Genetic testing can predict who is at risk of abacavir hypersensitivity

No patient who tested negative for the gene HLA-B*5701, which is associated with a potentially life-threatening allergic reaction to the drug abacavir (Ziagen) went on to develop the hypersensitivity reaction when they subsequently started treatment with the drug, according to an Australian study published in the July 1^st edition of Clinical Infectious Diseases. Three patients who tested positive for the gene started treatment with abacavir and all three patients developed clinical symptoms of a hypersensitivity reaction, which was subsequently confirmed by patch testing. Two of the patients initiated therapy with abacavir before the results of their HLA-B*5701 test were available.

An editorial accompanying the study states that the Australian data shows that genetic testing can help prevent the hypersensitivity reaction, but also cautions that it is important to await the results of a large randomised controlled trial into the value of HLA-B*5701 testing, that the drug's manufacturer is planning, before definitive conclusions about the test's utility are reached.

A severe allergic reaction, characterised by symptoms including fever, rash, stomach problems, lethargy and malaise, occurs in approximately 8% of individuals who start treatment with abacavir. Most individuals who experience this hypersensitivity reaction do so within the first six weeks of treatment with the drug. If treatment with abacavir is stopped after the development of the hypersensitivity reaction, it must never be restarted as this can have potentially fatal consequences.

The hypersensitivity reaction appears to occur less frequently in individuals of African origin, men, and patients with more advanced HIV disease. However, a higher CD8 cell count at the time abacavir therapy is started has been associated with an increased risk of hypersensitivity occurring. Tests also suggest that the presence of the HLA-B*5701gene is associated with an increased risk of hypersensitivity to abacavir. The distribution of this gene varies around the world and is found most frequently amongst Caucasians in northern Europe, north America and Australia.

Doctors from Perth tested all abacavir-naive individuals who were starting anti-HIV therapy for the first time or switching HIV treatment for the presence of the HLA-B*-5701 gene. The study involved 260 patients and ran between early 2002 and late 2005.

Of the 121 treatment-naive individuals, 112 (93%) were HLA-B*5701-negative and 42 initiated therapy with abacavir. Two stopped treatment with the drug within six weeks, but in neither case was this because of a suspected hypersensitivity reaction.

A total of nine treatment-naive patients were HLA-B*5701-positive and one of these patients started therapy with abacavir before the result of his genetic test was known. He developed symptoms consistent with an abacavir hypersensitivity reaction within six days of starting treatment with the drug, and this reaction was confirmed by patch testing. Treatment with the drug was stopped and the symptoms quickly resolved.

Of the 178 treatment-experienced patients included in the investigators’ analysis, 164 (92%) were negative for HLA-B*5701. Abacavir was prescribed to just under two thirds of these individuals and although four patients stopped therapy with the drug because of side-effects in the first six weeks of treatment, none developed an allergic reaction to the drug.

Fourteen treatment-experienced patients were positive for HLA-B*5701 and two started treatment with abacavir. One patient had limited treatment options and was made fully aware of the risks of an allergic reaction before initiating therapy with the drug, but the results of the test were not available for the second patient before treatment was started. Both patients subsequently developed clinical symptoms of a hypersensitivity reaction and in both patients this was confirmed by patch testing.

The investigators note that the prevalence of HLA-B*5701 carriage was 8% - consistent with that seen in other studies. They emphasise that results of HLA-B*5701 testing need to be readily available before treatment decisions are made.

An accompanying editorial states, “the data from western Australia reassure us that genetic screening can prevent true abacavir hypersensitivity reaction and…may also lower the rate of false-positive diagnosis.” However, it cautions that genetic testing should not be a substitute for clinical judgment or “pharmacovigilence.” The editorial also states that that the randomised controlled trial into HLA-B*5701 testing that the manufacturer of abacavir, GlaxoSmithKline, is planning to conduct will "provide more definitive information on the utility and generalizability of HLA-B*5701 screening in diverse populations."