10: Abacavir Pharmacogenomics

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 ...