July 25, 2007
Retrospective analyses of abacavir (ABC, Ziagen)-treated individuals who have experienced hypersensitivity reaction (HSR) have suggested that the majority of these abacavir-related events, at least in white and Thai persons, occur in the presence of a familial haplotype involving the HLA-B*5701 allele. This allele can be rapidly and inexpensively identified through screening, which can help guide decisions about whether to use abacavir when designing an antiretroviral regimen.
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Adapted from Simon Mallal, M.D., et al.
The PREDICT-1 study1 prospectively evaluated the use of HLA-B*5701 testing in a group of abacavir-naive individuals commencing abacavir-based therapy. Individuals were randomized to begin abacavir without HLA testing (i.e., the standard of care) or to undergo HLA screening prior to abacavir initiation. Any HLA-B*5701-positive individuals identified in the screening arm were excluded from the use of abacavir. Individuals with a suspected HSR during abacavir therapy underwent a standardized patch test to immunologically confirm the HSR.
The study enrolled 1,956 abacavir-naive patients, but only 1,772 actually received at least one dose of abacavir-containing medication, thus constituting the "exposed" population. Among the exposed individuals, 84% were white, and 71% to 74% were male. In addition, the majority (81% to 82%) were treatment experienced.
The overall prevalence of HLA-B*5701 was 5.7%; 60% of these individuals were white, whereas less than 1% were black (one of 232 participants). Abacavir HSR was clinically diagnosed in 7.8% and 3.4% of individuals in the control and screened arms, respectively (P P < .0001). Risk factors for suspected HSR included white race, commencing a non-nucleoside reverse transcriptase inhibitor (NNRTI) simultaneously with abacavir and concurrent protease inhibitor (PI) use.
|Factor Associated With Abacavir HSR, OR (P Value)||Abacavir HSR|
|Clinically Suspected||Immunologically Confirmed||Clinically Suspected but Not Immunologically Confirmed|
|Prospective HLA-B*5701 screening vs. control||0.40 (< .0001)||0.03 (< .000001)||0.69 (.1513)|
|White vs. non-white||2.19 (.0242)||4.21 (.2239)||2.00 (.0879)|
|Introduction of NNRTI: yes vs. no||3.19 (.0011)||1.45 (.5693)||4.04 (.0008)|
|Concurrent PI use: yes vs. no||1.86 (.0094)||1.05 (.9123)||2.38 (.0031)|
OR = odds ratio.
The sensitivity and specificity of immunologically confirmed HSR following HLA-B*5701 screening was 100% and 97%, respectively. In accord, the negative predicted value of HLA-B*5701 screening for immunologically confirmed HSR was 100%. Abacavir tolerance for up to six weeks or more is known to occur in some HLA-B*5701-positive individuals; thus, the positive predictive value of immunologically confirmed HSR following HLA-B*5701 screening was only 48%.
Although this study does not fully validate the HLA-B*5701 screening test across all racial groups, the data indicate that if testing for HLA-B*5701 becomes the standard of care, it could substantially reduce and possibly eliminate abacavir HSR while denying abacavir to only a very few individuals who test positive for HLA-B*5701. As such, the investigators argued that clinicians should consider screening for the HLA-B*5701 allele in any HIV-infected, abacavir-naive patient for whom abacavir therapy is being considered if validated screening methods are available.
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