Elsevier

The Lancet

Volume 359, Issue 9308, 2 March 2002, Pages 727-732
The Lancet

Fast track — Articles
Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir

https://doi.org/10.1016/S0140-6736(02)07873-XGet rights and content

Summary

Background

The use of abacavir a potent HIV—1 nucleosideanalogue reverse—transcriptase inhibitor is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV—1-positive individuals treated with abacavir.

Methods

MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (pc) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined.

Findings

HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29–481], pc<0·0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20–268], pc<0·0001). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43–15 675], pc<0·0001). Other MHC markers also present on the 57·1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%.

Interpretation

Genetic susceptibility to abacavir hypersensitivity is carried on the 57·1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2·5% without inappropriately denying abacavir to any patient.

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)

  • RL Dawkins et al.

    Disease associations with complotypes, supratypes and haplotypes

    Immunol Rev

    (1983)
  • Cited by (1272)

    • Drug Allergy Mimics

      2024, Journal of Allergy and Clinical Immunology: In Practice
    • Skin testing as a biomarker in drug allergy

      2023, Annals of Allergy, Asthma and Immunology
    View all citing articles on Scopus
    View full text