The abacavir hypersensitivity reaction and interruptions in therapy

Hypersensitivity reactions to abacavir are generally well defined, and once the diagnosis has been made, patients must never be restarted on abacavir or abacavir-containing products (i.e. ziagen and trizivir). The re-introduction of abacavir after the resolution of the initial hypersensitivity reaction may lead to a rapid onset, life-threatening reaction (rechallenge reaction). Frissen et al. ^[1] described a patient with multiple complications of HIV disease in whom abacavir was discontinued for elevated liver function tests. The patient experienced an acute onset, rechallenge-like hypersensitivity reaction after the re-introduction of abacavir. Importantly, there was no clear evidence of an abacavir hypersensitivity reaction at the time of interruption of antiretroviral therapy.

As indicated on our label, on very rare occasions acute onset hypersensitivity reactions have been reported in patients who have re-started therapy and who have not previously experienced symptoms of a hypersensitivity reaction during abacavir therapy. This type of hypersensitivity reaction is being closely monitored. In an analysis of 1442 cases of hypersensitivity, we found only seven reports of patients who met the following criteria: (i) they had interrupted abacavir for any reason; (ii) they had no symptoms of abacavir hypersensitivity or unrelated symptoms at the time of interruption; and (iii) they developed symptoms of a hypersensitivity reaction within one day of restarting abacavir. None of these cases were fatal and only two had symptoms of a severe, rapidly progressive, 'rechallenge-type' reaction. These cases, including the well-documented case described by Frissen et al. ^[1] should be viewed in the context of over 95 000 patient-years of exposure to marketed abacavir.

Structured treatment interruptions are becoming more common, and concern has been raised regarding a possible association between hypersensitivity and interruptions of therapy. Therefore we performed an analysis of all patients in our clinical trials database who had treatment interruptions, in order to see whether they were at increased risk of hypersensitivity. Of 1201 patients treated with abacavir in nine phase II/III clinical trials, 164 (16.1%) had at least one treatment interruption (not for abacavir hypersensitivity) lasting at least 24 h. There were 219 interruptions among these patients and none developed hypersensitivity upon the re-introduction of abacavir. These data are consistent with data presented by Thomson et al. ^[2], who evaluated the frequency and duration of therapy interruptions in patients treated with combivir and abacavir, and the relationship between interruptions in therapy and the incidence of hypersensitivity reactions. In this study, 195 antiretroviral naive patients received combivir and abacavir twice a day for 24 weeks in bottles equipped with Medication Event Monitoring System (MEMS) track caps. Among the 161 subjects for whom MEMS cap data was available, 70% had a treatment interruption of more than 2 days. None experienced a hypersensitivity reaction to abacavir. None of the four out of 195 (2%) subjects with a suspected hypersensitivity reaction to abacavir had evidence of treatment interruption either by MEMS cap data (three patients) or pill counts (one patient).

These data indicate that treatment interruptions do not increase the risk of developing a hypersensitivity reaction to abacavir, and that a rechallenge-type hypersensitivity reaction, without apparent prevous symptoms, is extremely rare. We are actively conducting research into the immunological and biochemical mechanisms of abacavir hypersensitivity and into individual risk factors. The results of these studies may help to guide the clinician in selecting patients who will benefit the most from an abacavir-containing regimen with a minimum of risk.

A. Edde Loeligera

Helen Steela

Sue McGuirka

Wendy S. Powellb

Seth V. Hetheringtonb