November 16, 2006
Abacavir (ABC, Ziagen) is a convenient nucleoside reverse transcriptase inhibitor with an excellent long-term tolerability profile. Of course, it has one key drawback: a systemic hypersensitivity reaction. Abacavir hypersensitivity reactions typically occur in the first six weeks of therapy and consist of a range of signs and symptoms that are also common to viral infections, making the diagnosis a clinical challenge. The event is typically diagnosed in 5% to 9% of persons who receive abacavir; the rates vary depending on population characteristics, particularly ethnicity. For example, people of black African decent have lower rates of hypersensitivity reaction.
Retrospective, case-control studies identified the HLA-B*5701 allele, together with some linked alleles, to be closely associated with abacavir hypersensitivity reactions,1,2 and a molecular mechanism for this association has been described. These studies suggested that testing for the presence of HLA-B*5701 may have a negative predictive value greater than 94%. Thus, preventing HLA-B*5701-positive persons from receiving abacavir has the potential to dramatically reduce the rate of hypersensitivity events seen in clinical practice. Several cohort studies have now been reported and suggest that prospective use of HLA-B*5701 testing can have a significant impact on the hypersensitivity event rate observed with abacavir use.3,4
Prospective use of the HLA-B*5701 test was introduced in the Chelsea and Westminster Hospital in London in August 2005. The experience of the first 11 months of this program was compared with a retrospective case review of all individuals commencing abacavir in the year prior to HLA-B*5701 testing.5
Over the first 11 months of testing, 739 tests were performed with only four test failures. A total of 54 individuals (7.3%) were HLA-B*5701 positive, with similar rates observed in men and women (6.9% and 9.9%, respectively; P = .35). Positive tests were reported in both white (7.6%) and black (9.0%) individuals; however, these rates may have been overestimated due to methodological issues with the test.
Two treatment-naive individuals who tested positive for HLA-B*5701 commenced abacavir therapy, and both subsequently developed hypersensitivity reactions. In contrast, 47 treatment-naive individuals negative for HLA-B*5701 commenced abacavir therapy, and none discontinued treatment.
An additional 151 treatment-experienced individuals without HLA-B*5701 switched to abacavir-containing therapy, and eight (5.3%) discontinued abacavir during the first three months of treatment, four (2.6%) due to suspected abacavir hypersensitivity reaction. The signs and symptoms experienced by these individuals -- typically fever with other systemic symptoms -- were consistent with abacavir hypersensitivity reaction. Two of the four patients agreed to skin patch testing, with one individual demonstrating a positive reaction. Further investigation of this individual is ongoing.
In the year prior to HLA-B*5701 testing, 10 out of 134 individuals (7.5%) discontinued abacavir use due to a possible hypersensitivity reaction. After the introduction of prospective HLA-B*5701 testing, the event rate dropped to 2.0%, a statistically significant reduction in the event rate (P = .03).
These and other prospective cohort data support the use of HLA-B*5701 testing to reduce the relative risk of abacavir hypersensitivity reaction in clinical practice. However, several cases reported here suggest that continued vigilance for hypersensitivity reaction is required even when abacavir is used in individuals without this genetic marker. A large, prospective study of this test is now underway, and data on more than 1,400 persons commencing abacavir are likely to be reported at the 4th International AIDS Society Conference on HIV Pathogenesis and Treatment, in Sydney, Australia, in July 2007.