February 27, 2002
A genetic link with abacavir hypersensitivity reaction was pursued because of observations that abacavir hypersensitivity reaction has occurred in family members (familial predisposition), the rate of abacavir hypersensitivity reaction appears to be lower in African Americans, and other multi-system hypersensitivity drug reactions have involved genetic associations.
The first 200 patients taking abacavir in the Western Australian HIV Cohort Study underwent major histocompatability testing. Using strict clinical criteria, abacavir hypersensitivity reaction was diagnosed in 18 of the 200. HLA-B57 was present in 78 percent of patients who had an abacavir hypersensitivity reaction and 2.3 percent of abacavir tolerant subjects (odds ratio = 117, p<0.0001). The HLA-DRB1 and -DQ3 combination was found in 72 percent of those who had an abacavir hypersensitivity reaction and in none of the abacavir tolerant subjects. If prospective haplotyping had been performed and abacavir withheld from persons positive for HLA-B57, -DRB1, and -DQ3, then the rate of hypersensitivity would have dropped from 9 percent to 2.5 percent.
Importantly, testing for the haplotype is not 100 percent sensitive and cannot be considered a screening test. Management of abacavir hypersensitivity reaction still requires clinical awareness. This type of testing also could not be used to decide whether to re-challenge with abacavir. The authors stressed that this linkage was noted only for a mostly Caucasian population in Western Australia. This data was recently published in The Lancet (2002; 359: 727-732). This study is an interesting approach to the evolving field of pharmacogenomics but can't be applied to clinical practice at the present time.
This study describes their work with Phase I. Eighty-five abacavir hypersensitivity reaction cases were identified along with 115 matched controls who were abacavir tolerant for at least six weeks. Overall, 92 percent of subjects were male and 74 percent Caucasian. Analysis identified a known polymorphism of TNF-alpha (-238A) among 25 of 58 (43 percent) of cases compared to 7 percent of controls (p<0.001). HLA-B57 was present in 39 of 84 (46 percent) of abacavir hypersensitivity reaction subjects versus 4 of 113 controls (3.5 percent; p<0.001). The authors emphasized that their study involved mostly Caucasians and that their modeling of the genetic linkages is incomplete. In the end, the following implications of their data were emphasized:
Like the paper by Mallal et al., this study is a voyage into the field of pharmacogenomics. For the present, these papers are a proof-of-concept endeavor that cannot be translated into clinical practice but perhaps gives us a glimpse into the future of pharmacogenetics.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|