RESUMO
Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Dependovirus , Terapia Genética , Hemofilia A , Humanos , Dependovirus/imunologia , Dependovirus/genética , Masculino , Hemofilia A/imunologia , Hemofilia A/terapia , Adulto , Estudos Longitudinais , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Terapia Genética/métodos , Imunidade Adaptativa , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
OBJECTIVES: This study estimated the cost of prophylaxis with activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa) in surgical patients with haemophilia A and inhibitors in Spain. METHODS: A decision-analytic model was developed to estimate the cost to the Spanish National Health System of providing haemostatic coverage in this haemophilia population, with age distribution and average weight derived from the literature, and the annual number of surgeries (0.33 per patient) from local data. Drug costs were calculated from official ex-factory prices with a 7.5% mandatory deduction and recommended dosing regimens. RESULTS: The estimated average costs per patient were 10 100.73 (aPCC) and 14 265.89 (rFVIIa) for dental extraction, 24 043.88 (aPCC) and 62 301.08 (rFVIIa) for minor surgery and 126 595.81 (aPCC) and 347 731.09 (rFVIIa) for major surgery. Assuming an estimated 23 annual surgeries in this population (N = 69), distributed as 19% dental extraction, 50% minor surgery and 31% major surgery, the total annual cost of prophylaxis was 1 209 682.35 with aPCC and 3 221 929.28 with rFVIIa. CONCLUSIONS: aPCC costs were 62.5% lower than rFVIIa. Assuming potential clinical equivalence, aPCC is a potentially cost-saving option for surgical patients with haemophilia A and inhibitors.