Abacavir (ABC) is a potent and generally well tolerated antiretroviral agent for the treatment of HIV. The primary treatment-limiting toxicity is a well described hypersensitivity reaction (HSR), which has been reported in approximately 2–8% of patients. Patients with HSR symptoms must contact their physician immediately and permanently discontinue abacavir if a HSR is suspected and never reintroduce abacavir . Research into the genetic predisposition to ABC HSR has identified the human leukocyte antigen (HLA) on the class I major histocompatibility complex as a predictor of HSR risk [2–4]. The presence of the HLA-B*5701 allele confers the highest risk of developing ABC HSR. The frequency of this allele varies by race; therefore, observations of an increased risk of ABC HSR in patients of Caucasian versus African descent is likely related to higher HLA-B*5701 carriage rates in Caucasians [2–5].
Recently, the Prospective Randomized Evaluation of DNA Screening in a Clinical Trial (PREDICT)-1, a prospective, randomized, double-blind study investigating the utility of HLA-B*5701 screening to reduce the incidence of ABC HSR, was undertaken in Europe and Australia. Individuals and investigators were blinded to both the randomized group and HLA-B*5701 status; therefore, all individuals were assessed consistently on the basis of clinical vigilance alone. A significant reduction of clinically suspected ABC HSR after HLA-B*5701 screening compared with individuals not prospectively screened (3.4% versus 7.8%, P < 0.001) was observed . Additionally, several cohort studies utilizing HLA-B*5701 screening with prospective knowledge of HLA-B*5701 status have demonstrated similar and significant reductions in HSR [7–10]. Furthermore, all PREDICT-1 individuals diagnosed with a clinically suspected HSR underwent a standardized, investigational skin patch testing procedure to identify individuals who experienced an immune-mediated HSR. No individuals in the screening arm had a positive skin patch test in contrast to 2.7% among nonscreened individuals. However, a limitation of this study was the number of non-white individuals (<20%), which limits the ability to apply results to non-white populations.
The retrospective Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation (SHAPE) study , conducted in 130 white and 69 black individuals from the USA with a previous diagnosis of ABC HSR, demonstrated that among 42 white and five black individuals with positive skin patch tests (47/199), 100% carried the HLA-B*5701 allele. Therefore, the authors recommend prospective HLA-B*5701 screening in all patients considering abacavir therapy regardless of racial or ethnic background.
In the present study, we excluded HLA-B*5701-positive individuals and determined the rate of ABC HSR among a large group of HLA-B*5701-negative individuals through the first 30 weeks of the Atazanavir Ritonavir Induction/Simplification with Epzicom Study (ARIES) trial. ARIES is a randomized (1: 1), open-label, multicenter, North American study of antiretroviral-naïve patients who initially receive abacavir/lamivudine, atazanavir, and ritonavir followed by either continuation of the initial regimen or simplification to abacavir/lamivudine and atazanavir.
A total of 725 individuals (16% female) were screened for HLA-B*5701 status. Forty-one (5.7%) individuals were HLA-B*5701-positive, including 7.2% whites, 2.8% blacks, and 5.6% of other race. Results by racial distribution are presented in Table 1.
The study subsequently enrolled 517 HLA-B*5701-negative individuals between 28 March and 7 September 2007 who commenced abacavir-containing therapy. Four individuals (0.8%) were diagnosed with clinically suspected ABC HSR during the first 30 weeks; two Caucasian males, one Hispanic female, and one Native Hawaiian female. Demographics and clinical features of individuals with HSR are presented in Table 2. The time to onset was less than 2 weeks from therapy initiation for all individuals. Not all individuals met the case definition of HSR that requires the presence of at least two symptoms from five symptom categories. However, all four individuals reported rash as part of HSR [rash only in (individual A), rash plus fever, constitutional symptoms and chest pains (B), rash plus fever, cough, gastrointestinal symptoms and constitutional symptoms (C), and rash plus fever (D)]. In each case, the entire regimen, including abacavir, was stopped with resultant symptom resolution. The individuals resumed study with atazanavir, ritonavir, lamivudine, and zidovudine, which was substituted for abacavir. In one individual (D), transient rash symptoms reappeared shortly after resumption of atazanavir, ritonavir, and lamivudine/zidovudine; rash due to atazanavir was later suspected. Individual D initially complained only of a skin rash 10 days after starting therapy, and thus was instructed to take that evening's dose. The individual reported subjective fever of 101°F that evening and all study medications were discontinued the following morning. The individual switched abacavir for zidovudine and returned to clinic 8 days later, reporting a recurrence of the rash localized to chest and extremities.
Additionally, all four individuals underwent standardized abacavir skin patch testing at least 6 weeks after symptom resolution. Skin patch test results were negative for all four individuals. Although it is impossible to definitively rule out HSR in these cases, the absence of both HLA-B*5701 and a positive skin patch test suggests that the reported symptoms may have been caused by an alternative agent and/or disease process.
In this study, ABC HSR rates were dramatically lower after implementation of HLA-B*5701 screening compared with historical studies without prospective screening in this diverse patient population. Among HLA-B*5701-negative individuals, less than 1% of individuals were diagnosed with a suspected ABC HSR through 30 weeks and no individual had a positive skin patch test. The recent update to the Department of Health and Human Service adult antiretroviral treatment guidelines recommends HLA-B*5701 screening prior to initiating abacavir and confirms the important role of clinical vigilance for HSR . Use of prospective HLA-B*5701 screening will help North American healthcare providers individualize treatment and identify appropriate candidates for abacavir therapy by excluding patients at high risk of developing HSR.
The ARIES study (sponsored by GlaxoSmithKline) team thanks the research participants, study investigators and personnel for their contributions to this trial.
Drs Young and Squires are co-lead investigators in the ARIES study and co-authored, reviewed, and provided substantial comments to the manuscript. Dr Patel co-authored, edited, reviewed and compiled the final manuscript. Drs DeJesus, Bellos and Berger reviewed and provided critical comments to the manuscript. Dr Sutherland-Phillips provides study medical governance, reviewed and provided critical comments to the manuscript. Dr Liao provided statistical guidance and Dr Shaefer and Mr Wannamaker reviewed, edited, and provided critical comments to the manuscript.
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