The sequencing of the human genome has focused much attention on finding genetic causes for both common and uncommon diseases. The field of pharmacogenetics (or pharmacogenomics) identifies genes associated with drug responsiveness. So far, this field has produced little of real clinical consequence.

One of the most dramatic pieces of pharmacogenetic research involving any drug was unveiled at the 9th CROI. Teams of investigators from GlaxoSmithKline and Western Australia, working independently, identified a strong association between a rare HLA type and the risk of developing abacavir hypersensitivity.

Abacavir hypersensitivity reaction (AHSR) is characterized by fever, rash, abdominal complaints, and lethargy, symptoms that almost always occur within the first six weeks of starting the drug. Fortunately, this syndrome is rare, affecting only 4-5% of recipients. However, AHSR may be fatal, especially if the drug is discontinued and then restarted. The low incidence of AHSR, its time-course, and its greater severity with re-challenge prompted speculation that it might be genetically linked. It has also been shown that AHSR occurs less frequently in African-Americans than in Caucasians. This focused attention on genes controlling immune response, which have previously been associated with severe hypersensitivity to sulfa drugs.

A team of immunologists and geneticists in Western Australia had a unique opportunity to study this connection when abacavir was first introduced into their province a few years ago. There is only one large city (Perth), and most HIV-infected patients are treated at a handful of clinics. Further, most inhabitants of this province are of English or Irish decent, and this ethnic homogeneity makes it easier to pick out genes that might be associated with rare conditions.

This team identified 18 cases of AHSR in 200 treated patients. They developed a very stringent case definition for AHSR, excluding 15 patients with borderline or partial symptoms, and leaving 167 controls [Mallal, Abstract 91]. They then examined the HLA and DR regions (associated with regulating immune response) in all 200 patients, and discovered that 14 cases (78%) but only 4 controls (2%) had a rare HLA type, B5701. This HLA type is present in 8% of Irish Caucasians, but in only 2.4% of African Americans. The odds ratio for this association, 117, was highly statistically significant. The combination of HLA B5701 plus two other loci, HLA-DR7 and HLA-DQ3, was present in 13 of the cases but none of the controls, for an odds ratio of 822! (See table, above.) This genetic association is as strong as that between HLA B27 and ankylosing spondylitis.

An article describing the full results of this study was published in the Lancet on the same day the presentation was made [Lancet 2002 Mar 2;359(9308):727-32]. One interesting conclusion of this article is that HLA B5701 is probably not the causative gene, but is linked to another genetic region encoding a family of human heat shock proteins (HSP), which is the more likely culprit.

A second group of investigators from GlaxoSmithKline performed a retrospective analysis of DNA samples collected from patients suffering from AHSR in company-sponsored trials and compared them to matched controls [Hetherington, Abstract 92]. After establishing a rigid case definition similar to that used by the Australians, they identified 50 cases of AHSR and matched them (by race, sex, and CD4 count) to 80 controls. They examined 114 candidate genes associated with drug metabolism and immune responsiveness, and found the same association as the Australian group: HLA B57 was most strongly associated with AHSR, occurring in 46% of cases but only 4% of controls. There was also a strong association between a point mutation (SNP) in the tumor necrosis factor- (TNF-) gene and AHSR. However, as was pointed out in both this presentation and in the Lancet article, the TNF- SNP and HLA B57 genes are linked, which suggests that this is probably a secondary, rather than a primary association.

It is important to point out several caveats about both of these studies. First, genetic linkages are highly dependent on the population studied, hence the stronger B57 association in the Western Australian patients. In fact, the majority of the AHSR cases in the GSK study were not HLA B57 positive. This emphasizes the complex nature of these genetic associations, and the fact that more than one gene may be involved.

HLA B5701 should not be used as a diagnostic test for abacavir hypersensitivity, since the majority of U.S. patients (especially non-Caucasians) who have the syndrome will not have the gene. However, in a largely English-Irish community, such as that in Western Australia, having HLA B5701 places a patient at high risk for developing AHSR. Many patients in that province are now being screened for HLA B5701 prior to starting abacavir, and the drug is avoided in those who have the gene. In Western Australia, this will reduce the overall risk of AHSR by nearly five-fold, while denying abacavir treatment to only a handful of patients.

The use of genetic screening to avoid AHSR in ethnically diverse places like Baltimore will require much more work. Still, these two studies have brought HIV care providers into the genetic age, ready or not.

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