Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.
BACKGROUND
The use of abacavir--a potent HIV-1 nucleoside-analogue 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 (p(c)) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined.


RESULTS
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], p(c)<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], p(c)<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], p(c)<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%.


CONCLUSIONS
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.
Mallal
S
S
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia, Perth, Australia. mallal@prodigal.murdoch.edu.au
Nolan
D
D
Witt
C
C
Masel
G
G
Martin
A M
AM
Moore
C
C
Sayer
D
D
Castley
A
A
Mamotte
C
C
Maxwell
D
D
James
I
I
Christiansen
F T
FT
D000328:Adult; D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D015224:Dideoxynucleosides / Q000009:adverse effects* / Q000627:therapeutic use; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D015235:HLA-B Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics*; D015809:HLA-DR7 Antigen / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D005819:Genetic Markers; D015235:HLA-B Antigens; D006683:HLA-DQ Antigens; D015809:HLA-DR7 Antigen; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir; C103707:HLA-B57 antigen; C051569:HLA-DQ3 antigen