621   Epidemiological Risk Factors and Immunological Mechanisms of Hypersensitivity Reactions to Abacavir.

P. J. Easterbrook*, D. King, A. Waters, N. Ives, A. Vyakarnam, C. Taylor, and D. Thorburn.
King's Coll. Hosp., London and Glaxo Wellcome, Greenford, UK.

Background:Approximately 3% of patients who receive abacavir (ABC), a novel nucleoside analogue reverse transcriptase inhibitor, develop an idiosyncratic hypersensitivity reaction (HSR) that requires treatment discontinuation. Our objective was to characterize potential predisposing factors and immunological mechanisms for HSR.

Methods:An unmatched case-control study design was used. Cases were patients who received ABC as part of the European GW ABC clinical development program and who developed HSR. Control patients were recruited from the King's College Hospital HIV outpatient clinic and comprised two groups. Group 1 (Grp 1) comprised patients who had received ABC for 6 months as part of an HAART regimen and did not develop an HSR; Group 2 (Grp 2) comprised patients initiating ABC as part of an HAART regimen with follow-up at 1, 3 and 6 months after starting ABC. As of October 2000, 32 HSR cases and 30 controls (18 in Gp 1 and 12 in Gp 2) have been enrolled. Logistic regression analysis was used to identify risk factors for HSR. Cytokine production was assessed by four-colour flow cytometry. PBMCs were stained with fluorochrome-conjugated antibodies to CD3, CD8, IFN-gamma and IL4 both ex vivo and after mitogenic stimulation.

Results:The median time to HSR onset in the 32 cases was 11 days (range: 1 to 63). The most common symptoms were fever (69%), rash (66%) (gd 1, n = 2; gd 2, n = 10; and gd>3, n = 5), and gastrointestinal symptoms (47%). Univariate analysis showed a significant association between HSR and a lower baseline weight (61 vs. 69 kg, p = 0.01) compared to controls, with borderline significance for white race (88% for cases vs. 56% for Gp 1 vs. 83% for Gp 2, p = 0.06). HSR cases had a similar frequency of IFN-g⁺CD4 and IFN-g⁺CD8 T cells but a significantly higher frequency of IL4⁺CD4 (p = 0.006) and IL4⁺CD8 (p = 0.0004) T cells compared to Gp 2 controls prior to initiation of ABC.

Conclusions:The signs and symptoms seen in the 32 HSR cases were consistent with other reports. This preliminary analysis also suggests an association with HSR in patients with lower weight or body mass index and in Caucasians. An increased T cell IL4 production characteristic of other allergic states was observed among HSR cases.