Genetic basis for abacavir hypersensitivity

Association Between Presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and Hypersensitivity to HIV-1 Reverse-Transcriptase Inhibitor Abacavir [Mallal S et al. Lancet 2002;359:727]: The authors studied the association between MHC alleles and abacavir hypersensitivity in 200 consecutive participants in the Western Australian HIV Cohort Study exposed to abacavir. There were 18 cases of abacavir hypersensitivity in this cohort, defined by the following criteria: 1) onset of symptoms within six weeks of abacavir initiation; 2) typical symptoms, including at least two of the following: rash, fever, GI symptoms, lethargy, arthralgias, myalgias, or respiratory symptoms; 3) resolution within 72 hours of discontinuing abacavir; and 4) no alternative explanation. HLA-B*5701 was found in 14 of the 18 hypersensitivity cases (78%) compared to only 4 of the 167 who tolerated abacavir (2%). The odds ratio was 117. The HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of the hypersensitive patients and 5 (3%) of the tolerant patients. These results are summarized in the following table:

 

Genetic susceptibility to abacavir hypersensitivity
	Hypersensitive n = 18	Not hypersensitive n = 167
HLA-B*5701 HLA-DR7 + HLA-DQ3	14 (78%) 13 (72%)	4 (2%)* 5 (3%)*

The authors conclude that hypersensitivity to abacavir is carried on the 57·1 ancestral haplotype, and that detection of these allelic variants could reduce the likelihood of the hypersensitivity reaction from 9% to 2.5%.

Comment: This is an extraordinary report with important implications that are highlighted in the accompanying editorial authored by Amalio Telenti et al. from Switzerland (Lancet 2002;359:722). There were two major issues raised: First, should MHC testing be offered to all persons who are potential recipients of abacavir? The cost of the test is about $500. The frequency of the indicated haplotypes is 1-5% in the general population, so that the cost per case prevented would be $10,000-$50,000 if it were 100% predictive. The second and perhaps more profound question concerns the use of MHC typing to detect other idiosyncratic drug reactions such as those noted with nevirapine, efavirenz or amprenavir. Such typing could also be used to detect markers of HIV progression to facilitate the decision regarding initiation of treatment. It should be noted that these results were reported by S. Mallal in Lancet and at the 9th CROI in Seattle, February 2002 (Abstract 91). S. Hetherington presented similar results 9th CROI (Abstract 92).

back to news table of contents