Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations.

BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.

Cost-effectiveness analysis of HLA-B*5701 typing in the prevention of hypersensitivity to abacavir in HIV+ patients in Spain.

INTRODUCTION: Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hypersensitivity reaction (HSR). Various studies have shown a direct association between human leukocyte antigen (HLA)-B*5701 and HSR to abacavir. The objective of this study was to analyze whether systematic HLA-B*5701 testing to prevent HSR in patients treated with abacavir is a cost-effective option for the Spanish National Health System. METHODS: An analytical decision-making model was constructed as a decision tree model for a simulated cohort of 1000 HIV patients to evaluate whether HLA-B*5701 testing to prevent HSR to abacavir was cost effective compared with not performing the test. The parameters included in the model and the use of healthcare resources should the patient develop HSR were taken from the PREDICT-1 study and the opinion of clinical experts. The principal result obtained was the incremental cost per HSR avoided. The time horizon of the analysis was to 2 months [corrected] . All costs were expressed in 2008 Euros. RESULTS: The analysis showed that the total direct healthcare costs per patient were €1344 and €1322 with and without HLA-B*5701 testing respectively, and that 36 cases of HSR were prevented per 1000 screened patients. These results yielded a cost per HSR avoided of €630. The sensitivity analysis showed that the results were sensitive to the cost of the test, with an economic saving of €102 or a cost-effectiveness ratio of €4234. CONCLUSIONS: The model predicts that generalized use of the HLA-B*5701 test before prescribing abacavir in HIV+ patients could represent an economic saving or a limited additional cost for the National Health System which may be counterbalanced by the benefits in terms of a lower incidence of HSR.