Australian researchers have reported that people with a specific genetic pattern are 822 times more likely to develop a potentially fatal hypersensitivity reaction to abacavir than people.
The findings were presented at last week’s Ninth Annual Retroviruses Conference in Seattle, and published in The Lancet.
Professor Simon Mallal of the Royal Perth Hospital in Western Australia reported that a genetic sequence that is passed from one generation to another with little alteration contains particular gene arrangements that are associated with an increased risk of hypersensitivity.
The pattern is called a haplotype, and refer to the markers on the surface of cells. The combination of HLA-B*5701, HLA-DR7 and HLA-DQ3 was found in 12 out of 18 patients prescribed abacavir who developed a hypersensitivity reaction. No one with this haplotype tolerated abacavir.
This haplotype is most common in Northern Europeans, according to Dr Mallal, but it may have differing frequencies in other Caucasian populations. Further research will also be necessary to define whether abacavir hypersensitivity is associated with a specific genetic pattern in non-Caucasians that differs from the pattern seen in this study. Although the genetic sequence identified in this study is characteristic of Caucasian descent, and although abacavir hypersensitivity is less common in non-Caucasians, the reaction has been reported in non-Caucasians.
HLA-B*5701 is also associated with a lower risk of disease progression; US National Institute of Allergy and Infectious Diseases researchers have previously reported that 11 of 13 long term non-progressor patients (85 percent) had this haplotype, while only 19 of 200 progressors (9.5 percent) carried this gene.
However, not everyone who experienced a hypersensitivity reaction in the cohort studied had the complete haplotype. Four out of eighteen patients had other haplotypes, leading Prof. Mallal to note that a negative test for the haplotype must not be used as evidence to re-challenge patients who have stopped abacavir treatment due to a suspected hypersensitivity reaction. However, withholding abacavir treatment from patients with this haplotype is likely to reduce the incidence of hypersensitivity reactions, suggesting that where access to molecular tissue typing is available, clinical centres may be able to institute testing for patients beginning abacavir treatment.
The long-term clinical applications of this area of research are less clear. Dr Amalio Telenti of the Lausanne University Hospital in Switzerland points out that each gene test will cost around $500, and if the genetic pattern predicting a hypersensitivity reaction is present in 1-5% of the population, the cost of preventing each case of hypersensitivity would range from $10,000 to $50,000, assuming that the genetic pattern is 100% predictive of hypersensitivity.
Whilst the Australian group found that a combination of three polymorphisms was 100% predictive of a hypersensitivity reaction, the Glaxo Smith Kline study failed to find a predictive effect in a US clinic population using a single haplotype. HLA-B57 was present in 39 of 84 (46%) cases vs 4 of 113 (3.5%) controls (p
Hetherington S et al. HLA-B57 and TNF-alpha variants associated with hypersensitivity reactions to abacavir among HIV-1-positive subjects. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 92, 2002.
Mallal S et al. The presence of HLA-B*5701, -DRB1*0701, and -DQ3 Is highly predictive of hypersensitivity to the HIV reverse transcriptase inhibitor abacavir Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 91, 2002.