cell responses in HIV-1 exposed seronegative (HESN) neonates/infants. Our objective in this study was to examine the rate of decay in their HIV-1 specific T cell response over time from birth. DESIGN: Cross-sectional and longitudinal studies of HIV-1 specific T cell responses in HESN infants were performed. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 18 HIV-1 DNA PCR negative infants born to HIV-1 infected mothers receiving care at the Jacobi Medical Center, Bronx, NY, USA. PBMC were examined for T cell responses to HIV-1 antigens by interferon-gamma (IFN-γ) ELISPOT. RESULTS: PBMC from 15 HESN neonates/infants were analyzed. We observed a decay of HIV-1 specific T cell responses from birth at a rate of -0.599 spot forming unit/106 cells per day, with a median half-life decay rate of 21.38 weeks (13.39-115.8). CONCLUSION: Our results support the dynamic nature of T cell immunity in the context of a developing immune system. The disparate rate of decay with studies of adults placed on antiretroviral drugs suggests that antigen specific T cell responses are driven by the natural rate of decay of the T cell sub-populations themselves.
RESUMO
Two bioequivalence (BE) studies in healthy volunteers comparing new formulations of the recombinant human growth hormone (rhGH) Nutropin AQ (somatropin [rDNA origin] injection; Genentech, Inc., South San Francisco, CA) with the currently marketed formulation (5 mg/mL) were conducted to extend available dosing options. All formulations were administered by subcutaneous (SC) injection ranging in volume from 0.25 to 1.0 mL depending on the formulation concentration. Study A was a 2-period crossover design to assess the BE of 5 and 10 mg/mL. The estimate for relative bioavailability (AUC(0-24 h)) was within the prespecified BE interval (0.80-1.25). However, while the C(max) estimate (1.17) was contained within the range for BE, the 90% CI (0.986-1.38) extended beyond the prespecified BE interval. As a result, Study A failed to show BE between the 5 and 10mg/mL formulations. Review of the data showed unexpected increased variability in the observed C(max). Further review of individual data suggested that in 4 subjects, the GH concentration profile of 1 of the 2 injections closely resembled the absorption kinetics of an intramuscular injection rather than an SC injection. Because study conduct may have contributed to these results, we performed a second study, Study B. This study incorporated injection technique training, a defined injection site, and a larger sample size to accommodate variability. It also included a third formulation, creating a 3-period crossover design to assess the BE of 2.5, 5, and 10 mg/mL. Study B results demonstrated BE of the new 2.5- and 10-mg/mL formulations to the reference 5-mg/mL formulation, and BE to each other, with all 90% CIs within the BE range of 0.80 to 1.25. Thus the challenge of recognizing that design issues could affect outcomes gave us the tools to perform a second study, and the positive results taught us that demonstrating BE is an issue not only of pharmacology, but also of study methodology and execution.
Assuntos
Hormônio do Crescimento Humano/farmacocinética , Proteínas Recombinantes/farmacocinética , Adolescente , Adulto , Disponibilidade Biológica , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Equivalência Terapêutica , Adulto JovemRESUMO
Human endogenous retrovirus K (HERV-K) is distinctive among the retroviruses that comprise about 8% of the human genome in that multiple HERV-K proviruses encode full-length viral proteins, and many HERV-K proviruses formed during recent human evolution. HERV-K gag proteins are found in the cytoplasm of primary tumor cells of patients with seminoma. We identified HERV-K-specific T cells in patients with a past history of seminoma using the interferon-gamma ELISPOT assay and an MHC-HERV-K peptide-specific tetramer. A minority of apparently healthy subjects without evident germ cell tumors also made HERV-K-specific T cell responses. In summary, we detected T cell reactivity to HERV-K peptides in both past seminoma patients and a minority of apparently healthy controls.