HIV Pharmacology Workshop: Patch-testing to identify the genetic and clinical characteristics of abacavir hypersensitivity reaction - don’t try this at home

Summary of key messages from the study

1. Clinical diagnosis of abacavir hypersensitivity reaction is imprecise.

The clinical diagnosis of abacavir HSR syndrome is imprecise and hence using clinical diagnosis as the "gold standard" for abacavir HSR in itself could and has led to:

• inaccurate clinical characterisation of the disease from clinical studies (e.g. patients who develop "abacavir HSR" on the first dose or after three weeks with continuous exposure are truly unlikely abacavir HSR).
• the assumption, due to clinical misclassification, that there may be HLA associations with abacavir HSR other than HLA-B*5701.

2. Patch-testing could become the new gold standard for diagnosis – but more work needs to be done to validate this.

As Charles Boucher from Utrecht University noted, patch testing may become the new gold standard for diagnosis but certainly much more work needs to be done in this area. Charles Flexner from Johns Hopkins University and Co-Chair of the Workshop confirmed that in other clinical disciplines, such classification tools already exist. This is the traditional way, he added, that allergists and immunologists separate patients with a true drug reaction from those that may have simply been labelled with a drug reaction and can truly tolerate the drug.

3. Patch-testing for abacavir HSR is currently a research tool

Since the potential costs of re-challenge with abacavir are high and the genetic predisposition to abacavir HSR is lifelong (unlike penicillin allergy where 10% of patients per year lose their allergic tendency) this is currently a research tool only and not something to be practised in routine clinical setting. Dr Phillips emphasised again that re-challenge is NOT something that should be pursued outside of a hospital research environment that is able to provide strict monitoring support.

Previous research has shown a strong association between a life-threatening abacavir hypersensitivity reaction and the presence of a haplotype, or genetic marker, called HLA-B*5701, that is present in between 5 and 15% of northern Europeans, and which may occur at lower frequencies in other ethnic groups, particularly Africans.

However, research into the genetic predictors of abacavir hypersensitivity is hampered by difficulties in distinguishing a true hypersensitivity reaction to abacavir from symptoms of common illnesses. Abacavir hypersensitivity reaction generally involves fever, gastrointestinal symptoms and an accumulating pattern of symptoms as it worsens, and although it may be accompanied by respiratory symptoms, it is not clear that these are a feature of the syndrome.

Establishing a reliable method that can distinguish true cases of abacavir hypersensitivity reaction (HSR) from other illnesses may also eventually allow patients who would once have been barred from taking the drug to receive abacavir. Re-challenge with abacavir in patients who have experienced a true hypersensitivity reaction can result in the rapid onset of hypersensitivity reaction and death.

Elizabeth Phillips from the British-Columbia Centre for Excellence in HIV/AIDS in Vancouver presented a study that aims to profile the clinical and genetic characteristics of patients labelled with abacavir hypersensitivity reaction (HSR) obtained from international sites. The purpose of the study was to investigate if patch testing could be developed as a more precise phenotypic indicator and classification tool to identify genetic and clinical characteristics of true abacavir HSR in contrast to those patients who may have received a false clinical diagnosis of abacavir HSR.

The study identified 23 patch test negative and 23 patch test positive patients. 100% of the patch test positive patients were also positive for HLA-B*5701 which reinforces the robustness of the association between patch test positivity, true abacavir HSR and HLA-B*5701. Two of 23 (approx 9%) of patch test negative patients were also positive for HLA-B*5701. Dr Phillips observed that it is difficult to interpret this result as a proportion of the patients with HLA-B*5701 alone (around 21%) are likely to tolerate abacavir. Interestingly, the research outlined clinical differences between the patch test positive and negative group and suggested that patch test positive patients, i.e. true abacavir HSR were more likely to have multiple symptoms (more than two) and that patch test negative patients were more likely to have symptoms occurring at the time extremes at day one or at more than three weeks. Data from this study suggest that patch testing may eventually be useful to redefine the clinical syndrome of what constitutes true abacavir HSR.

Dr Phillips stressed that the purpose of the study was not to endorse patch testing as a diagnostic tool in the clinic setting that would lead to re-challenge.