Fast track — ArticlesAssociation between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir
Introduction
Abacavir is a commonly used nucleoside analogue with potent antiviral activity against HIV-1. About 5% (range 0–14%) of patients treated with abacavir develop a hypersensitivity reaction characterised by multisystem involvement that can be fatal in rare cases.1 Symptoms usually appear within the first 6 weeks of treatment (median time to onset 11 days) and characteristically include fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhoea, or abdominal pain) and lethargy or malaise. Less common manifestations include respiratory or musculoskeletal symptoms, headache, paraesthesia, oedema, renal or hepatic failure, or anaphylaxis.1 Symptoms related to the hypersensitivity reaction worsen with continued therapy and usually improve within 24 h of abacavir discontinuation. Rechallenge with abacavir after a hypersensitivity reaction typically results in recurrence of symptoms within hours, with the potential to induce a more severe clinical syndrome with increased risk of lifethreatening hypotension and death.2
Several observations support the possibility that genetic susceptibility factors for this idiosyncratic hypersensitivity syndrome exist, and more specifically that involved genetic loci lie within the MHC region. First, only a subset of individuals exposed to abacavir develop hypersensitivity, typically within 6 weeks of starting therapy, and those who do not develop the syndrome within this time remain at low risk despite continued therapy. Second, a meta-analysis of 25 clinical studies involving 5248 participants showed that ethnic origin might influence abacavir hypersensitivity, with decreased risk associated with black race.3 Familial predisposition has also been reported.4 Third, there is evidence that the pathogenesis of several similar multisystem drug hypersensitivity reactions involves MHC-restricted presentation of drug or drug metabolites, with direct binding of these non-peptide antigens to MHC molecules or haptenation to endogenous proteins before T-cell presentation.5, 6, 7
Investigation of associations between MHC alleles and clinical phenotypes can be facilitated by an understanding of expected linkage disequilibrium across the MHC. Particular arrangements of alleles, referred to as ancestral haplotypes, are known to be maintained and transmitted through generations en bloc, with a low frequency of recombination events within these genetic blocks.8, 9 Ancestral haplotypes and their simple recombinants (ie, a haplotype resulting from one historical crossover event between two ancestral haplotypes) have been suggested to account for at least 70% of the observed haplotypes in white populations.10 Individual alleles can be haplospecific (eg, HLA-B*5701 and the 57·1 ancestral haplotype) or common to multiple ancestral haplotypes (eg, HLA-DRB1*0701 represented in 57·1, 47·1 and 13·1 haplotypes).8, 9, 10
We therefore sought associations between MHC alleles and abacavir hypersensitivity in the first 200 individuals treated with abacavir in the Western Australian HIV Cohort.
Section snippets
Patients
581 active participants in the Western Australian HIV Cohort Study on Dec 31, 2001 were considered for this study. These patients had been HLA-typed at the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci at enrolment into the cohort study, and had been followed up at 1–3-monthly intervals. A clinician recorded details of the antiretroviral treatment history and adverse drug reactions, especially to abacavir, at each visit. The first 200 participants of the cohort prescribed abacavir until Dec 31,
Prevalence of abacavir hypersensitivity
In the cohort of 200 individuals, 18 definite cases of abacavir hypersensitivity were identified, and 167 individuals had had more than 6 weeks' exposure to abacavir without developing hypersensitivity (abacavir tolerant). Among the patients defined as having definite abacavir hypersensitivity reactions, one started therapy with efavirenz and two started nevirapine (which can also cause hypersensitivity reactions) at the time abacavir was introduced. These individuals were included in the
Discussion
The major finding in this study of 200 consecutive abacavir-treated individuals in the Western Australian HIV Cohort is that the presence of the HLA-B*5701, HLA-DR7, HLA-DQ3 haplotype is strongly associated with susceptibility to abacavir hypersensitivity—a serious and potentially life-threatening clinical syndrome encountered in about 5% of abacavir-treated patients. The presence of this allelic combination is associated with greatly increased risk of developing the syndrome, with an odds
References (22)
- et al.
Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir
Clin Ther
(2001) - et al.
Metabolic activation in drug allergies
Toxicology
(2001) - et al.
Studies of MHC haplotypes by pulsed field gel electrophoresis
Baillieres Clin Endocrinol Metabol
(1991) - et al.
Localization of central MHC genes influencing type I diabetes
Hum Immunol
(2001) - et al.
Ankylosing spondylitis and HLA-B27
Lancet
(1973) - et al.
Abacavir rechallenge has to be avoided in case of hypersensitivity reaction
AIDS
(1999) - et al.
Risk factor analysis of hypersensitivity reactions to abacavir: retrospective analysis of 25 clinical trials
Program and abstracts of the 1st IAS Conference on HIV Pathogenesis and Treatment; 8–11 July 2001; Argentina
(2001) - et al.
Hypersensitivity related to abacavir in two members of a family
Ann Pharmacother
(2001) - et al.
HLA-restricted processing-and metabolism-independent pathway of drug recognition by human αβ T lymphocytes
J Clin Invest
(1998) - et al.
Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals
J Immunol
(2000)
Disease associations with complotypes, supratypes and haplotypes
Immunol Rev
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