HLA-B*5701 Screening for Hypersensitivity to Abacavir

Mallal, Simon
Phillips, Elizabeth
Carosi, Giampiero
Molina, Jean-Michel
Workman, Cassy
Tomazic, Janez
Jagel-Guedes, Eva
Rugina, Sorin
Kozyrev, Oleg
Cid, Juan Flores
Hay, Phillip
Nolan, David
Hughes, Sara
Hughes, Arlene
Ryan, Susanna
Fitch, Nicholas
Thorborn, Daren
Benbow, Alastair

for the PREDICT-1 Study Team*
From Royal Perth Hospital and Murdoch University - both in Perth, Australia (S.M., E.P., D.N.); Universita degli Studi di Brescia, Brescia, Italy (G.C.); Hopital Saint Louis, Paris (J.-M.M.); AIDS Research Initiative, Darlinghurst, Australia (C.W.); University Medical Center Ljubljana, Ljubljana, Slovenia (J.T.); HIV Research and Clinical Care Center Munich, Munich, Germany (E.J.-G.); Infectioase Constanta, Bucharest, Romania (S.R.); Volgograd Regional Center for AIDS, Volgograd, Russia (O.K.); Hospital Arnau de Vilanova, Valencia, Spain (J.F.C.); St. George's Hospital (P.H.) and MediTech Media (S.R.) - both in London; GlaxoSmithKline, Greenford, United Kingdom (S.H.); GlaxoSmithKline, Research Triangle Park, NC (A.H.); and GlaxoSmithKline, Brentford, United Kingdom (N.F., D.T., A.B.). Address reprint requests to Dr. Mallal at the Institute for Immunology and Infectious Diseases, Murdoch University, South St., Murdoch, WA 6150, Australia, or at [email protected].
*Members of the Prospective Randomized Evaluation of DNA Screening in aClinical Trial (PREDICT-1) study team are listed in the Appendix.

New England Journal of Medicine 358(6):p 568-579, February 7, 2008.

Background

Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B5701 allele. This study was designed to establish the effectiveness of prospective HLA-B5701 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-B5701 screening, with exclusion of HLA-B5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B5701 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-B5701 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-B5701 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-B5701 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. (ClinicalTrials.gov number, NCT00340080.)

N Engl J Med 2008;358

568-79.