Correspondence
Abacavir Hypersensitivity
N Engl J Med 2008; 358:2514-2516June 5, 2008
- Article
To the Editor:
The Prospective Randomized Evaluation of DNA Screening in a Clinical Trial (PREDICT-1) by Mallal et al. (Feb. 7 issue)1 showed that screening for HLA-B*5701 resulted in a significant reduction in the rate of hypersensitivity reactions (from 7.8% to 3.4%) among patients who were positive for the human immunodeficiency virus (HIV) and were receiving abacavir. However, because of methodologic limitations, this study will only modestly alter clinical practice. In the HLA-B*5701–negative group, all patients appeared to have a negative epicutaneous patch test (immunologic confirmation of a hypersensitivity reaction to abacavir). Notwithstanding the risks associated with rechallenge,2 the investigators should have taken this opportunity to perform a rechallenge with abacavir in controlled circumstances, especially in patients in whom the hypersensitivity reaction could be explained by other factors, including coadministered drugs. Furthermore, no information is provided about the reversibility of clinical “hypersensitivity” symptoms after discontinuing abacavir and perhaps other drugs. These clinical decisions were not peer reviewed. Hence, it remains unclear whether rechallenge with abacavir in patients without HLA-B*5701 and with a negative patch test may be worthwhile. This might have provided information with an effect on clinical practice.
2 ReferencesLinos Vandekerckhove, M.D., Ph.D.
Stijn Blot, Ph.D.
Dirk Vogelaers, M.D., Ph.D.
Ghent University Hospital, 9000 Ghent, Belgium
stijn.blot@ugent. be 1
Mallal S ,Phillips E ,Carosi G , et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358:568-579
Full Text | Web of Science | Medline2
Hetherington S ,McGuirk S ,Powell G , et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 2001;23:1603-1614
CrossRef | Web of Science | Medline
To the Editor:
In PREDICT-1, Mallal and colleagues found that prospective HLA-B*5701 screening reduced the incidence of hypersensitivity reactions to abacavir in a predominantly white population. In our 2006 study involving Martinican patients with HIV infection or AIDS, most of whom were of sub-Saharan African origin, abacavir had to be discontinued in 10 of 414 patients because of probable hypersensitivity reactions (2.4%; 95% confidence interval, 1.2 to 4.5). None of the black patients in this study carried the HLA-B*5701 allele. We subsequently screened 617 consecutive patients, seen at our hospital, for HLA-B*5701 (Table 1Table 1
HLA-B*5701 Results According to Race.). In this Martinican cohort of mainly black African ancestry, abacavir exposure was frequent, hypersensitivity reactions were rare, and the prevalence of HLA-B*5701 was low. In the Caribbean region, which is significantly affected by the HIV pandemic, black populations of African ancestry do not appear to be at high risk for hypersensitivity reactions, and it therefore seems inappropriate to restrict the prescription of abacavir in this population when HLA-B*5701 genotyping is not possible.Sylvie Abel, M.D.
Laure Paturel, M.D.
University Hospital of Fort-de-France, 97200 Fort-de-France, France
sylvie.abel@chu-fortdefrance. fr André Cabié, M.D.
Clinical Research Center of Antilles–Guyane, 97200 Fort-de-France, FranceAuthor/Editor Response
The PREDICT-1 study was specifically designed to study the effectiveness of screening for the HLA-B*5701 allele to prevent hypersensitivity to abacavir. The negative predictive value of HLA-B*5701 for patch-test–positive abacavir hypersensitivity was found to be 100%; we therefore disagree with Vandekerckhove et al. that our study will only modestly alter clinical practice. Randomized, placebo-controlled, double-blind clinical studies have shown a 2 to 7% rate of hypersensitivity among patients who were not receiving abacavir.1 Therefore, the 3.4% rate among patients with a clinical diagnosis of hypersensitivity but a negative patch test was expected. Indeed, for the purposes of our calculation of statistical power, we anticipated a rate of clinical overdiagnosis of 3.6% among patients in the screened group. In addition, nonblinded studies have shown that clinical overdiagnosis decreases dramatically over time, further providing support for the clinical impact of HLA-B*5701 screening and therefore lessening the need for a rechallenge study.1 Finally, it would not have been safe, practical, or methodologically sound to incorporate a double-blind, placebo-controlled rechallenge component into our study.
We commend Abel et al. for the approach that they took to establish the very low frequency of HLA-B*5701 carriage in a population of Martinican blacks. However, the clinical usefulness of screening is predicated on the reduction in both immunologically confirmed and false positive clinical diagnoses, and Abel et al. do not state whether the discontinuation rate of 2.4% observed in the prescreening phase decreased toward zero after screening was introduced; this decrease has been observed in unblinded screening programs reported on elsewhere.1 The approach that Abel and colleagues propose may be reasonable to use in small, static, and select populations in which the epidemiology of HLA-B*5701 carriage has been defined and access to screening may be unavailable; however, we caution against the generalization of this approach to other nonwhite populations with a low prevalence of HLA-B*5701. Given that HLA-B*5701 has been shown to have 100% sensitivity for immunologically confirmed hypersensitivity to abacavir in both black and white patients in the United States,2 selective screening on the basis of the perceived race or ethnic background of the patient is unlikely to be practical, ethical, or safe in most settings because of increasing rates of racial or ethnic admixture and global migration and because of the unreliability of the assignment of race or ethnic group by the patient or his or her clinician.3
3 ReferencesElizabeth Phillips, M.D.
David Nolan, M.B., B.S.
Simon Mallal, M.B., B.S.
Murdoch University, Murdoch, WA 6150, Australia
s.mallal@murdoch. edu. au 1
Phillips EJ ,Mallal SA . Pharmacogenetics and the potential for the individualization of antiretroviral therapy. Curr Opin Infect Dis 2008;21:16-24
CrossRef | Web of Science | Medline2
Saag M ,Balu R ,Phillips E , et al. High sensitivity of human leukocyte antigen-B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46:1111-1118
CrossRef | Web of Science | Medline3
Phillips EJ . Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis 2006;43:103-105
CrossRef | Web of Science | Medline
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