Key Points
Disease summary:
Abacavir is a nucleoside reverse transcriptase inhibitor used in combination therapy for the treatment of the human immunodeficiency virus type 1 (HIV-1) that has been associated with a hypersensitivity reaction in approximately 8% of those starting the drug.
Abacavir hypersensitivity reaction is characterized by greater than or equal to two progressive symptoms typically starting from the second week of therapy (median 9 days) with fever, malaise, nausea, vomiting, diarrhea, and later mild-to-moderate skin rash (present in 70% of patients).
Symptoms of abacavir hypersensitivity resolve rapidly with 24 to 72 hours after drug discontinuation.
A previous clinical history compatible with abacavir hypersensitivity is a contraindication to future rechallenge as severe morbidity and even mortality characterized by hypotension and shock has been described.
Differential diagnosis:
The symptoms and signs associated with abacavir hypersensitivity are nonspecific and may be confused with other diseases occurring in HIV-positive patients such as infections, immune restoration disease, and hypersensitivity reactions associated with other drugs (eg, nevirapine, amprenavir or fosamprenavir, trimethoprim-sulfamethoxazole etc).
Family history:
A description of the disease in a father and daughter, and predilection for white race, were early clues to the genetic basis.
Environmental factors:
A higher prevalence of true immunologically mediated abacavir hypersensitivity syndrome is seen in white race which is related to the high prevalence of HLA-B*5701 in this group. There are no other demographic or environmental factors known to predispose to abacavir hypersensitivity.
False-positive clinical diagnosis and skin patch testing:
The apparent low sensitivity of HLA-B*5701 for clinically diagnosed abacavir hypersensitivity was related to high false-positive clinical diagnosis which caused a differential misclassification error in the original studies. Randomized double-blinded HIV treatment studies involving abacavir consistently showed 2% to 7% diagnosed abacavir hypersensitivity in the arm not receiving abacavir.
Early barriers to the widespread implementation of HLA-B*5701 as a screening test included the doubt shed on the sensitivity of HLA-B*5701 for abacavir hypersensitivity and the generalizability of the test to nonwhite ethnic groups.
Early studies on a abacavir skin patch test showed a high proportion of patients meeting stringent clinical criteria for abacavir hypersensitivity were patch test positive and later on that 100% of patch test-positive patients with a clinical history compatible with abacavir hypersensitivity carried HLA-B*5701. This suggested that patch testing would be useful in a research context to increase the specificity of the diagnosis of abacavir hypersensitivity.
Pharmacogenomics and evidence leading to translation of HLA-B*5701 testing into clinical practice:
In 2002, two independent groups published on the association between the major histocompatibility class I allele, HLA-B*5701 and abacavir hypersensitivity reactions.
Subsequent case control studies suggested an apparent low sensitivity for HLA-B*5701 in blacks and other nonwhite races but this was found to be related to the low prevalence of HLA-B*5701 in blacks and the high false-positive clinical diagnosis of abacavir hypersensitivity.
Observational studies have been important to establish the utility of HLA-B*5701 in real clinical practice, showing significant reduction in both true and false-positive diagnosis of abacavir hypersensitivity.
Two seminal studies published in 2008 confirmed the 100% negative predictive value of HLA-B*5701 for true immunologically abacavir hypersensitivity generalizable across ethnicity:
PREDICT-1 study: This was a randomized double-blinded controlled study in HIV treatment-naíve patients enrolling 1956 (84% Caucasian) subjects from 265 centers across Europe and Australia. The design was to randomize patients to (1) exclusion from abacavir based on positive HLA-B*5701 versus (2) no real-time HLA-B*5701 screening and clinical monitoring and thereby ascertain the clinical utility of HLA-B*5701 screening to prevent abacavir hypersensitivity. The coprimary endpoints of clinical diagnosis of abacavir hypersensitivity and clinical diagnosis + patch test positivity were utilized. There were no cases of patch test-positive abacavir hypersensitivity in the screened arm confirming 100% negative predictive value of HLA-B*5701 for immunologically confirmed abacavir hypersensitivity.
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