The presence of HLA-B*5701, -DRB1*0701 and -DQ3 is highly predictive of hypersensitivity to the HIV reverse transcriptase inihibitor abacavir
Mallal, S., Witt, C., Martin, A.M., Masel, G., Moore, C., Sayer, D., Castley, A., Mamotte, C., Nolan, D., James, I. and Christiansen, F.T. (2002) The presence of HLA-B*5701, -DRB1*0701 and -DQ3 is highly predictive of hypersensitivity to the HIV reverse transcriptase inihibitor abacavir. In: XIII International Congress of Histocompatibility and Immunogenetics, 18 - 22 May 2002, Seattle, U.S.A.
Abacavir (ABC) is a potent nucleoside analogue inhibitor of HIV reverse transcriptase. Approximately 5% of individuals given abacavir develop a potentially life threatening hypersensitivity reaction. These reactions typically occur within six weeks of exposure and recur rapidly on rechallenge. It has been proposed that patients may be predisposed to such reactions by genetic polymorphisms in genes involved in systemic inflammatory responses. We investigated the effect of MHC alleles on the risk of hypersensitivity to abacavir in 200 participants in the Western Australian HIV Cohort Study exposed to the drug. Eighteen definite cases of abacavir hypersensitivity (ABC HSR) were identified and 167 individuals had more than six weeks exposure to abacavir without developing hypersensitivity (ABC non-HSR). Fifteen individuals who experienced some symptoms but did not meet the criteria for definite ABC HSR were excluded.
There were striking differences in the frequency of some of the HLA alleles in the ABC HSR and non-HSR groups. In the ABC HSR group, HLA- B*5701 was found in 14/18 cases (78%) compared to 4/167 (2.3%) in the ABC non-HSR group (OR = 117, p < 0.0001) whilst the combination of DRB1*0701and DQ3 was found in 13/18 (72%) of the HSR cases and 5/167 (3.0%) of the non-HSR cases (OR = 72, p < 0.0001).
These alleles HLA-B*5701, DRB1*0701 and DQ3 are markers of the 57.1 ancestral haplotype (AH). We therefore examined the presence of the combination of all three markers in the 2 groups: 13/18 (72%) of the HSR cases and none of the 167 ABC non-HSR patients had all 3 markers (OR = 822, p < 0.0001). Other markers characteristic of the 57.1 AH (D6S1014*137, C4A6, D6S273*135, TNF-238A, MICA*194, MIB*344) were examined to confirm the presence of and to map the extent of the 57.1 AH. All 14 ABC HSR cases with HLA-B*5701 had markers characteristic of 57.1 AH centromeric of HLA-B up to and including D6S273. Two additional control populations (381 HIV infected patients unexposed to ABC and 3212 HIV negative bone marrow donors) had similar distribution of alleles of the 57.1 AH to the ABC exposed patients.
These results suggest that the susceptibility loci involved in ABC HSR are present on the 57.1 AH. Although the genes remain to be characterized, these results have immediate clinical implications. Within the entire ABC exposed cohort, the positive predictive value (PV) of the presence of both HLA-B*5701 and DRB1*0701+DQ3 for ABC HSR was 100% with a negative PV of 97.3%.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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