HLA-B*5701 screening for hypersensitivity to Abacavir

Background Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. Methods This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701–positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. Results The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). Conclusions HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug

PREDICT-1: A novel randomized prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects

Objective: Retrospective analyses have identified several risk factors for abacavir (ABC) HSR, however carriage of the HLA-B*5701 allele is the dominant risk factor. The PREDICT-1 study (clinicaltrials.gov identifier NCT00340080) was designed to provide robust and definitive data on the clinical utility of prospective screening for HLA-B*5701 on the incidence of ABC HSR. Methods: ABC-naive adults from 314 centres in Europe/Australia were randomised (1:1) to receive an ABC containing regimen according to standard of care [SOC] (retrospective pharmacogenetic screening) or SOC plus prospective pharmacogenetic screening (to exclude HLA-B*5701 carriers). Co-primary endpoints are incidence of (i) clinically suspected ABC HSR and (ii) clinically suspected ABC HSR with immunological confirmation. Immunologically confirmed ABC HSR was determined approximately 6 weeks following initial clinical diagnosis (ABC stopped at initial diagnosis) using epicutaneous patch testing (EPT). EPT results were evaluated by an Independent Committee. Results: 1956 patients were randomised. Baseline characteristics were similar between the two study arms. The incidence of both clinically diagnosed and immunologically confirmed HSR was significantly lower in the prospective screening arm compared with the control arm; no cases of immunologically confirmed HSR were observed in the prospective screening arm. Conclusion: The results from this landmark study demonstrate that prospective HLA-B*5701 screening results in a dramatic, clinically relevant and statistically significant reduction in abacavir HSR. The PREDICT-1 study provides the high level of evidence required to support the implementation of HLA-B*5701 screening into routine clinical practice and is the first randomised, blinded and powered study to validate pharmacogenetic screening as a clinical tool to personalise therapy