It is important to understand the hypersensitivity reaction to abacavir (Ziagen¨, Glaxo SmithKline) which is estimated to occur in up to 5% of adult and pediatric patients who take this potent HIV-1 nucleoside reverse transcriptase inhibitor.1 The abacavir hypersensitivity reaction typically presents several weeks after starting the medication and includes such symptoms as fever, skin rash, and difficulty breathing. There have been only a few reported cases of fatal outcomes to the hypersensitivity reaction; once patients experience any of these symptoms, they should never be rechallenged with this agent.
The emerging science of pharmacogenetics, sometimes called pharamcogenomics, may help us understand the hypersensitivity reaction to abacavir and other drugs as well.
Pharmacogenetics is the study of how genes affect the way people respond to medicines, including antibiotics, antivirals, antidepressants, chemotherapy agents, asthma drugs, and many other agents. While this science is still in its infancy, pharmacogenetics may ultimately help with drug selection and more appropriate use of abacavir and other agents. In the meantime, investigators suggest that careful monitoring of patients taking abacavir should continue and that the drug be discontinued and not be restarted if patients are found to have the hypersensitivity reaction.
Mallal, et al recently published the results of their experience with 200 subjects who were exposed to abacavir in the Australian HIV Cohort Study.2 Definite abacavir hypersensitivity was identified in 18 cases (9%, all Caucasian) and was excluded in 167 ("abacavir tolerant") individuals with more than 6 weeks of exposure to the drug.
The authors used a method that involves taking DNA from the whole blood of individual subjects; the DNA is then subjected to genotyping at 100 or more sites among various gene groups or "gene families." These sites are selected for their potential involvement or for their known association with abacavir metabolism or the immune response.
The genetic marker HLA-B57 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in 4 (2%) of the 167 abacavir tolerant patients (P < 0.0001). A combination the markers HLA-DR7 and HLA-DQ3 was found in 13 (72%) of hypersensitive and 5 (3%) of tolerant patients (P<0.0001). HLA-B57, HLA-DR7 , and HLA-DQ3 were present in varying combinations in 13 (72%) hypersensitive patients and in none of the tolerant patients (P < 0.0001).
The authors concluded that in this population, withholding abacavir in patients with HLA-B57, HLA-DR7, and HLA-DQ3 markers should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient.
Hetherington, et al have reported the results of a retrospective, case-control study to identify multiple genetic markers in the vicinity of the so-called HLA-B marker, which has been associated with hypersensitivity reactions.3 HLA-B57 was present in 39 (46%) of 84 patients versus 4 (4%) of 113 controls (P < 0.0001). However, because of the low numbers of women and other ethnic groups enrolled, these findings relate largely to white men.
Note that in this study, the marker HLA-B57 was less sensitive in predicting abacavir hypersensitivity than it was in the findings of Mallal; that is, HLA-B57 occurred less frequently in Hetherington's group than in Mallal's group. This suggests that predictive values for markers will vary across populations and that further study is necessary.
Both studies add to the growing body of evidence that genetic factors could be used to improve the effectiveness and safety of pharmaceuticals if genetic markers of sufficient predictive value can be identified.
The studies also suggest that pharmacogenetic results can vary by study population. The frequency of HLA-B57 varies substantially among different ethnic groups. And the lower frequency of HLA-B57 among Hetherington's patients compared to the group studied by Mallal, et al suggests that differences can occur even within Caucasian subgroups. The results of neither study can be generalizable to the whole population. Analyses by sex are also insufficient. The predictive value of any marker depends on the frequencies of that marker and a particular medical event, in this case hypersensitivity, in the study population.
These studies have opened up new avenues in our understanding of the infrequent, but troubling, hypersensitivity reaction to drugs. Both studies conclude that clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir should remain unchanged for now. This may change, however, as we learn more about the predictive value of these and other markers and as these genotyping assays become more readily available and easier to interpret.
See Dr. Valenti's bio on page 66.
References
1. Hewitt RG. Abacavir hypersensitivity reaction.
Clin Infect Dis. 2002;34:.
2. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7,
and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359:.
3. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359:.
Other Resources
JP Morgan H&Q's Annual Genomics Conference - October 1-2, 2001 <http://www.gsk.com/ financial/roses_jp_morgan_02oct01.htm>
Hetherington S, McGuirk S, Powell G, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther. 2002;23:.