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HLA B-5701 and Abacavir Hypersensitivity

Trial findings described at the 4th IAS Conference elucidated the association between HLA B-5701 and abacavir HSR.

Abacavir hypersensitivity reaction (HSR) is a rare but potentially serious adverse event associated with re-exposure to abacavir. Because its pathophysiology is poorly understood, HSR remains one of the major obstacles to more widespread use of abacavir. Several reports at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention elegantly elucidated the pathophysiology of abacavir HSR and its association with human leukocyte antigen (HLA) B-5701.

HLA Typing and Skin-Patch Testing for HSR
Early studies of abacavir HSR lacked a confirmatory test and relied on a clinical syndromic definition, which encouraged overdiagnosis. With the availability of a skin-patch test, however, it has become possible to confirm HSR immunologically. Two large trials have used this new definition to study the association between HLA B-5701 and HSR.

In the industry-supported SHAPE study, Saag and colleagues performed HLA typing and skin-patch testing in 199 HIV-infected patients with a previous clinical diagnosis of HSR [Abstract WEAB305]. Positive skin-patch results were seen in 42 of 130 white patients but in only 5 of 69 black patients. All skin-patch–positive patients were HLA B-5701 carriers, however, resulting in 100% sensitivity for immunologically confirmed HSR.

In the large, prospective, double-blind PREDICT-1 trial, Mallal and colleagues confirmed the utility of HLA typing, using skin-patch results as the confirmatory test for HSR diagnosis, among 1956 HIV-infected patients who were scheduled to start regimens containing abacavir [Abstract WESS101]. Half the patients were randomized to undergo HLA screening at baseline, and half were not. Those who underwent screening were allowed to start abacavir therapy only if they tested negative for HLA B-5701; those who did not undergo screening started abacavir therapy immediately and provided blood samples for later HLA typing. All patients who developed clinical signs of HSR underwent skin-patch testing. Screening significantly reduced the incidence of both clinically suspected HSR (from 7.8% to 3.4%) and immunologically confirmed HSR (from 2.7% to 0%). Sensitivity of B-5701 testing for immunologically confirmed HSR was 100%, and, perhaps more importantly, the negative predictive value was also 100%.

The HLA screening test used in these studies is currently offered by several commercial laboratories for less than US$200 and is also available in some hospital laboratories. Already used extensively in some countries (notably Australia, Great Britain, and Ireland), HLA testing has increasingly been adopted in other sites as well, with dramatic declines in both true and "false call" cases of abacavir HSR. The overall cost-effectiveness of HLA testing remains unknown, as does the question of whether to use the test in racial and ethnic groups that tend to have low rates of B-5701 carriage.

The Pathway to HSR
Many questions surround abacavir HSR, including how it is triggered and why about half of patients can tolerate abacavir despite being B-5701–positive. To address these questions, McCluskey and colleagues studied the molecular mechanisms underlying the association between HLA B-5701 and abacavir HSR [Abstract WEAB3LB]. They found that HSR is CD8 T-cell–dependent. CD8 activation was seen in B-5701–positive donors but not in carriers of very closely related alleles, such as 5702 or 5703, and the T-cell activation pattern observed in vitro closely mimicked those seen in patients with abacavir HSR. Pretreatment with aldehydes or introduction of mutations into the antigen-presenting cells abrogated the response, indicating that a major histocompatibility complex class I–type mechanism is responsible for this activation. CD8 T-cell reactivity was found in slightly more than half of the HLA B-5701–positive donors’ cells, which correlates well with the ratio observed in naturally occurring HSR. Mutations in certain areas of the gene, such as residue 116, could be responsible for this observation.

— Helmut Albrecht, MD

Published in Journal Watch HIV/AIDS Clinical Care September 10, 2007

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